Clinical trial NCT03153137
Conditions: Congenital Heart Disease
Sponsor: Actelion
Start date: 2017-08-14; Completion date: 2021-07-26
Enrollment: 142 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to assess the effect of macitentan 10 mg as compared to placebo on exercise capacity through cardiopulmonary exercise testing.

Detailed description:

Arms: arm 1: Macitentan 10 mg per day; film-coated tablet; oral use arm 2: film-coated tablet; oral use
Interventions: intervention 1: Macitentan 10 mg intervention 2: Placebo
Intervention descriptions: intervention 1: film-coated tablet; oral use intervention 2: film-coated tablet; oral use

Protocol documents:
Prot_000.pdf: 
Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H301 
 
RUBATO 
Prospective, multi-center, double-blind, randomized, placebo-controlled, 
parallel-group study assessing the efficacy and safety of macitentan in 
Fontan-palliated adult and adolescent subjects 
 
 
Study Phase: 
3 
EudraCT Number: 
2016-003320-23 
Status and version: 
Final Version 10  
Date: 
19 November 2020 
Document type: 
Amended Global Protocol 
Document number (Doc No.): 
D-20.425 
 
*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. 
 
 
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. 
 
NCT03153137


Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H301, RUBATO 
Final Version 10 
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Confidential 
EudraCT 2016-003320-23 
Doc No D-20.425 
 
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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:  
+41 61 227 05 63 
Site-specific toll telephone numbers and toll-free 
numbers for the Medical Emergency Hotline can be 
found in the Investigator Site File 
 
 
 
COORDINATING INVESTIGATOR 
Name / Title 
Address 
Paul Clift / MD 
Consultant Cardiologist 
 
 
 
PPD


Macitentan / ACT-064992 
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Protocol AC-055H301, RUBATO 
Final Version 10 
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CONTRACT RESEARCH ORGANIZATION INFORMATION 
 
CENTRAL LABORATORY 
 
Covance, Inc. / 8211 SciCor Drive, 
Indianapolis, IN 46214, USA 
BIOANALYTICAL 
LABORATORY 
PRA Health Sciences / Amerikaweg 18,  
9407 TK Assen, The Netherlands 
CENTRAL RANDOMIZATION 
/ IRT 
 
Almac Clinical Technologies / 25 Fretz Road, 
Souderton, PA 18964, USA 
CENTRAL READING 
FACILITY FOR 
CARDIOPULMONARY 
EXERCISE TESTING (CPET) 
 
Henry Ford Health System /  
Henry Ford Clinical Exercise Physiology Core 
Laboratory, Preventive Cardiology, 6525 Second 
Avenue, Detroit, MI 48202, USA 
CENTRAL READING 
FACILITY FOR 
ACCELEROMETRY 
ActiGraph LLC /  
49 East Chase Street, Pensacola, FL 32502, USA 
A list of site-specific contact details for Contract Research Organizations (CROs) can 
be found in the Investigator Site File. 
 
 
 


Macitentan / ACT-064992 
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Protocol AC-055H301, RUBATO 
Final Version 10 
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SPONSOR SIGNATURE PAGE 
 
 
 
PPD
PPD


Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H301, RUBATO 
Final Version 10 
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EudraCT 2016-003320-23 
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INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
Macitentan / ACT-064992 
Indication 
Macitentan in Fontan-palliated subjects  
Protocol number, study acronym, study title 
AC-055H301, 
RUBATO, 
Prospective, 
multi-center, 
double-blind, 
randomized, 
placebo-controlled, parallel-group study assessing the efficacy and safety of macitentan in 
Fontan-palliated adult and adolescent subjects. 
I agree to the terms and conditions relating to this study as defined in this protocol, the Case Report 
Form (CRF), and any other protocol-related documents. I fully understand that any changes 
instituted by the investigator(s) without previous agreement with the sponsor would constitute a 
protocol deviation, including any ancillary studies or procedures performed on study subjects (other 
than those procedures necessary for the wellbeing of the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, International 
Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, and applicable 
regulations and laws. I will obtain approval by an Independent Ethics Committee or Institutional 
Review Board (IEC/IRB) prior to study start and signed informed consent from all subjects 
included in this study. If an amendment to the protocol is necessary, I will obtain approval by an 
IEC/IRB and ensure approval by regulatory authorities has been obtained before the 
implementation of changes described in the amendment, and I will re-consent the subjects (if 
applicable). I will allow direct access to source documents and study facilities to sponsor 
representative(s), particularly Clinical Research Associate(s) (CRA[s]) and auditor(s), and agree to 
inspection by regulatory authorities or IEC/IRB representative(s). I will ensure that the study 
treatment(s) supplied by the sponsor is/are being used only as described in this protocol. I will 
ensure that all subjects or legally designated representatives have understood the nature, objectives, 
benefits, implications, risks and inconveniences for participating in this study. During the conduct 
of the study, I will constantly monitor the risk-benefit balance for an individual subject. I confirm 
herewith that the sponsor is allowed to enter and utilize my professional contact details and function 
in an electronic database for internal purposes and for submission to health authorities worldwide. 
 
Country 
Site 
number 
Town 
Date 
 
Signature 
Principal 
Investigator 
 
 
 
 
 
 
 
 


Macitentan / ACT-064992 
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Protocol AC-055H301, RUBATO 
Final Version 10 
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Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment 9, Version 10 
19 November 2020 
Amendment 8, Version 9 
15 July 2020 
Amendment 7, Version 8 
18 December 2019 
Amendment 6, Version 7 
19 November 2018 
Amendment 5, Version 6 
27 August 2018 
Amendment 4, Version 5 
20 February 2018 
Amendment 3, Version 4 
27 June 2017 
Amendment 2, Version 3 
26 April 2017 
Amendment 1, Version 2 
01 February 2017 
Original Protocol, Version 1 
24 August 2016 
Amendment 9 (19 November 2020) 
Overall Rationale for the Amendment: The purpose of this amendment is to make global 
safety updates, and align the protocol with Janssen processes as part of the Actelion and 
Janssen integration. 
Study treatment supply and storage information was simplified as part of the Actelion and 
Janssen integration. 
Furthermore, an appendix was added to facilitate evaluation of exclusion criterion 6.3. 
A Protocol Amendment Summary of Changes Table for the current amendment is 
provided below. 
 
Section number 
and Name 
Description of Change 
Brief Rationale 
Synopsis; 
3.1 
Study 
design; 
3.3 
Study 
committees; 
5.1.5 
Blinding; 
5.1.6.2 
Unblinding for IDMC; 
10. Statistical methods; 
10.4 Interim analysis 
Addition of statistical support group 
(SSG). 
Updated for accuracy 
5.1.3 Study treatment 
administration 
Reference added to sections detailing the 
new IMP overdose definition. 
Definition of overdose was 
added to provide more 
clarity.  


Macitentan / ACT-064992 
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Protocol AC-055H301, RUBATO 
Final Version 10 
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EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
Section number 
and Name 
Description of Change 
Brief Rationale 
5.1.6.3 Unblinding for 
suspect 
unexpected 
serious 
adverse 
reactions; 5.1.11.2 Liver 
aminotransferase 
abnormalities; 
7.2.4.1 
Type 
of 
laboratory; 
9.1.1 
Definition 
of 
adverse 
event; 
9.2.3 
Follow-up of serious 
adverse events; 9.2.4 
After the 30-day follow-
up 
period; 
9.2.5 
Reporting procedures; 
12.10 Audit. 
“Actelion Global Drug Safety” and/or 
“Actelion” updated to “the sponsor” 
Updated as part of Actelion 
Pharmaceuticals and Janssen 
pharmaceuticals integration. 
5.1.7 Study treatment 
supply 
Information about study treatment 
manufacturing sites is deleted. 
Information removed to allow 
greater flexibility. 
5.1.7.2.2 
study 
treatment storage 
Specific temperature range for study 
treatment storage removed. Highly detailed 
information regarding study treatment 
storage temperature regulations and 
deviation reporting requirements removed 
Superfluous information 
removed for clarity. 
5.1.11.1 
Pregnancy; 
7.2.4.1 
Type 
of 
laboratory 
“Pregnancy Form” updated to “Pregnancy 
Notification Form” 
Updated to align with Janssen 
processes 
7.2.7.1 Pharmacokinetic 
assessments 
Additional local equivalent added as an 
alternative to the bioanalytical 
laboratory. 
Updated in case samples are 
not able to be exported from 
their country of origin 
7.2.3.6 
VSFU; 
8.2 
Premature 
withdrawal 
from study 
Addition of “including the use of locator 
agencies” 
Included for clarity 
9 Safety definitions and 
reporting requirements 
Details of reporting requirements and 
SOPs added. 
Updated to align with Janssen 
processes 
9.1.5 
Follow-up 
of 
adverse events 
Details of investigator obligations to 
perform or arrange supplemental 
measurements and evaluations added. 
Updated to align with Janssen 
processes 
9.2.1 
Definitions 
of 
serious adverse events 
Inclusion of suspected transmission of any 
infectious agent via a medicinal product. 
Included to align with Janssen 
processes. 


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Protocol AC-055H301, RUBATO 
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Section number 
and Name 
Description of Change 
Brief Rationale 
9.2.2 
Reporting 
of 
serious adverse events 
Inclusion of PQCs as a reporting 
requirement 
Updated to align with Janssen 
processes 
9.2.5 
Reporting 
procedures 
Reporting requirements for SUSARs was 
updated to provide additional information. 
Text updated to align with 
Janssen processes. 
9.3 Pregnancy 
9.3.1 Reporting of pregnancy 
Updated to include partners of male 
subjects, and to clarify that the sponsor 
must be informed within 24-hours of site 
staff knowledge of the event. 
“Actelion Pregnancy Form” updated to 
“Pregnancy Notification Form” 
 
9.3.2 Follow-up of pregnancy 
Additional information added regarding 
product exposure during pregnancy 
collection and end of pregnancy collection 
forms. 
Information regarding abnormal pregnancy 
outcomes to be considered as SAEs added. 
The pregnancy reporting 
section was 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 
9.5 
Product 
quality 
complaints  
Section added. 
Added to align with Janssen 
processes 
9.6 Special reporting 
situations 
Section added. 
Added to align with Janssen 
processes 
9.7 Contacting sponsor 
regarding 
product 
quality 
Section added. 
Added to align with Janssen 
processes 
10.3.5.1 Peak VO2 at 
other visits, VE/VEO2, 
VO2/HE, VO2 at VAT, 
OUES and %predicted 
peak VO2 
‘Reference with information about 
classification for VE/VCO2 slope and peak 
VO2 categorization was deleted.  
Reference removed as it does 
not correspond to the 
population of this study. 
13. References 
Removal of the following reference: 
[Arena 2007] Arena R, Myers J, Abella J. 
Development of a Ventilatory 
Classification System in Patients 
With Heart Failure. Circulation. 
2007;115:2410-7. 
 
Removed as not required. 


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Protocol AC-055H301, RUBATO 
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Section number 
and Name 
Description of Change 
Brief Rationale 
Appendix 
10 
Child-
Pugh Classification 
Appendix Added. 
Added as an aid to correctly 
evaluate exclusion criterion 
6.3. 
Abbreviations: IMP=investigational medicinal product; PQC=Product quality complaint;  
SUSAR= Suspected unexpected serious adverse reaction. 


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TABLE OF CONTENTS 
SPONSOR CONTACT DETAILS ......................................................................................2 
COORDINATING INVESTIGATOR.................................................................................2 
CONTRACT RESEARCH ORGANIZATION INFORMATION ......................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ................................6 
TABLE OF CONTENTS ...................................................................................................10 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................17 
PROTOCOL SYNOPSIS AC-055H301 ............................................................................22 
PROTOCOL ......................................................................................................................36 
1 
BACKGROUND .........................................................................................................36 
1.1 
Indication ......................................................................................................36 
1.2 
Study treatment .............................................................................................36 
1.2.1 
Macitentan ........................................................................................36 
1.2.2 
Physico-chemical properties of macitentan ......................................37 
1.3 
Purpose and rationale of the study ................................................................37 
1.4 
Summary of known and potential risks and benefits ....................................38 
2 
STUDY OBJECTIVES ...............................................................................................40 
2.1 
Primary objective ..........................................................................................40 
2.2 
Secondary objectives ....................................................................................40 
2.3 
Other objectives ............................................................................................40 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................40 
3.1 
Study design .................................................................................................40 
3.1.1 
Study periods ....................................................................................41 
3.1.2 
Study duration ...................................................................................45 
3.2 
Study design rationale ..................................................................................45 
3.3 
Study committees .........................................................................................46 
4 
SUBJECT POPULATION ..........................................................................................46 
4.1 
Subject population description .....................................................................46 
4.2 
Rationale for the selection of the study population ......................................47 


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4.3 
Inclusion criteria ...........................................................................................47 
4.4 
Exclusion criteria ..........................................................................................48 
4.5 
Criteria for women of childbearing potential ...............................................50 
4.5.1 
Definition of childbearing potential ..................................................50 
4.5.2 
Acceptable methods of contraception ...............................................51 
4.5.2.1 
Countries having taken part in the VHP (Voluntary 
Harmonization Procedure), or countries with a restricted  
list of contraception methods ..................................................51 
4.5.2.2 
Countries not having taken part in the VHP (excluding  
France) or countries without a restricted list of contraception 
methods ...................................................................................52 
4.5.2.3 
France ......................................................................................52 
4.5.2.4 
North America .........................................................................52 
4.5.2.5 
Asia and Oceania .....................................................................54 
5 
TREATMENTS ..........................................................................................................54 
5.1 
Study treatment .............................................................................................54 
5.1.1 
Investigational treatment: Description and rationale ........................54 
5.1.2 
Comparator: Description and rationale .............................................54 
5.1.3 
Study treatment administration .........................................................54 
5.1.4 
Treatment assignment .......................................................................55 
5.1.5 
Blinding ............................................................................................55 
5.1.6 
Unblinding ........................................................................................56 
5.1.6.1 
Unblinding for final analyses ..................................................56 
5.1.6.2 
Unblinding for IDMC ..............................................................56 
5.1.6.3 
Unblinding for suspected unexpected serious adverse  
reactions ...................................................................................56 
5.1.6.4 
Emergency procedure for unblinding ......................................56 
5.1.7 
Study treatment supply .....................................................................57 
5.1.7.1 
Study treatment packaging and labeling .................................57 
5.1.7.2 
Study treatment distribution and storage .................................57 
5.1.7.3 
Study treatment dispensing .....................................................58 
5.1.7.4 
Study treatment return and destruction ...................................58 
5.1.8 
Study treatment accountability and compliance with study 
treatment ...........................................................................................59 
5.1.8.1 
Study treatment accountability ................................................59 
5.1.8.2 
Study treatment compliance ....................................................59 
5.1.9 
Study treatment dose adjustments and interruptions ........................60 
5.1.10 
Premature discontinuation of study treatment ..................................60 


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Protocol AC-055H301, RUBATO 
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5.1.11 
Study-specific criteria for interruption / premature 
discontinuation of study treatment ....................................................61 
5.1.11.1 
Pregnancy ................................................................................61 
5.1.11.2 
Liver aminotransferase abnormalities .....................................61 
5.1.11.3 
Hemoglobin abnormalities ......................................................62 
5.1.11.4 
Drop in BP ...............................................................................63 
5.1.11.5 
Initiation of forbidden medication ...........................................63 
5.2 
Previous and concomitant therapy ................................................................64 
5.2.1 
Definitions ........................................................................................64 
5.2.2 
Reporting of previous/concomitant therapy / auxiliary 
medicinal products in the eCRF ........................................................64 
5.2.3 
Allowed concomitant therapy ...........................................................64 
5.2.4 
Forbidden concomitant therapy ........................................................64 
6 
STUDY ENDPOINTS ................................................................................................65 
6.1 
Efficacy endpoints ........................................................................................65 
6.1.1 
Primary efficacy endpoint .................................................................65 
6.1.2 
Secondary efficacy endpoints ...........................................................65 
6.1.3 
Other efficacy endpoints ...................................................................65 
6.2 
Safety endpoints ...........................................................................................67 
6.3 
Quality of life endpoints ...............................................................................67 
6.4 
Pharmacoeconomic endpoints ......................................................................68 
6.5 
Pharmacokinetic endpoints ...........................................................................68 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS ................................................68 
7.1 
General information ......................................................................................68 
7.1.1 
Screening/re-screening ......................................................................68 
7.1.2 
Unscheduled visits ............................................................................69 
7.2 
Study assessments .........................................................................................74 
7.2.1 
Demographics / baseline characteristics ...........................................75 
7.2.2 
Efficacy assessments .........................................................................75 
7.2.2.1 
Cardiopulmonary exercise testing ...........................................75 
7.2.2.2 
PA-Ac ......................................................................................77 
7.2.2.3 
NT-proBNP measurement .......................................................77 
7.2.2.4 
Composite endpoint of time to clinical worsening ..................78 
7.2.3 
Safety assessments ............................................................................78 
7.2.3.1 
Physical examination ...............................................................78 
7.2.3.2 
Vital signs ................................................................................79 
7.2.3.3 
Weight and height ...................................................................79 
7.2.3.4 
ECG assessment ......................................................................79 


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7.2.3.5 
Echocardiography ....................................................................79 
7.2.3.6 
VSFU .......................................................................................80 
7.2.4 
Laboratory assessments ....................................................................80 
7.2.4.1 
Type of laboratory ...................................................................80 
7.2.4.2 
Laboratory tests .......................................................................83 
7.2.5 
Quality of life assessments ...............................................................84 
7.2.6 
Pharmacoeconomic assessments .......................................................85 
7.2.7 
Pharmacokinetic and pharmacodynamics assessments ....................85 
7.2.7.1 
Pharmacokinetic assessments ..................................................85 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL 
CARE ..........................................................................................................................86 
8.1 
Study completion as per protocol .................................................................86 
8.2 
Premature withdrawal from study ................................................................87 
8.3 
Premature termination or suspension of the study ........................................88 
8.4 
Medical care of subjects after study completion / withdrawal from 
study ..............................................................................................................88 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................88 
9.1 
Adverse events ..............................................................................................89 
9.1.1 
Definition of adverse events .............................................................89 
9.1.2 
Intensity of adverse events ................................................................90 
9.1.3 
Relationship to study treatment ........................................................90 
9.1.4 
Reporting of adverse events ..............................................................90 
9.1.5 
Follow-up of adverse events .............................................................91 
9.2 
Serious adverse events ..................................................................................91 
9.2.1 
Definitions of serious adverse events ...............................................91 
9.2.2 
Reporting of serious adverse events .................................................92 
9.2.3 
Follow-up of serious adverse events .................................................92 
9.2.4 
After the 30-day follow-up period ....................................................92 
9.2.5 
Reporting procedures ........................................................................92 
9.3 
Pregnancy .....................................................................................................93 
9.3.1 
Reporting of pregnancy ....................................................................93 
9.3.2 
Follow-up of pregnancy ....................................................................94 
9.4 
Study safety monitoring ................................................................................94 
9.5 
Product quality complaints ...........................................................................94 
9.5.1 
Procedures .........................................................................................94 
9.6 
Special reporting situations ..........................................................................95 
9.7 
Contacting Sponsor Regarding Product Quality ..........................................95 


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Final Version 10 
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10 STATISTICAL METHODS .......................................................................................95 
10.1 
Analysis sets .................................................................................................96 
10.1.1 
Screened Analysis Set .......................................................................96 
10.1.2 
Full Analysis Set ...............................................................................96 
10.1.3 
Per-Protocol Set ................................................................................96 
10.1.4 
Safety Set ..........................................................................................97 
10.1.5 
Pharmacokinetic analysis set ............................................................97 
10.1.6 
Usage of the analysis sets .................................................................97 
10.2 
Variables .......................................................................................................97 
10.2.1 
Primary efficacy variable(s) ..............................................................97 
10.2.2 
Secondary efficacy variables ............................................................98 
10.2.2.1 
Peak VO2 over 52 weeks .........................................................98 
10.2.2.2 
Change from Baseline to Week 16 in mean count per  
minute of daily PA-Ac ............................................................98 
10.2.3 
Other efficacy variables ....................................................................98 
10.2.4 
Safety variables .................................................................................99 
10.2.5 
Quality of life variables ..................................................................100 
10.2.6 
Pharmacoeconomic variables .........................................................100 
10.2.7 
Pharmacokinetic variables ..............................................................101 
10.3 
General Description of statistical analyses .................................................101 
10.3.1 
Overall testing strategy ...................................................................101 
10.3.2 
Analysis of the primary efficacy variable(s) ...................................102 
10.3.2.1 
Hypotheses and statistical model ..........................................102 
10.3.2.2 
Handling of missing data .......................................................104 
10.3.2.3 
Main analysis .........................................................................105 
10.3.2.4 
Supportive/sensitivity analyses .............................................106 
10.3.3 
Analysis of secondary efficacy variables ........................................107 
10.3.3.1 
Change from baseline over 52 weeks in peak VO2 ...............107 
10.3.3.2 
Change from Baseline to Week 16 in mean count per  
minute of daily PA-Ac ..........................................................108 
10.3.3.3 
Sub-group analyses ................................................................109 
10.3.4 
Analysis of the safety variable(s) ....................................................110 
10.3.4.1 
Adverse events ......................................................................110 
10.3.4.2 
Laboratory data ......................................................................110 
10.3.4.3 
Vital signs ..............................................................................111 
10.3.4.4 
Echocardiography ..................................................................111 
10.3.5 
Analysis of other efficacy variables ................................................111 
10.3.5.1 
Peak VO2 at other visits, VE/VCO2 slope, VO2/HR, VO2 at 
VAT, OUES and % predicted peak VO2 ...............................112 
10.3.5.2 
NT-proBNP ...........................................................................112 


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10.3.5.3 
Mean time in minutes spent in different physical activities  
and mean count per minute of daily PA-Ac over time ..........112 
10.3.5.4 
Clinical events .......................................................................113 
10.3.6 
Overall survival ...............................................................................113 
10.3.7 
Analysis of quality of life variables ................................................113 
10.3.8 
Analysis of pharmacoeconomic variables ......................................114 
10.3.9 
Analysis of pharmacokinetic variables ...........................................114 
10.3.10 
Exposure to and compliance with the study treatment ...................114 
10.3.11 
Demographic and baseline characteristics ......................................114 
10.3.12 
Subject disposition ..........................................................................115 
10.4 
Interim analysis ...........................................................................................115 
10.5 
Sample size .................................................................................................116 
10.5.1 
Sample size and justification ..........................................................116 
10.5.2 
Sample size sensitivity ....................................................................117 
10.5.3 
Unblinded sample size re-estimation ..............................................117 
11 DATA HANDLING ..................................................................................................117 
11.1 
Data collection ............................................................................................117 
11.2 
Maintenance of data confidentiality ...........................................................118 
11.3 
Database management and quality control .................................................118 
12 PROCEDURES AND GOOD CLINICAL PRACTICE ...........................................119 
12.1 
Ethics and Good Clinical Practice ..............................................................119 
12.2 
Independent Ethics Committee / Institutional Review Board ....................119 
12.3 
Informed consent ........................................................................................120 
12.4 
Indemnification, compensation and refund of expenses to subjects and 
investigators ................................................................................................121 
12.5 
Protocol adherence/compliance ..................................................................121 
12.6 
Protocol amendments .................................................................................122 
12.7 
Essential documents and retention of documents .......................................122 
12.8 
Monitoring ..................................................................................................123 
12.9 
Investigator Site File ...................................................................................124 
12.10 
Audit ...........................................................................................................124 
12.11 
Inspections ..................................................................................................124 
12.12 
Reporting of study results and publication .................................................125 
13 REFERENCES ..........................................................................................................126 
14 APPENDICES ...........................................................................................................132 
 
 


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LIST OF TABLES 
 
Table 1 
Dosing scheme ..............................................................................................55 
Table 2 
Visit and assessment schedule ......................................................................70 
Table 3 
Visit and assessment schedule in PTOP .......................................................73 
Table 4 
Sample size with treatment effect of 2.4 mL/kg/min and statistical power 1-
β of 80% in a 1:1 randomization ratio by level of significance α and effect 
size (with selected sample size in bold face) ..............................................117 
Table 5 
Thresholds for marked laboratory abnormalities ........................................133 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design .................................................................................................43 
Figure 2 
PTOP (example of discontinuation after Visit 4) .........................................43 
Figure 3 
OL extension study (entry at Visit 6) ...........................................................44 
Figure 4 
Acceptable birth-control options ..................................................................53 
LIST OF APPENDICES 
 
Appendix 1 Central laboratory abnormalities and alert flags .........................................132 
Appendix 2 Echocardiography .......................................................................................136 
Appendix 3 Cardiopulmonary exercise testing ..............................................................139 
Appendix 4 Specific Activity Scale ...............................................................................144 
Appendix 5 Tanner stages (self-assessment) ..................................................................145 
Appendix 6 Comparison of RUBATO procedures versus standard of care: comparison 
of burden and risks .....................................................................................146 
Appendix 7 Disease Severity and Impression of Change questionnaires ......................161 
Appendix 8 EQ-5D-5L questionnaire ............................................................................166 
Appendix 9 Protocol Amendment History .....................................................................169 
Appendix 10 Child-Pugh Score ........................................................................................171 


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LIST OF ABBREVIATIONS AND ACRONYMS 
6MWD  
6-minute walk distance 
AE  
Adverse event 
ALT  
Alanine aminotransferase 
ANCOVA  
Analysis of covariance 
AP  
Alkaline phosphatase 
AST  
Aspartate aminotransferase 
AV  
Atrioventricular 
BMI  
Body mass index 
BP  
Blood pressure 
BR  
Breathing reserve 
CGI-C  
Clinician Global Impression of Change 
CGI-S  
Clinician Global Impression of Severity 
CHD  
Congenital heart disease 
CKD-EPI  
Chronic Kidney Disease Epidemiology Collaboration 
CL  
Confidence limit 
CPET  
Cardiopulmonary exercise testing 
CRA  
Clinical research associate 
CRO  
Contract Research Organization 
CSR  
Clinical study report 
CTCAE  
Common Terminology Criteria for Adverse Events 
CTT  
Clinical trial team 
CYP3A4  
Cytochrome P450 3A4 
ECG  
Electrocardiogram 
ECHOC  
Echocardiography 
eCRF  
electronic Case Report Form 
EC-TCPC  
Extra cardiac tunnel total cavopulmonary connection 
EDC  
Electronic data capture  
EMA  
European Medicines Agency 
EOP  
End-of-post-treatment observation period 
EOS  
End-of-Study 


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EOT  
End-of-Treatment 
EQ-5D-5L  
Euro Quality of Life 5D(imensions) 
ERA  
Endothelin receptor antagonist 
ET  
Endothelin 
FAS  
Full Analysis Set 
FC  
Functional class 
FDA  
Food and Drug Administration (US) 
FEV1  
Forced expiratory volume over 1 second 
GCP  
Good Clinical Practice 
GFR  
Glomerular filtration rate 
GQM  
Global Quality Management 
HF  
Heart failure 
HR  
Heart rate 
IB  
Investigator’s Brochure 
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 
IMP  
Investigational Medicinal Product 
IRB  
Institutional review board 
IRT  
Interactive response technology 
ISAC  
Independent statistical analysis center 
ISF  
Investigator site file 
KM  
Kaplan-Meier 
LS  
Least square 
LT-TCPC  
Lateral tunnel total cavopulmonary connection 
LV  
Left ventricle 
M  
Arithmetic mean 
MAESTRO  
Macitentan in Eisenmenger Syndrome To Restore exercise 
capacity 


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MedDRA  
Medical Dictionary for Regulatory Activities 
MI  
Multiple imputation 
MMRM  
Mixed Model Repeated Measures 
MVV  
Maximal voluntary ventilation 
NT-proBNP  
N-terminal prohormone of brain natriuretic peptide 
NYHA  
New York Heart Association 
o.d.  
Once daily 
OL  
Open-label (extension) 
OS  
Overall survival 
OUES  
Oxygen uptake efficiency slope 
PA-Ac  
Physical Activity measured by Accelerometer 
PAH  
Pulmonary arterial hypertension 
PDE5i  
Phosphodiesterase 5 inhibitor 
PGA-S  
Patient Global Assessment of Disease Severity 
PGI-C  
Patient Global Impression of Change 
PH  
Pulmonary hypertension 
PI  
Principal investigator 
PK  
Pharmacokinetic(s) 
PKS  
Pharmacokinetic Analysis Set 
PLE  
Protein-losing enteropathy 
PORTICO  
PORtopulmonary Hypertension Treatment wIth maCitentan – a 
randOmized Clinical Trial 
PPS  
Per-Protocol Set 
PQC  
Product quality complaint 
PTOP  
Post-treatment observation period 
PVR  
Pulmonary vascular resistance 
Q-Q  
Quantile-quantile 
QoL  
Quality of life 
QS  
Quality System 
RER  
Respiratory exchange ratio 
RSI  
Reference safety information 


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RV  
Right ventricle 
SAE  
Serious adverse event 
SAP  
Statistical Analysis Plan 
SAS  
Statistical Analysis System 
SCL  
Study Closure 
SCR  
Screened Analysis Set 
SD  
Standard deviation 
SERAPHIN  
Study with endothelin receptor antagonist in pulmonary arterial 
hypertension to improve clinical outcome 
S-FU  
Safety follow-up 
SI  
International System of Units 
SIV  
Site initiation visit 
SOC  
System organ class 
SpO2  
Peripheral oxygen saturation 
SS  
Safety Set 
SSG  
Statistical support group 
SUSAR  
Suspected unexpected serious adverse reaction 
SVDV  
Systemic ventricle diastolic volume 
SVSV  
Systemic ventricle systolic volume 
TCPC  
Total cavopulmonary connection 
TEMPO  
Treatment with endothelin receptor antagonist in fontan patients, 
a randomized, placebo-controlled, double-blind study measuring 
peak oxygen consumption 
ULN  
Upper limit of normal 
VAS  
Visual analogue scale 
VAT  
Ventilatory anaerobic threshold 
VCO2  
Carbon dioxide production 
VE  
Minute ventilation 
VHP  
Voluntary Harmonization Procedure  
VO2  
Oxygen uptake/consumption (V̇ O2 is a flow = a ratio of a volume 
by unit of time) 
VSFU  
Vital Status Follow-Up 


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WHO  
World Health Organization 
WU  
Wood unit 
 
 


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PROTOCOL SYNOPSIS AC-055H301 
TITLE 
Prospective, 
multi-center, 
double-blind, 
randomized, 
placebo-controlled, parallel-group study assessing the efficacy 
and safety of macitentan in Fontan-palliated adult and 
adolescent subjects. 
ACRONYM 
RUBATO 
PRospective, 
mUlti-center, 
double-Blind, 
rAndomized, 
placebo-conTrolled, parallel-group study assessing the 
efficacy and safety of macitentan in FOntan-palliated adult and 
adolescent subjects. 
OBJECTIVES 
Primary objective 
To assess the effect of macitentan on exercise capacity 
(measured by peak oxygen uptake [VO2]) in comparison with 
placebo in Fontan-palliated subjects. 
Secondary objectives 
To assess the effect of macitentan on long-term exercise 
capacity (measured by peak VO2 over 52 weeks). 
To assess the effect of macitentan on daily Physical Activity 
measured by Accelerometer (PA-Ac).  
To evaluate the safety and tolerability of macitentan. 
Other objectives 
Other objectives are described in Section 2.3. 
DESIGN 
A 
prospective, 
adaptive, 
multi-center, 
double-blind, 
randomized, placebo-controlled, parallel-group, Phase 3 study.  
The study contains an interim analysis (IA) for unblinded 
sample size adaptation, based on comparative interim results 
on the primary efficacy endpoint. This IA will be implemented 
through an Independent Data Monitoring Committee (IDMC), 
providing recommendations to the Sponsor Committee. Only 
the IDMC and the Independent Statistical Analysis Center 
(ISAC)/statistical Support Group (SSG) will be unblinded to 
the data. 


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PERIODS 
Screening period:  
Lasts up to 30 days; starts with the signature of the informed 
consent (Visit 1) and ends with the subject’s Randomization 
(Visit 2). 
Treatment period:  
Starts with the administration of the first dose of study 
treatment (Visit 2) and ends on the day of the last dose of study 
treatment, expected to be at 52 weeks.  
Subjects who prematurely and permanently discontinue study 
treatment before Week 52 (Visit 6) must have a premature 
End-of-Treatment (EOT) visit as soon as possible but not later 
than 7 days after the last dose of study drug. 
Safety follow-up (S-FU) period:  
After permanent study treatment discontinuation, subjects will 
be followed up for a minimum of 30 days (S-FU).  
Subjects eligible to enter the AC 055H302 open-label (OL) 
extension study may do so as soon as their eligibility has been 
confirmed, even prior to completion of the full S-FU period. 
The period ends with administration of first study drug in the 
OL extension study. 
Post-treatment observation period (PTOP): 
Those subjects who prematurely and permanently discontinue 
study treatment will enter the PTOP after their S-FU period is 
completed. The PTOP lasts until the planned study EOT (at 
most 52 weeks after Randomization) for each individual 
subject. This last visit of the PTOP is called End-of-PTOP 
(EOP). The PTOP consists of an abbreviated schedule of 
assessments at 90-day intervals. 
End-of-Study (EOS): 
EOS is reached by an individual subject: 
• when the S-FU period has been completed (for those 
subjects who do not discontinue study treatment 
prematurely), or 


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• when the S-FU period and PTOP have been completed 
(for those subjects who discontinue study treatment 
prematurely), or 
• if subjects enter the AC-055H302 RUBATO open-
label (OL) extension study, with first administration of 
OL study drug. 
For all subjects, EOS corresponds to the last visit performed in 
this AC-055H301 RUBATO double-blind study.  
Study Closure (SCL) will be announced by the sponsor when 
all subjects have reached their EOS in AC-055H301 
RUBATO.  
Vital Status Follow-up (VSFU): 
A VSFU will be performed within 8 weeks after the SCL 
announcement to determine each vital status of all subjects 
randomized in AC-055H301 RUBATO, irrespective of 
whether the subject is included in the AC-055H302 OL 
extension study. 
Study Closure (SCL): 
The SCL applies to all randomized subjects and will occur: 
• when all subjects have had their individual VSFU, and 
• no later than 8 weeks after SCL announcement. 
PLANNED DURATION 
Approximately 34 months from first subject, first visit to last 
subject, last visit. 
SITE(S) 
/ COUNTRY(IES) 
31 investigational sites in 11 countries (planned).  
SUBJECTS / GROUPS 
At least 134 adults and adolescents will be randomized in a 
1:1 ratio to macitentan 10 mg or placebo. Randomization will 
be stratified by geographical region (America, Europe, Asia, 
Oceania). 
The sample size will be re-estimated at the time of the IA based 
on treatment effect and variability estimates for the primary 
efficacy endpoint (i.e., change from baseline to Week 16 in 
peak VO2), following rules as described in the Statistical 


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Analysis Plan (SAP). Only upwards adjustment of the pre-
planned sample size is allowed. An upper bound of the 
sample-size adjustment is considered up to a 100% increase of 
the initially planned sample size (i.e., total sample size of 
268 subjects).  
INCLUSION CRITERIA 
1. Written informed consent/assent from the subject and/or a 
legal 
representative 
prior 
to 
initiation 
of 
any 
study-mandated procedures. 
2. Male or female ≥ 12 years old.  
3. Fontan-palliated subjects with either intra-atrial lateral 
tunnel total cavopulmonary connection (LT-TCPC), or 
extra cardiac tunnel TCPC (EC-TCPC) surgery > 1 year 
before Screening. Either LT- or EC-TCPC can be primary 
or secondary to atrio-pulmonary connection. 
4. New York Heart Association (NYHA) functional 
class (FC) II or III (assessed by the investigator using the 
Specific Activity Scale [Appendix 4]). 
5. Ability to understand and comply with the instructions, and 
ability to physically perform the cardiopulmonary exercise 
testing (CPET). 
6. Women of childbearing potential must: 
6.1. Have a negative serum pregnancy test at the Screening 
visit and a negative urine pregnancy test at the 
Randomization visit (Visit 2), and, 
6.2. Agree to perform monthly pregnancy tests up to the 
end of the S-FU period, and, 
6.3. Agree to use reliable contraception [Section 4.5.2] 
from at least 30 days prior to Visit 2 and up to at least 
30 days after study drug discontinuation. 
EXCLUSION CRITERIA 
1. Pattern of Fontan circulation severity. Any of the 
following: 
1.1. Known severely reduced single ventricle ejection 
fraction (< 30%) 
1.2. Known Fontan circulation stenosis, affected area 
> 50% of the diameter  
1.3. Known valvular defects (severe atrioventricular [AV] 
valve regurgitation, outflow obstruction)  
1.4. Known pulmonary-venous pathway obstruction 


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1.5. Peripheral oxygen saturation (SpO2) of < 88% at rest 
at Screening 
2. Deterioration of the Fontan-palliated condition. Any of the 
following events within 3 months prior to Screening: 
2.1. Candidate on the active list for heart transplantation  
2.2. Clinical worsening leading to medical interventions 
including 
reoperation 
of 
Fontan 
circulation 
(e.g., mechanical 
circulatory 
support, 
Fontan 
take-down, Fontan revision/conversion, AV valve 
repair/replacement).  
2.3. Unscheduled hospitalization due to deterioration of the 
Fontan-palliated condition1 
2.4. Signs and symptoms of heart failure2 requiring change 
in diuretic therapy 
2.5. Ventricular 
tachyarrhythmia 
or 
supraventricular 
tachyarrhythmia3 
2.6. Peritoneal, 
pleural, 
mediastinal, 
or 
pericardial 
effusions 
2.7. Thrombotic or hemorrhagic complications (including 
thromboembolism and hemoptysis) 
2.8. Protein-losing enteropathy (serum albumin < 30 g/L 
and total protein < 50 g/L) 
2.9. Plastic bronchitis/chyloptysis 
2.10. Signs and symptoms requiring the addition of a new 
class of cardiovascular medication (e.g., nitrates, 
alpha-blockers, or endothelin receptor antagonists 
[ERAs])  
 
3. Limitations to CPET: 
3.1. History of syncope during exercise  
3.2. Symptomatic coronary artery disease at Screening. 
 
 
1 Only applicable as an event if hospitalization/intervention was unscheduled / not related to routine 
Fontan-related follow-up, and hospital stay was > 24 hours. 
2 Includes orthopnea, nocturnal dyspnea, pulmonary edema, or radiological signs. Persistent congestion 
with edema only qualifies if the peripheral edema is moderate-to-severe despite optimal diuretic 
therapy. 
3 Subjects are excluded for arrhythmia only if it requires hospitalization, or cardioversion, addition/increase 
in antiarrhythmic treatment, or invasive tests or treatment. 


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3.3. Respiratory limitation with a breathing reserve of 
< 10% 
3.4. Iron deficiency defined as ferritin < 10 µg/L at 
Screening 
3.5. Iron 
supplementation, 
regardless 
of 
route 
of 
administration, unless already present at stable dose 
for more than 3 months prior to Screening 
3.6. Body mass index (BMI)-for-age reference (z-scored) 
equivalent to BMI > 35 kg/m2 (for adults) at Screening 
3.7. Exercise training program for cardiopulmonary 
rehabilitation in the 3-month period prior to Screening 
3.8. Myocardial infarction < 6 months before Screening 
3.9. Pacemaker at Screening 
4. Peak VO2 < 15 mL/kg/min at Baseline. 
5. Systolic blood pressure (BP) < 90 mmHg (< 85 mmHg for 
subjects < 18 years old and < 150 cm of height) at rest or 
during CPET at Screening or at Baseline. 
6. Criteria related to macitentan use: 
6.1. Hemoglobin < 75% of the lower limit of normal 
assessed by central laboratory at Screening 
6.2. Known or suspected pulmonary veno-occlusive 
disease 
6.3. Known and documented severe hepatic impairment 
defined as Child-Pugh Score C [Appendix 10], based 
on measurement of total bilirubin, serum albumin, 
international normalized ratio or prothrombin time 
(except for patients under non-Vitamin K antagonists) 
and based also on presence/absence and severity of 
ascites and hepatic encephalopathy 
6.4. Serum aspartate aminotransferase and/or alanine 
aminotransferase > 3 × upper limit of normal range 
assessed by central laboratory at Screening 
6.5. Severe renal impairment (estimated creatinine 
clearance < 30 mL/min/1.73m2) assessed by central 
laboratory at Screening 


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6.6. Pregnancy, breastfeeding, or intention to become 
pregnant during the study, or women of childbearing 
potential not using a reliable method of contraception 
6.7. Hypersensitivity to any active substance or excipient 
of any of the study drugs 
6.8. Treatment with a strong cytochrome P450 3A4 
(CYP3A4) inducer such as carbamazepine, rifampin, 
rifampicin, 
rifabutin, 
rifapentin, 
phenobarbital, 
phenytoin, and St. John’s wort, within 1 month prior 
to Randomization (Visit 2) 
6.9. Treatment with a strong CYP3A4 inhibitor such as 
ketoconazole, 
itraconazole, 
voriconazole, 
clarithromycin, telithromycin, nefazodone, ritonavir, 
and 
saquinavir, 
within 
1 month 
prior 
to 
Randomization (Visit 2) 
7. General exclusion criteria: 
7.1. Any factor or condition likely to affect protocol 
compliance of the subject as judged by the investigator 
7.2. Treatment with another investigational therapy in the 
3-month period prior to Screening 
7.3. Treatment with nitrates, alpha-blockers, or ERAs in 
the 3-month period prior to Screening 
7.4. Introduction or change of dose of pulmonary 
hypertension-specific drugs (other than ERAs) in the 
3-month period prior to Screening 
7.5. Known drug or substance (e.g., alcohol) abuse, 
unstable psychiatric illness, or any other condition 
that, in the opinion of the investigator, may interfere 
with participation in the study 
7.6. Any planned surgical intervention (e.g., organ 
transplant) during the study period, except minor 
interventions (e.g., tooth extraction) 
8. Any known factor or disease that may interfere with 
treatment compliance or full participation in the study 
(e.g., chemotherapy treatment for cancer) or illness with an 
anticipated life expectancy of less than 12 months. 


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STUDY TREATMENTS 
Investigational treatment 
Macitentan 10 mg, oral tablet, once daily, with or without food. 
Comparator and/or placebo 
Matching placebo oral tablet, once daily, with or without food. 
ENDPOINTS 
Primary efficacy endpoint 
The primary endpoint is the change in peak VO2 from Baseline 
(Randomization/Visit 2) to Week 16 (Visit 4). 
Secondary efficacy endpoints 
• Change from Baseline (Visit 2) over 52 weeks in 
peak VO2.  
• Change from Baseline (Visit 2) to Week 16 (Visit 4) in 
mean count per minute of daily PA-Ac.  
Other efficacy endpoints 
Other efficacy endpoints are described in Section 6.1.3. 
Safety endpoints 
• Treatment-emergent adverse events (AEs) and serious AEs 
up to 30 days after study treatment discontinuation or until 
initiation of study drug in the AC-055H302 OL extension 
study, whichever occurs first. 
• AEs leading to premature discontinuation of study 
treatment. 
• Change in vital signs (systolic and diastolic arterial BP and 
pulse rate), including SpO2 and body weight from Baseline 
(Visit 2) to all assessed time points during the study. 
• Treatment-emergent marked laboratory abnormalities up 
to 30 days after study treatment discontinuation or until 
initiation of study drug in the AC-055H302 OL extension 
study, whichever occurs first. 
• Change in laboratory parameters from Baseline (Visit 2) to 
all assessed time points during the study. 
Quality of life endpoints 
Quality of life (QoL) endpoints are described in Section 6.3. 
 
Pharmacoeconomic endpoints 
Pharmacoeconomic endpoints are described in Section 6.3. 


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Pharmacokinetic endpoints 
Pharmacokinetic (PK) endpoints are described in Section 6.3. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 2 and Table 3. 
STATISTICAL 
METHODOLOGY 
All statistical analyses will be conducted by Actelion or by 
designated CROs supervised by Actelion, except for the IA, 
which will be conducted by the ISAC/SSG who will provide 
results to the IDMC. 
A Statistical Analysis Plan (SAP) will provide full details of 
the analyses, data displays, and algorithms to be used for data 
derivations.  
This study implements one IA for unblinded sample size 
re-estimation and the statistical methods are described below.  
Analysis sets 
Analyses for the primary, secondary and other efficacy 
endpoints will be carried out on the Full Analysis Set (FAS), 
which comprises all randomized subjects within the treatment 
group to which they were randomized.  
Additional sensitivity analyses of the primary endpoint will be 
conducted on the FAS, applying ranking, observed case 
approach without imputation, and on the Per-Protocol Set 
(PPS) to assess the robustness of the results of the primary 
statistical analysis. 
PPS includes all subjects from the FAS without protocol 
deviations, which would affect the main analysis of the 
primary variable. 
The Safety Set (SS) will be evaluated for safety endpoints in a 
descriptive manner. SS includes all subjects who received at 
least one dose of study treatment, based on the actual treatment 
received. 
The Pharmacokinetic Analysis Set (PKS) includes all 
randomized and treated subjects, for whom a PK blood sample 
at trough has been taken and who do not deviate from the 
protocol in a way that might affect the evaluation of the trough 
concentrations. 


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Primary variable 
The primary endpoint for the study is the change in peak VO2 
from Baseline (Visit 2) to Week 16 (Visit 4). 
Null and alternative hypotheses 
The statistical hypotheses for the primary endpoint are 
formulated in terms of the arithmetic means (M) of the change 
in peak VO2 in subjects treated with either placebo or 
macitentan 10 mg from Baseline (Visit 2) to Week 16 (Visit 4). 
H0: M macitentan 10 mg = M placebo versus 
HA: M macitentan 10 mg ≠ M placebo  
The null hypothesis is tested as per primary endpoint at a 
two-sided Type I error of 1%. The study would be ‘conclusive’ 
at the two-sided 1% level; it could also be declared ‘positive’ 
at a significance level of 5% on the primary endpoint. 
Primary statistical analysis  
The null hypothesis will be tested by means of an analysis of 
covariance (ANCOVA) model on the change in peak VO2. 
Model covariates will include randomized treatment, 
geographical region, and peak VO2 at Baseline (Visit 2). 
For the control of type-I error at final analysis, the primary 
efficacy endpoint will be tested by combining the p-values 
from the ANCOVA of first-stage (based on actual number of 
subjects available at the time of IA) and second-stage (based 
on the remaining number of subjects required to reach the total 
sample 
size 
after 
IA 
results), 
using 
the 
weighted 
inverse-normal combination method [Lehmacher 1999] with 
fixed weights proportional to the information available at the 
time of the IA.  
At final analysis, the difference in the change in peak VO2 from 
Baseline to Week 16 between macitentan 10 mg and placebo 
and corresponding p-value will be estimated at each stage 
separately (first-stage and second-stage) from the main 
ANCOVA model using a population-wise splitting of data 
approach. Final interpretation of the results will then be based 
on the final adjusted p-value, median unbiased estimator for 
the overall treatment effect and corresponding Repeated 


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Confidence 
Intervals 
obtained 
by 
ADDPLAN™ 
6.1 
(ADDPLAN, Inc., an Aptiv Solutions company).  
Absolute values at Baseline and at Week 16 as well as absolute 
change in peak VO2 from Baseline to Week 16 will also be 
summarized using descriptive statistics. 
Missing values will be imputed as specified in the statistical 
section of this protocol and detailed in the SAP. 
Assumptions of normality of residuals and homogeneity of 
variance (assessment of ANCOVA model assumptions) will be 
investigated and graphically presented when applicable 
(e.g., Q-Q and residual plots).  
Sensitivity and supportive analyses include separate extended 
models on the FAS with factors of NYHA FC and geographical 
region. 
Subgroup analyses will be conducted for adolescent subjects, 
adult subjects, geographical region, US subjects, non-US 
subjects, and ventricular dominance: Left ventricle (LV) 
versus right ventricle (RV) / mixed. Treatment-by-subgroup 
variable interaction will be tested for heterogeneity. 
Secondary efficacy endpoints  
If the primary endpoint is statistically significant at alpha 
significance level of α=1% two sided in the final analysis, the 
secondary efficacy endpoints, i.e., change from Baseline over 
52 weeks in peak VO2 and change from Baseline to Week 16 
in mean count per minute of daily PA-Ac, will be analyzed at 
the same alpha-level as the primary endpoint using a 
hierarchical testing procedure following the order specified in 
the secondary endpoints [Section 10.3.3]. 
The final analysis of the secondary efficacy endpoints will be 
conducted using the inverse normal combination method with 
pre-specified weights to combine first and second stage p-
values, similar to the primary endpoint main analyses. 
The change from Baseline over 52 weeks in peak VO2 will be 
evaluated on the FAS population by means of a mixed model 
repeated measures (MMRM). The model will include 


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randomized treatment group, time (via a categorical variable 
for visit), treatment-by-time interaction, Baseline-by-time 
interaction, and peak VO2 at Baseline as fixed effects. An 
unstructured variance-covariance matrix will be specified. 
The change from Baseline to Week 16 in mean count per 
minute of daily PA-Ac will be analyzed by means of an 
ANCOVA including treatment group and baseline mean count 
per minute of daily PA-Ac as covariates. 
Final interpretation of the results for the secondary endpoints 
will be similar to the primary endpoints and will be performed 
on the final adjusted p-value, median unbiased estimator for 
the overall treatment effect and corresponding 99% confidence 
intervals obtained by ADDPLAN™ 6.1 (ADDPLAN, Inc., an 
Aptiv Solutions company). 
Other efficacy endpoints  
Other efficacy endpoints will be analyzed for exploratory 
purposes. Time-to-composite endpoint will be analyzed using 
a Kaplan-Meier approach and a Cox regression model. 
Safety and tolerability endpoints 
Safety and tolerability endpoints will be analyzed descriptively 
by actual treatment on the SS. 
As per treatment received, AE incidences will be summarized 
for the entire study period, from Screening to EOT plus 
30 days. Incidences of treatment-emergent AEs will be 
displayed. 
Changes in laboratory parameters and vital signs will be 
presented from Baseline (Visit 2) to post-baseline visits and to 
worst and last post-baseline. 
Drop-out patterns, i.e., reasons for premature discontinuation 
by treatment group, will be investigated. 
Quality of life endpoints 
The QoL endpoints will be analyzed descriptively by 
randomized treatment group using the FAS. Continuous scales 
EQ-5D Visual Analogue Scale (VAS) will be summarized as 
absolute and changes from baseline values at each time point. 


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Categorical scales (Patient Global Assessment of Disease 
Severity [PGA-S], Clinician Global Impression of Severity 
[CGI-S], Patient Global Impression of Change [PGI-C], 
Clinician Global Impression of Change [CGI-C] and Euro QoL 
5D [EQ-5D-5L]) will be summarized as the proportion of 
patients within each response category at each time point.  
Pharmacoeconomic endpoints 
Those endpoints will be summarized descriptively by 
randomized treatment group using the FAS. 
Pharmacokinetic endpoints 
Trough concentrations of macitentan and its metabolite will be 
analyzed descriptively on the PKS.  
Sample-size assumptions 
The family-wise Type I error is set to 1%. The study sample 
size necessary for comparison of the primary endpoint, change 
in peak VO2 from Baseline (Visit 2) to Week 16 (Visit 4), 
between subjects randomized in a 1:1 ratio to macitentan 
10 mg or placebo is based on the following assumptions:  
Type-I and -II errors – Power 
• A two-sided Type I error of 1% and a Type II error of 20% 
(80% power). 
Effect and variability assumptions  
• Assumptions are based on previous studies in subjects with 
Fontan-palliated circulation (TEMPO study [Hebert 2013, 
Hebert 2014] with bosentan and other studies, e.g., with 
bosentan, sildenafil, or iloprost): 
– A difference equal to 2.4 mL/kg/min, and 
– A standard deviation of the difference of 
4.0 mL/kg/min, and 
– A normal distribution for the primary endpoint. 
Based on the above assumptions, a total of 134 subjects, 
i.e., 67 per treatment group, are required to establish 
superiority of macitentan 10 mg over placebo with 80% power 
to correctly reject the null hypothesis, when it is false, in favor 
of the alternative hypothesis. This test is based on a two-sample 
t-test for independent samples with a two-sided significance 
level 0.01 and equal per-group variances.   


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The sample size will be re-estimated in the IA, based on 
observed unblinded treatment effect and standard deviation, 
following rules as described in the SAP.  
The IA will be conducted approximately when the first 
95 randomized subjects (i.e., 70% of pre-planned sample size) 
are randomized and have completed their Week 16 CPET 
assessment (i.e., Visit 4/Week 16), or withdrew from the study 
without a Week 16 CPET assessment. This sample size 
re-estimation allows the sample size to be potentially increased 
up to 268 subjects based on conditional power considerations 
for the primary efficacy endpoint [see Section 10.5.3]. 
The total sample size of the study shall not exceed 268 subjects 
and shall not be below the initial sample size of 134 subjects.  
STUDY COMMITTEES 
An independent data monitoring committee (IDMC) will 
review data at regular intervals according to the IDMC charter. 
The IDMC has overall responsibility for safeguarding the 
interests of subjects by monitoring safety and efficacy data 
obtained 
in 
the 
study 
and 
making 
appropriate 
recommendations based on the reported data. The IDMC will 
also interpret the results of the interim analysis planned for 
sample size re-estimation and provide the Sponsor Committee 
with the appropriate recommendation regarding the new target 
sample size. 
STUDY EXTENSION 
 
Subjects who complete the study will be offered to participate 
in an open-label extension study, AC-055H302 RUBATO OL 
under a separate protocol.  
 


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PROTOCOL 
1 
BACKGROUND 
1.1 Indication  
The Fontan procedure was introduced in 1968 to treat patients with tricuspid atresia. This 
surgical approach has subsequently been applied to a range of complex congenital heart 
malformations characterized by the presence of only one functional ventricular chamber, 
in patients in whom biventricular repair is not possible. The introduction of the Fontan 
surgical operations and their subsequent modifications brought expected survival into 
adulthood, although short-term (e.g., arrhythmia, thrombosis, etc.) and long-term 
complications (e.g., heart failure [HF], liver, and renal failure) are as yet unavoidable and 
life expectancy is reduced. Recent studies in the US have found Kaplan-Meier (KM) 
survival estimates for patients operated in the modern Fontan surgical era (from the 1990s 
onward) of about 96%, 90%, 80%, and 70% at 1, 10, 20 and 25 years post-Fontan operation, 
respectively [Pundi 2015, Dabal 2014, Khairy 2008]. 
After successfully completed surgeries, Fontan-palliated patients are affected by a number 
of complications associated with considerable morbidity and mortality. Their exercise 
capacity (measured by peak oxygen uptake [VO2]) remains limited, with peak VO2 ranging 
from 48% to 65% of predicted value, and their exercise capacity decreases with time. When 
exercise capacity of Fontan-palliated patients falls below about 45% to 50% of peak VO2 
predicted for age and sex [Goldberg 2014], there is an associated increased risk of 
hospitalization or death [Diller 2005, Diller 2010]. 
[Diller 2015] estimated that a 40-year old patient with Fontan physiology has a 5-year risk 
of death (18.0%; 95% confidence interval, 11.9% to 24.6%) comparable with that of a 75-
year old person from the general UK population.  
Currently, there are no medicinal products approved for use in the treatment of 
Fontan-palliated patients. 
1.2 Study treatment 
1.2.1 Macitentan 
Macitentan (ACT-064992, Opsumit®) is an orally active, non-peptide, potent dual 
endothelin ETA and ETB receptor antagonist (ERA).  
There are several publications [Derk 2015] on the efficacy and tolerability of endothelin 
(ET) receptor blockade in Fontan-palliated patients, after successful surgery. Among these 
studies, the placebo-controlled clinical study TEMPO [Hebert 2014], was conducted in 
Denmark and Sweden with bosentan in 75 Fontan-palliated patients. Sixty-nine patients 
(30 adolescents, 39 adults) completed this study, that showed that bosentan, administered 


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for 14 weeks, significantly increased peak VO2 and exercise duration during 
cardiopulmonary exercise testing (CPET), as well as improved New York Heart 
Association (NYHA) functional class (FC), and N-terminal prohormone of brain 
natriuretic peptide (NT-proBNP) compared to placebo. No serious adverse effects were 
seen.  
A recently published study further supports that ERAs might provide most pronounced 
hemodynamic (PVR decrease) and functional improvement (NYHA) in adults and 
adolescents. 
This small prospective cohort study conducted without a control group by 
[Agnoletti 2017], was the first study that assessed the effects of ERAs (bosentan, 
macitentan) in patients with a Fontan circulation with increased pulmonary vascular 
resistance (PVR), using cardiac catheterization and CPET. These patients were reevaluated 
after 6 months. Pre- and post-treatment hemodynamic variables were assessed by cardiac 
catheterization. The main study inclusion was PVR ≥ 2 Wood units (WU)*m2. Functional 
capacity was evaluated by CPET. The primary endpoint was to obtain a reduction of PVR, 
while the secondary endpoint was to obtain an improvement of functional capacity. 
A cohort of 8 adult patients with a Fontan circulation was treated with macitentan. NYHA 
FC improved, PVR decreased and cardiac index increased, while CPET showed no 
significant functional improvement. For 8 adolescents on bosentan (local legislative 
authority and the ethic committee allowed macitentan use only in adult patients), NYHA 
FC improved, PVR decreased, cardiac index increased, and CPET showed significant 
functional improvement, with improvement in anaerobic threshold VO2 and VO2 max as 
well as oxygen pulse. 
Systolic blood pressure diminished in all adolescents (all on bosentan) and adults (all on 
macitentan), significantly so only for adolescents. No significant differences were detected 
in diastolic blood pressure and oxygen saturation. Blood tests of hepatic and renal function 
were unchanged, no hepatic toxicity developed, and anemia never occurred. 
For detailed information on macitentan, please see the most recent version of the 
macitentan Investigator’s Brochure (IB). Detailed information on ‘Special warnings and 
precautions’ and ‘General precautions’ are provided in sections 1.7 and 1.8 of the IB 
[Macitentan IB]. 
1.2.2 Physico-chemical properties of macitentan 
Please refer to the Macitentan IB.  
1.3 Purpose and rationale of the study 
The purpose of the AC-055H301 study is to assess the efficacy and safety of macitentan 
10 mg once daily (o.d.) in Fontan-palliated adult and adolescent subjects. The main goal 


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of the study is to assess the benefit on exercise capacity as measured by the primary efficacy 
endpoint, namely the change from baseline of peak VO2. 
Prior randomized, placebo-controlled clinical studies performed with pulmonary 
hypertension (PH)-specific vasodilatory medications (other than macitentan) showed 
statistically significant benefits in Fontan-palliated adolescents and adults. The benefit was 
measured by exercise capacity, and these studies also showed satisfactory safety effects. 
The Hebert 2014 study was performed in adolescents and in adults, with bosentan (an 
ERA, like macitentan) administered for 14 weeks. The Shang 2013 study was performed 
in children only, with bosentan administered for 1 year and the children followed up for 
2 years. 
The 
Phase 1/2 
range-finding 
study 
[Goldberg 2015] 
administered 
a 
phosphodiesterase-5 inhibitor (udenafil) to adolescents. The Cedars 2016 cross-over study 
administered ambrisentan (another ERA) to adults only. 
In Fontan-palliated patients, the trans-pulmonary gradient corresponds to PVR in patients 
with pulmonary arterial hypertension (PAH). High PVR index is associated with low 6-
minute walk distance (6MWD) and survival in children with PAH (whether idiopathic 
PAH or PAH associated with congenital heart disease [CHD]) [Sajan 2011]. Therefore, 
macitentan, which is expected to have a beneficial effect on hemodynamics 
[Agnoletti 2017] as well as on vascular remodeling, may be beneficial in Fontan-palliated 
subjects through an effect that cannot be measured short-term, i.e., during the duration of 
the proposed Phase 3 study. Macitentan is specifically expected to provide short-to-
medium-term benefit on exercise capacity (measured by peak VO2), and potentially a 
longer-term effect on morbidity (effect on progressive HF). 
The rationale for this study is to assess the efficacy, safety, and pharmacokinetics (PK) of 
macitentan in Fontan-palliated adolescents and adults. 
1.4 Summary of known and potential risks and benefits  
Macitentan is approved for the treatment of PAH based on data generated in the 
SERAPHIN study [Pulido 2013]. In addition, macitentan was investigated in another CHD 
indication (Eisenmenger Syndrome) in the MAESTRO study [Gatzoulis 2019]. Safety and 
tolerability are well documented in both indications. 
Effects on blood pressure 
This drug is a vasodilator. However, in the pivotal study in PAH, no difference in mean 
change from baseline in blood pressure (BP) was observed. 
Effect on hemoglobin 
In placebo-controlled Phase 2 and 3 studies, treatment with macitentan was associated with 
mild to moderate decreases in hemoglobin concentration, which stabilized after the first 


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few weeks of macitentan treatment. Few patients discontinued macitentan treatment due to 
anemia. 
Effect on liver enzymes 
Elevations of liver aminotransferases (aspartate aminotransferase [AST], alanine 
aminotransferase [ALT]) have been associated with PAH and with other ERAs. In a 
long-term placebo-controlled trial in PAH [Pulido 2013], macitentan 10 mg was not 
associated with increased incidences of treatment-emergent elevations of AST and/or ALT 
versus placebo. Based on the cumulative review of the macitentan liver cases by an 
independent liver safety data review board (ILSDRB), there was no clear evidence of 
hepatotoxicity. 
Effect on edema/fluid retention 
Events of edema/fluid retention are frequent symptoms of PAH worsening and associated 
complications such as right ventricular failure. Such events were reported with similar 
incidences for macitentan and placebo patients in the pivotal placebo-controlled study in 
PAH [Pulido 2013]. Based on the observation of individual post-marketing cases where a 
causal relationship could not be excluded, and on other observations linked to the use of 
ERAs in various heart conditions, ‘edema/fluid retention’ was added to the undesirable 
effects section in the Prescribing Information of macitentan. 
Hypersensitivity reactions 
During post-marketing experience, hypersensitivity reactions (angioedema, pruritus, rash) 
have been reported. 
Pregnancy 
Macitentan must not be administered to a pregnant female because it may cause fetal harm. 
Women of childbearing potential will be included in the trial only if they do not intend to 
become pregnant during the study, are not breastfeeding, and agree to use reliable 
contraception [Section 4.5] from 30 days before start of treatment until one month after 
end of study drug treatment. Pregnancy tests will be performed monthly during treatment 
and 1 month after stopping treatment. 
More comprehensive safety data is provided in the IB [Macitentan IB]. 
Benefit 
It is expected that macitentan treatment in Fontan-palliated patients in NYHA FC II and III 
will positively impact exercise capacity and possibly delay disease progression. 


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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’ well-being. 
2 
STUDY OBJECTIVES 
2.1 Primary objective 
To assess the effect of macitentan on exercise capacity (measured by peak VO2) in 
comparison with placebo in Fontan-palliated subjects. 
2.2 Secondary objectives 
• To assess the effect of macitentan on long-term exercise capacity (measured by peak 
VO2 over 52 weeks). 
• To assess the effect of macitentan on daily Physical Activity measured by 
Accelerometer (PA-Ac). 
• To evaluate the safety and tolerability of macitentan.  
2.3 Other objectives 
• To assess the efficacy of macitentan on endpoints related to exercise capacity. 
• To assess the effect of macitentan on NT-proBNP. 
• To assess the effect of macitentan on clinical worsening. 
• To assess the effect of macitentan on Quality of life (QoL). 
• To assess the effect of macitentan on pharmacoeconomic endpoints. 
• To assess the plasma concentration of macitentan and its metabolite at trough. 
3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
This 
is 
a 
prospective, 
adaptive, 
multi-center, 
double-blind, 
randomized, 
placebo-controlled, parallel-group Phase 3 study. 
At least 134 subjects will be randomized in a 1:1 ratio to either macitentan or placebo. 
Randomization will be stratified by geographical region (America, Europe, Asia, Oceania). 
The study will be conducted in approximately 31 investigational sites in 11 countries. 
Given the uncertainty about both the true treatment effect and variability of the primary 
efficacy endpoint variable, an interim analysis (IA) will be conducted for unblinded sample 
size re-estimation. This IA will be performed by an Independent Statistical Analysis 


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Center/Statistical Support Group (ISAC/SSG) [see Section 3.3] for the Independent Data 
Monitoring Committee (IDMC). Only the IDMC and the ISAC/SSG will be unblinded to 
the data. This sample size re-estimation allows the sample size to be potentially increased 
up to a total sample size of 268 subjects [see Section 10.5.3]. 
3.1.1 Study periods 
The study comprises the following consecutive periods: 
Screening period: Lasts up to 30 days; starts with the signature of the informed consent 
(Visit 1) and ends with the subject’s Randomization (Visit 2). 
Treatment period: Starts with the administration of the first dose of study treatment (Visit 
2) and ends on the day of the last dose of study treatment, expected to be at 52 weeks. 
Subjects who prematurely and permanently discontinue study treatment before Week 52 
(Visit 6) must have a premature End-of-Treatment (EOT) visit as soon as possible but not 
later than 7 days after last dose of study drug.  
Safety follow-up (S-FU) period:  
After permanent study treatment discontinuation, subjects will be followed up for a 
minimum of 30 days (S-FU).  
Subjects eligible to enter the AC 055H302 open-label (OL) extension study may do so as 
soon as their eligibility has been confirmed, even prior to completion of the full S-FU 
period. The period ends with administration of first study drug in the OL extension study. 
Post-treatment observation period (PTOP): 
Subjects who prematurely and permanently discontinue study treatment will enter the 
PTOP after their S-FU period is completed. The PTOP lasts until the planned study EOT 
(at most 52 weeks after Randomization) for each individual subject. This last visit of the 
PTOP is called End-of-PTOP (EOP). The PTOP consists of an abbreviated schedule of 
assessments at 90-day intervals. 
End-of-Study (EOS): 
EOS is reached by an individual subject: 
• when the S-FU period has been completed (for those subjects who do not 
discontinue study treatment prematurely), or 
• when the S-FU period and PTOP have been completed (for those subjects who 
discontinue study treatment prematurely), or 


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• if subjects enter the AC-055H302 RUBATO open-label (OL) extension study, with 
first administration of OL study drug. 
For all subjects, EOS corresponds to the last visit performed in this AC-055H301 
RUBATO double-blind study.  
Study Closure (SCL) will be announced by the sponsor when all subjects have reached 
their EOS in AC-055H301 RUBATO. 
Vital Status Follow-up (VSFU): 
A VSFU will be performed within 8 weeks after the SCL announcement to determine each 
vital status of all subjects randomized in AC-055H301 RUBATO, irrespective of whether 
the subject is included in the AC-055H302 OL extension study [see Section 7.2.3.6]. 
Study Closure (SCL): 
The SCL applies to all randomized subjects and will occur: 
• when all subjects have had their individual VSFU, and 
• no later than 8 weeks after SCL announcement. 
The visit schedule and protocol-mandated procedures are performed according to the table 
of assessments [Table 2 and see Table 3 for subjects entering the PTOP], and are described 
in Section 7. 
The overall study design is depicted in Figure 1. An example of premature discontinuation 
and PTOP is depicted in Figure 2.  
Figure 3 depicts the design for a subject who enters the AC-055H302 OL extension study 
at Week 52. 


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Figure 1 
Study design 
 
 
EOS = End-of-Study; EOT = End-of-Treatment; SCL = Study Closure; V = visit; VSFU = Vital Status Follow-Up; 
 = Telephone call (for visit). 
Figure 2 
PTOP (example of discontinuation after Visit 4) 
 
EOS = End-of-Study; EOP = End-of-PTOP; EOT = End-of-Treatment; P = PTOP visit; PTOP = Post-treatment 
observation period; SCL = Study Closure; V = visit; VSFU = Vital Status Follow-Up; = Telephone call (for 
visit). 
 


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Figure 3 
OL extension study (entry at Visit 6) 
 
DB = Double-blind; EOS = End-of-Study; EOT = End-of-Treatment; OL = Open-label (extension); SCL = Study 
Closure; V = visit; VSFU = Vital Status Follow-Up; = Telephone call (for visit). 
 
No S-FU will be performed in subjects entering the AC-055H302 RUBATO-OL extension 
study at individual subject’s EOT/EOS for the AC-055H301 RUBATO study. 
In instances where administration of AC-055H302 OL study drug does not immediately 
follow EOT in the AC-055H301 RUBATO study, the subject will enter the normal S-FU 
period until administration of the first dose of the OL study drug occurs. 
 
 


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3.1.2 Study duration 
The study starts with the first act of recruitment (i.e., Informed Consent Form [ICF] signed) 
and ends with the last visit of the last subject. This is expected to last approximately 
34 months. 
The subjects will be treated for 52 weeks. Subjects who prematurely and permanently 
discontinue study treatment will enter a PTOP, which lasts until 52 weeks after 
randomization to monitor the medical condition of those individual subjects after stopping 
macitentan. For an individual subject, the study is completed with the EOS visit either 
when the S-FU period has been completed (for those subjects who do not discontinue study 
treatment prematurely), or when the S-FU period and PTOP have been completed (for 
those subjects who discontinue study treatment prematurely), or if subjects enter the 
AC-055H302 RUBATO OL extension study, with first administration of OL study drug. 
At the end of the trial, when all subjects have completed their EOS, a SCL announcement 
will be made which is followed by an 8 week period within which each vital status of all 
subjects randomized in AC-055H301 RUBATO will be collected, irrespective of whether 
the subject is included in the AC-055H302 OL extension study [VSFU, see Section 
7.2.3.6], unless already known.  
This information will be collected in the eCRF after study completion.  
3.2 Study design rationale 
The study will assess the efficacy, safety, and PK of treating Fontan-palliated subjects with 
macitentan compared to placebo.  
As there are no approved medications for treatment of patients with Fontan 
circulation-associated reduced exercise capacity and / or progressive HF, a 
placebo-controlled study as add-on to standard of care is ethically appropriate. 
As described in Section 1.2.1, evidence from a study conducted with an ERA (bosentan) 
in Fontan-palliated patients indicated a clinically and statistically significant beneficial 
impact on exercise capacity at Week 14 [Hebert 2014]. Considering past experience on 
time to maximal effect of macitentan on exercise capacity in patients with PAH (in the 
SERAPHIN study, 10 mg macitentan given o.d. improved the functional capacity of adult 
patients with PAH, as measured by the 6MWD test at 3 months [AC-055-302 SERAPHIN, 
post-hoc analysis, data on file] and at 6 months [Pulido 2013]), a time point of 16 weeks 
was chosen for assessing the primary endpoint.  
A recent study administering bosentan in adolescents and macitentan in Fontan-palliated 
adults [Agnoletti 2017] further supports that ERAs might provide most pronounced 
hemodynamic (PVR decrease) and functional improvement (NYHA) in adults and 
adolescents. 


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Very limited evidence on long-term follow up of treatment of Fontan-palliated patients 
with PH-specific vasodilators is available. In the [Shang 2013] study, Fontan-palliated 
children were treated for 1 year and followed up for 2 years. Considering the 
recommendation of at least a yearly follow-up of Fontan-palliated patients, a 1-year study 
duration was defined. Additional assessments of peak VO2 in this time frame will help to 
understand the dynamics of the impact on exercise capacity and possibly disease 
progression.  
3.3 Study committees 
An IDMC has overall responsibility for safeguarding the interests of subjects by 
monitoring safety and efficacy data obtained in the study and making appropriate 
recommendations based on the reported data, 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 and is supported by an 
Independent Statistical Analysis Center/Statistical Support Group (ISAC/SSG). The 
composition and operation of the IDMC are described in the IDMC charter. 
In addition, the IDMC will review the report of the IA provided by the ISAC/SSG and 
provide a recommendation to the Sponsor Committee on potential sample size adjustments 
following rules described in the IDMC charter. 
An ILSDRB (an external expert committee of hepatologists) has been appointed to monitor 
all Actelion studies with macitentan, as well as post-marketing cases, and to provide 
ongoing assessment and advice regarding serious hepatic adverse events (AEs) of special 
interest during the study as per the ILSDRB charter. 
4 
SUBJECT POPULATION 
4.1 Subject population description 
This study will enroll adolescent and adult male and female subjects aged 12 years and 
older, with either Lateral Tunnel Total Cavopulmonary Connection (LT-TCPC), or Extra 
Cardiac Tunnel Total Cavopulmonary Connection (EC-TCPC). 
They must be in NYHA FC II or III (confirmed by the investigator with the Specific 
Activity Scale) [Appendix 4] and be able and willing to perform CPET (confirmed by the 
ability to reach a respiratory exchange ratio of 1.1, based on historical and/or baseline 
CPET). 
Women of childbearing potential must not be pregnant, breastfeeding, or have the intention 
of becoming pregnant during the study and agree to use reliable contraception throughout 
the study. 


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Eligible subjects and/or legal representatives must be able and willing to give informed 
consent/assent for participation in the clinical study. 
Treatment with ERAs is not permitted. 
4.2 Rationale for the selection of the study population 
LT-TCPC and EC-TCPC Fontan-palliated patients constitute the majority of present-day 
Fontan-palliated patients and are considered to constitute a homogeneous group in terms 
of prognosis. The medical need in Fontan-palliated patients with NYHA FC II and III is 
greater than in patients with milder disease (FC I), as higher FC is both an indicator of 
decreased exercise tolerance and progression of their HF. FC IV patients are considered 
too severe, heterogeneous, and are likely to be late failing-Fontan patients with overt 
clinical signs of HF and/or other signs of Fontan-related serious complications. 
Furthermore, the only true treatment of FC IV Fontan-palliated patients is heart 
transplantation. Failing-Fontan patients are not planned to be included in this study. 
The LT-TCPC and EC-TCPC Fontan-palliated surviving patient population is a relatively 
young population in which medical need is high because their exercise capacity is 
significantly reduced. In this population, patients are expected to derive a significant 
beneficial effect on their exercise capacity and, potentially, disease progression can be 
delayed. Within this population, adolescents have the greatest need for improvement of 
their exercise capacity as they are at an age where their exercise intolerance progresses the 
most rapidly [Giardini 2008, Kempny 2012, Fernandes 2010]. 
4.3 Inclusion criteria 
For inclusion in the study, all of the following inclusion criteria must be fulfilled. It is not 
permitted to waive any of the criteria for any subject: 
1. Written informed consent/assent from the subject and/or a legal representative prior to 
initiation of any study-mandated procedures. 
2. Male or female ≥ 12 years old.  
3. Fontan-palliated subjects with either LT-TCPC, or EC-TCPC surgery > 1 year before 
Screening. LT-TCPC, or EC-TCPC surgery can be primary or secondary to 
atrio-pulmonary connection.  
4. NYHA FC II or III (assessed by the investigator using the Specific Activity Scale 
[Appendix 4]).  
5. Ability to understand and comply with the instructions, and ability to physically 
perform the CPET. 
6. Women of childbearing potential must: 


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6.1. Have a negative serum pregnancy test at the Screening visit and a negative urine 
pregnancy test at the Randomization visit (Visit 2), and, 
6.2. Agree to perform monthly pregnancy tests up to the end of the S-FU period, and, 
6.3. Agree to use reliable contraception [Section 4.5.2] from at least 30 days prior to 
Visit 2 and up to at least 30 days after study drug discontinuation. 
4.4 Exclusion criteria 
Subjects must not fulfill any of the following exclusion criteria. It is not permitted to waive 
any of the criteria for any subject: 
1. Pattern of Fontan circulation severity. Any of the following: 
1.1. Known severely reduced single ventricle ejection fraction (< 30%) 
1.2. Known Fontan circulation stenosis, affected area > 50% of the diameter  
1.3. Known valvular defects (severe atrioventricular [AV] valve regurgitation, outflow 
obstruction) 
1.4. Known pulmonary-venous pathway obstruction 
1.5. Peripheral oxygen saturation (SpO2) of < 88% at rest at Screening 
2. Deterioration of the Fontan-palliated condition. Any of the following events within 
3 months prior to Screening: 
2.1. Candidate on the active list for heart transplantation  
2.2. Clinical worsening leading to medical interventions including reoperation of 
Fontan circulation (e.g., mechanical circulatory support, Fontan take-down, 
Fontan revision/conversion, AV valve repair/replacement).  
2.3. Unscheduled hospitalization due to deterioration of the Fontan-palliated condition1 
2.4. Signs and symptoms of HF2 requiring change in diuretic therapy  
2.5. Ventricular tachyarrhythmia or supraventricular tachyarrhythmia3 
2.6. Peritoneal, pleural, mediastinal, or pericardial effusions 
2.7. Thrombotic or hemorrhagic complications (including thromboembolism and 
hemoptysis) 
2.8. Protein losing enteropathy (PLE) (serum albumin < 30 g/L and total 
protein < 50 g/L) 
2.9. Plastic bronchitis/chyloptysis 
 
 
1 Only applicable as an event if hospitalization/intervention was unscheduled / not related to routine 
Fontan-related follow-up, and hospital stay was > 24 hours. 
2 Include orthopnea, nocturnal dyspnea, pulmonary edema, or radiological signs. Persistent congestion with 
edema only qualifies if the peripheral edema is moderate-to-severe despite optimal diuretic therapy. 
3 Subjects are excluded for arrhythmia only if it requires hospitalization, or cardioversion, addition/increase 
in antiarrhythmic treatment, or invasive tests or treatment. 


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2.10. Signs and symptoms requiring the addition of a new class of cardiovascular 
medication (e.g., nitrates, alpha-blockers, or ERAs) 
 
3. Limitations to CPET: 
3.1. History of syncope during exercise  
3.2. Symptomatic coronary artery disease at Screening 
3.3. Respiratory limitation with a breathing reserve of < 10% 
3.4. Iron deficiency defined as ferritin < 10 µg/L at Screening 
3.5. Iron supplementation, regardless of route of administration, unless already present 
at stable dose for more than 3 months prior to Screening 
3.6. Body mass index (BMI)-for-age reference (z-scored) equivalent to BMI > 35 kg/m2 
(for adults) at Screening 
3.7. Exercise training program for cardiopulmonary rehabilitation in the 3-month period 
prior to Screening 
3.8. Myocardial infarction < 6 months before Screening 
3.9. Pacemaker at Screening 
 
4. Peak VO2 < 15 mL/kg/min at Baseline. 
5. Systolic BP < 90 mmHg (< 85 mmHg for subjects < 18 years old and < 150 cm of 
height) at rest or during CPET at Screening or at Baseline. 
6. Criteria related to macitentan use: 
6.1. Hemoglobin < 75% of the lower limit of normal assessed by central laboratory at 
Screening 
6.2. Known or suspected pulmonary veno-occlusive disease 
6.3. Known and documented severe hepatic impairment defined as Child-Pugh Score C 
[Appendix 10], based on measurement of total bilirubin, serum albumin, 
international normalized ratio or prothrombin time (except for patients under 
non-Vitamin K antagonists) and based also on presence/absence and severity of 
ascites and hepatic encephalopathy 
6.4. Serum AST and/or ALT > 3 × upper limit of normal range assessed by central 
laboratory at Screening 
6.5. Severe renal impairment (estimated creatinine clearance < 30 mL/min/1.73m2) 
assessed by central laboratory at Screening 
6.6. Pregnancy, breastfeeding, or intention to become pregnant during the study, or 
women of childbearing potential not using a reliable method of contraception 
6.7. Hypersensitivity to any active substance or excipient of any of the study drugs 
6.8. Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer such as 
carbamazepine, rifampin, rifampicin, rifabutin, rifapentin, phenobarbital, 
phenytoin, and St. John’s wort, within 1 month prior to Randomization (Visit 2) 


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6.9. Treatment with a strong CYP3A4 inhibitor such as ketoconazole, itraconazole, 
voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir, 
within 1 month prior to Randomization (Visit 2) 
7. General exclusion criteria: 
7.1. Any factor or condition likely to affect protocol compliance of the subject, as 
judged by the investigator 
7.2. Treatment with another investigational therapy in the 3-month period prior to 
Screening 
7.3. Treatment with nitrates, alpha-blockers, or ERAs in the 3-month period prior to 
Screening  
7.4. Introduction or change of dose of PH-specific drugs (other than ERAs) in the 
3-month period prior to Screening 
7.5. Known drug or substance (e.g., alcohol) abuse, unstable psychiatric illness, or any 
other condition that, in the opinion of the investigator, may interfere with 
participation in the study 
7.6. Any planned surgical intervention (e.g., organ transplant) during the study period, 
except minor interventions (e.g., tooth extraction) 
8. Any known factor or disease that may interfere with treatment compliance or full 
participation in the study (e.g., chemotherapy treatment for cancer) or illness with an 
anticipated life expectancy of less than 12 months. 
4.5 Criteria for women of childbearing potential 
4.5.1 Definition of childbearing potential 
A woman is considered to be of childbearing potential unless she meets at least one of the 
following criteria: 
• Previous bilateral salpingectomy, bilateral salpingo-oophorectomy or hysterectomy, 
• Postmenopausal (defined as 12 consecutive months with no menses without an 
alternative medical cause [ICH M3 definition]), 
• Premature ovarian failure (confirmed by a specialist), XY genotype, Turner syndrome, 
uterine agenesis, 
• Pre-pubescence (pre-pubescent females must have their childbearing potential status 
reassessed at each visit and recorded in the electronic Case Report Form [eCRF]). 
To determine pre-pubescent status of female subjects who have not reached menarche, the 
subject will do a self-assessment in the presence of the investigator (or female counselor 


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when applicable) according to the Tanner stages described in Appendix 5. The onset of 
puberty is defined as reaching stage 2 on the Tanner scale. 
The site study personnel will record the Tanner stage and the childbearing potential in the 
eCRF. Once childbearing potential is achieved, the Tanner stage will no longer be self-
assessed. For abstinent subjects of childbearing potential, the study personnel will ask at 
each visit whether the subject currently is or might become sexually active. If confirmed 
the study personnel will counsel the female on the appropriate methods of contraception as 
applicable [see to Section 4.5.2]. 
The reason for not being of childbearing potential will be recorded in the eCRF. 
4.5.2 Acceptable methods of contraception 
Women of childbearing potential [see definition in Section 4.5.1] must use acceptable birth 
control from Screening up to at least 30 days after study treatment discontinuation. Reliable 
contraception must be started at least 30 days prior to Visit 2. 
The methods of birth control used (including non-pharmacological methods) must be 
recorded in the eCRF. 
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.  
4.5.2.1 Countries having taken part in the VHP (Voluntary Harmonization 
Procedure), or countries with a restricted list of contraception methods 
Study treatment should only be initiated in women of childbearing potential when the 
absence of pregnancy has been verified, appropriate advice on contraception provided, and 
reliable contraception is practiced. It must be ensured that a female counselor is available 
to discuss this topic, if requested.  
In countries having taken part in the VHP, namely Denmark, Germany and UK,  
one of the following highly effective contraception methods is required: 
• combined (estrogen and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:  
− oral 
− intravaginal 
− transdermal 


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• progestogen-only hormonal contraception associated with inhibition of ovulation: 
− oral 
− injectable 
− implantable 
• intrauterine device 
• intrauterine hormone-releasing system 
• bilateral tubal occlusion  
• vasectomized partner (provided that partner is the sole sexual partner of the women of 
childbearing potential trial subject and that the vasectomized partner has received 
medical assessment of the surgical success). 
Other countries may have adopted the same restricted list of contraception methods. Please 
refer to your country-specific approval documents and approved local Informed Consent. 
4.5.2.2 Countries not having taken part in the VHP (excluding France) or countries 
without a restricted list of contraception methods 
In the Czech Republic, Poland and Ireland, study treatment should only be initiated in 
women of childbearing potential when the absence of pregnancy has been verified, 
appropriate advice on contraception provided, and reliable contraception is practiced. It 
must be ensured that a female counselor is available to discuss this topic, if requested.  
True abstinence from intercourse with a male partner, only when this is in line with the 
preferred lifestyle of the subject, is considered an acceptable birth control method. 
Other countries may have adopted the same approach regarding contraception methods. 
Please refer to your country-specific approval documents and approved local Informed 
Consent. 
4.5.2.3  France 
Study treatment should only be initiated in women of childbearing potential when the 
absence of pregnancy has been verified, appropriate advice on contraception provided, and 
reliable contraception is practiced. It must be ensured that a female counselor is available 
to discuss this topic, if requested.  
4.5.2.4 North America 
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 4]. 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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In addition to acceptable birth control methods identified in Figure 4, true abstinence from 
intercourse with a male partner, only when this is in line with the preferred lifestyle of the 
subject, is considered an acceptable birth control method. 
The investigator must counsel subjects on pregnancy planning and prevention, including 
emergency contraception, or designate counseling by another healthcare provider trained 
in contraceptive measures. 
Figure 4 
Acceptable birth-control options 
 


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4.5.2.5 Asia and Oceania 
Study treatment should only be initiated in women of childbearing potential when the 
absence of pregnancy has been verified, appropriate advice on contraception provided, and 
reliable contraception is practiced. It must be ensured that a female counselor is available 
to discuss this topic, if requested.  
True abstinence from intercourse with a male partner, only when this is in line with the 
preferred lifestyle of the subject, is considered an acceptable birth control method. 
5 
TREATMENTS 
5.1 Study treatment 
5.1.1 Investigational treatment: Description and rationale 
Macitentan 10 mg will be provided as film-coated tablets debossed with ‘10’ on one side, 
for o.d. oral administration with or without food.  
Inactive ingredients of the macitentan tablet formulation are the following: lactose, 
magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate type A, 
polysorbate. The film coat contains titanium dioxide, talc, xanthan gum, polyvinyl alcohol, 
and soy lecithin. 
The macitentan 10 mg o.d. dose selected for the proposed study is based on the formulation 
and the dose regimen approved for treatment of adult patients with PAH from World Health 
Organization (WHO) FC II and III. Treatment with another related ERA, bosentan, has 
shown efficacy and safety in Fontan-palliated adolescent and adults with the dose regimen 
approved for PAH [Hebert 2014] and dose adjusted on body weight [Shang 2013]. 
5.1.2 Comparator: Description and rationale 
The treatment comparator will be matching placebo tablets, for o.d. oral administration 
with or without food.  
As no approved medicinal treatment for patients with Fontan-palliation exists and the 
disease progression is rather slow, it is ethical to compare the investigational medicinal 
product to placebo as add on to standard of care. 
5.1.3 Study treatment administration 
If the subject is eligible, the first intake of study treatment will take place at site, during the 
Randomization visit (Visit 2), after successful completion of all Screening (Visit 1) and 
Randomization (Visit 2) assessments. 
The subjects must be instructed not to take study treatment in the morning of study visit 
days. 


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On the days of study visits, the dose of the study treatment should be withheld until all 
assessments have been performed. Study treatment will then be administered from the 
newly dispensed batch. 
If a dose is missed, it should not be taken as compensation the following day, but instead 
the subject should continue with the regular dosing. The interruption should be noted in the 
eCRF. 
For this study, any dose of study treatment higher than the planned total daily dose in a 
single day will be considered an overdose [see Sections 9.1 and 9.6]. 
In the event of an overdose, standard supportive measures must be taken, as required. 
Table 1 
Dosing scheme 
Treatment period 
Duration 
Study treatment 
Dose regimen 
Screening 
Day −30 to Day −1 
NA 
NA 
Treatment 
Day 1 to 
Day 364/EOT 
Placebo or macitentan 
10 mg o.d. 
Safety follow-up 
30 days after EOT 
NA 
NA 
PTOP* 
Immediately after 
Safety follow-up 
NA 
NA 
* PTOP is only entered if subject prematurely and permanently discontinues treatment with macitentan. 
Any treatment initiated during the PTOP is captured in the concomitant medications page in the eCRF. 
eCRF = electronic Case Report Form; EOT = End-of-Treatment; NA = not applicable; o.d. = once daily; 
PTOP = post-treatment observation period. 
5.1.4 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 Visit 2 to randomize the subject. The IRT assigns a randomization number to the 
subject and assigns the treatment kit number, which matches the treatment arm assigned 
by the randomization list to the randomization number. 
Subjects are assigned to the two treatment arms in a 1:1 ratio based on a permutated-block 
randomization stratified by the geographical region (America, Europe, Asia, Oceania) in 
order to balance treatment arms throughout the conduct of the trial. 
The randomization list is generated by an independent Contract Research Organization 
(CRO), Almac Clinical Technologies, using SAS® v9.3. 
5.1.5 Blinding 
This study will be performed in a double-blind fashion. The investigator and study 
personnel, the subjects, the clinical research associates (CRAs), Actelion personnel, and 


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CRO personnel involved in the conduct of the study will remain blinded to the study 
treatment until study completion [see Section 8.1]. Actelion personnel responsible for 
clinical study supply distribution will need to be unblinded to ensure adequate supply of 
study treatment. These persons will be clearly identified, their unblinding will be 
documented in the trial master file and they will not take part in any clinical trial team 
(CTT) meetings after study set-up has been completed. 
Until the time of unblinding for final data analysis, the randomization list is kept strictly 
confidential and accessible only to authorized persons, e.g., Global Quality Management 
(GQM), and the ISAC/SSG, who are not involved in the conduct of the study. 
The investigational treatment and its matching placebo are indistinguishable, and all 
treatment kits will be packaged in the same way. 
5.1.6 Unblinding 
5.1.6.1 Unblinding for final analyses 
Full randomization information will be made available for data analysis only after database 
closure, in accordance with Actelion Quality System (QS) documents. 
5.1.6.2 Unblinding for IDMC 
The ISAC/SSG not otherwise involved in the design, conduct and analysis of the study, 
will have access to the randomization code in order to prepare unblinded reports and IA 
results for review by the IDMC, as described in the IDMC charter. The randomization code 
will be made available only to the ISAC/SSG in accordance with Actelion’s quality 
documents. 
5.1.6.3 Unblinding for suspected unexpected serious adverse reactions 
If a suspected unexpected serious adverse reaction (SUSAR) occurs for a subject 
participating in the study, the sponsor will request the unblinding of the treatment 
assignment. The treatment assignment will not be communicated to site personnel or to the 
Actelion personnel. Unblinded SUSAR information will be provided to respective health 
authorities and independent ethics committees (IECs) or institutional review boards (IRBs) 
only. SUSARs will be reported to investigators in a blinded fashion. 
5.1.6.4 Emergency procedure for unblinding 
The investigator, study personnel and Actelion personnel must remain blinded to the 
subject’s treatment assignment. The identity of the study treatment may be revealed only 
if the subject experiences a medical event, the management of which would require 
knowledge of the blinded treatment assignment. In this case, the investigator can receive 
the unblinded treatment assignment through the IRT. In these situations, the decision to 
unblind resides solely with the investigator. Whenever it is possible, and if it does not 


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interfere with (or does not delay) any decision in the best interest of the subject, the 
investigator is invited to discuss the intended unblinding with Actelion personnel. 
The occurrence of any unblinding during the study must be clearly justified and explained 
by the investigator. In all cases, Actelion personnel must be informed as soon as possible 
before or after the unblinding. 
A subject may stay on study treatment after unblinding provided the following conditions 
are met: 
• The treating physician believes that the benefit/risk balance remains favorable. 
• Unblinding was not due to an intentional overdose of study drug. 
Unblinding will not be allowed for the sole purpose of entering the AC-055H302 OL 
extension. 
The circumstances leading to unblinding must be documented in the Investigator Site File 
(ISF) and eCRF. 
5.1.7 Study treatment supply 
Manufacture, labeling, packaging, and supply of study treatment will be conducted 
according to Good Manufacturing Practice, Good Clinical Practice (GCP), and any local 
or national regulatory requirements. 
All study treatment supplies are to be used only in accordance with this protocol, and not 
for any other purpose. 
5.1.7.1 Study treatment packaging and labeling 
Study treatment is provided as tablets and supplied in childproof bottles containing 
36 tablets. 
Study treatment is labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located. Each medication bottle has a booklet affixed, 
detailing all relevant information. The booklet contains a tear-off part specifying the study 
protocol number, the packaging batch number and the bottle number. When the study 
treatment is given to the subject, the investigator, pharmacist (if applicable), or designee 
must remove the tear-off part and attach it to the Investigational Medicinal Product (IMP) 
Label Dispensing Log. 
5.1.7.2 Study treatment distribution and storage 
The investigator is responsible for safe and proper handling and storage of the study 
treatment at the investigational site and for ensuring that the study treatment is administered 
only to subjects enrolled in the study and in accordance with the protocol. 


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5.1.7.2.1 Study treatment distribution 
The study centers will be supplied with study treatment according to the centers’ needs, 
depending on the rate of subject enrollment. Each center will have an individual stock of 
study treatment, which will be re-supplied continuously as soon as a predefined minimum 
level of study treatment has been reached.  
5.1.7.2.2 Study treatment storage 
Study treatment must be kept in a locked room or a locked cupboard in a restricted access 
room, which can be accessed only by the pharmacist, the investigator, or another duly 
designated person as specified on the delegation of authority form.  
The subject must be educated on the proper study treatment storage conditions at home.  
Bottles containing study treatment tablets must be stored according to conditions specified 
on the label. Refer to the pharmacy manual/study site investigational product and 
procedures manual for additional guidance on study treatment handling and storage. 
5.1.7.3 Study treatment dispensing 
The subjects will receive sufficient study treatment to cover the period up to the next 
scheduled visit. Subjects are asked to return all used and unused study treatment (including 
empty bottles) at each visit. The protocol-mandated study-treatment dispensing procedures 
may not be altered without prior written approval from Actelion. An accurate record of the 
date and amount of study treatment dispensed/returned to/by each subject must be available 
for inspection at any time.  
Once a subject has been enrolled and study treatment assigned, the corresponding 
bottles/packs must not be used for another subject. If a subject has been dispensed a 
bottle/pack in error (one that has not been allocated yet to another subject), the IRT system 
helpdesk must immediately be contacted. 
At the time study treatment is dispensed, the subject should be educated on the proper 
storage conditions at home [see Section 5.1.7.2.2].  
5.1.7.4 Study treatment return and destruction 
The protocol-mandated study treatment return procedures may not be altered without prior 
written approval from Actelion. On an ongoing basis (if required) or on termination of the 
study at site level, the CRA will collect used and unused treatment kits, which will be sent 
to the warehouse, where Actelion personnel or a deputy will check treatment reconciliation. 
In certain circumstances, used and unused study treatment containers may be destroyed at 
the site once study treatment accountability is finalized and has been checked by Actelion 
personnel or the deputy, and written permission for destruction has been obtained from 
Actelion. 


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In case study treatment cannot be reconciled by the CRA before destruction, a note to file 
is written by the study team. 
5.1.8 Study treatment accountability and compliance with study treatment 
5.1.8.1 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 Accountability and Compliance Log and in the eCRF and checked by 
the CRA during the monitoring visits and once each individual subject has terminated the 
study. The study treatment accountability log in the eCRF will include at least the following 
information for each study treatment unit (i.e., bottle) dispensed to the subject: 
• Allocated bottle number (pre-populated in the eCRF) 
• Dispensed bottles number 
• Date dispensed / number of tablets dispensed 
• Date returned / number of tablets returned 
All study treatment supplies, including unused, 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. 
5.1.8.2 Study treatment compliance 
Study treatment compliance must be evaluated by the site staff prior to each new 
dispensation. It is based on study treatment accountability. Study treatment compliance 
will be calculated by site personnel at each visit when the IMP is returned and new IMP 
dispensed, using the below formula, and entered in the eCRF: 
Compliance = [(number of tablets dispensed − number of tablets returned) / Total number 
of tablets that should have been taken since the last visit*] × 100. 
* The number of tablets that should have been taken since the last visit is derived from the 
number of planned treatment days between the previous visit and the day before the current 
visit. It is defined as current visit date − previous visit date.  
Between visits, 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 eCRF by the CRA. Permanent discontinuation of study treatment may be considered 
after consultation with Actelion. 


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5.1.9 Study treatment dose adjustments and interruptions 
Study treatment dose adjustments are not permitted. 
Study treatment may be temporarily interrupted in response to an AE, a diagnostic or 
therapeutic procedure, a laboratory abnormality, or for administrative reasons. 
Study-specific criteria for interruption of study treatment are described in Section 5.1.11. 
If study treatment is interrupted by the subject for any reason, she/he must immediately 
inform the investigator. 
Interruptions of study treatment must be kept as short as possible. If treatment is stopped 
for more than 4 consecutive weeks, re-introduction is not permitted, and treatment must be 
permanently discontinued [see Section 5.1.10]. 
Study treatment interruptions as well as reasons for interruptions must be recorded in the 
eCRF. 
5.1.10 Premature discontinuation of study treatment 
The decision to prematurely discontinue study treatment may be made by the subject, the 
investigator, or Actelion 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 eCRF. 
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, including the VSFU (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 5.1.11. 
A subject who prematurely discontinues study treatment is NOT considered as withdrawn 
from the study and will be followed up until at least the S-FU visit and, if applicable, during 
the PTOP until Week 52, as well as for collection of vital status at SCL, provided that the 
subject’s consent for this limited participation in the study has not been withdrawn. 
The subject will be asked to return for an EOT visit within 7 days of last intake of study 
treatment and assessed for a S-FU visit 30 days after the last intake of study treatment. If 


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the subject enters the PTOP, the subject will be called on the telephone for follow-up visits 
as described in Table 3. The assessments that are performed at each visit are described in 
Table 3 [see Section 7.1]. Importantly, if discontinuation occurs prior to the Week 16 
CPET assessment for the primary endpoint, it is requested that the subject returns to the 
site at Week 16 for a CPET evaluation. 
A subject who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered as withdrawn from the study. 
Subjects who die or are lost to follow-up are also considered as withdrawn from the study. 
Withdrawal from the study and follow-up medical care of subjects withdrawn from the 
study is described in Sections 8.2 and 8.4, respectively. 
5.1.11 Study-specific criteria for interruption / premature discontinuation of study 
treatment 
Study treatment interruptions exceeding 4 consecutive weeks must lead to permanent 
discontinuation of study treatment. 
5.1.11.1 Pregnancy 
If a female subject becomes pregnant while on study treatment, study treatment must be 
interrupted immediately, and a Pregnancy Notification Form must be completed [see 
Section 9.3.1].  
5.1.11.2 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 × upper limit of normal (ULN) 
 
A re-test of aminotransferases (ALT and AST), total and direct bilirubin, and alkaline 
phosphatase (AP) must be performed within one week. If AST and/or ALT elevation is 
confirmed, aminotransferases, total and direct bilirubin, and AP levels must be monitored 
weekly until values return to pre-treatment levels or within normal ranges. If the 
aminotransferase values return to pre-treatment levels or within normal ranges, 
re-introduction of study treatment can be considered.  
Re-introduction of study treatment after treatment interruption should only be considered 
if the potential benefits of study treatment outweigh the potential risks and when liver 
aminotransferase values are within pre-treatment levels or within normal ranges. The 
advice of a hepatologist is recommended. 
Liver aminotransferase levels must then be checked within 3 days after re-introduction, 
then again after a further 2 weeks and thereafter according to the recommendations above 
(e.g., at monthly intervals). 


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Permanent discontinuation of study treatment 
Study treatment must be stopped, and its re-introduction is not to be considered in the 
following cases: 
• Aminotransferases (ALT and/or AST) ≥ 8 × ULN 
• Aminotransferases (ALT and/or 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 (ALT and/or AST) ≥ 3 × ULN and associated increase in total 
bilirubin ≥ 2 × ULN 
 
A re-test of aminotransferases (ALT and AST), total and direct bilirubin, and AP must be 
performed. Aminotransferases, total and direct bilirubin, and AP levels must be monitored 
weekly after study treatment discontinuation until values return to pre-treatment levels or 
within normal ranges. 
Other diagnoses (e.g., viral hepatitis, mononucleosis, toxoplasmosis, cytomegalovirus, 
alcoholic hepatitis, non-alcoholic steatohepatitis, autoimmune disease) and/or etiologies 
(e.g., hepatic toxicity of concomitant medication[s] or other substances) should be 
considered and ruled out by performing the appropriate tests. 
All liver aminotransferases abnormalities leading to study treatment interruption or 
discontinuation must be recorded as AEs [see Section 9].  
To ensure the proper and comprehensive evaluation of cases of ALT and/or AST 
increase > 3 × ULN, additional subject data may be collected in the hepatic event 
questionnaire distributed by the sponsor. 
An independent ILSDRB (an external expert committee of hepatologists) provides ongoing 
assessments and advice regarding any hepatic events that may require further evaluation 
during the study.  
5.1.11.3 Hemoglobin abnormalities 
If there is a case of hemoglobin < 100 g/L accompanied by a change from baseline4 of 
≥ 50 g/L during the treatment period (up to and including Visit 7), or a blood transfusion, 
a re-test must be performed within 10 days of the initial test showing the decrease, with 
additional laboratory evaluations that may include, but are not limited to, any of the 
following: 
 
 
4 Baseline hemoglobin refers to the last hemoglobin value obtained prior to first intake of study treatment. 


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• Red blood cell cellular indices (mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration), peripheral blood smear, 
reticulocyte count, iron status (iron level, serum ferritin, total iron binding capacity, 
transferrin saturation), lactate dehydrogenase, indirect bilirubin. 
Study treatment must be temporarily interrupted if clinically mandated based on the 
investigator’s judgment. 
Any hemoglobin decrease equivalent to CTCAE version 4.03 grade 3 or higher 
(i.e., hemoglobin < 8.0 g/dL; < 4.9 mmol/L; < 80 g/L) should result in interruption of study 
medication, unless an underlying blood loss event caused this decrease. 
Re-introduction of study treatment may be considered by the investigator if hemoglobin 
recovery, defined as a return of hemoglobin above the lower limit of the normal range or 
to baseline, is achieved. 
5.1.11.4 Drop in BP 
BP is measured at each visit and at regular intervals during the conduct of CPET. Study 
treatment must be temporarily interrupted if systolic BP drops to < 90 mmHg (< 85 mmHg 
for subjects < 18 years old and < 150 cm of height). 
Re-introduction of study treatment after treatment interruption should only be considered 
if the potential benefits of study treatment outweigh the potential risks and when BP values 
are within pre-treatment levels or within normal ranges.  
BP must then be checked within 3 days after re-introduction, then again after a further 
2 weeks and thereafter according to the recommendations of the treating physician. These 
checks need not occur at the study site and results may be communicated to the site via 
phone. 
5.1.11.5 Initiation of forbidden medication 
Study treatment must be permanently discontinued if any forbidden medications are started 
during the treatment period. 
However, if subjects are currently stable on a moderate dual CYP3A4/CYP2C9 inhibitors 
(e.g., fluconazole, amiodarone) or co-administration of a combination of moderate 
CYP3A4 (e.g., ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) and 
moderate CYP2C9 inhibitors (e.g., miconazole, piperine), the subject may remain on 
current treatment per the investigator’s discretion based on his/her clinical judgement and 
risk-benefit assessment. However, the subject will not be eligible to enter the OL study 
unless the forbidden medication is discontinued 1 month prior to OL enrollment. 


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5.2 Previous and concomitant therapy 
5.2.1 Definitions 
A previous therapy is any treatment for which the end date is prior to signing of informed 
consent. 
A therapy that is study-concomitant is any treatment that is ongoing or initiated after 
signing of informed consent. 
A therapy that is study treatment-concomitant is any treatment that is either ongoing at the 
start of study treatment or is initiated during the treatment period. 
5.2.2 Reporting of previous/concomitant therapy / auxiliary medicinal products in 
the eCRF 
The use of all study-concomitant therapy (including contraceptives and traditional and 
alternative medicines, e.g., plant-, animal- or mineral-based medicines) will be recorded in 
the eCRF. Previous therapy must be recorded in the eCRF if discontinued less than 30 days 
prior to signing of the informed consent. The generic name, start/end dates of 
administration (as well as whether it was ongoing at start of treatment and/or EOS), route, 
dose, frequency, and indication will be recorded in the eCRF. 
5.2.3 Allowed concomitant therapy 
Allowed therapy consists of agents typically prescribed to manage conditions associated 
with Fontan palliation. 
• Antiplatelet agents 
• Anticoagulants (Vitamin K antagonist, new oral anticoagulants [oral non-vitamin K 
antagonist anticoagulants]), etc.) 
• Angiotensin-converting enzyme inhibitors 
• Angiotensin receptor blockers 
• Oral diuretics  
• Antiarrhythmics 
• Beta blockers 
• PH-specific drugs except ERAs 
5.2.4 Forbidden concomitant therapy 
Forbidden therapy includes agents interfering with CPET, influencing drug exposure 
and/or affecting the primary endpoint. 
• Therapies interfering with the CPET evaluation 
– Pacemakers 
– Nitrates 


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• Vasodilators 
– Alpha-blockers 
– ERAs other than macitentan 
• CYP3A4 and drug-drug-interaction 
– Strong inducers of CYP3A4 (e.g., carbamazepine, rifampin, rifampicin, rifabutin, 
rifapentin, phenobarbital, phenytoin, and St. John’s wort) 
– Strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, 
clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir)  
– 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*. For other examples of CYP inhibitors, refer to the Food and Drug 
Administration website [FDA 2020]. 
• Iron supplementation, regardless of the route of administration, unless already present 
at stable dose for more than 3 months prior to Screening 
• Any investigational therapy. 
 
* If subjects are currently stable on a moderate dual CYP3A4/CYP2C9 inhibitors (e.g. 
fluconazole, amiodarone) or co-administration of a combination of moderate CYP3A4 
(e.g. ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) and moderate 
CYP2C9 inhibitors (e.g. miconazole, piperine), the subject may remain on current 
treatment per the investigator’s discretion based on his/her clinical judgement and risk-
benefit assessment. However, the subject will not be eligible to enter the OL study unless 
the forbidden medication is discontinued 1 month prior to OL enrollment. 
 
6 
STUDY ENDPOINTS 
6.1 Efficacy endpoints 
6.1.1 Primary efficacy endpoint 
The primary efficacy endpoint is the change in peak VO2, from Baseline 
(Randomization/Visit 2) to Week 16 (Visit 4). 
6.1.2 Secondary efficacy endpoints 
• Change from Baseline (Visit 2) over 52 weeks in peak VO2. 
• Change from Baseline (Visit 2) to Week 16 (Visit 4) in mean count per minute of 
daily PA-Ac.  
6.1.3 Other efficacy endpoints 
• Endpoints related to exercise capacity from Baseline (Visit 2) to Week 16 (Visit 4), 
and Week 52 (Visit 6): 


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− Change in peak VO2 (other than to Week 16 [Visit 4])  
− Change in ventilatory efficiency (assessed as minute ventilation [VE] / carbon 
dioxide production [VCO2] slope)  
− Change in VO2 at ventilatory anaerobic threshold (VAT) 
− Change in oxygen uptake efficiency slope (OUES) 
• Percent of Baseline (Visit 2) at Week 16 (Visit 4) in NT-proBNP.  
• Percent of Baseline (Visit 2) in NT-proBNP over 52 weeks. 
• Composite endpoint of event related to Fontan-palliated clinical worsening, time from 
Randomization (Visit 2) to first occurrence up to EOS of one or more of the 
following: 
− Unscheduled hospitalization for Fontan-palliated morbidity event5 
− Signs and symptoms of HF6, requiring change in diuretic therapy 
− Clinical worsening leading to interventions related to the Fontan-palliated 
condition 
− Worsening to NYHA FC III, investigator assessed using the Specific Activity 
Scale [Appendix 4]. 
− Signs and symptoms requiring the addition of a new class of cardiovascular 
medication (e.g., nitrates, alpha-blockers, or ERAs), or insertion of a pacemaker. 
− Failing-Fontan defined as one or more of the following: 
o Enlisted on the active list for heart transplantation or effective heart 
transplantation 
o Reoperation (e.g., mechanical circulatory support, Fontan take down, 
Fontan revision / conversion, AV valve repair/replacement) 
o Worsening to NYHA FC IV, investigator assessed using the Specific 
Activity Scale [Appendix 4]. 
o PLE 
o Plastic bronchitis/chyloptysis 
o Peritoneal, pleural, mediastinal, or pericardial effusions 
o Severe hepatic impairment (as described in exclusion criterion 6.3) 
o Severe renal impairment (as described in exclusion criterion 6.5)  
o Death related to Failing-Fontan  
• Events related to Fontan-palliated morbidity, time from Randomization (Visit 2) to 
first occurrence up to EOS of one or more of the following: 
 
 
5 Only applicable as an event if hospitalization / intervention was unscheduled/not related to routine Fontan 
related follow-up, and hospital stay was (≥ 24 hours). 
6 Note: Include orthopnea, nocturnal dyspnea, pulmonary edema, or radiological signs. Persistent 
congestion with edema only qualifies as a sign of heart failure if the peripheral edema is 
moderate-to-severe despite optimal diuretic therapy. 


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− Ventricular tachyarrhythmia or supraventricular tachyarrhythmia7 
− Thrombotic or hemorrhagic complications (including thromboembolism and 
hemoptysis) 
• Change from Baseline (Visit 2) to Week 16 (Visit 4) in daily mean time in minutes 
spent in sedentary, light, moderate, or vigorous PA-Ac. 
• Change from Baseline (Visit 2) over 52 weeks in mean count per minute of daily 
PA-Ac. 
• Change from Baseline (Visit 2) over 52 weeks in daily mean time in minutes spent in 
sedentary, light, moderate, or vigorous PA-Ac. 
6.2 Safety endpoints 
• Treatment-emergent AEs8 and serious AEs (SAEs) up to 30 days after study treatment 
discontinuation, or until initiation of study drug in the AC-055H302 OL extension 
study, whichever occurs first. 
• AEs leading to premature discontinuation of study treatment. 
• Change in vital signs (systolic and diastolic arterial BP and pulse rate), including SpO2 
and body weight from Baseline (Visit 2) to all assessed time points during the study.  
• Treatment-emergent marked laboratory abnormalities up to 30 days after study 
treatment discontinuation, or until initiation of study drug in the AC-055H302 OL 
extension study, whichever occurs first. 
• Change in laboratory parameters from Baseline (Visit 2) to all assessed time points 
during the study. 
6.3 Quality of life endpoints 
• Patient Global Assessment of Disease Severity (PGA-S) and Clinician Global 
Impression of Severity (CGI-S) at Baseline (Visit 2), Week 16 (Visit 4), and Week 52 
(Visit 6). 
• Patient Global Impression of Change (PGI-C) and Clinician Global Impression of 
Change (CGI-C) questionnaire at Week 16 (Visit 4) and Week 52 (Visit 6). 
• Proportion of subjects in each level of each dimension of the Euro QoL 5D (EQ-5D-
5L) questionnaire at Baseline (Visit 2), Week 16 (Visit 4), and Week 52 (Visit 6). 
• Self-rated health status assessed by the EQ-5D Visual Analogue Scale (VAS) at 
Baseline (Visit 2), Week 16 (Visit 4), and Week 52 (Visit 6). 
 
 
7 Arrhythmia qualifies as an event only if it requires hospitalization, cardioversion, addition/increase in 
antiarrhythmic treatment, or invasive tests or treatment. 
8 A treatment-emergent AE is any AE temporally associated with the use of study treatment (from study 
treatment start until 30 days after study treatment discontinuation) whether or not considered by the 
investigator as related to study treatment. 


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6.4 Pharmacoeconomic endpoints 
• Number per year of all-cause and Fontan-related hospitalizations, from baseline up to 
EOT. 
• Number per year of in-patient hospital days for all causes and Fontan-related causes, 
from baseline up to EOT. 
6.5 Pharmacokinetic endpoints 
Trough (pre-dose) plasma concentrations of macitentan and its metabolite ACT-132577, at 
Week 4 (during the regular corresponding monthly blood draw) and Week 16 (Visit 4), or 
at EOT in the case of premature study drug discontinuation prior to Week 16. 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS 
7.1 General information 
The study visits are listed in Table 2 (and Table 3 for PTOP). For all visits, the subjects 
must be seen on the designated (calendar) day with an allowed visit window of ± 7 days. 
A visit may occur over more than one day. A follow-up safety visit (S-FU) must be 
performed at earliest 30 days, but not later than 35 days, after intake of the last dose of 
study treatment. 
The assessments pertaining to a visit may be performed within the allowed time window. 
In addition, unscheduled visits can occur at any time [Section 7.1.2]. 
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 the last dose of study treatment. Subjects 
who prematurely discontinue study treatment for any reason will not be replaced. 
7.1.1 Screening/re-screening 
Screening starts with the signature of the informed consent. The date on which the first 
screening assessment is performed corresponds to the date of the Screening visit. 
It is the responsibility of the investigator/delegate to obtain written informed consent from 
each subject participating in this study after adequate face-to-face explanation of the 
objectives, methods, and potential hazards of the study. The subjects (and if applicable 
their legal representative) who agree to participate in the study and the 
investigator/delegate must sign the ICF (and if applicable assent form) prior to any 
study-related assessment or procedure. 
Subjects who have signed informed consent and are in screening when the enrollment 
target has been met may still be randomized if they meet all the selection criteria. 


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It is permitted to re-screen subjects once, if the reason for non-eligibility was transient 
(e.g., abnormal laboratory test, insufficient wash-out period of a forbidden medication). In 
this case, re-consent is required if the initial consent signature is more than 30 days old or 
if a new informed consent version is available. 
All screening assessments should be repeated at the time of re-screening. The PA-Ac is 
mandatory at re-screening. 
7.1.2 Unscheduled visits 
Unscheduled visits may be performed at any time during the study. 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 eCRF. 
After an unscheduled visit, the regular scheduled study visits must continue according to 
the planned visit and assessment schedule. 


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Table 2 
Visit and assessment schedule 
PERIODS 
Name 
SCREENING 
TREATMENT 
 
FOLLOW-UP 
 
Duration 
30 days 
52 Weeks 
 
30 days 
 
VISITS11 
Number 
1 
2 
3 
4 
5 
 
6 
U1, U2, … 
7 
8 
 
Name 
Screening 
Randomization 
Week 8 
 
Week 16 
Week 32 
 
 
Week 52 / EOT Unscheduled 
visit5 
Safety FU1 
(S-FU)  
Vital Status 
FU (VSFU)14 
 
 
Time 
Within 30 
days of Day 1 
Day 1 
(≥ 9 days after 
Screening) 
Day 57 
(± 7 days) 
Day 113 
(± 7 days) 
Day 225 
(± 7 days) 
 
Day 365 
(± 7 days) or 
within 7 days 
after 
premature 
discontinuation 
Any day 
between Day 1 
and end of 
S-FU 
30-35 days 
after EOT 
Within 8 
weeks of 
sponsor’s 
announced 
Study 
Closure 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Disease severity diagnosis3  
X 
 
 
 
 
 
 
 
 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination 
X 
X8 
 
X8 
 
X 
X 
 
 
Vital signs (BP, HR, weight, 
height, SpO2) 
X 
X 
 
X 
 
X 
X 
 
 
NYHA FC (using Specific 
Activity Scale) 
X 
X 
X 
X 
X 
X 
X 
X 
 
Echocardiography 
X 
 
 
 
 
X 
X 
 
 
12-lead ECG6 
X 
 
 
 
 
 
X 
 
 
Laboratory tests*7  
X 
X 
X7 
X 
X7 
X 
X 
X7 
 
NT-proBNP 
 
X 
 
X 
 
X 
X 
 
 


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Pregnancy test. 
contraception & 
reassessment of 
childbearing potential9 
X 
Monthly (28 ± 7 days) 
X 
X 
 
CPET (incl. ECG, 
spirometry) 
X13 
X 
 
X 
 
X 
X 
 
 
Physical Activity measured 
by Accelerometer (PA-Ac)12 
X 
 
 
X 
 
X 
 
 
 
PK sampling10 
 
 
 
X 
 
X10 
 
 
 
PGA-S/CGI-S 
 
X 
  
X 
 
X 
X 
 
 
PGI-C/CGI-C 
 
 
  
X 
 
X 
X 
 
 
EQ-5D-5L questionnaire 
 
X 
 
X 
  
X 
X 
 
 
Study treatment 
dispensing/return2 
– 
X 
 
X 
 
X 
X 
– 
 
Worsening/morbidity event 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
SAEs/AEs4 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Status 
 
 
 
 
 
 
 
 
X 
*Transferred electronically by an external service provider. 
1 Visit may be performed by telephone, as long as laboratory assessments are done with central lab kits. 
2 Scheduled study medication dispensing/return procedures may be adapted according to the site practice. 
3 Disease severity diagnosis is based on exclusion criteria 1–2. 
4 All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after study treatment discontinuation, or until initiation of study drug in the OL 
study, whichever occurs first, must be reported. 
5 Unscheduled visits may be performed at any time during the study and may include all or some of the indicated assessments, based on the judgment of the investigator. 
6 ECG will be collected as part of CPET assessments except at Screening. 
7 Laboratory assessments at Visit 1, 2, 4, and 6 are full panels, while they are done for aminotransferases and hemoglobin monthly (28 ± 7 days) until Week 24. 
Subsequently, aminotransferases and hemoglobin are done at Week 32, Week 40, Week 52, and at S-FU. Additional liver tests may be performed as clinically 
indicated, and as recommended per local label. 
8 Physical examination is tailored to organs that are prompted by ad hoc anamnesis or are needed to be assessed to detect morbidity events (e.g., edema). 
9 Serum pregnancy test at Screening and monthly (28 ± 7 days) urine pregnancy tests afterwards. If urine tests are done at site, subjects will be re-assessed for contraceptive 
measures and childbearing potential (otherwise this is done at the next site visit). Results are checked via telephone calls from the site. 
10 PK sample taken at Week 4 at the same time as regular monthly blood draw; Sample at EOT is only taken if EOT is prior to Week 16. 


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11 A visit may occur over more than one day. 
12 Daily PA-Ac will be collected during the screening period to establish the baseline in the 9 days following the visit. For subsequent visits (Week 16), data collection will 
start (following CPET) within the allowed time window of the corresponding visit and finish 9 days later. For Visit 6 (Week 52), data collection will be during the 9 
days preceding the visit. 
13 A CPET test for training purposes is conducted during Screening. Results are collected in the eCRF. 
14 The VSFU does NOT need to be conducted if the subject’s individual EOS was not more than 4 weeks prior to the sponsor’s announcement of the Study Closure. 
AE = adverse event; BP = blood pressure; CGI-C = Clinician Global Impression of Change; CGI-S = Clinician Global Impression of Severity; CPET = cardiopulmonary 
exercise testing; ECG = electrocardiogram; eCRF = electronic case report form; EOS = End-of-Study; EOT = End-of-Treatment; EQ-5D-5L = Euro QoL 5D; FC = 
functional class; HR = heart rate; NYHA = New York Heart Association; OL = open-label; PA-Ac = Physical Activity measured by Accelerometer; PGI-C = Patient 
Global Impression of Change; PGA-S = Patient Global Assessment of Disease Severity; PK = pharmacokinetic; SAE = serious adverse event; S-FU = safety follow-
up; SpO2 = peripheral oxygen saturation, VSFU = Vital Status Follow-Up;  = Telephone call (for visit). 
 


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Table 3 
Visit and assessment schedule in PTOP 
PERIODS Name 
POST-TREATMENT OBSERVATION PERIOD 
 
FOLLOW-UP  
 
VISITS  Number 
P1, P2, … 
16 P 
UP1, UP2, … 
EOP  
8 
 
Name 
Telephone call  
Week 16 P 
Unscheduled visit 
End-of-PTOP5 
Vital Status FU 
(VSFU)4  
 
Time 
Every 90 (± 7 days) days 
after end of S-FU period 
Day 113 (± 7 days)  
Any time 
Week 52 
Within 8 weeks of 
sponsor’s announced 
Study Closure 
Concomitant therapy1 
X 
X 
X 
 
 
CPET2 
 
X 
X 
 
 
EQ-5D-5L questionnaire3 
X 
X 
X 
X 
 
Worsening/morbidity event 
assessment 
X 
X 
X 
 
 
Serious adverse events 
X 
X 
X 
X 
 
Vital Status 
 
 
 
 
X 
 
1 Change in dose will not be collected. 
2 CPET during the PTOP is at the discretion of the treating physician but requested at Week 16 if not performed already during the treatment period. 
3 To administer the EQ-5D over the phone, use designated scripts. 
4 The VSFU does NOT need to be conducted if the subject’s individual EOS was not more than 4 weeks prior to the sponsor announcement of the Study Closure. 
5 The EOP visit could be done as a telephone call unless the subject plans to enroll in the AC-055H302 OL. 
CPET = cardiopulmonary exercise testing; EOP = End-of-PTOP; EOS = End-of-Study; EQ-5D-5L = Euro QoL 5D; PTOP = post-treatment observation period;  
S-FU = safety follow-up, VSFU = Vital Status Follow-Up; = Telephone call (for visit). 
 


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7.2 Study assessments 
The study assessments are listed in Table 2. The assessments that are mandatory during a 
visit are marked with an ‘X’. Optional assessments (during unscheduled visits) are marked 
with an ‘X’. 
An evaluation of how these assessments relate to standard of care is found in Appendix 6. 
All study assessments are performed by qualified study personnel (medical, nursing, or 
specialist technical personnel) and are recorded in the eCRF, unless otherwise specified. If 
an assessment does not produce evaluable results, the treating physician may decide to 
repeat the assessment during the study visit, or at an unscheduled visit. Study assessments 
performed during unscheduled visits will also be recorded in the eCRF. When applicable, 
the following order of assessments is recommended: 
1. Quality of life questionnaires (CGI-C, CGI-S, EQ-5D-5L, PGI-C, PGA-S) 
2. Physical examination, vital signs and echocardiography 
3. Electrocardiogram (ECG) / CPET 
4. Blood sampling (including PK), pregnancy test. 
If the principal investigator (PI) delegates any study procedure/assessment for a subject, 
e.g., CPET, echocardiography, blood sampling [see Section 7.2.4.1], 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.  
Any incidental finding of an abnormality discovered by this external facility must be shared 
with the PI who is responsible for reporting the event (e.g., AE) in the eCRF as appropriate. 
Clinically relevant incidental findings will be followed up per local medical practice. 
Calibration certificates / evidence of equipment maintenance or calibration for the 
below-listed equipment used to perform study assessments must be available prior to the 
screening of the first subject.  
• 
Temperature measurement devices for study treatment storage area and freezer. 
• 
CPET equipment (metabolic cart including ECG device, ergometer). 
 
Evidence of equipment calibration must be present in the ISF. 


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7.2.1 Demographics / baseline characteristics 
Demographic and baseline characteristic data to be collected on all randomized subjects 
include: age, sex, race and ethnicity12, body weight, height, NYHA FC (assessed using the 
Specific Activity Scale), as well as the reason why a woman is not considered to be of 
childbearing potential (if applicable). Relevant medical history / current medical conditions 
based on investigator’s judgment (e.g., chronic and ongoing acute conditions, serious past 
conditions) present before and/or at the time of signing informed consent will be recorded 
on the medical history page. These include the original congenital heart defect leading to 
Fontan-palliation, concomitant procedures (e.g., Norwood, Glenn, fenestration), type of 
current TCPC (LT- or EC-TCPC), and whether TCPC is primary or secondary (conversion 
from another Fontan-palliated type), in addition to the date of Fontan surgery completion. 
Where possible, diagnoses and not symptoms will be recorded. 
For subjects who failed screening, the following data will be recorded in the eCRF if 
available: 
• Age, sex, race and ethnicity14  
• Reason for screen failure; 
− subject not eligible as per inclusion/exclusion criteria, 
− subject withdrew consent, 
− other (specify), e.g., concomitant medication related to inclusion/exclusion 
criteria. 
7.2.2 Efficacy assessments 
7.2.2.1 Cardiopulmonary exercise testing 
CPET will be conducted at study sites for Visits 1 (training CPET during Screening), 
2 (Randomization), 4 (Week 16), and 6 (Week 52).  
Furthermore, if a subject discontinues treatment prematurely, a CPET will be conducted 
within 7 days of EOT. If treatment is discontinued prior to Visit 4 (Week 16), and the 
subject enters the PTOP, it is requested that the subject returns for a CPET assessment at 
Week 16. 
A CPET test will be conducted during the screening period. Results of the training CPET 
are captured in the eCRF. 
Detailed guidelines on correct execution of the test, the Actelion CPET guidelines, are 
provided in Appendix 3. Additional information is provided in the central reading facility’s 
 
 
12 For countries that do not allow the collection of race/ethnicity, ensure that 1) the ICF makes the collection of race 
possible in these countries; or 2) race/ethnicity will be collected in the eCRF only where it is allowed. 


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manual. Site staff conducting the tests must be trained on these CPET guidelines and a 
training log must be collected upon completion of the training. For each individual subject, 
the CPET should be conducted under the same conditions throughout the study 
(e.g., same device, about the same time of the day, etc.). 
Variables that are assessed include VO2, VCO2, heart rate (HR), and VE. 
Basic spirometry to determine breathing reserve will also be part of the CPET procedure. 
Spirometry testing will be performed according to recommendations from the American 
Thoracic Society / European Respiratory Society guidelines [Miller 2005a, Miller 2005b].  
Breathing reserve (BR) is calculated from estimating maximal voluntary ventilation 
(MVV) by assessing the forced expiratory volume in one second (FEV1) × 40, as well as 
the peak VE using the following formula. 
BR% = ([MVV - VE]/MVV) × 100 
Peak VO2 (highest volume of oxygen taken up per kg and minute) is assessed during CPET 
via metabolic cart (breath-by-breath analysis) and calculated as the highest value reached 
over a 30-second interval [Guazzi 2012, Guazzi 2016a, Guazzi 2016b]. 
The % predicted value for peak VO2 is calculated according to the Wasserman-Hansen 
equations [Wasserman 2005, Guazzi 2012], using age, height, and weight at the time of 
the test. 
The respiratory exchange ratio (RER) defined as VCO2/VO2 is an indication of good 
exercise effort and achieving a value of 1.1 is expected for validating the primary endpoint 
and reaching exhaustion. 
Ventilatory efficiency is defined as VE/VCO2 slope (from the beginning of exercise to 
maximal effort), and oxygen pulse, a surrogate of stroke volume, as VO2/HR. 
VO2 at VAT is determined using the modified V-slope method. The OUES is derived from 
the relationship between VO2 and the log transformation of VE [Guazzi 2016a]. 
Validity of CPET will be confirmed by the site staff in the eCRF and the raw data will be 
made available to the central reading facility. Re-evaluation of the results based on raw 
data will be done in a blinded fashion. Data is then provided to Actelion. 
Inclusion will be based on CPET data collected at Baseline and on interpretation of 
peak VO2, RER and BR by the CPET site staff. These values will be captured in the eCRF. 
Furthermore, the baseline resting VO2 will be captured in the eCRF. 


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Any incidental finding of an abnormality discovered by this external facility must be shared 
with the PI who is responsible for reporting the event (e.g., AE) in the eCRF as appropriate. 
Clinically relevant incidental findings will be followed up per local medical practice. 
7.2.2.2 PA-Ac 
The daily physical activity (counts/min) of the subject is assessed via accelerometer during 
daytime. The accelerometer is given to the subject at Visit 1 (Screening visit), and data is 
collected for 9 consecutive daily daytime periods after Visit 1, Visit 4 (Week 16), and 
before Visit 6 (Week 52). To establish a sufficient baseline, Visit 2 will have to occur 
≥ 9 days after Visit 1. The duration of physical activity data collection will allow including 
data during week days and weekend days and will provide a reliable estimate of the usual 
physical activity of the subject. Only data collected during these 9-day periods will be used 
for the analysis of physical activity. 
The investigator (or delegate) instructs subjects on how and when to wear the 
accelerometer (refer to the RUBATO Accelerometry Manual). The accelerometer is worn 
during waking hours of the subject and may be worn during activities when the device 
could get wet (except swimming). Subjects will receive a reminder from the site staff 
(e.g., telephone call, text message) to ensure that they are wearing the accelerometer during 
these periods. The accelerometers are pre-programmed to minimize patient handling and 
do not display the collected data. The subjects return the device to the study site and the 
investigator (or delegate) transfers the data to the accelerometry central reading facility as 
described in the RUBATO Accelerometry Manual.  
The central reading facility will read daily counts/min and will analyze duration of daily 
activity and time (minutes) spent in sedentary, light, moderate, and vigorous physical 
activity based on the [Freedson 1998] and [Evenson 2008] cut-points for adults and 
adolescents, respectively. These data will be transferred to Actelion. 
To be considered evaluable, physical activity should be measured for at least 4 complete 
daily daytime periods (out of 9 consecutive days) at a specific time point of assessment. A 
complete day is defined as a record of at least 7 hours of daily data (after excluding the 
periods when the device was apparently not worn [Troiano 2008]). 
Accelerometer devices will be provided to the investigational site before the start of the 
study. 
7.2.2.3 NT-proBNP measurement 
NT-proBNP is measured at Visits 2 (Randomization), 4 (Week 16), and 6 (Week 52), 
according to central laboratory working procedures. The results will be disclosed after 
database lock and unblinding. 


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7.2.2.4 Composite endpoint of time to clinical worsening 
Occurrence of a component of the time to clinical worsening endpoint is captured by the 
investigator via AE reporting, anamnesis (change in FC), appearance of laboratory 
abnormalities, assessment, or concomitant medication (initiation of new treatment). 
These could occur at any time, although some parameters are only assessed at site visits 
[see Table 2]. 
7.2.3 Safety assessments 
The definitions, reporting and follow-up of AEs, SAEs and pregnancies are described in 
Section 9. 
• 
Treatment-emergent AEs and SAEs up to 30 days after study treatment discontinuation 
are captured in the eCRF. Details include severity, causality with treatment, action 
taken with treatment, duration, outcome, need for hospitalization, relatedness of 
hospitalization due to Fontan-circulation problems, and duration of hospitalization. 
• 
AEs leading to premature discontinuation of study treatment are derived from the 
reported AEs in the eCRF. 
• 
Change in vital signs (systolic and diastolic BP and pulse rate), and body weight from 
Baseline (Visit 2) to all assessed time points during the study. Vital signs are assessed 
at each study visit and body weight is assessed during each CPET. 
• 
Treatment-emergent marked laboratory abnormalities up to 30 days after study 
treatment discontinuation. 
• 
Change in laboratory parameters from Baseline (Visit 2) to all assessed time points 
during the study. Laboratory data will be provided via the central laboratory; the details 
on alert flags and normal ranges can be found in Appendix 1. 
7.2.3.1 Physical examination 
Physical examination at screening includes the examination of the general appearance, 
head, ears, eyes, nose, throat, neck, lymph nodes, extremities, neurological system, skin, 
musculoskeletal system, gastro-intestinal, heart and lungs. At subsequent visits, physical 
examination is tailored to organs that are prompted by ad hoc anamnesis or are needed to 
be assessed to detect morbidity events (e.g., edema). 
Information from all physical examinations must be included in the source documentation 
at the study site. The observations should be reported according to body system in the eCRF 
as either normal or abnormal. If an abnormality is found it should be specified on the 
corresponding eCRF page, describing the signs related to the abnormality (e.g., systolic 
murmur) and not the diagnosis (e.g., mitral valve insufficiency). Clinically relevant 
findings (other than those related to Fontan circulation) that are present prior to signing of 
informed consent must be recorded on the Medical History eCRF page. Physical 


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examination findings made after signing of informed consent, which meet the definition of 
an AE [Section 9.1.1], must be recorded on the AE page of the eCRF. 
7.2.3.2 Vital signs 
Vital signs (BP, pulse rate) will be measured at all scheduled visits except S-FU. 
Systolic and diastolic BP 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. The 
same position (supine or sitting) and same location (left/right arm) must be used throughout 
the study for an individual subject. 
In addition, SpO2 will be measured (by pulse oximeter) at all scheduled visits. 
For each individual subject, the same device should be used throughout the study. 
When applicable, vital signs are recommended to be measured before the CPET. 
7.2.3.3 Weight and height 
Height and body weight will be measured at all scheduled visits except S-FU. These are 
captured in the eCRF. Body weight will be measured in indoor clothing but without shoes. 
For each individual subject, the same device should be used throughout the study. 
7.2.3.4 ECG assessment 
ECG is assessed at Screening (Visit 1) and abnormalities (assessed by a cardiologist), if 
any, are reported as part of medical history in the eCRF. 
Subsequently, ECG is assessed as part of CPET, and data are evaluated at site. ECG data 
will not be transmitted to the central reading facility apart from pre-exercise rhythm and 
HR for evaluation of CPET. 
7.2.3.5 Echocardiography 
Standard 2D/Doppler trans-thoracic echocardiography (ECHOC) is performed at 
Screening to determine the subject’s eligibility and at EOT. The ECHOC will be read 
locally at the investigational site. 
The measures/assessments evaluated by the ECHOC include, but are not limited to: single 
ventricle ejection fraction, Fontan circulation stenosis, and valvular defects (severe AV 
valve regurgitation, outflow obstruction). 
The ejection fraction measured locally at Screening and at EOT will be recorded in the 
eCRF. If post-baseline ECHOC is performed according to medical practice or in case of 
deteriorating patient conditions, the results of the exams should be reported in the eCRF. 
Detailed instructions on how to record ECHOC are provided in Appendix 2. 


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7.2.3.6 VSFU 
A VSFU will be performed by the sponsor within 8 weeks after SCL announcement to 
determine each subject’s vital status (alive, dead, or unknown) at this time: 
This VSFU will be performed either: 
• by the investigational site via a contact with the subject or parents/legal 
representatives/caregivers (phone call or any other means allowed per local 
regulations, e.g., access to public registries including the use of locator agencies) 
during the first 4 weeks following SCL announcement. 
Or, if unsuccessful, 
• by the investigational site assessing the vital status of the subject by any other means 
allowed per local regulations, e.g., access to medical registries, public, or 
governmental registries including the use of locator agencies during the following 4 
weeks.  
If the subject’s individual EOS occurs within 4 weeks of the SCL announcement, VSFU 
does not need to be performed. 
The outcome of the VSFU is reported in the eCRF. 
7.2.4 Laboratory assessments 
Laboratory tests are conducted at each visit. Full hematology and clinical chemistry panels 
[see Section 7.2.4.2] are done at Screening, Visits 2 (Randomization), 4 (Week 16), and 6 
(Week 52). Laboratory assessments are done for aminotransferases, hemoglobin, and 
pregnancy monthly (28 ± 7 days) until Week 24. Subsequently, aminotransferases and 
hemoglobin are done at Week 32, Week 40, Week 52, and at S-FU. Additional liver tests 
may be performed as clinically indicated, and as recommended per local label. Pregnancy 
testing continues on a monthly basis. 
7.2.4.1 Type of laboratory 
A central laboratory (see central laboratory manual for contact details) will be used for the 
analysis of all protocol-mandated laboratory tests, including re-tests due to laboratory 
abnormalities and laboratory tests performed at unscheduled visits. Central laboratory data 
will be automatically transferred from the central laboratory database to Actelion’s clinical 
database. 
Whenever possible, blood samples will be collected at site and sent for analysis to the 
central laboratory. 


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If the results from the central laboratory are not available in time for randomization of the 
subject, an additional blood sample may be drawn to verify eligibility based on a local 
laboratory test. The local laboratory results (with the corresponding normal ranges) must 
be recorded in the eCRF. 
A serum pregnancy test (for females of childbearing potential) will be analyzed at Visit 1 
(Screening) and complemented with urine pregnancy tests up to 30 days after study drug 
discontinuation. Any positive urine pregnancy test must be followed up by a serum 
pregnancy test. 
Other exceptional circumstances that will require recording of local laboratory results of 
the parameters described 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 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. 
Under specific circumstances (e.g., if the subject lives far from the site and cannot return 
every month), laboratory samples may be collected at a laboratory close to where the 
subject lives (satellite laboratory for blood draw) and sent to the central laboratory for 
analysis. In such a case, the satellite laboratory must be provided with the central laboratory 
sampling kits. Shipment of the samples will be organized by the satellite laboratory. The 
supervision of the satellite laboratory remains the responsibility of the PI. 
As an alternative option, the laboratory samples may be collected from subjects by a flying 
nurse service using central laboratory sampling kits.  
In the exceptional event that a local laboratory is utilized for the collection and analysis of 
blood samples (e.g., the subject is admitted in a hospital other than the site), laboratory 
certification / reference ranges / laboratory director’s curriculum vitae will be collected 
retrospectively by Actelion. Local laboratory results* and reference ranges will be 
collected in the eCRF.  
*As a minimum, the following local laboratory results (i.e., results from samples collected 
and analyzed locally) will be collected in the eCRF:  
• Any local laboratory result related to the diagnostic work-up (i.e., detection, 
confirmation and/or monitoring) of ALT and/or AST elevations of ≥ 3 × ULN. In such 
cases, the minimum data to be analyzed and entered in the eCRF are ALT, AST, AP, 
and total and direct bilirubin.  


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• Any local laboratory result related to the diagnostic work-up (i.e., detection, 
confirmation and/or monitoring) of hemoglobin decrease from baseline of ≥ 50 g/L, a 
value of hemoglobin < 100 g/L, or a hemoglobin decrease requiring transfusion.  
• Any local laboratory test documenting the result of an assessment requested per 
protocol and for which no central laboratory result is available (e.g., in the case that no 
sample was sent to the central laboratory at a planned visit because the subject was 
hospitalized at another hospital, or in the case that the sample sent to the central 
laboratory is uninterpretable [e.g., hemolyzed]).  
• Any local laboratory result related to the documentation or follow-up of an AE or an 
SAE, including clinically significant abnormal laboratory results and their follow-up.  
In the event that several local laboratory samples have been collected on the same day, or 
if the sample was tested several times, the “worst” value (e.g., highest value for ALT/AST) 
should be reported in the eCRF (together with the local laboratory reference ranges). 
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 1. 
All laboratory reports must be reviewed, signed and dated by the investigator or delegate 
within 5 working days of receipt and filed with the hospital chart. The investigator/delegate 
must indicate on the laboratory report whether abnormal values are considered clinically 
relevant or not. Clinically relevant laboratory findings that are known at the time of signing 
of informed consent must be recorded on the Medical History page of the eCRF. Any 
clinically relevant laboratory abnormalities (including ALT/AST abnormalities ≥3 × ULN) 
detected after signing of informed consent must be reported as an AE or SAE as appropriate 
[see Section 9], and must be followed until the value returns to within the normal range or 
is stable, or until the change is no longer clinically relevant, except when otherwise 
specified (e.g., in the case of ALT/AST abnormalities [see Section 5.1.11.2]). Further 
laboratory analysis should be performed as indicated and according to the judgment of the 
investigator. 
Any pregnancy occurring during the treatment period and up to 30 days after study drug 
discontinuation must be reported immediately to the sponsor using the Pregnancy 
Notification Form [see Section 9.3.1].Details about the collection, sampling, storage, 
shipment procedures, and reporting of results and abnormal findings can be found in the 
laboratory manual. 


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7.2.4.2 Laboratory tests 
Hematology 
Serum ferritin will be assessed at Visit 1 (Screening), the subsequent parameters for all 
regular visits. 
• Hemoglobin 
• Hematocrit 
• Erythrocyte count (reticulocyte count) 
• Leukocyte count with differential counts (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils) 
• Platelet count 
Rules for study treatment interruption in case of hemoglobin abnormalities including 
assessment of additional parameters are provided in Section 5.1.11.3. 
Clinical chemistry 
• ALT 
• AST 
• AP 
• Total and direct bilirubin 
• Gamma glutamyl transpeptidase  
• Creatinine 
• Blood urea nitrogen 
• Uric acid 
• Glucose 
• Cholesterol 
• Triglycerides 
• Sodium, potassium, chloride, calcium 
• Serum albumin 
• Total protein 
• Alpha-fetoprotein 
• NT-proBNP*  
• Cystatin-C 
* Data of the samples from subjects will be provided after database closure. 
Rules for study treatment interruption / permanent discontinuation and laboratory re-tests 
in case of ALT and/or AST elevation are provided in Section 5.1.11.2. 


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If creatinine clearance is estimated, the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation [Levey 2009] will be used for adults and the Bedside 
Schwartz equation [Schwartz 2009] for adolescents, for determining glomerular filtration 
rate (GFR). 
Adults: 
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 
[if black] 
 
Scr: serum creatinine in mg/dL 
κ is 0.7 for females and 0.9 for males, 
α is −0.329 for females and −0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
 
Adolescents: 
GFR (mL/min/1.73m2) = (0.41 × Height in cm) / Creatinine in mg/dL 
Coagulation tests 
• Prothrombin time and/or international normalized ratio 
Pregnancy test 
A serum pregnancy test for women of childbearing potential will be performed at 
screening, and subsequent monthly tests must be performed. These monthly tests can be 
done via urine dipstick. If pregnancy is suspected during the study, a serum pregnancy test 
must be performed immediately. 
During each visit at site, it must be verified whether the methods of contraception used 
previously are still valid, in accordance with the protocol, and correctly used by the subject. 
Reassessment of childbearing potential of female subjects is to be done at each study visit. 
Documentation that the discussion with the subject took place must be available in the 
subject’s source documents. 
7.2.5 Quality of life assessments 
Quality of life parameters will be assessed for all subjects by 2 sets of QoL questionnaires 
including the EQ-5D-5L and the patient/clinician assessment of severity and assessment of 
change (PGA-S, PGI-C and CGI-S, CGI-C, respectively). These will be completed on 
paper, and site staff will enter the corresponding values in the eCRF. 
The PGA-S and PGI-C are completed by subjects, while the CGI-S and CGI-C are 
completed by clinicians (a physician, either an investigator or sub-investigator). 
Completion should occur at the beginning of the visit [Appendix 7]. 


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Disease Severity (PGA-S and CGI-S) is assessed at Randomization (Visit 2), Week 16 
(Visit 4), and Week 52 (Visit 6), or EOT in case it occurs prior to Week 52. 
Impression of Change (PGI-C and CGI-C) is assessed at Week 16 (Visit 4), and Week 52 
(Visit 6), or EOT in case it occurs prior to Week 52. 
The EQ-5D-5L questionnaires [Appendix 8] are completed by subjects at Randomization 
(Visit 2), Week 16 (Visit 4), Week 52 (Visit 6), or EOT in case it occurs prior to Week 52. 
If subjects enter the PTOP, the questionnaire will be also be completed using designated 
scripts. 
Actelion has been granted license agreements for the use of the EQ-5D-5L questionnaires. 
7.2.6 Pharmacoeconomic assessments 
Pharmacoeconomic parameters will be assessed as described in Section 6.4. 
Data elements to be collected on the eCRF include: Hospitalization admission date, 
discharge date, reason for admission. 
7.2.7 Pharmacokinetic and pharmacodynamics assessments 
7.2.7.1 Pharmacokinetic assessments 
Trough (pre-dose) plasma concentrations of macitentan and its metabolite ACT-132577, 
are obtained via blood samples taken at Week 4 (during the regular corresponding monthly 
blood draw) and Week 16 (Visit 4), or at EOT in the case of premature study drug 
discontinuation prior to Week 16. 
Importantly, blood samples must be drawn before the morning dose of study treatment and 
after BP measurement. 
Approximately 2 mL of blood will be collected by direct venipuncture in an antecubital 
vein 
in 
the 
arm 
in 
Monovette 
tubes 
(or 
equivalent) 
containing 
K3-ethylenediaminetetraacetic acid. Immediately following collection of the required 
blood volume, the tubes will be slowly tilted backwards and forwards (no shaking) to bring 
the anti-coagulant into solution, and immediately cooled on ice. Within 30 minutes of 
collection, the tubes will be centrifuged at approximately 1500 G for 10 minutes at 2-8° C. 
When a centrifuge that can be cooled is not available, the blood samples and the bucket of 
the centrifuge must be cooled on ice prior to centrifugation. The plasma will be transferred 
into one labeled polypropylene tube avoiding carry-over of erythrocytes. All samples will 
be stored in an upright position at −20° C (± 4° C).  
Note: a short duration of storage at temperatures below −20° C (± 4° C) is acceptable. 


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The date and the exact actual clock time of collection of the blood sample, time and date 
of last study treatment intake prior to PK sampling, as well as the time of intake of the next 
study treatment, will be entered in the eCRF. 
Labeling and shipment 
Details of the collection and regular shipment of the samples to the central laboratory can 
be found in the central laboratory manual. The tubes and labels for the samples will be 
provided to the site by the central laboratory. The labeling will comply with the applicable 
laws and regulations of the countries in which the study is conducted. The central 
laboratory will forward the samples to the bioanalytical laboratory or equivalent local 
option. 
Bioanalysis 
Data of the samples from subjects will be provided after database closure by the 
bioanalytical laboratory. No samples should be destroyed until the study report is signed 
off. 
Macitentan and ACT-132577 plasma concentrations will be determined using a validated 
liquid chromatography coupled to mass spectrometry assay. The foreseen limit of 
quantitation is 1.00 ng/mL. Concentrations will be calculated by interpolation from a 
calibration curve. Quality control samples will be analyzed throughout the study, their 
measured concentrations will be used to determine between-run and overall precision and 
accuracy of the analyses. 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE 
8.1 Study completion as per protocol 
A subject who completes the full 52 weeks and the S-FU period is considered to have 
completed the study as per protocol. This is true regardless of whether the 52 weeks were 
on treatment or not.  
For an individual subject, the study is completed with the EOS, which corresponds to the 
S-FU visit performed 30–35 days after the EOT visit and the EOP (if applicable). 
Note that the S-FU visit may not be needed for subjects who enter the AC-055H302 OL 
extension at EOT of AC-055H301; these subjects are still considered to have completed 
the study. 
Study completion is reached once all subjects have completed the EOS and is 
communicated to the sites via the SCL announcement.  


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The VSFU will be collected in the eCRF and is performed after study completion. 
8.2 Premature withdrawal from study 
Subjects may voluntarily withdraw from the study without justification for any reason at 
any time. Subjects are considered withdrawn if they state an intention to withdraw further 
participation in all components of the study (i.e., withdrawal of consent), die, or are lost to 
follow-up. If a subject withdraws consent, no further data will be collected in the eCRF 
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 eCRF. The following methods must be used: at least three telephone calls must be 
placed to the last available telephone number, and one registered letter must be sent by post 
to the last available home address. Additional methods may be acceptable if they are 
compliant with local rules/regulations (e.g., a visit by site personnel to the subject’s home, 
use of locator agencies), 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 eCRF, if known. 
If for whatever reason (except death or loss-to-follow-up) a subject is withdrawn from the 
study, the investigator should make efforts to schedule a last appointment / telephone call 
to assess the safety and well-being of the subject, collect unused study treatment and 
discuss follow-up medical care. Data obtained during this last appointment / telephone call 
will be recorded in the subjects’ medical records, but it will not be collected in the eCRF. 
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. 


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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 a study is prematurely suspended or terminated, Actelion will promptly inform the 
investigators, the IECs/IRBs, and health authorities, as appropriate, and provide the reasons 
for the suspension or termination. 
If the study is suspended or prematurely terminated for any reason, the investigator – in 
agreement with Actelion – must promptly inform all enrolled subjects and ensure their 
appropriate treatment and follow-up, as described in Section 8.4. Actelion may inform the 
investigator of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the subjects’ interests. 
In addition, if the investigator suspends or terminates a 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 a 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. 
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. 
Contraceptive measures must continue up to at least 30 days after EOT. 
Following completion of the AC-055H301 study, subjects are offered participation in the 
AC-055H302 OL extension study, if the study is approved at the respective investigational 
site.  
Enrollment into the AC-055H302 OL extension study will depend on whether eligibility 
criteria for the AC-055H302 OL extension study are met, as well as the investigator’s 
judgment about whether treatment with macitentan could be beneficial. The assessment of 
the benefit/risk will be performed at subject level, by the investigator. 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
Timely, accurate, and complete reporting and analysis of safety information, including 
AEs, SAEs, and PQC, from clinical studies are crucial for the protection of participants, 
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The 


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sponsor has established Standard Operating Procedures in conformity with regulatory 
requirements worldwide to ensure appropriate reporting of safety information; all clinical 
studies conducted by the sponsor or its affiliates will be conducted in accordance with those 
procedures. 
9.1 Adverse events 
9.1.1 Definition of adverse events 
An AE is any untoward medical occurrence, i.e., any unfavorable and unintended sign, 
including an abnormal laboratory finding, symptom, or disease that occurs in a subject 
during the course of the study, whether or not considered by the investigator as related to 
study treatment. 
A treatment emergent AE is any AE temporally associated with the use of study treatment 
(from study treatment initiation until 30 days after study treatment discontinuation) 
whether or not considered by the investigator as related to study treatment. 
AEs include: 
• Exacerbation of a pre-existing disease. 
• Exacerbation of a pre-existing disease with the exception of efficacy endpoints and 
associated symptoms. 
• 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, that 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. 
Hepatic AEs of special interest may be followed up using the hepatic event questionnaire 
distributed by the sponsor. 
Overdose, misuse, abuse of the study treatment and study treatment errors will be reported 
as an AE [see Section 9.6]. 


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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 eCRF. 
If the intensity of an AE worsens during the study, only the worst intensity should be 
reported on the AE page. If the AE lessens in intensity, no change in the severity is required 
to be reported. 
For AEs ongoing at the start of study treatment, if the intensity worsens after the start of 
study treatment, the change in intensity and the date on which it occurred must be reported 
in the eCRF. 
The three categories of intensity are defined as follows: 
 Mild 
The event may be noticeable to the subject. It does not usually influence daily activities, 
and normally does not require intervention. 
 Moderate 
The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed. 
 Severe 
The event may cause noticeable discomfort and usually interferes with daily activities. The 
subject may not be able to continue in the study, and treatment or intervention is usually 
needed. 
A mild, moderate, or severe AE may or may not be serious [see Section 9.2.1]. These terms 
are used to describe the intensity of a specific event. Medical judgment should be used on 
a case-by-case basis. 
Seriousness, rather than intensity assessment, determines the regulatory reporting 
obligations. 
9.1.3 Relationship to study treatment 
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the study treatment and reported as either related or not 
related. The determination of the likelihood that the study treatment caused the AE will be 
provided by the investigator who is a qualified physician. 
9.1.4 Reporting of adverse events 
All AEs with an onset date after signing of informed consent and up to 30 days after study 
treatment discontinuation or until initiation of study drug in the AC-055H302 OL extension 


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study, whichever occurs first, must be recorded on specific AE pages of the AC-055H301 
eCRF.  
All AEs must be documented in the corresponding subject medical records. Data such as 
evaluation of maximum intensity and evaluation of possible relationship to study treatment 
are also to be documented in the source documents. The investigator who performed the 
AE assessment should be identifiable in the source documents. 
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) [see Section 9.5] 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 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, except in the case of serious adverse events [Section 9.2.4]. 
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 as SAEs: 
• Hospitalization for cosmetic elective surgery, or social and/or convenience reasons. 


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• Hospitalization for pre-planned (i.e., planned prior to signing informed consent) 
surgery or standard monitoring of a pre-existing disease or medical condition that did 
not worsen, e.g., hospitalization for coronary angiography in a subject with stable 
angina pectoris. 
However, complications that occur during such hospitalization are AEs or SAEs. 
9.2.2 Reporting of serious adverse events 
All SAEs, as well as PQCs, occurring after signing of informed consent up to 30 days after 
study treatment discontinuation or until initiation of study drug in the OL extension study, 
whichever occurs first, must be reported on AE pages in the eCRF and on an SAE form, 
regardless of the investigator-attributed causal relationship with study treatment or 
study-mandated procedures. 
An SAE is defined as related to protocol-mandated procedures if it appears to have a 
reasonable possibility of a causal relationship to either the study design or to 
protocol-mandated procedures (e.g., conduct of CPET). 
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 / telephone call must be reported 
to the sponsor, but it is not recorded in the eCRF. 
9.2.4 After the 30-day follow-up period 
For subjects in the PTOP, all SAEs until Week 52 have to be reported in the eCRF and to 
the sponsor within 24 hours of the investigator’s knowledge of the event. 
For subjects not participating in the PTOP, new SAEs occurring after the 30-day follow-up 
period must be reported to the 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 the sponsor (or the CRO’s drug safety 
department) 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. 


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The SAE forms must be sent to the 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. 
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. Any SAE 
that is assessed as related and unexpected against the RSI is known as a SUSAR 
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 
interrupted. 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 occurring 
after study start (i.e., signing of informed consent) and with an estimated conception date 
up to 30 days following study treatment discontinuation must be reported to the sponsor by 
the study-site personnel within 24 hours of the investigator’s knowledge of the event. 
Pregnancies must be reported on the Pregnancy Notification form, which is sent to the 
sponsor (or the CRO’s drug safety department; see contact details provided on the 
Pregnancy form), and in the eCRF on an AE page. 


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9.3.2 Follow-up of pregnancy 
Follow-up information regarding the outcome of the pregnancy in female subjects or 
partners of male subjects and any postnatal sequelae in the infant will be required and 
reported using the Product Exposure During Pregnancy Collection and End of Pregnancy 
Collection forms. Follow-up information exceeding the 30-day S-FU will only be entered 
in the Global Medical Safety database and will not affect SCL. 
Any AE associated with the pregnancy occurring during the follow-up period after study 
treatment discontinuation must be reported on separate AE pages in the eCRF. Abnormal 
pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital 
abnormalities, ectopic pregnancy) are considered SAEs and must be reported on an SAE 
form as described in Section 9.2.5. 
9.4 Study safety monitoring 
Study safety information (AEs, SAEs, laboratory values, ECGs, vital signs, and 
study-specific examinations as required) is monitored and reviewed on a continuous basis 
by the Actelion Clinical Team (in charge of ensuring subjects’ safety as well as data 
quality). In addition, an IDMC is monitoring safety data in an unblinded manner [see 
Section 3.3]. Actelion may request additional data pertaining to the diagnostic work-up of 
an AE or SAE (e.g., medical imaging, local laboratory values) for the purpose of safety 
monitoring. Such additional data may be shared with external experts. 
9.5 Product quality complaints 
A product quality complaint (PQC) is defined as any suspicion of a product defect related 
to manufacturing, labeling, or packaging, i.e., any dissatisfaction relative to the identity, 
quality, durability, or reliability of a product, including its labeling 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, storage and 
distribution of the product. 
9.5.1 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. 
If the defect is combined with an SAE, the study site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines [refer to Section 9.2.5]. 


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9.6 
Special reporting situations 
Safety events of interest on a sponsor study intervention in an interventional study that may 
require expedited reporting or safety evaluation include, but are not limited to: 
• 
Overdose of a sponsor study intervention 
• 
Suspected abuse/misuse of a sponsor study intervention 
• 
Accidental or occupational exposure to a sponsor study intervention 
• 
Medication error, intercepted medication error, or potential medication error involving 
a Johnson & Johnson medicinal product (with or without patient exposure to the 
Johnson & Johnson medicinal product, e.g., 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 eCRF. Any special reporting situation 
that meets the criteria of an SAE should be recorded as an SAE on the AE page of the 
eCRF. 
9.7 
Contacting Sponsor Regarding Product Quality 
The names (and corresponding telephone numbers) of the individuals who should be 
contacted regarding product quality issues are listed in the Contact Information page(s), 
which will be provided as a separate document. 
10 STATISTICAL METHODS 
All statistical analyses will be conducted by Actelion or by designated CROs supervised 
by Actelion, except for the IA, which will be conducted by the ISAC/SSG who will provide 
results to the IDMC.  
A Statistical Analysis Plan (SAP) will provide full details of the analyses, data displays, 
and algorithms to be used for data derivations.  
The SAP will include the definition of protocol deviations leading to exclusion from 
analysis sets. The list of protocol deviations which might affect the evaluation of the effect 
of the study treatment on the primary efficacy endpoint is provided in Section 10.1.3 of 
this document. The protocol deviations will be identified by medically trained staff on an 
ongoing basis during study conduct before study database closure. 
Individual subject listings will be provided for efficacy, quality of life, pharmacoeconomic, 
PK, and safety endpoints, as well as for baseline and other subject characteristics. Each 
listing will be broken down by treatment group, site, subject number, and assessment date 
as appropriate. 


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Wherever possible, the data will be graphically presented, e.g., via box plots, scatter plots, 
KM curves, etc. The graphical presentation for KM follows the recommendations from 
Pocock on the following aspects [Pocock 2002]: 
• Rules for KM curves going upwards or downwards (e.g., upwards if there is a low 
number of events) 
• Termination of the vertical axis 
• Truncation of the x-axis when only around 10–20% of the subjects are still in follow-
up.  
10.1 Analysis sets 
10.1.1 Screened Analysis Set 
The Screened Analysis Set (SCR) includes all subjects who are screened and have a subject 
identification number. 
10.1.2 Full Analysis Set 
The Full Analysis Set (FAS) includes all subjects assigned to a study treatment. In order to 
adhere to the intention-to-treat principle as much as possible: 
• Subjects are evaluated according to the study treatment they have been assigned to 
(which may be different from the study treatment they have received); 
• All available data are included. 
10.1.3 Per-Protocol Set 
The Per-Protocol Set (PPS) comprises all subjects who received actual study treatment 
assigned by IVRS and who complied with the protocol sufficiently up to and including the 
Week 16 visit (Visit 4) to be likely to exhibit the treatment effects. 
Criteria for sufficient compliance include: 
• 
exposure to the study randomized treatment over 16 weeks, including the Week 16 
window [Section 10.3.2.2], with a treatment compliance of at least 80% and no more 
than 120% and without study treatment interruptions of more than 4 consecutive weeks 
at any time prior to, and until the Week 16 visit (Visit 4), 
• 
availability of peak VO2 at Week 16 (Visit 4), 
• 
absence of protocol deviations that have an impact on the treatment effect including, 
but not limited to: 
– Intake of forbidden concomitant therapy up to the Week 16 visit (Visit 4) as listed 
in Section 5.2.4,  
– Deviations from the selection criteria as listed in Sections 4.3 and 4.4 such that, in 
the opinion of the study team in blinded review, assessment of efficacy with 
respect to the primary endpoint is compromised, such as: 


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o 
Less than 12 years old at Screening, 
o 
No LT- or EC-TCPC surgery, 
o 
NYHA FC I or IV at Screening, 
o 
Peak VO2 < 15 mL/kg/min at Baseline. 
The full list of criteria will be detailed in the SAP before making the full randomization 
information available. 
10.1.4 Safety Set 
The Safety Set (SS) includes all subjects who received at least one dose of study treatment. 
10.1.5 Pharmacokinetic analysis set 
The Pharmacokinetic Analysis Set (PKS) includes all randomized and treated subjects, for 
whom a PK blood sample at trough has been collected and who do not deviate from the 
protocol in a way that might affect the evaluation of the trough concentrations. 
10.1.6 Usage of the analysis sets 
The FAS is used for the main and sensitivity analyses of the primary efficacy variable, for 
analyses of all secondary and other efficacy variables and for the description of the study 
population at baseline. 
The PPS is used to perform sensitivity analyses on the primary and first secondary efficacy 
variables. 
The SS is used for the analysis of the safety variables. 
The PKS is used for analysis of the PK variables. 
The SCR is used for the description of subject disposition. 
Unless specified otherwise, individual subject data listings are prepared on the SCR, by 
randomized treatment group and for screening failures where appropriate. 
10.2 Variables 
All variables correspond to the respective study endpoints as described in Section 6. 
10.2.1 Primary efficacy variable(s) 
The primary efficacy variable is the change in peak VO2 from Baseline to Week 16, 
defined as Week 16 value minus Baseline value. The values used for peak VO2 at Baseline 
and Week 16 will be based on data evaluation by the central reading facility. 


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10.2.2 Secondary efficacy variables 
10.2.2.1 Peak VO2 over 52 weeks 
This secondary efficacy variable is defined as the average change in peak VO2 from 
baseline over time, i.e., averaged over the entire observation period with post-baseline 
assessments up to Week 52 (CPET is planned at Baseline and at Weeks 16 and 52; in 
addition, unscheduled CPET can occur). Per time point of assessment, the change is 
defined as post-baseline value minus baseline value. The overall average change over 52 
weeks is the mean change thereof. The values used for peak VO2 will be based on data 
evaluation by the central reading facility. 
10.2.2.2 Change from Baseline to Week 16 in mean count per minute of daily PA-Ac 
This secondary efficacy variable is defined as a Week 16 mean count per minute of daily 
PA-Ac minus the mean count per minute of baseline daily values. The values used for 
PA-Ac at Baseline and Week 16 will be based on data evaluation by the central reading 
facility. 
10.2.3 Other efficacy variables 
Variables related to exercise capacity: 
Peak VO2 at other visits than Week 16, VE/VCO2 slope, VO2/HR, % predicted peak VO2, 
VO2 at VAT, and OUES are collected at all visits with CPET. Details are given in 
Section 7.2.2.1. Per variable of exercise capacity and per post-baseline assessment, 
changes from baseline are defined as post-baseline value minus baseline value. 
NT-proBNP: 
Percent of baseline at Week 16 and percent of baseline in NT-proBNP over 52 weeks will 
be evaluated. The percent of baseline in NT-proBNP is defined as 100 times the 
post-baseline value divided by the baseline value.  
Time to clinical events: 
The individual components of the following two clinical events endpoints are defined in 
Section 6.1.3:  
• Composite endpoint of events related to Fontan-palliated clinical worsening and,  
• Composite endpoint of events related to Fontan-palliated morbidity. 
The dates of occurrence of each component of the above two clinical event endpoints are 
reported in the eCRF.  
For each composite endpoint, a subject is considered as having an event if the investigator 
reports the occurrence of any of the individual component in the eCRF.  
Subjects who did not experience an event will be censored. 


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The times to clinical events are expressed in weeks and calculated as: 
• for subjects with an event: the earliest date of occurrence of any of the individual 
components minus date of Randomization plus 1 divided by 7, 
• for censored subjects: the EOS date minus date of Randomization plus 1 divided by 7. 
 
Overall survival (OS): 
The vital status (alive, dead, or unknown) will be reported in the eCRF [see 
Section 7.2.3.6].  
Subjects who are known to be alive at the time of VSFU will be censored at the date of 
VSFU. Subjects with unknown vital status at VSFU will be censored at the time of the last 
contact (e.g., at the date of last study visit, last treatment day or EOS). 
Time to death is expressed in weeks and calculated as the date of death minus date of 
Randomization plus 1, divided by 7 or, for censored subjects, as censoring date minus date 
of Randomization plus 1, divided by 7. 
Physical activity: 
Physical activity efficacy variables include: 
• the change from Baseline to Week 52 in mean count per minute of daily activity and  
• the change from Baseline to Weeks 16 and 52 in daily mean time in minutes spent in 
sedentary, light, moderate, or vigorous physical activity.  
Changes from Baseline are defined as post-baseline value minus baseline value. 
10.2.4 Safety variables 
Adverse events: 
An AE is defined as any event that is recorded on the AE eCRF module regardless of the 
onset date. 
Treatment-emergent events are those with onset date/time ≥ start date/time of study 
treatment and ≤ 30 days after EOT. 
Serious events are those with seriousness assessed as ‘serious’ by the investigator 
according to the definition in Section 9.2.1. 
Related AEs are those with relationship to the use of study treatment judged as ‘reasonably 
possible’ by the investigator. 
AEs leading to premature discontinuation of study treatment are those with action taken 
with study drug reported as ‘permanently discontinued’ by the investigator. 


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Laboratory data: 
Laboratory analyses are based on data received from the central laboratory. All transferred 
central laboratory data are taken into account regardless of whether they correspond to 
scheduled or unscheduled assessments. 
Baseline laboratory test refers to the latest laboratory test performed prior to the start of 
study treatment. 
EOT laboratory test refers to the laboratory test performed at the EOT visit. If no laboratory 
data are available for the EOT visit, the results of the latest available post-baseline 
laboratory tests performed prior to EOT date/time are used for the analysis. 
For a list of laboratory tests see Section 7.2.4.2. Per laboratory test and post-baseline 
assessment, changes from baseline are defined as post-baseline value minus baseline value. 
Marked laboratory abnormalities are those defined in Appendix 1. Treatment-emergent 
laboratory abnormalities are those with a sampling after the start of study treatment 
and ≤ 30 days after EOT. 
Vital signs: 
Systolic BP, diastolic BP, pulse rate, SpO2, height and body weight are measured at all 
scheduled visits and reported in the eCRF. Per vital sign and post-baseline assessment, 
changes from baseline are defined as post-baseline value minus baseline value. 
Baseline vital sign refers to the latest vital sign measurement performed prior to the start 
of study treatment.  
Echocardiography: 
Single ventricle ejection fraction, Fontan circulation stenosis, and valvular defects (severe 
AV valve regurgitation, outflow obstruction) are measured at the Screening and EOT visit 
and reported in the eCRF. Per ECHOC parameters and post-baseline assessment, changes 
from baseline are defined as post-baseline value minus baseline value. 
10.2.5 Quality of life variables 
Details will be included in the statistical analysis plan.  
10.2.6 Pharmacoeconomic variables 
The annualized rate of all-cause and Fontan-related hospitalizations will be calculated 
during the double-blind treatment period.  
The all-cause hospitalizations are any hospitalization reported in the eCRF with an 
admission date during the treatment period. 


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Fontan-related hospitalizations are any hospitalization reported as part of a clinical 
worsening event in the eCRF.  
10.2.7 Pharmacokinetic variables 
To assess exposure to macitentan and its metabolite in this population, trough 
concentrations of macitentan and its metabolite ACT-132577 in plasma at Week 4 and 
Week 16, or at EOT in case of premature study drug discontinuation before Week 16, will 
be determined. 
10.3 General Description of statistical analyses 
Data are listed and summarized by appropriate descriptive statistics (tables or figures), 
including: 
• Number of non-missing observations, mean, standard deviation (SD), minimum, Q1, 
median, Q3 and maximum for continuous variables, 
• Number of events, number of censored observations, number of subjects at risk, and KM 
estimates of the survival function for time-to-event variables, hazard ratios and 
corresponding 95% confidence intervals,  
• Number of non-missing observations, frequency with percentage per category 
(percentages based on the number of non-missing observations) for categorical safety 
variables, 
• Number of missing observations and frequency with percentage per category 
(percentages based on the total number of observations) for categorical variables other 
than safety variables. 
The number of missing values is displayed only if > 0. For continuous variables it is 
displayed after the number of non-missing observations, for categorical variables after the 
last category. 
10.3.1 Overall testing strategy 
The effect of macitentan 10 mg as compared to placebo will be statistically tested on the 
primary efficacy variable at an overall Type I error of 1% two-sided. The study would be 
‘conclusive’ at the two-sided 1% level, it could also be declared ‘positive’ at a significance 
level of 5% on the primary efficacy variable. 
This study implements one IA for unblinded sample size re-estimation which will be 
conducted approximately when the first 95 subjects (i.e., 70% of the pre-planned sample 
size) are randomized and have completed their Week 16 CPET assessment (i.e., 
Visit 4/Week 16), or withdrew from the study without a Week 16 CPET assessment. This 
sample size re-estimation allows the sample size to be potentially increased up to 
268 subjects based on conditional power considerations for the primary efficacy endpoint 
[see Section 10.5.3]. This IA will be implemented through an IDMC. The SAP written by 


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Actelion will include the description of the statistical methods and analyses to be applied 
to the primary efficacy endpoint and the details on the statistical decision rules for the 
implementation of the IA, which may be used as guidance. The inverse normal combination 
method will be utilized to combine first-stage p-value (based on actual number of subjects 
available at the time of IA) and second-stage p-value (based on the remaining number of 
subjects required to reach the total sample size after IA results) for the control of the type-1 
error rate [Lehmacher 1999]. The guideline for calculating the combination weights will 
be included in the SAP and will be based on the available individual information fractions 
at the time of the IA. Combination weights will not be adjusted based on the IA decision.  
If the primary endpoint is statistically significant at a significance level α = 1% two-sided 
at final analysis, the secondary efficacy endpoints will be analyzed at the same significance 
level as the primary efficacy endpoint (i.e., 1% two-sided) using a hierarchical testing 
procedure following the order of the endpoints as listed in Section 6.1.2.  
Similar to the primary efficacy endpoint, the final analysis of the secondary efficacy 
endpoints will be conducted using the inverse normal combination method with 
pre-specified weights to combine first and second stage p-values. 
Safety variables and other variables will not be formally statistically tested. 
Guidelines for sample size re-estimation are defined in the SAP. Procedures to maintain 
data integrity in the presence of sample size adaptation are given in a separate document. 
10.3.2 Analysis of the primary efficacy variable(s) 
10.3.2.1 Hypotheses and statistical model 
The statistical hypotheses for the primary endpoint are formulated in terms of the arithmetic 
means (M) of change in peak VO2 in subjects treated with either placebo or macitentan 
10 mg from Baseline (Visit 2) to Week 16 (Visit 4). 
H0: M macitentan 10 mg = M placebo versus 
HA: M macitentan 10 mg ≠ M placebo  
The null hypothesis will be tested as per primary variable at a two-sided Type I error of 
1% for conclusiveness. 
Assuming the normal distribution of the primary variable, the null hypothesis will be tested 
by means of an analysis of covariance (ANCOVA) model on the change in peak VO2 at 
Week 16. Model covariates will include randomized treatment, geographical region and 
peak VO2 at Baseline (Visit 2).  


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For subject k in geographical region j under treatment i, the additive linear statistical model 
is 
 
yijk = a + β1Ti + β2Rj + β3xijk + eijk,  
where,  
• yijk denotes the change from baseline to Week 16 (Visit 4) in peak VO2 for subject k 
in geographical region j under treatment i, 
• a denotes the common intercept, 
• Ti denotes the treatment group i with i=1 for macitentan 10 mg and i=0 for placebo, 
• Rj denotes geographical region j with j=1 to the total number of regions (America, 
Europe, Asia, Oceania), 
• xijk denotes the peak VO2 value at Baseline (Visit 2) for subject k in geographical 
region j under treatment i, 
• eijk denotes the random error term for subject k in geographical region j under 
treatment i, assumed to follow a normal distribution with mean 0 and SD σ, and  
• β1, β2 and β3 denote the model coefficients of the treatment, geographical region and 
baseline value effects, respectively. 
The difference between treatments at Week 16 will be used to test the null hypothesis of 
equality of treatment effects. According to the model notation, null and alternative 
hypotheses above conform to H0: β1 = 0 versus H1: β1 ≠ 0. 
The primary estimand for the primary efficacy endpoint is defined as:  
A. Population: All randomized Fontan-palliated adult and adolescent subjects defined 
through protocol inclusion/exclusion criteria (i.e., FAS). 
B. Variable: peak VO2 as change from baseline to Week 16. 
C. Intercurrent events:  
• Death occurring before W eek 16 
In case of death prior to Week 16, this will result in imputing the change from baseline 
to Week 16. A worst-case imputation will be applied as detailed in Section 10.3.2.2. 
• Non-missing peak VO2 value at Week 16 assessed as ‘invalid’ by the central 
reading facility 
In case an assessment at Week 16 has been evaluated as “invalid” by the independent 
central reading facility, it will not be included in the analysis and it will be handled as 
detailed in Section 10.3.2.2. 


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• Premature study treatment discontinuation before Week 16 
Premature study treatment discontinuation prior to Week 16 will be addressed by a 
“treatment-policy” estimand strategy by including any assessment in the Week 16 time 
window, irrespective of premature study treatment discontinuation, in the main 
analysis. 
Population-level summary measure: difference in change in peak VO2 from baseline to 
Week 16 between macitentan 10 mg and placebo, as estimated from the ANCOVA model 
including randomized treatment group, geographical region and baseline peak VO2 as 
covariates in the model. 
Based on the inverse normal combination of the stagewise test statistics to control for the 
adaptive design, the main estimator at final analysis will be the median unbiased estimator 
for the overall treatment effect and corresponding repeated confidence intervals (RCIs) 
based on the stage-wise ordering [see Section 10.3.2.3]. 
10.3.2.2 Handling of missing data 
The primary variable is the change in peak VO2 from Baseline (Visit 2) to Week 16 
(Visit 4) and calculated as the Week 16 value minus baseline value in peak VO2. 
At baseline, no subject will have a missing value for peak VO2 because the subject will not 
be able to be randomized via IRT in the event of missing peak VO2. In case a subject has 
been randomized with a non-missing baseline value that has subsequently been evaluated 
as “invalid” by the independent central reading facility, it will be imputed with the median 
peak VO2 value observed at baseline from the remaining subjects (across treatment 
groups). 
During the conduct of the study, all efforts will be made to avoid missing values in 
peak VO2 at Week 16. For Week 16, the time window interval is from study Day 99 
(Week 14) to study Day 168 (Week 24).  
Furthermore, if a subject discontinues treatment prematurely, a CPET will be conducted 
within 7 days of EOT. If treatment is discontinued prior to Week 16, and the subject enters 
the PTOP, it is requested that the subject return for a CPET assessment at Week 16 (in 
addition to the EOT assessment). 
Any unscheduled visit will also be mapped to a time window. 
Intercurrent events as defined in Section 10.3.2.1 will be handled as in table below as well 
as any other missing values which may occur in peak VO2 at Week 16. 


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Reason 
Strategy in handling the change from Baseline to Week 16 
Death before 
Week 16 
Imputed with the lowest observed change in peak VO2 from Baseline 
to Week 16 (across both treatment groups) – Worst case. 
Invalid peak 
VO2 at Week 
16/Other* 
Imputed with the 25th percentile of the observed changes in peak VO2 
from baseline to Week 16 (across both treatment groups). If this leads 
to an improvement, a change of 0 (no change) will be imputed. 
*Other could include: premature study treatment discontinuation because of an adverse event, lack of efficacy, or lost-to 
follow up. 
After the imputation is applied, the ANCOVA model, as described in Section 10.3.2.1, will 
be used. 
10.3.2.3 Main analysis 
The primary statistical analysis will be performed on the FAS population using the model 
described in Section 10.3.2.1 for the 16-week change in peak VO2 as a dependent variable. 
The ANCOVA model considers study treatment (macitentan 10 mg or placebo) and 
geographical region as fixed categorical factors and the baseline value of peak VO2 as a 
fixed continuous covariate. Missing data will be imputed as described in Section 10.3.2.2 
for the main analysis. Geographical regions are defined as Americas, Europe, Asia, 
Oceania.  
Assumptions of normality and homogeneity of variance and assessing of ANCOVA model 
assumptions will be investigated and graphically presented when applicable (e.g., Q-Q and 
residual plots). 
At final analysis, the primary efficacy endpoint will be tested by combining the p-values 
from the main ANCOVA analysis of first-stage (based on actual number of subjects 
available at the time of IA) and second-stage (based on the remaining number of subjects 
to reach the total sample size after IA results), using the weighted inverse-normal 
combination method [Lehmacher 1999] with fixed weights proportional to the information 
available at the time of the IA. The difference in the change in peak VO2 from Baseline to 
Week 16 between macitentan 10 mg and placebo and corresponding p-value will be 
estimated at each stage separately (first-stage and second-stage) from the main ANCOVA 
model using a population-wise splitting of data approach. Final interpretation of the results 
will then be based on the final adjusted p-value, median unbiased estimator for the overall 
treatment effect and corresponding RCIs obtained by ADDPLAN™ 6.1 (ADDPLAN, Inc., 
an Aptiv Solutions company). 


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Absolute values at Baseline and at Week 16 as well as absolute change in peak VO2 from 
Baseline to Week 16 (for observed and imputed values) will also be summarized using 
descriptive statistics.  
10.3.2.4 Supportive/sensitivity analyses 
i) Sensitivity analyses for missing values at Baseline and Week 16 in peak VO2 
• The main ANCOVA model will be applied on the set of subjects with observed values 
only, i.e., without replacing missing values.  
• The main ANCOVA model will be applied excluding subjects with invalid peak VO2 
at Baseline. 
The resulting least square (LS) means and corresponding 95% and 99% CLs obtained in 
each treatment group, and the LS-means differences (95% and 99% CLs) for macitentan 
10 mg vs placebo will be obtained from the ANCOVA model carried out on the total 
sample size (without the population wise splitting approach for the control of the adaptive 
design).  
ii) Other sensitivity analyses 
Other sensitivity analyses carried out on the total sample size, without the population-wise 
splitting approach for the control of the adaptive design, are:  
• ANCOVA model applied for the PPS population 
• ANCOVA model following while ‘on-treatment’ strategy. The assessments in the 
Week 16 time window will only be included in the analysis if assessed up to 7 days 
after last dose of study treatment. 
• A first ANCOVA on ranks will be implemented to address possible deviations from 
the normality assumptions. It will be performed as follows:  
– imputation approach for Week 16 will be applied as per the primary endpoint 
analysis 
– ranking will be performed on the primary variable (changes in peak VO2 from 
baseline to Week 16) and baseline peak VO2 
• A second ANCOVA on ranks will be implemented as a sensitivity to the primary 
imputation method. It will be performed as follows:  
– Each Week 16 value that is missing due to the patient’s death prior to the Week 
16 assessment receives a rank score corresponding to a value of the measurement 
that is worse than any actually observed 
– Each Week 16 value that is missing in patients not known to have died prior to 
the Week 16 assessment receives a rank score corresponding to a value of the 


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measurement that is worse than any actually observed but better than for any 
patient who died prior to Week 16 
– The above imputation guarantees the following: 
– rank (subjects who die) < rank (subjects with missing values) < rank (subjects without missing values) 
• ANCOVA model with treatment-by-geographical region interaction effect added to the 
primary model proposed in Section 10.3.4.2, 
• ANCOVA model with NYHA FC added to the primary model proposed in the 
Section 10.3.2.1. 
Further details and potential further supportive analyses will be described in the SAP. 
10.3.3 Analysis of secondary efficacy variables 
10.3.3.1 Change from baseline over 52 weeks in peak VO2 
The change in peak VO2 over 52 weeks is evaluated on the FAS population with the use of 
a mixed model repeated measures. The model will include randomized treatment group, 
time (via a categorical variable for visit), treatment-by-time interaction, baseline-by-time 
interaction and peak VO2 at Baseline as fixed effects. An unstructured variance-covariance 
matrix will be specified. 
Invalid peak VO2 at Baseline will be handled similarly to the primary efficacy endpoint. 
In case of missing values in peak VO2 at Week 52 the following approach for imputation 
will be applied 
• Death occurring before Week 52.  
In case of death prior to Week 52, all scheduled assessments following the date of death 
will be imputed by a worst-case imputation (i.e., lowest observed change in peak VO2 
from Baseline value across both treatment groups and over all assessments). 
• Peak VO2 at Week 16 or Week 52 assessed as ‘invalid’ by the central reading 
facility. 
In case an assessment at Week 52 has been evaluated as “invalid” by the independent 
central reading facility, it will be ignored. This will result in imputing the change from 
Baseline to Week 52 with the 25th percentile of the observed changes in peak VO2 from 
Baseline value (across both treatment groups and over all assessments). If this leads to 
an improvement, a change of 0 (no change) will be imputed. 
• Premature study treatment discontinuation before Week 52 
If the premature study treatment discontinuation occurs prior to Week 16: 


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o if a valid assessment is available within the time window of Week 16, this 
will result in imputing only the change from Baseline to Week 52 with the 
25th percentile of the observed changes in peak VO2 from Baseline value 
(across both treatment groups and over all assessments). If this leads to an 
improvement, a change of 0 (no change) will be imputed. 
o if no valid assessment is available within the time window of Week 16, all 
scheduled assessments following the date of event will be imputed by 
applying the 25th percentile of the observed changes in peak VO2 from 
Baseline value (across both treatment groups and over all assessments). If 
this leads to an improvement, a change of 0 (no change) will be imputed.  
If the premature study treatment discontinuation occurs after Week 16 and before Week 
52 (and no valid assessment is available within the time window of Week 52), this will 
result in imputing the change from baseline to Week 52 with the 25th percentile of the 
observed changes in peak VO2 from Baseline value (across both treatment groups and 
over all assessments). If this leads to an improvement, a change of 0 (no change) will 
be imputed.  
Missing data arising from any other reason (e.g., administrative reason) are assumed to be 
missing at random, and as such, will require no further imputation, since the MMRM 
approach will implicitly impute these values.  
Supportive/Sensitivity Analyses: 
Additional sensitivity analyses will be similar to the primary endpoint (e.g., PPS, excluding 
subjects with invalid peak VO2 at baseline and “while on treatment”. For all sensitivity 
analyses, similar to the primary endpoint, the main MMRM model will be carried out on 
the total sample size (without the population wise splitting approach for the control of the 
adaptive design). At Week 52, the resulting LS means and corresponding 95% and 99% 
CLs obtained in each treatment group, and the LS-means differences (95% and 99% CLs) 
for macitentan 10 mg vs placebo will be provided. 
10.3.3.2 Change from Baseline to Week 16 in mean count per minute of daily PA-Ac 
The change from Baseline to Week 16 in mean count per minute of daily PA-Ac is 
evaluated on the FAS population by means of an ANCOVA including treatment group and 
baseline accelerometry value as covariates. Similar to the approach for the primary 
endpoint (main analyses) and based on the inverse normal combination of the stagewise 
test statistics to control for the adaptive design, the main estimator at final analysis will be 
the median unbiased estimator for the overall treatment effect and corresponding 99% 
confidence intervals based on the stage-wise ordering. 


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Only subjects with evaluable 9-day time period for the daily physical activity at Baseline 
will be included in the main analysis. In case of missing values in mean count per minute 
of daily PA-Ac at Week 16, the following approach for imputation will be applied: 
Reason 
Strategy in handling the missing change from Baseline to 
Week 16 
Death 
before 
Week 16 
Imputed with the lowest observed change in mean count per minute 
of daily PA-Ac from Baseline to Week 16 (across both treatment 
groups) – Worst case. 
Other 
A change of 0 (no change) will be imputed. 
 
Supportive/Sensitivity analyses:  
Additional sensitivity analyses will be on the PPS, based on observed cases. 
The main model for all sensitivity analyses will be the same ANCOVA model as specified 
for the primary endpoint but carried out on the total sample size (without the population 
wise splitting approach for the control of the adaptive design). 
10.3.3.3 Sub-group analyses 
In order to assess the consistency of the treatment effect across different subject subgroups, 
analyses will be performed on the primary and secondary efficacy variables classifying 
subjects according to relevant demographic characteristics.  
The subgroups to be considered are: 
• Age group (adults of 18 years of age or more, adolescents of less than 18 years of age 
at Screening), 
• Geographical region (America, Europe, Asia, Oceania), 
• Region (US, non-US), 
• Ventricular dominance: left ventricle (LV) versus right ventricle (RV) / mixed. 
 
Analyses in subgroups on the FAS population are carried out the same way as on the entire 
population as described in Sections 10.3.2, 10.3.3.1, and 10.3.3.2 for primary and 
secondary efficacy variables, respectively. The treatment effect within subgroups will 
primarily be displayed with their corresponding 95% CLs and presented in a forest plot. 
An additional forest plot will be produced for the primary endpoint only, displaying 99% 
CLs instead of 95% CLs. Treatment-by-subgroup interaction is investigated by means of 
tests of heterogeneity. 
Further details will be provided in the SAP. 


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10.3.4 Analysis of the safety variable(s) 
The SS will be used to perform all safety analyses. Safety variables will be analyzed by 
actual treatment received. 
10.3.4.1 Adverse events 
AEs will be coded using the latest available version of the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary. 
Listings will be provided for all reported AEs, including SAEs. Treatment-emergent AEs 
are flagged. In addition, separate listings will be provided for SAEs, for AEs leading to 
premature discontinuation of study treatment, and for AEs with fatal outcome.  
The number and percentage of subjects experiencing treatment-emergent AEs, SAEs, 
related AEs, related SAEs, AEs with fatal outcome, and AEs leading to premature 
discontinuation of study treatment will be tabulated by treatment group, system organ class 
(SOC) and individual preferred term within each SOC, in descending order of incidence 
within the macitentan 10 mg treatment group. For SAEs, the number of such events is 
added to the table. In addition, tabulation will be by treatment group and individual 
preferred term, irrespective of SOC, in descending order of incidence within the macitentan 
10 mg treatment group. 
Furthermore, treatment-emergent AEs will be tabulated by treatment group, individual 
preferred term and maximum intensity. 
The number and percentage of subjects experiencing treatment-emergent non-serious AEs, 
together with the number of such events, will be tabulated by treatment group, SOC and 
individual preferred term within each SOC, in descending order of incidence within the 
macitentan 10 mg treatment group, if the frequency of subjects exceeds 5% in any 
treatment group. 
10.3.4.2 Laboratory data 
All laboratory data, local and central, are listed in original, International System of Units 
(SI) and conventional units. Abnormal values and values representing treatment-emergent 
marked abnormalities are flagged. Measured values and changes in laboratory data from 
baseline are described by visit and treatment group by means of summary tables in SI units. 
All recorded assessments, including scheduled and unscheduled visits, will be assigned to 
the most appropriate visit time point according to the best-fitting time window for the 
assessment. In addition, worst low, worst high and last values post baseline will be 
described in the same way. 
Treatment-emergent marked laboratory abnormalities will be summarized for each 
laboratory parameter by treatment group providing their incidence and frequency. In 
addition, shift tables of categories of marked laboratory abnormalities at baseline versus 


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post-baseline visits, worst low, worst high and last post-baseline will be displayed. 
Furthermore, frequency tables of liver, hemoglobin, estimated creatinine clearance, and 
albumin abnormalities will be presented: 
• Proportion of patients with treatment-emergent ALT and/or AST abnormalities from 
baseline up to EOT defined as values:  
– 
≥ 3 × ULN;  
– 
≥ 3 × ULN and < 5 × ULN;  
– 
≥ 5 × ULN and < 8 × ULN;  
– 
≥ 8 × ULN.  
• Proportion of patients with ALT and/or AST abnormality (≥ 3 × ULN) in 
combination with total bilirubin ≥ 2 × ULN from baseline up to EOT.  
• Proportion of patients with treatment-emergent hemoglobin abnormalities up to EOT, 
classified as:  
– 
< 80 g/L  
– 
< 100 g/L  
• Proportion of patients with treatment-emergent estimated creatinine clearance 
< 30 mL/min/1.73m2. 
• Proportion of patients with treatment-emergent albumin abnormalities < 30 g/L in 
combination with total protein < 50 g/L. 
10.3.4.3 Vital signs 
Listings will provide all data of vital signs, including SpO2, height and body weight. 
Measured values and changes from baseline are described by visit and treatment group by 
means of summary tables.  
Number of subjects with systolic BP drops to < 90 mmHg (< 85 mmHg for subjects 
< 18 years old and < 150 cm of height) over 52 weeks will be tabulated and listed. 
All recorded assessments, including scheduled and unscheduled visits, will be assigned to 
the most appropriate visit time point according to the best-fitting time window for the 
assessment. 
10.3.4.4 Echocardiography 
Listings will provide data of ECHOC parameters at Screening and EOT visits, together 
with the respective changes from baseline. 
10.3.5 Analysis of other efficacy variables 
Exploratory analysis of other efficacy variables will be conducted on the FAS. Missing 
values will not be imputed. 


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10.3.5.1 Peak VO2 at other visits, VE/VCO2 slope, VO2/HR, VO2 at VAT, OUES and % 
predicted peak VO2 
Other efficacy variables related to exercise capacity are summarized by treatment groups 
in tabular forms.  
Changes from baseline in peak VO2 at Week 52 will be analyzed by means of an ANCOVA 
including treatment group and baseline value as covariates. 
Separate receiver operating characteristic curve analysis will be performed in order to 
identify the best cut-offs of VE/VCO2 slope and peak VO2 that discriminate patients with 
and without clinical events. In addition, the variables VE/VCO2 slope and peak VO2 will 
be categorized and the number and proportion of patients with clinical events will be 
presented overall and by treatment group for each category. 
The % predicted peak VO2 will be analyzed using a MMRM [Section 10.3.3.1] on the 
changes from Baseline over 52 weeks. 
Changes from baseline to Week 16 in VO2 at VAT and in OUES will be analyzed by means 
of an ANCOVA, including treatment group and baseline value as covariates.  
In addition, the VO2 at VAT and OUES will be analyzed using a MMRM [Section 10.3.3.1] 
on the changes from Baseline over 52 weeks. 
If normal assumptions are not valid then ANCOVA on the transformed variable or 
ANCOVA on ranks will be applied. 
10.3.5.2 NT-proBNP 
The percent of baseline at Week 16 in NT-proBNP will be analyzed like the primary 
efficacy variable by means of an ANCOVA model as described in Section 10.3.2.1.  
NT-proBNP is assumed to follow a log-normal distribution. Therefore, data is 
log transformed before analysis. Summary tables provide back transformed data by means 
of geometric means and 95% CL of NT-proBNP expressed as percent of baseline. 
Back-transformation is done by means of the exponential function of the least-squares 
mean of treatment difference and its corresponding CLs obtained on the log scale.  
NT-proBNP at other visits than Week 16 will be summarized and presented graphically 
over time. 
10.3.5.3 Mean time in minutes spent in different physical activities and mean count per 
minute of daily PA-Ac over time 
The mean time in minutes spent in: 
• sedentary physical activity, 


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• light physical activity, 
• moderate physical activity and 
• vigorous physical activity 
will be described at each time point of assessment by calculating for each treatment group 
the average time spent in each category and will be displayed in both a graphical (bar plots) 
and a tabular form. The number of subjects who spent time in physical activity categories 
as defined above will be summarized in shift tables (categories at Baseline vs categories at 
post-baseline visits). 
Repeated measure statistical methodology (a random coefficient regression model) that 
was proposed for the secondary endpoint [Section 10.3.3.1] will also be applied for change 
from Baseline (Visit 2) over 52 weeks in mean count per minute of daily PA-Ac.  
In addition, the number of valid days of wearing the accelerometer at Baseline, Week 16, 
and Week 52, will also be summarized descriptively. 
10.3.5.4 Clinical events 
Time to clinical events will be analyzed using KM estimates along with 95% 
two-sided CLs at relevant time points for each treatment group in both graphical and 
tabular form. The estimated hazard ratio and corresponding 95% confidence interval will 
be obtained from a Cox regression model. In addition, the number of subjects with events, 
the number of subjects at risk, and the number of subjects censored will be computed at 
each time point for each group. Subjects without events will be right-censored at the last 
time known to be without the respective event. 
10.3.6 Overall survival 
Time to death up to SCL will be analyzed using the KM methodology as described in 
Sections 10.2.3 and 10.3.5.4 for the clinical events.  
KM curves over time by treatment group will be graphically displayed. The number of 
subjects at risk, number of events (deaths), number of censored cases, KM estimate of the 
event-free rate at these time points, and corresponding confidence intervals for the 
estimated event-free rate at Weeks 16, and 52 will be presented. Additionally, a listing with 
all subjects and their vital status with corresponding date of death or censoring date will be 
provided. 
10.3.7 Analysis of quality of life variables 
The QoL endpoints will be analyzed descriptively on the FAS by randomized treatment 
group. Continuous scales (EQ-5D VAS) will be summarized as absolute and changes from 
baseline values at each time point. Categorical scales (PGA-S, CGI-S, PGI-C, CGI-C and 
EQ-5D-5L) will be summarized as the proportion of patients within each response category 
at each time point.  


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10.3.8 Analysis of pharmacoeconomic variables 
Those endpoints will be summarized descriptively on the FAS by randomized treatment 
group. 
10.3.9 Analysis of pharmacokinetic variables 
Analysis of PK (i.e., trough concentration of macitentan and active metabolite) will be 
conducted on the PKS.  
Individual subject listings of trough plasma concentrations will be provided. 
Trough plasma concentrations of macitentan and its metabolite will be described by visit 
by means of summary tables. In addition, separate summary tables will be given by age 
group and by gender.  
10.3.10 
Exposure to and compliance with the study treatment 
Exposure to study drug will be described in terms of duration and dose. The duration of 
study treatment is defined as the time in days elapsing between start and end of study 
treatment, inclusive. It includes potential periods of study treatment interruption. The end 
of study treatment is defined as the time of permanent discontinuation of study treatment. 
The duration of exposure in days is defined as the number of days with study treatment, 
excluding days without study treatment, i.e., excluding periods of study treatment 
interruption. 
Compliance with study treatment, in percent, is defined as percent of doses taken divided 
by expected number of doses. The expected number of doses is derived from the planned 
duration of study treatment during the period of interest. 
Analysis of study treatment exposure and compliance data is performed on the SS. 
Individual subject listings of study treatment exposure and compliance data will be 
provided. 
The duration of exposure, the duration of study treatment, and compliance will be described 
by treatment group by means of summary tables. It will be also summarized as a categorical 
variable: the cumulative distribution of exposure time by different class intervals (i.e., at 
least 4 weeks, at least 8 weeks, at least 16 weeks, and so on up to 52 weeks) will be 
tabulated to show counts and percentages of subjects in each class interval. The sum of 
duration of exposure across all subjects in years will be displayed as subject year exposure. 
10.3.11 
Demographic and baseline characteristics 
Summaries for demographic and baseline characteristics will be performed on the FAS and 
displayed per treatment group and overall. In addition, demographic and baseline 
characteristics will be tabulated by geographical region, gender, and age group. 
Demographic variables include age (in years), age groups (adolescents, adults), gender, 


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body weight, height, BMI, race, ethnicity, country, and geographical region. Baseline 
characteristics include disease and other characteristics, medical history, previous and 
concomitant medications. Baseline disease variables include type of initial uni-ventricular 
heart, time since Fontan-palliation completion, type of TCPC, NYHA FC, peak VO2 at 
baseline, NT-proBNP at baseline, and fenestration patency. 
Previous and concomitant medications will be coded according to the WHO drug code and 
the Anatomical Therapeutic Chemical class code and summarized by tabulating the number 
and percentages of subjects having received each treatment. 
Medical history will be coded using MedDRA and summarized in a similar manner to 
AEs. 
10.3.12 
Subject disposition 
A study flowchart will show the disposition of study subjects throughout the progression 
of the study. It will display the numbers of subjects screened and undergoing randomization 
with the latter divided into the placebo and macitentan 10 mg treatment groups to which 
they were randomized. The number of subjects by treatment group continuing and 
discontinuing treatment and the study, along with reasons for discontinuations will be 
displayed. The final row of the flowchart will result in the number of subjects completing 
the study in each treatment group. 
The items in the flowchart will be supported by tables and listings on the FAS related to 
each level and will be presented by randomized treatment group. In addition, it will be 
presented by geographical region, country and age group. 
The number and percent of subjects included in and excluded from each analysis set, based 
on the set definitions in Section 10.1, will be summarized, supported by a summary table 
of protocol deviations leading to exclusion from FAS (i.e., used for derivation of PPS). 
Protocol deviations will be displayed by treatment, geographical region, country and site. 
10.4 Interim analysis 
One IA for unblinded sample size re-estimation will be implemented through an IDMC. 
Only the IDMC and the ISAC/SSG will be unblinded to the data. 
The IA will be conducted by the ISAC/SSG on the primary efficacy endpoint to allow 
unblinded sample size re-estimation when approximately the first 95 subjects i.e., 70% of 
pre-planned sample size) are randomized and have completed their Week 16 CPET 
assessment (i.e., Visit 4/Week 16), or withdrew from the study without a Week 16 CPET 
assessment. The ISAC/SSG will make unblinded results available to the IDMC. The IDMC 
will review the interim results and make corresponding recommendation to the Sponsor 
Committee in line with the IDMC charter. The IDMC may recommend, based on the 


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unblinded interim data, that the sponsor continues the study as initially planned (i.e., a total 
of 134 subjects) or with reassessed sample size, to a total between 134 < N ≤ 268 subjects. 
Under the IDMC recommendation of sample size adaptation, the sample size will be 
re-estimated at the IA based on treatment effect and variability for the primary efficacy 
endpoint (i.e., change from baseline to Week 16 in peak VO2), following rules as described 
in the SAP. Only an upward adjustment of the initially planned sample size is allowed. An 
upper bound of the sample-size adjustment is considered up to a 100% increase of the 
initially planned sample size (i.e., total sample size of 268 subjects).  
Detailed guidelines for interim decision-making are further described in the SAP written 
by Actelion for the ISAC/SSG [see Section 10.5.3, for preliminary details], outlining the 
statistical methods and analyses to be applied to the primary efficacy endpoint for the 
sample size re-estimation. 
10.5 Sample size 
The sample size is based on the primary efficacy endpoint, the 16-week change from 
baseline in peak VO2. The study is powered for the treatment comparison on a FAS. The 
aim of the trial is to reject the statistical hypothesis of no treatment difference. 
All calculations were performed using the East software version 6.3.  
10.5.1 Sample size and justification 
Assuming that the macitentan versus placebo difference is expected to be no worse than 
the bosentan versus placebo difference, a 2.4 mL/kg/min difference of macitentan to 
placebo on the change in peak VO2 is hypothesized. The variation of macitentan is assumed 
to be greater than that observed in the TEMPO study of bosentan versus placebo in subjects 
with Fontan-palliated circulation [Hebert 2013, Hebert 2014], namely a standard deviation 
of 4.0 mL/kg/min yielding an effect size of 0.6. 
It is further assumed that all randomized subjects are evaluable. The family-wise two-sided 
Type I error is set to 1% (i.e., the level of significance), and the minimum statistical power 
to achieve is set to 80% (i.e., Type II error β of 20%). 
Under the assumption of normal distributions (based on a two-sample t-test with equal 
unknown variances), sample size is determined for different scenarios. Data will be 
analyzed by means of ANCOVA taking further explanatory potentially confounding 
factors into account, therefore adjusting for the estimated treatment difference and reducing 
variability in the data. If the assumptions are not met, it is only a slight acceptable loss in 
efficiency.  
Based on the above assumptions and with a 1:1 randomization ratio, a total of 134 subjects, 
i.e., 67 per treatment group, are required to establish superiority of macitentan 10 mg over 


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placebo to correctly reject the null hypothesis, when it is false, in favor of the alternative 
hypothesis.  
10.5.2 Sample size sensitivity 
In a range of effect size from 0.4 to 0.8, here corresponding to a range of SD from 3.0 to 
6.0 mL/kg/min for the primary efficacy endpoint, the 16-week change from baseline in 
peak VO2, alternative sample size scenarios are given in Table 4. 
Table 4 
Sample size with treatment effect of 2.4 mL/kg/min and statistical 
power 1-β of 80% in a 1:1 randomization ratio by level of 
significance α and effect size (with selected sample size in bold face) 
α 
Effect size 
SD 
n per arm 
Total N 
1% 
0.4 
6.0 
148 
296 
 
0.5 
4.8 
96 
192 
 
0.6* 
4.0 
67 
134 
 
0.8 
3.0 
39 
78 
5% 
0.4 
6.0 
100 
200 
 
0.5 
4.8 
64 
128 
 
0.6 
4.0 
45 
90 
 
0.8 
3.0 
26 
52 
SD: standard deviation with a treatment difference of 2.4 mL/kg/min; n: sample size per arm (macitentan 
10 mg or placebo) with a 1:1 ratio; N: total sample size required for randomization. 
*selected 
10.5.3 Unblinded sample size re-estimation 
The sample size will be re-estimated at the IA [see Section 10.4] based on conditional 
power considerations under the observed unblinded treatment effect estimates. Sample size 
may be increased to a maximum of 268 subjects to target 80% conditional power. If the 
conditional power at the IA is below 5% or is above 80%, the sample size shall not be 
changed.   
The detailed methodology for sample size re-estimation as well as the operating 
characteristics of the design under a range of effect sizes are described in the SAP.  
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 


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manner to ensure accurate interpretation of the data. Data reported in the eCRF derived 
from source documents must be consistent with the source documents. 
eCRF data will be captured via electronic data capture (EDC; using the Rave system 
provided by Medidata Solutions, Inc, a web-based tool). The investigator and site personnel 
will be trained to enter and edit the data via a secure network, with secure access features 
(username, password, and identification – an electronic password system). A complete 
electronic audit trail will be maintained. The investigator/delegate will approve the data 
(i.e., confirm the accuracy of the data recorded) using an electronic signature (ref. to 
US 21 CFR Part 11). 
Subject screening and enrollment data will be completed for all subjects (i.e., eligible and 
non-eligible) through the IRT system and eCRF. 
For each subject enrolled, regardless of study treatment initiation, an eCRF must be 
completed and signed by the investigator/delegate. This also applies to those subjects who 
fail to complete the study. If a subject withdraws from the study, the reason must be noted 
on the eCRF. Refer to Section 7.2.1 for the data to be collected in the eCRF for subjects 
who failed screening. 
11.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On eCRFs or 
other documents (e.g., documents attached to SAE forms / Pregnancy forms) submitted to 
Actelion and any CROs, subjects must be identified only by number and never by their 
name or initials, hospital numbers, or any other identifier. The investigator/delegate must 
keep a subject identification code list at the site, showing the screening/randomization 
number, the subject’s name, date of birth, and address or any other locally accepted 
identifiers. Documents identifying the subjects (e.g., signed ICFs) must not be sent to 
Actelion, and must be kept in strict confidence by the investigator/delegate. 
11.3 Database management and quality control 
eCRFs will be used for all subjects. The investigators will have access to the site eCRF 
data until the database is closed. Thereafter, they will have read-only access. The eCRF 
must be kept current to reflect subject status at any time point during the course of the 
study. 
While entering the data, the investigator/delegate will be instantly alerted to data queries 
by validated programmed checks. Additional data review will be performed by Actelion 
personnel on an ongoing basis to look for unexpected patterns in data and for study 
monitoring. If discrepant data are detected, a query specifying the problem and requesting 
clarification will be issued and visible to the investigator/delegate via the eCRF. All 
electronic queries visible in the system either require a data correction (when applicable) 


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and a response from the investigator/delegate to clarify the queried data directly in the 
eCRF, or simply a data correction in the eCRF. The investigator/delegate must, on request, 
supply Actelion with any required background data from the study documentation or 
clinical records. This is particularly important when errors in data transcription are 
suspected. In the case of health authority queries, it is also necessary to have access to the 
complete study records, provided that subject confidentiality is protected. 
This process will continue until database closure. 
Laboratory samples will be processed through a central laboratory and the results will be 
electronically sent to Actelion. PK samples will be shipped at regular intervals and 
analyzed by the bioanalytical lab. 
CPET and PA-Ac data are processed by a central reading facility and results will be sent 
to Actelion. 
AEs are coded according to the latest 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 QS docs. After database closure, the investigator will receive the 
eCRFs 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 countries in which the study is conducted. 
12.2 Independent Ethics Committee / Institutional Review Board 
The investigator or sponsor will submit this protocol and any related document(s) provided 
to the subject or parent(s)/ legally designated representative and 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, investigator, the documents reviewed, and the date of approval. 
Modifications made to the protocol or the ICF after receipt of the approval must also be 
submitted as amendments by the investigator to the IEC/IRB in accordance with local 
procedures and regulations [see Section 12.6]. 
A list of members participating in the IEC/IRB meetings must be provided, including the 
names, qualifications, and functions of these members. If that is not possible, the attempts 


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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 
Pediatric subjects are legally unable to provide informed consent. Therefore, full informed 
consent must be obtained from parent(s) or a legally designated representative. 
Assent must be obtained from study participants who are developmentally capable. The 
criteria for developmental capability to give assent follows local requirements. Distinct 
assent forms are provided per age categories. Subjects who come of age during their study 
participation must be consented to continue their participation in the study. The age when 
subjects are considered capable to give informed consent must follow local regulations. 
It is the responsibility of the investigator/delegate to obtain informed consent according to 
ICH-GCP and Declaration of Helsinki guidelines and local regulations from each 
individual participating in this study and/or legally designated representative. The 
investigator/delegate must explain to subjects that they are completely free to refuse to 
enter the study, or to voluntarily withdraw from the study at any time for any reason without 
having to provide any justification. Special attention shall be paid to the information needs 
of specific subject populations and of individual subjects, as well as to the methods used 
to give the information. Adequate time shall be given for the subject and/or legally 
designated representative to consider his or her decision to participate in the study and it 
shall be verified that the subject has understood the information (e.g., by asking the subject 
to explain what is going to happen). 
The ICF will be provided in the country local language(s). 
Site personnel authorized (according to local regulation) to participate in the consent 
process and/or to obtain consent from the subject and/or legally designated representative 
will be listed on the Delegation of Authority form supplied by Actelion. In European 
countries the informed consent must be obtained by a physician. A study physician must 
always be involved in the consent process. 
The subject and/or legally designated representative and authorized site personnel listed on 
the Delegation of Authority form supplied by Actelion must sign, personally date, and time 
(if the first study-mandated procedure is to be performed on the same day informed consent 
is obtained) the ICF before any study-related procedures (i.e., any procedures required by 
the protocol) begin.  


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A copy of the signed and dated ICF is given to the subject and/or legally designated 
representative; the original is filed in the site documentation. The informed consent process 
must be fully documented in the subject’s medical records. This must include at a minimum 
the study reference, the subject number, the date and, if applicable, time when the subject 
was first introduced to the study, the date and, if applicable, time of consent, who 
participated in the consent discussion, who consented the subject, and any additional third 
party (e.g., legally designated representative, impartial witness) present during the consent 
process (relationship with the subject), and the information that a copy of the signed ICF 
was given to the subject / third party (e.g., legally designated representative, impartial 
witness). 
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. Study subjects will be reimbursed for the study-related expenses 
(e.g., travel costs, meals, hotel) and may be offered financial compensation for their 
participation in the study only to the extent permitted by applicable local 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. 


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All protocol deviations will be reported in the clinical study report (CSR). IECs/IRBs will 
be provided with listings of protocol deviations as per local requirements. 
12.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. An 
amended protocol must be submitted to the IEC/IRB and regulatory authorities, according 
to their requirements. 
12.7 Essential documents and retention of documents 
The investigator/delegate must maintain adequate records necessary for the reconstruction 
and evaluation of the study. A number of attributes are considered of universal importance 
to source data and the records that hold those data. These include that the data and records 
are accurate, legible, contemporaneous, original (or certified copy), attributable, and for 
electronic source data also complete, consistent, enduring, and available when needed. 
These records are to be classified into two different categories of documents: ISF and 
subjects’ source documents. 
These records must be kept by the investigator for as long as is necessary to comply with 
Actelion’s requirements (i.e., as specified in the clinical study agreement), and national 
and/or international regulations, whichever would be the longest period. If the investigator 
cannot guarantee this archiving requirement at the site for any or all of the documents, 
special arrangements, respecting the data confidentiality, must be made between the 
investigator and Actelion to store these documents outside the site, so that they can be 
retrieved in case of a regulatory inspection. No study document should be destroyed 
without prior written approval from Actelion. Should the investigator wish to assign the 
study records to another party, or move them to another location, Actelion must be notified 
in advance. 
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, read-only and restricted 
access to study subjects only, to verify consistency between electronic source data and the 
eCRF during monitoring visits. 
If the site is using an electronic/computerized system to store subject medical records but 
it could not be confirmed that the system is validated or if the CRA could not be provided 
access to the system according to the requirements of Actelion QS documents, 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 


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information as the original source data. The printouts will be considered as the official 
clinical study records and must be filed with the subject’s medical records. 
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 random and for key data only 
(e.g., eligibility criteria, primary and key secondary endpoints) as per Actelion’s 
instructions.  
12.8 Monitoring 
Prior to study start, a site initiation visit (SIV) will be performed after the required essential 
study documents are approved by Actelion. The study treatment will be shipped to the site 
upon approval of the required essential documents. 
The PI must ensure that all site personnel involved in the study are present during the SIV 
and will dedicate enough time to it. Site Information Technology support should also be 
available during the SIV. 
The SIV must be completed before the site can start the screening of study subjects. 
Following the SIV, a copy of the completed initiation visit report and follow-up letter will 
be provided to the PI and filed in the ISF. 
During the study, the CRA will contact and visit the site regularly and must be permitted, 
on request, to have access to study facilities and all source documents needed to verify 
adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered in the eCRFs and other protocol-related documents. Actelion monitoring standards 
require full verification that informed consent has been provided, verification of adherence 
to the inclusion/exclusion criteria, documentation of SAEs, and the recording of the main 
efficacy, safety, and tolerability endpoints. Additional checks of the consistency of the 
source data with the eCRFs will be performed according to the study-specific monitoring 
guidelines. The frequency of the monitoring visits will be specified in the monitoring 
guidelines based on subject recruitment rate and critical data-collection times. 
The PI must ensure that the eCRF 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 


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hospital other than the study site, the investigator is responsible for contacting that hospital 
in order to document the SAE, in accordance with local regulations. 
A close-out visit will be performed for any initiated site when there are no more active 
subjects and all follow-up issues have been resolved. In case a site does not enroll any 
subjects, the close-out visit may be performed prior to study database closure at the 
discretion of Actelion. 
12.9 Investigator Site File 
Each site will be provided with an ISF prior to the SIV. It will contain all the essential 
documents that are required to be up-to-date and filed at site as per ICH-GCP section 8. 
The ISF will include a table of content listing the essential documents. All study-related 
documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the CRA regarding the filing of the study 
documents outside the ISF. It should be clearly documented where each document is filed. 
This note to file should be present in the specific tab of the document in the ISF. 
The ISF must be stored in a secure and access-restricted area during and after the study. It 
must be kept by the site for as long as needed to comply with any applicable rules and 
regulations, ICH-GCP, as well as instructions from Actelion. If the site needs to transfer 
the ISF to another location and/or if site facility can no longer store the ISF, the PI must 
immediately inform Actelion. 
If the PI will change, or if the site will relocate, the CRA must be notified as soon as 
possible. 
12.10 Audit 
Sponsor’s 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) 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. 


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Should an inspection be announced by a health authority and/or IEC/IRB, the investigator 
must immediately inform Actelion (usually via the CRA) that such a request has been 
made. 
The investigator and site personnel must cooperate with inspector(s) and allow access to 
all study documentation (e.g., subject records) and study facilities. 
12.12 Reporting of study results and publication 
Actelion will post the key elements of this protocol and the summary of results on 
Actelion’s Clinical Trial Register and within the required timelines on publicly accessible 
databases (e.g., clinicaltrials.gov, EU database), as required by law and regulation. 
Study results will be documented in a CSR that will be signed by Actelion representatives 
and the Coordinating Investigator (or PI for single-center studies). 
In accordance with the Good Publication Practices and ethical practice, the results of the 
study will be submitted for publication in a peer-reviewed journal. Study results can be 
submitted for presentation at a congress before submission to a peer-reviewed journal. 
The Coordinating Investigator, 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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14 APPENDICES 
Appendix 1 
Central laboratory abnormalities and alert flags  
The adult ranges below are valid at the time of protocol finalization. Any changes to these 
ranges during the course of the study will be reflected in the ranges displayed in the 
laboratory reports sent from the central laboratory to the investigational sites. 
Laboratory abnormalities 
Laboratory values below or above the normal range will be graded at three levels (H, HH, 
HHH for values above normal range and L, LL, LLL for values below the normal range) 
where L stands for “low”, H for “high”. 
The term “marked abnormality” describes laboratory values with grading of abnormalities 
at two levels: LL/HH and LLL/HHH. These thresholds have been defined by the sponsor 
in order to flag and/or communicate abnormal laboratory results from the central laboratory 
to the investigators, and for the purpose of standardized data analysis and reporting by the 
sponsor. The definitions of marked abnormal values are based mainly on the Common 
Terminology Criteria for Adverse Events (CTCAE) [CTCAE 2010] grading system and, 
in specific cases (e.g., lymphocyte levels), are adjusted based on the known 
pharmacodynamic effect of the study drugs (e.g., LLL threshold for lymphocytes).  
The term ALERT here corresponds to a protocol-defined test result threshold requiring an 
action from the investigator as described in the protocol (e.g., repeat the test; interrupt or 
discontinue the study drug) and should not be confused with the term “call alert” used by 
the central laboratory for laboratory results, which will be communicated to the 
investigator. Not all ALERTS listed in this table will be “call alerts” from the central 
laboratory and vice versa. 
PLEASE NOTE: Thresholds for abnormality of level L or H are not provided in this 
appendix but will be provided in the central laboratory manual. Parameters for which no 
threshold is defined in Table 5 may be defined in the central laboratory manual.  
 


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Table 5 
Thresholds for marked laboratory abnormalities 
Parameter (SI unit) 
LL 
LLL 
HH 
HHH 
Hemoglobin (g/L) 
< 100  
ALERT:  
< 100 (re-test)  
 
< 80 
ALERT:  
< 80 (re-test)  
 
Increase in > 20 g/L 
above ULN or above 
baseline (if baseline is 
above ULN) 
Increase in > 40 g/L above 
ULN or above baseline (if 
baseline is above ULN) 
MCH (pg/Cell) 
ND 
ND 
ND 
ND 
MCV (fL) 
ND 
ND 
ND 
ND 
Hematocrit (L/L) 
< 0.28 (female) 
< 0.32 (male) 
< 0.20 
> 0.55 (female) 
> 0.60 (male) 
> 0.65 
Platelet count (109 /L) 
< 75  
< 50 
 
> 600 
> 999 
 
 
Eythrocyte count (1012 /L) 
ND 
ND 
ND 
ND 
Leukocyte count (109 /L) 
NA 
< 1.9 
> 20.0 
> 100.0 
Lymphocyte (109 /L) 
ND 
< 0.2 
> 4.0 
> 20 
Neutrophils (109 /L)  
< 1.5  
< 1.0 
 
ND 
ND 
Eosinophils (109 /L)  
ND 
ND 
> 5.0 
ND 
Monocytes (109 /L) 
ND 
ND 
ND 
ND 
Basophils (109 /L) 
ND 
ND 
ND 
ND 
Polymorphonuclear leucocyte/Band cells (%) 
ND 
ND 
> 90% 
> 95% 
AST (U/L)* 
ND 
ND 
≥ 3 ULN 
ALERT:  
≥ 3 ULN (exclusion at 
baseline or re-test) 
 
≥ 5 ULN 
ALERT:  
≥ 5 ULN (re-test) 
≥ 8 ULN (discontinuation) 


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Parameter (SI unit) 
LL 
LLL 
HH 
HHH 
ALT (U/L)* 
ND 
ND 
≥ 3 ULN 
ALERT:  
≥ 3 ULN (exclusion at 
baseline or re-test) 
 
≥ 5 ULN 
ALERT:  
≥ 5 ULN (re-test) 
≥ 8 ULN (discontinuation) 
Total bilirubin (umol/L) 
ND 
ND 
≥ 2 ULN  
ALERT:  
≥ 2 ULN combined 
with ALT or AST ≥ 3 
ULN (discontinuation) 
≥ 5 ULN 
 
 
Alkaline Phosphatase (U/L) 
ND 
ND 
> 2.5 ULN 
> 5 ULN 
INR* 
ND 
ND 
≥ 1.5 ULN or 
≥ 1.5 × above baseline if 
on anticoagulation 
≥ 2.5 ULN or 
≥ 2.5 × above baseline if 
on anticoagulation 
 
Lactate dehydrogenase 
ND 
ND 
ND 
ND 
Creatinine (umol/L)* 
ND 
ND 
>1.5 ULN or >1.5  
baseline  
> 3 ULN or >3 × baseline 
 
eGFR (mL/min/1.73 m2) 
< 60  
< 30  
ALERT: < 30 
(exclusion at baseline)  
ND 
ND 
Urea (mmol/L) 
ND 
ND 
> 2.5 ULN 
> 5 ULN 
Albumin (g/L) 
< 30  
ALERT: < 30 
combined with total 
protein < 50 
(exclusion at baseline) 
< 20 
ND 
ND 
Protein total (g/L) 
ND 
ND 
ND 
ND 
C-reactive protein (mg/L) 
ND 
ND 
ND 
ND 
Glucose (mmol/L) 
< 3.0 
< 2.2 
> 8.9 
>13.9 


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Parameter (SI unit) 
LL 
LLL 
HH 
HHH 
Potassium (mmol/L) 
< 3.2 
< 3.0 
> 5.5 
> 6.0 
Sodium (mmol/L) 
ND 
< 130 
> 150  
> 155  
Calcium (mmol/L) 
< 2.0  
< 1.75 
> 2.9 
> 3.1 
Chloride (mmol/L) 
ND 
ND 
ND 
ND 
Triglyceride (mmol/L) 
ND 
ND 
> 3.42 
> 11.4 
Cholesterol (mmol/L) 
ND 
ND 
> 7.75 
> 12.92 
Serum pregnancy test 
ND 
ND 
ND 
Positive 
ALERT:  
Positive 
* HH and HHH based on CTCAE 2010 v4.03 [CTCAE 2010] 
 
ALERT = study-specific alerts that trigger specific actions by the investigator [see Section 5.1.11]; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = International Normalized Ratio; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; may be complemented by definitions provided by the 
central laboratory (see central laboratory manual); NA = not applicable; ND = not defined; SI = international system of units; ULN = upper limit of normal. 


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Appendix 2 
Echocardiography  
Image optimization 
• Using maximal frequency to increase axial resolution  
• Reducing sector width to area of interest in order to increase frame rate. 
• Reducing depth to increase size of image on the screen. 
• Bringing focus at point of interest to increase lateral resolution 
• Adjusting time gain compensation in order to optimize the distribution of gain at 
different penetration depths 
• Optimizing gain and resolution to identify endocardial borders and structures 
2D Biplane Simpson method 
The Simpson method assumes that the ventricle is cylindrical in shape, which may not 
apply to a univentricular heart. The Simpson method will split the trace of the ventricle 
into sections from the apex to the mitral valve. The volume of each section is calculated by 
multiplying the diameter and the thickness of the slice. The volume of each section is then 
summed to calculate the total left ventricle volume. It is more accurate to carry out a 
Simpson measurement in two planes (apical 4 chamber and apical 2 chamber). If done in 
a single plane it is assumed that the ventricle is circular at each level. By carrying out a 
Simpson measurement in both the apical 4 and 2 chamber views, the cross-sectional area 
of each section can be more accurately measured [Leeson 2012]. 
Apical 1 chamber view  
The apical 1 chamber view is obtained by placing the probe at the apical window, which is 
usually located on the anterior axillary line in the fifth intercostal space. The image 
obtained should show the chambers at their maximum size and clear images of the 
infero-septal and antero-lateral walls with optimized views of the endocardial borders.  
The ventricular diastolic volume is obtained using the Simpson method: 
The end diastolic frame is selected using ECG identification of the R wave. 
The endocardial border is then traced from where the basal systemic ventricle wall meets 
the systemic valve’s annulus of the septal wall, to where the basal systemic ventricular wall 
meets the systemic valve’s annulus of the antero-lateral wall. 
The ventricular systolic volume is obtained using the Simpson method: 
The end systolic frame is selected using ECG identification of the end of the T wave. 


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The endocardial border is then traced from where the basal systemic ventricular wall meets 
the systemic valve’s annulus of the septal wall, to where the basal systemic ventricular wall 
meets the systemic valve’s annulus of the antero-lateral wall. 
The stroke volume is the volume of blood ejected from the heart at end-systole. It is 
calculated by: 
• Systemic ventricle diastolic volume (mL) − systemic ventricle systolic volume 
(mL) = stroke volume(mL) 
The ejection fraction is the percentage change in systemic ventricle volume divided by the 
initial volume [Otto 2002]. This is calculated by: 
• (Systemic ventricle diastolic volume (mL) − systemic ventricle systolic volume 
(mL))/ systemic ventricle systolic volume × 100 = ejection fraction (%) 
The first of the atrial volumes are also measured in this frame using the area length method. 
The border of the atrium is traced starting from the one side of the AV valve annulus, 
following the contour of the atrial wall, and finishing at the other side of the valve annulus.  
Apical 2 chamber view 
To obtain the apical 2 chamber view, begin with the apical 1 chamber image. The probe is 
then rotated to around 90 degrees in an anticlockwise direction, just before the left 
ventricular outflow tract is shown. The mitral valve should be kept in the same place and 
the image shouldn’t be foreshortened. The image should then be optimized so clear 
endocardial borders can be seen. 
The ventricular diastolic volume is obtained using the Simpson method: 
The end diastolic frame is selected using ECG identification of the R wave. 
The endocardial border is then traced from where the basal systemic ventricular wall meets 
the systemic valve’s annulus of the inferior wall, to where the basal systemic ventricular 
wall meets the systemic valve’s annulus of the anterior wall. 
The ventricular systolic volume is obtained using the Simpson method: 
The end systolic frame is selected using ECG identification of the end of the T wave. 
The endocardial border is then traced from where the basal systemic ventricular wall meets 
the systemic valve’s annulus of the inferior wall, to where the basal systemic ventricular 
wall meets the systemic valve’s annulus of the anterior wall. 
The following data will be obtained from this method: 


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• Systemic ventricle diastolic volume (SVDV) 
• Systemic ventricle systolic volume (SVSV) 
• Stroke volume (mL)  
• Ejection fraction.  
Those measurements will then form the biplane SVDV, SVSV, stroke volume and ejection 
fraction results.  
The second of the atrial volumes are also measured in this frame, again using the area 
length method. The border of the atrium is traced starting from the one side of the AV valve 
annulus, following the contour of the atrial wall, and finishing at the other side of the valve 
annulus.  
Three Chamber apical view 
The probe is rotated a further 30 degrees anticlockwise beyond the apical 2 chamber view 
to bring the left ventricular outflow tract into view and to display the anterolateral and 
anterior walls of the ventricle. 
Cut-off values for valvular defects  
Severe AV valve regurgitation is present where the vena contracta is ≥ 7 mm and/or the 
effective regurgitant orifice is ≥ 0.4 cm2. 
Presence of left ventricular outflow obstruction is confirmed by a pulsed-wave Doppler 
velocity > 2.5 m/s.  
Sources: [AHA/ACC Guideline 2014], [Silversides 2010], [ESC Guidelines 2014]. 
 
 


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Appendix 3 
Cardiopulmonary exercise testing 
 
Important instructions: 
These instructions must be followed for the conduct of the study and supersede any local guidelines for 
conducting cardiopulmonary exercise testing (CPET). Any deviation from the guideline for the conduct of 
CPET must be reported to Actelion.  
Conditions should be in line with the protocol. Baseline conditions (e.g., same device, about the same time of 
the day, etc.) for a patient should apply for subsequent tests as much as possible to minimize variability. 
 
General instructions: 
CPET is to be carried out within the Cardiology Departments or a dedicated research lab of the hospital/clinic. 
 
 
1. Prior to the test, eligibility of the patient for CPET needs to be confirmed (including confirmation of adherence 
to local safety regulations). 
 
2. Staffing  
A minimum of two members of staff are needed for a technician-led CPET, consisting of either: 
• 
Two qualified cardiac physiologists/physiotherapists (or local equivalent).  
• 
A qualified cardiac physiologist/physiotherapist (or local equivalent) and a student who has been 
signed off on exercise testing. 
• 
A qualified cardiac physiotherapist (or local equivalent)/supervising cardiologist.  
CPET led by a cardiologist may be performed without additional personnel. 
 
At least one member of staff must have been on a CPET course or have on the job training (leading the 
conduct of 25 or more CPET assessments). The leading member of staff should be at least intermediate life 
support trained and the assisting member of staff should be at least be basic life support certified. 
 
3. Equipment 
The following equipment is needed during CPET: 
• 
Bicycle ergometer 
• 
Control unit to control the ergometer 
• 
Electrocardiogram (ECG) recording equipment with printer 
• 
Blood pressure measuring unit and/or manual sphygmomanometer with appropriate cuff sizes 
• 
Chair 
• 
Couch/exam table  
• 
Resuscitation equipment 
• 
Height measure and scales 
• 
Calibration gas 
• 
Masks/mouth pieces and flow meters with associated fittings of various sizes 
• 
Gas and flow analysis equipment 
• 
Pulse-oximetry monitor 
 
All equipment should be appropriately checked before a test is started; the resuscitation equipment should be 
checked once daily. 
 
4. Before a test is started 
The following tasks will need to be completed before a test is started: 
• 
The gas analysis unit should be allowed a minimum of 30 minutes warm-up time. 
• 
The temperature, barometric pressure and humidity should be calibrated against the monitor 
mounted on the control unit. 
 


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5. Before the test 
• 
The gas analysers and flow meter used for this patient should be calibrated before start (best practice 
is that this occur within 10 minutes of the start of data collection). Calibration reports should be printed 
and kept in the site file. 
• 
The patient’s data should be entered into the control unit. 
• 
The patient’s identity should be confirmed. 
• 
The patient’s height and weight should be measured. 
• 
The patient should be encouraged to ask any questions(s) he might have about the test, which need 
to be answered as accurately as possible. 
• 
Explain the rating of the perceived exertion using the Borg scale to the patient. 
• 
A non-verbal sign for stopping the test should be agreed upon with the patient. 
• 
Ensure that the patient wears suitable/non-restrictive clothing for the test (e.g., no jeans, no sandals, 
not multiple layers of clothing) 
• 
ECG leads should be attached: 
 
Prepare the skin: shave if necessary, remove skin oils with a cleansing solution followed by light 
abrasion. If possible, check that the electrode impedance is as low as possible. 
 
Do not use baby wipes if the patient has eczema or dry skin as this might damage the skin further 
and is unlikely to decrease the skin-to-electrode impedance in these patients.  
 
Attach ECG electrodes to the patient’s skin using the modified Mason-Likar positions. (The 
electrodes normally placed on the extremities should be placed on the torso instead.) 
 
Female patients should be encouraged to wear a brassiere during exercise even if this has been 
removed to aid electrode positioning.  
 
• 
A blood pressure cuff should be place on the patient’s arm making sure that the diaphragm is 
positioned directly over the brachial artery.  
• 
A mask should be fitted to the patient’s face, making sure there are no leaks between the patient’s 
skin and the mask. The calibrated flow meter and the sampling line should be attached to the mask. 
Alternatively, a mouthpiece can be used.  
• 
A protocol should be chosen based on the patient’s ability to exercise.  
 
6. Data storage (full disclosure); keep original test measurements for transfer to central reading facility. 
 
 
 


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Patient dialogue 
 
 
Patient Consent  
 
Ensure written patient consent has been obtained before testing. 
The reason for the CPET should be clearly explained, including the risks and benefits of the test.  
The patient should be told that they are required to give “maximal effort”.  
They should be warned that they may feel discomfort, particularly close to maximal exertion.  
It should be explained that the test can be stopped at any time if the patient feels “extreme breathlessness, 
chest pain, light-headed, or nauseated”. 
 
The testing protocol should be briefly outlined to the patient: 
 
“This is an exercise test that requires maximal effort. The more effort you put in, the more information we will 
obtain. The test will begin with a collection of resting measurements, including a breathing test with no 
pedaling. You will then go into the exercise task and be asked to pedal at approximately 55–65 rpm. After a 
3-minute warm up, every minute the workload (resistance) will increase with pedaling becoming more difficult 
until you won’t be able to continue.”  
 
Patient information: 
 
“We expect that the test will take 6–12 minutes. It is usually only hard during the last few minutes when we 
collect the most important data. Throughout the test we want you to pedal between 55–65 rpm. During the 
test we will be taking your blood pressure and monitoring your heart rhythm to make sure it is safe to keep 
exercising. When the test has finished we want you to ride for another 5 minutes at a very low workload to 
help your body recover from the exercise. In the 5 minutes of recovery we will take the mask/mouthpiece off 
after 30 seconds but keep on the electrodes to measure heart beat and ECG reactions.”  
 
“If at any stage you feel any major discomfort such as strong chest pain, severe leg pain or nausea, let us 
know (we will keep checking with you) and we will stop the test. Otherwise, carry on pedaling until your legs 
or breathing prevents you from continuing. We will be asking you to indicate on a scale how short of breath 
you are and how tired your legs are.” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Standard operating procedure for a CPET assessment with a bicycle 
 
 
1. 
Physical measurements 
o 
Height (measure without shoes)  
o 
Weight (measure without shoes and with light clothing) 
2. 
CPET on bicycle with ergometry, ECG registration and blood pressure measurement. 
o 
Connect gas analyser and perform local calibration protocol before every CPET 
o 
Make sure patient cannot see the amount of Watt during cycling. Rotation per minute (rpm) 
should be visible. 
3. 
Test protocol for peak oxygen uptake (VO2): 
o 
Basic spirometry should be performed to measure the Forced Expired Volume over 1 
second (FEV1), which will then be used to calculate breathing reserve. 
o 
Allow patient to acclimatize for 3 minutes 
o 
During this time, collect gas exchange data to ensure the patient shows physiologic 
response. 
o 
Measure baseline blood pressure and heart rate (HR) while sitting on the bicycle 
o 
Cycle for 3 minutes at 10 Watt with an rpm between 55–65 
o 
Optimal test duration 6–12 minutes  
 
Choose individualized continuous RAMP protocol  
RAMP 60 (every minute 6 watt is added) 
 
RAMP 90 (every minute 9 watt is added) 
 
RAMP 120 (every minute 12 watt is added) 
 
Etc. 
o 
Use the same protocol at every test 
o 
Start RAMP and let patient cycle between 55–65 rpm 
Terminate the test when exhausted:   
o 
Aim to surpass the anaerobic threshold (ventilatory threshold 2/respiratory compensation 
point = rise of VE/VCO2)  
o 
Aim at RER > 1.1 
o 
Aim at Borg scale (6–20) > 17 
4. 
After termination of the test, let the patient cycle for 5 minutes at 10 Watt  
o 
Register reason for test termination and Borg score 
o 
Register HR after 1 minute (HR recovery) 
5. 
Keep original test measurements for transfer to core center.  
o 
Complete the CPET worksheet, and if needed the tabular data report for the core center. 
o 
Complete the source document for investigational sites with appropriate parameters, 
including resting VO2, peak VO2, RER at max, and breathing reserve. 
o 
Peak VO2 = mean of highest 30-sec measurement. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Borg-RPE-Scale®  
Perceived exertion 
 
We want you to rate your perception of exertion, i.e., how heavy and strenuous the exercise feels 
to you. This is mainly felt as strain and fatigue in your muscles and as breathlessness or possible 
aches. Try to be as honest as you can. Don’t think about the actual physical load. It is your own 
feeling of effort and exertion that is important. Don’t underestimate it, but don’t overestimate it 
either. Look at the scale and the expressions and then give a number. Use whatever numbers you 
want, also numbers between the expressions. 
 
 
 
                                                                                              
 
 


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Appendix 4 
Specific Activity Scale 
 
 
 
Modified from [Goldman 1981]. 


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Appendix 5 
Tanner stages (self-assessment) 
This assessment is only needed for girls who have not had their menarche. 
Instructions for the patient 
“Look at the pictures and read the descriptions in the images below. Think about which 
stage fits best with your own body and tick the box next to that stage.” 
 
 
 
Modified from [Rasmussen 2015]  


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Appendix 6 
Comparison of RUBATO procedures versus standard of care: comparison of burden and risks 
SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
Patients’ status 
  
  
  
  
Anamnesis, clinical  
& physical examinations 
(yearly or bi-yearly) 
4 site visits at a 
specialized cardiologist 
during a 14 month 
period. 
 
More frequent 
monitoring. 
Content of anamnesis 
and physical 
examination not more 
bothersome. 
No invasive 
procedures. 
  
Reduced risk, as more 
frequent visits could 
detect earlier signs of 
deterioration. 
Burden is reduced to a 
minimum and contributes to 
significant risk reduction (4 
site visits over 12 months in 
RUBATO, versus 1 or 2 for 
SoC). 
The significantly reduced 
natural disease evolution risks 
outweigh the inconvenience of 
more frequent visits.  
Electrocardiogram 
(yearly or bi-yearly) 
Once at the beginning 
of the study (and 3 
times, i.e., with each 
CPET) over 14 months. 
Performed outside of 
the CPET assessment. 
= 
Performed during the 
CPET: See CPET. 
= 
Same burden and same risk as 
SoC. 


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SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
Worsening/morbidity event 
assessment 
(yearly or bi-yearly) 
6 times (clinically) 
over 14 months. 
Monthly (clinically) for 
10 months, for liver 
enzymes and 
hemoglobin. 
 
More frequent 
monitoring visits. 
Content of physical 
examinations and 
anamnesis not more 
bothersome. 
No invasive 
procedures. 
 
Reduced risk: more 
frequent visits could 
detect earlier signs of 
deterioration. 
More frequent visits 
could detect adverse 
signs of tolerability or 
safety. 
Burden is reduced to a 
minimum and contributes to 
significant risk reduction (5 
visits over 12 months in 
RUBATO, versus 1 or 2 for 
SoC). 
The reduced study and natural 
disease evolution risks 
outweigh the inconvenience of 
more frequent visits.  
Adverse Events & Serious Adverse 
Events reporting 
Mandatory 
AE and SAE reporting 
likely more systematic 
during RUBATO. 
= 
Reporting of AEs or 
SAEs does not affect 
the patient 
 
Indirect risk reduction 
for each patient, as s/he 
could benefit from the 
experience provided by 
other patients in the 
study. 
No burden for the patients, but 
reduced risks. 
 
 
 


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SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
Imaging 
  
  
  
  
Echocardiogram (yearly) 
2 times over 14 
months. 
= 
Same monitoring in 
RUBATO. 
= 
Same burden and same risk as 
SoC. 
Exercise capacity 
  
  
  
  
NYHA Functional class (yearly) 
At each visit 
The Specific Activity 
Scale is used as an 
additional guideline. 
= 
The Specific Activity 
Scale questionnaire 
does not take much 
more time than asking 
for the NYHA 
Functional Class. 
 
The Specific Activity 
Questionnaire is a 
more systematic (and 
more objective) 
evaluation. It should 
reflect the 
investigator’s opinion, 
and therefore should 
avoid bias by patients 
who tend to 
underestimate their 
FC. 
Burden is reduced to a 
minimum and the test is more 
objective. 


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Protocol AC-055H301, RUBATO 
Final Version 10 
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Confidential 
EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
CPET (between twice a year to not 
necessarily every year) 
4 times over 14 
months. 
 
It is necessary to 
document the primary 
efficacy variable. 
 
Regular performance 
of CPET provides a 
detailed evaluation 
(including ECGs) of 
patient’s improvement 
or deterioration. 
Extra burden contributes to 
significant risk reduction by 
having a more frequent and 
thorough assessment of the 
patients’ exercise capacity.  
QoL questionnaires 
 
 
 
 
Patient interview (at regular visits) 
 up to 4 times 2–5 
questions over 14 
months. 
= 
Regular discourse on 
how the condition 
affects every day life 
is part of the 
interview, and 
although frequency is 
higher, the number of 
replies is minimal. 
 
Using a tool to 
consistently capture 
QoL at more frequent 
intervals provides a 
granular evaluation of 
patient’s improvement 
or deterioration. 
Using a tool to consistently 
capture QoL across sites and 
over time will help establish a 
baseline for the Fontan 
population in general. 
 
 
 
 
 
 


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Final Version 10 
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Doc No D-20.425 
 
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SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
Blood tests  
  
  
  
  
Many blood parameters are 
surveyed 
(yearly or bi-yearly) 
Comprehensive set of 
parameters are 
monitored in 
RUBATO. 
4 times over 14 
months 
 
More frequent 
monitoring blood tests 
= 
Content of blood tests 
not more bothersome 
 
Reduced risk, as more 
frequent, more 
systematic blood tests 
could detect earlier 
signs of deterioration 
Burden is reduced to a 
minimum and contributes to 
significant risk reduction by 
providing more frequent 
results on disease progression. 
The reduced study and natural 
disease evolution risks 
outweigh the inconvenience 
of more frequent visits.  
Is not universally (but increasingly) 
used as SoC 
NT-ProBNP 
4 times over 14 
months 
= 
Blood collected for 
NT-ProBNP does not 
add burden, as it does 
not entail more 
frequent collection, 
nor more blood 
collected at each blood 
draw. 
 
Reduced risk, as it 
may help assess early 
progression / 
improvement of heart 
failure 
No extra burden for the 
patients, but reduced risks. 
SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 


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Final Version 10 
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EudraCT 2016-003320-23 
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Is not (yet) SoC 
Cystatin-C 
4 times over 14 
months 
= 
Blood collected for 
Cystatin-C does not 
add burden, as it does 
not entail more 
frequent collection, 
nor more blood 
collected at each blood 
draw. 
 
Reduced risk, as it 
may help avoid a 
biased assessment 
(due to a likely 
decreased muscular 
mass of the patients) 
of the Glomerular 
Renal Function.   
No extra burden for the 
patients, but reduced risks. 
 
 


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Final Version 10 
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SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
Blood tests  
  
  
  
  
Liver function related common 
blood parameters 
Will be controlled 
monthly for the first 
6 months and then 
every 3 months until 
Week 52, 
 
More frequent, 
systematic monitoring. 
 
Reduced risk, as it 
may help detect early 
progression or liver 
fibrosis and or 
cirrhosis. 
Burden is reduced to a 
minimum (local blood draw 
allowed) and contributes to 
significant risk reduction by 
providing more frequent 
results on disease progression. 
The reduced study and natural 
disease evolution risks 
outweigh the inconvenience 
of more frequent visits.  
Alpha fetoprotein (may not be 
performed systematically enough) 
4 times over 14 
months. 
No invasive 
procedures. 
 
More frequent, 
systematic monitoring. 
 
Reduced risk, as it 
may give early 
information about liver 
carcinoma. 
Burden is reduced to a 
minimum and contributes to 
significant risk reduction by 
providing more frequent 
results on disease progression. 
The reduced study and natural 
disease evolution risks 
outweigh the inconvenience 
of more frequent visits.  


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Final Version 10 
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EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
Macitentan and metabolite 
Pharmacokinetics 
(PK) of macitentan 
and metabolites. 
 
These are not routine 
blood monitoring tests. 
The only burden 
involved are 2 extra 
venipunctures. 
 
Reduced risk, as it 
provides information 
that is yet unknown in 
patients with Fontan-
palliation. 
No macitentan PK 
data are currently 
known from 
adolescents. 
Some extra burden justified 
by the necessity to collect 
specific PK data in 
adolescents and adults being 
administered macitentan in 
Fontan-palliated patients. 
No PK data in in Fontan 
patients exist, so far. 
 
 
 


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Final Version 10 
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EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
Medicinal treatment 
  
  
  
  
There are no approved specific 
drug treatments available for the 
Fontan-palliated condition. Many 
medications, although neither 
approved for this condition nor 
confirmed for their benefit / risk, 
are commonly chronically 
administered to Fontan-palliated 
patients 
Same as for SoC + 
study drug 
Only the medications 
listed in forbidden 
medications are 
excluded. 
= 
= 
Same burden and same risk as 
SoC. 


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Final Version 10 
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EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
 
Study treatment 
interruption is allowed 
for a length of up to 
4 weeks 
= 
= 
Same burden and same risk as 
SoC. 
The extension of the allowed 
interruption from 2 to 
4 weeks provides more 
opportunity for subjects (who 
had a study treatment 
interruption) to resume study 
medication and continue to 
potentially benefit from it. 
Increased potential overall 
benefit with no expected 
negative impact on 
compliance (neither for adults 
nor adolescents). 


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Final Version 10 
19 November 2020, page 156/171 
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EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
Examples of these medications: 
  
  
  
  
Anti-aggregates or anticoagulants 
Allowed in RUBATO. 
Concomitant 
medications (with 
doses) are recorded at 
each visit. 
= 
= 
Same burden and same risk as 
SoC. 
Antiarrhythmics 
Allowed in RUBATO. 
Concomitant 
medications (with 
doses) are recorded at 
each visit.  
= 
= 
Same burden and same risk as 
SoC. 
Medical heart failure therapy, etc.  Allowed in RUBATO. 
Concomitant 
medications (with 
doses) are recorded at 
each visit.  
= 
= 
Same burden and same risk as 
SoC. 
Not part of SoC 
Medications triggering 
a drug-drug-
interaction with 
macitentan 
Not allowed in 
RUBATO. 
= 
Exclusion at baseline 
or forbidden 
concomitant 
medications. 
Concomitant 
medications (with 
 
This is to reduce the 
risk of DDI. 
If patients have 
potential drug 
interactions then they 
are excluded from the 
study. 
No extra burden for the 
patients, but reduced risks. 
These patients are not 
included in the study. 


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Final Version 10 
19 November 2020, page 157/171 
Confidential 
EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
doses) are recorded at 
each visit. 
 
 
 


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Protocol AC-055H301, RUBATO 
Final Version 10 
19 November 2020, page 158/171 
Confidential 
EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
Non-medicinal treatment 
 
  
  
  
  
Pacemaker 
Not allowed 
Patients with 
pacemakers are 
excluded from 
RUBATO, because it 
may interfere with the 
interpretation of the 
primary efficacy 
endpoint. 
No burden 
No risk 
Patients with 
pacemakers are 
excluded from study. 
These patients are not 
included in the study. 
Implanted defibrillators 
Allowed 
No burden 
No risk 
  


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Final Version 10 
19 November 2020, page 159/171 
Confidential 
EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
Life-Style recommendations 
  
  
  
  
Contraception (pregnancies advised 
only in rare cases) 
Initial blood 
pregnancy tests. 
Monthly urine tests. 
These tests are needed 
because macitentan, 
like all ERAs, is 
teratogenic 
(teratogenicity is a 
class effect of ERAs). 
Blood and urine 
pregnancy tests are 
needed to ascertain the 
compliance with the 
contra-indication. 
 
One initial blood test. 
Content of blood test 
not more bothersome. 
 
Monthly urine tests 
constraining. 
 
This is to reduce the 
risk of an undesired 
pregnancy, which in 
addition to mitigating 
the inherently 
increased risks due to 
a pregnancy in Fontan-
palliated patients, 
helps reduce the risk 
of a child’s congenital 
defects. 
Burden is reduced to a 
minimum and contributes to 
significant risk reduction by 
providing frequent 
confirmation of non-
pregnancy. 
Childbearing potential 
Self-assessment of 
puberty by Tanner 
stage (only for female 
pre-pubescent 
subjects) 
= 
Regular evaluation at 
site visits is not more 
constraining than 
answering a few 
questions. 
 
This is to reduce the 
risk of an undesired 
pregnancy, while 
ensuring contraceptive 
measures are only 
imposed on those who 
need them. 
Burden is small as it is a self-
assessment ensuring the 
subject’s privacy, while 
ensuring that appropriate 
contraceptive measures are 
initiated when necessary. 


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Final Version 10 
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EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
Participate in regular exercise 
Formal training 
program excluded. 
There are no 
recommendations for 
performance of 
physical exercise. 
This is entirely at the 
discretion of the 
patients. 
Daily physical 
activities recorded by 
accelerometer. 
= 
Needed to evaluate the 
secondary efficacy 
endpoint. 
This is a passive (non-
invasive) assessment 
performed for 4 visits, 
with 9-day sampling 
periods. 
This shall not be more 
constraining than 
wearing a “fitbit” type 
of activity device that 
are very commonly 
used by many people. 
 
Shall provide patients 
(once study is 
finished) with 
objective information 
on their lifestyle that 
could help implement 
corrective measures (if 
insufficient physical 
exercise is detected) or 
reinforce and 
encourage further 
activity (in case of 
adequate exercise 
regimen). 
Very limited extra burden 
justified by the necessity to 
collect daily spontaneous 
physical activity. 
Results may contribute to 
motivate individual patients 
to exercise more. 
Collectively these results may 
document recommendations 
for physical activity in 
Fontan-palliated patients. 
AE = adverse event; CPET = cardiopulmonary exercise testing; DDI = drug-drug interaction; ERAs = endothelin receptor antagonists; FC = functional 
class; NT-ProBNP = N-terminal prohormone of brain natriuretic peptide; NYHA = New York Heart Association; PK = pharmacokinetic(s); SAE = serious 
adverse event; SoC = standard of care; 


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Final Version 10 
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Confidential 
EudraCT 2016-003320-23 
Doc No D-20.425 
 
 
Appendix 7 
Disease Severity and Impression of Change questionnaires 
General Instructions 
Questionnaires are completed at the beginning of visits by patients (PGA-S and PGI-C) and 
clinicians (CGI-S and CGI-C) prior to any study assessment. Clinicians rely on patient interviews 
rather than assessments performed during past visits to complete the CGI-S and CGI-C. 
• 
Disease severity questionnaires (PGA-S and CGI-S) are completed at the beginning of each 
visit from Randomization (Visit 2) to Week 52 (Visit 6), or EOT in case it occurs prior to 
Week 52. 
• 
Impression of change questionnaires (PGI-C and CGI-C) are completed at the beginning 
of each visit from Week 16 (Visit 4) to Week 52 (Visit 6), or EOT in case it occurs prior to 
Week 52. 
 
7.1 Questionnaires to be answered by the subject 
The following questions refer to symptoms (e.g. shortness of breath) and impact (e.g. effort to 
perform daily activities) you may experience due to your heart condition. 
 
 


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Patient Global Assessment of Disease Severity (PGA-S) 
Please choose the response that best describes the overall severity of your symptoms and 
impact you may have experienced due to your heart condition over the past 7 days (week).  
(Check one response) 
 
 None 
 
 Mild 
 
 Moderate 
 
 Severe 
 
 
 


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Final Version 10 
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CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
Patient Global Impression of Change (PGI-C) 
Please think about the symptoms and impacts you may have experienced due to your heart 
condition over the past 7 days (week). Choose the response that best describes the change in 
overall severity of your symptoms and impact compared to the week before you started 
treatment.  
(Check one response) 
 
 Very Much Better 
 
 Moderately Better 
 
 A Little Better 
 
 No Change 
 
 A Little Worse 
 
 Moderately Worse 
 
 Very Much Worse 
 
 
 


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Protocol AC-055H301, RUBATO 
Final Version 10 
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Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
7.2 Questionnaires to be answered by the investigator 
The following questions refer to symptoms (e.g. shortness of breath) and impact (e.g. effort to 
perform daily activities) that the patient may have experienced due to their Fontan-palliated 
condition. 
 
 
Clinician Global Impression of Severity (CGI-S) 
Please choose the response that best describes the overall severity of the patient’s symptoms 
and impact due to their Fontan-palliated condition over the past 7 days (week). (Check one 
response) 
 None 
 
 Very mild 
 
 Mild 
 
 Moderate 
 
 Severe 
 
 Very severe 
 
 


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Final Version 10 
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Confidential 
EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
Clinician Global Impression of Change (CGI-C) 
Please think about the symptoms and impact the patient may have experienced due to their 
Fontan-palliated condition over the past 7 days (week). Choose the response that best describes 
the change in overall severity of the patients’ symptoms and impact compared to the week 
before the patient started treatment. (Check one response)  
 Very Much Better 
 
 Moderately Better 
 
 A Little Better 
 
 No Change 
 
 A Little Worse 
 
 Moderately Worse 
 
 Very Much Worse 
 
 


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Protocol AC-055H301, RUBATO 
Final Version 10 
19 November 2020, page 166/171 
Confidential 
EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
Appendix 8 
EQ-5D-5L questionnaire 
 
General Instructions 
Questionnaires are completed at the beginning of visits by subjects. 
• 
The EQ-5D-5L questionnaires are completed at Randomization (Visit 2), Week 16 (Visit 4) 
and Week 52 (Visit 6), or EOT in case it occurs prior to Week 52.  
• 
If subjects enter the PTOP, the questionnaire will be also be completed over the phone 
using designated scripts. 
 


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EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 


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Final Version 10 
19 November 2020, page 168/171 
Confidential 
EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 


Macitentan / ACT-064992 
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Final Version 10 
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Confidential 
EudraCT 2016-003320-23 
Doc No D-20.425 
 
 
Appendix 9 
Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents. A summary of previous amendments is 
provided below. 
 
Amendment 
Date 
Main reason(s) 
1 
1 Feb 
2017 
FDA requests in the context of a special protocol 
assessment: relegating NT-proBNP to other endpoints and 
adding accelerometry as secondary endpoint, changing the 
imputation rule for the primary endpoint and extending the 
time window for collection of data, including adjustment 
for missing data in the sample size re-estimation, adding 
safety measures with regard to hypotension 
2 
26 Apr 
2017 
FDA request for vital status at study closure and reporting 
by ventricular dominance; Voluntary Harmonization 
Procedure 
(VHP) 
request 
for 
highly 
effective 
contraceptive measures for Europe and comparison of 
study assessments to standard of care 
3 
27 Jun 
2017 
Address restrictions for contraceptive use for European 
countries (France) not participating in the VHP  
4 
20 Feb 
2018 
Introduction of an open-label extension for subjects 
completing the double-blind study; change of Tanner 
stage to self-assessment; increase in allowed time for 
treatment interruption; addition of quality of life and 
pharmacoeconomic variables 
5 
27 Aug 
2018 
Address concerns from BfArM, regarding the new 
protocol template by reverting to initial safety monitoring 
modalities.  
Clarification of subjects’ medical care after study 
completion by confirming that the proposed open-label 
extension will be accessible to all subjects who complete 
the study, including those who were in the post-treatment 
observation period (PTOP). 


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CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
 
 
 
6 
19 Nov 
2018 
Implementation of Advisory Board recommendations to 
make the protocol more patient-centric by converting two 
site visits to phone calls; reducing the number of monthly 
safety labs; introducing a flying nurse service to reduce the 
time commitment for the study; updating contraception 
requirements for new countries. 
7 
18 Dec 
2019 
Replacing the blinded SSRE with an IA/unblinded SSRE; 
formal testing of secondary endpoints; introducing 
additional 
exploratory 
CPET 
endpoints; 
adding 
clarifications for contraceptive use and study completion; 
introducing use of estimands for the primary endpoint 
analyses. 
8 
15 Jul 
2020 
Updates to forbidden medication and concomitant therapy 
sections based on newly identified drug-drug interactions. 


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Doc No D-20.425 
 
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Appendix 10 Child-Pugh Score 
 
Adapted from Child-Pugh (2012), FDA 2003 
 
Hepatic encephalopathy scoring will be based on the following criteria: 
• Grade 0: normal consciousness, personality, neurological examination, and 
electroencephalogram. 
• Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 
5 cycles per second waves.  
• Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic 
waves.  
• Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, 
slower waves.  
• Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2–3 cycles 
per second delta activity.  
 
 


 
Actelion Pharmaceuticals Ltd 
Janssen Research & Development * 
 
Clinical Protocol 
 
COVID-19 Appendix 
 
Protocol Title 
Prospective, multi-center, double-blind, randomized, placebo-controlled, parallel-group 
study assessing the efficacy and safety of macitentan in Fontan-palliated adult and 
adolescent subjects 
 
 
 RUBATO 
 
Macitentan in Fontan-palliated subjects 
 
 
Protocol AC-055H301; Phase 3 
 
 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). 
 
Status: 
Approved  
Date: 
17 June 2020 
Prepared by: Actelion Pharmaceuticals Ltd   
Document number: 
D-20.158 
 
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL 
 
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. 
NCT03153137


COVID-19 Appendix  
 
JNJ-67896062/ACT-064992 Macitentan  
Clinical Protocol AC-055H301  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
2 
Status: Approved, Date: 17 June 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 study 
participants/subjects 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 subject management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgement of the 
investigator to protect the health and well-being of subjects and site staff. If, at any time, a subject’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, subjects will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Subjects 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 subjects on study 
intervention, including follow-up. Modifications to protocol-required assessments may be 
permitted via COVID-19 Appendix after consultation with the subject, investigator, and the 
sponsor. Missed assessments/visits will be captured in the clinical trial management system for 
protocol deviations. Discontinuations of study interventions and withdrawal from the study should 
be documented with the prefix “COVID-19-related” in the electronic case report form (eCRF). 
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 subject 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  
 
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Status: Approved, Date: 17 June 2020 
GUIDANCE SPECIFIC TO THIS PROTOCOL  
Subject Visits and Assessments 
If the regular site visit schedule cannot be maintained due to COVID-19-related restrictions, the 
site staff must discuss available options with the subject (eg, discontinuation of treatment vs 
performing visits by telephone) and document the decision in the subject’s chart. If the decision is 
made to remain in the study, the guidance below is to be followed: 
• 
General handling of surrogacy for on-site assessments performed remotely: 
If a visit is conducted remotely, information on any adverse event, serious adverse event, 
clinical worsening/morbidity event, NYHA functional class, and concomitant medication, as 
well as the EQ-5D-5L questionnaire, should be collected, and data recorded in the eCRF with 
the actual date of the telephone call documented. Information on physical examinations and 
vital signs may also be reported, if these have been conducted locally. These will be captured 
in the source notes and any relevant abnormalities reported as adverse events. 
• 
Handling of safety monitoring  
If medical oversight of safety assessments (including but not limited to laboratory values) 
cannot be performed and reviewed by the investigator, the investigator may decide to interrupt 
or discontinue study intervention if it is in the best interest of the subject. 
Options for conduct of safety laboratory assessments are described in protocol section 7.2.4.1 
and include laboratory samples taken at study site, at a satellite laboratory, collected via home 
healthcare (HHC) visits service (also known as “flying nurse service)”, or taken and analyzed 
locally.  
If in-(subject) person collection of safety assessments at the investigational study site is not 
possible, these alternative options continue to be valid.  
For women of childbearing potential, monthly pregnancy tests are required. If a subject cannot 
come to the site, the urine pregnancy tests provided to the site for on-site visits may be shipped 
(if allowed per local regulation) to the subject for use at home under guidance from the site.  
Laboratory samples that are missed or delayed due to the COVID-19 pandemic will be 
identified as issues in the clinical trial management system (CTMS) as “COVID-19-related 
issue” and/or as protocol deviations in the Medidata RAVE system (eCRF) as “COVID-19-
related protocol deviation”. 
• 
Handling of pharmacokinetic (PK) assessments 
Pharmacokinetic (PK) samples that cannot be collected at study site may either be collected 
at a local laboratory or via HHC. If samples are collected by HHC, a central laboratory kit 
will be used. Missed PK samples may be collected at another study site visit, provided that 
the subject is still under study treatment. 


COVID-19 Appendix  
 
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Status: Approved, Date: 17 June 2020 
• 
Handling of efficacy assessments 
If subjects cannot have their cardiopulmonary exercise testing (CPET) assessments conducted 
at the study site as expected, these CPET should be done at the earliest possibility during a 
scheduled or unscheduled visit. 
For Week 52, the CPET assessment could be conducted up to 8 weeks later and as long as 
subjects have not started open-label treatment. 
If a site visit cannot be conducted, devices for data collection of Physical Activity measured 
by Accelerometer (PA-Ac) may be shipped to study subjects (and returned to site by them) as 
already described for certain visits in the RUBATO Accelerometry Manual (as applicable to 
protocol V 7 and V 8). 
CPET or PA-Ac assessments that were missed specifically due to COVID-19 will be identified 
in the CTMS as “COVID-19-related issue” and/or as protocol deviations in the Medidata 
RAVE system (eCRF) as “COVID-19-related protocol deviation”.  
• 
Handling of safety and efficacy data integrity 
The study Independent Data Monitoring Committee (IDMC) will be provided with listings of 
COVID-19-related protocol deviations and will be asked to evaluate their impact on study 
safety and efficacy outcomes at the next IDMC meeting. 
In parallel, the sponsor will continue to monitor the COVID-19 related protocol deviations and 
evaluate their impact on study safety and efficacy outcomes. 
Study treatment supply 
• Every effort should be made to keep study subjects on treatment as deemed clinically 
appropriate. If a subject cannot come to the site to receive study treatment, the study treatment 
may be provided via a direct-to-patient shipment to the subject’s home or distributed to a 
subject’s relative/caregiver in accordance with local regulations.  
The subject will be asked to return empty study medications bottles / unused tablets at their 
next site visit. Treatment compliance will meanwhile be assessed via monthly phone calls. 
This distribution and shipment of study treatment will be done if the treating physician can 
ensure that they maintain subject safety oversight (based on clinical evaluation, results of 
laboratory tests and pregnancy test [if applicable] as described in the section above “Handling 
of safety monitoring”). 
Premature discontinuations from study treatment or from the study due to the COVID-19 pandemic 
will be documented in the Medidata RAVE system (eCRF) with the reason “COVID-19-related”.  
Source Data Verification/Monitoring 
• 
Site monitoring will, in general, be limited to remote monitoring until further notice; however, 
certain regions and countries may continue to have on-site monitoring at this time, as allowed 
per country COVID-19 guidance/travel restrictions. The Site Manager will be in contact with 
the study site to schedule the next remote or on-site monitoring visit. 


COVID-19 Appendix  
 
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Clinical Protocol AC-055H301  
 
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5 
Status: Approved, Date: 17 June 2020 
COVID-19 Illness in Subjects 
• 
The investigator should consider the risk/benefit of continuing study treatment based on the 
nature and status of the subject’s underlying condition and the potential risks associated with 
COVID-19. 
 
• 
Positive test results for COVID-19 as well as any associated symptoms should be recorded as 
adverse events, and if the subject is hospitalized in relation to COVID-19, the event should be 
captured as a serious adverse event.  
 
 


COVID-19 Appendix  
 
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Clinical Protocol AC-055H301  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
6 
Status: Approved, Date: 17 June 2020 
INVESTIGATOR AGREEMENT 
 
PPD
PPD

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 23 August 2021
Actelion Pharmaceuticals Ltd
Janssen Research & Development
Statistical Analysis Plan
Prospective, multi-center, double-blind, randomized, placebo-controlled, parallel-group 
study assessing the efficacy and safety of macitentan in Fontan-palliated adult and 
adolescent subjects
Protocol AC-055H301; Phase 3
JNJ-67896062/ACT-064992 (Macitentan)
Status:
Approved
Date:
23 August 2021
Prepared by:
Actelion Pharmaceuticals Ltd., a Janssen Pharmaceutical Company of Johnson &
Johnson
Document No.: EDMS-RIM-264216, 3,0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT03153137


JNJ-67896062/ACT-064992  (Macitentan)
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Status: Approved, Date: 23 August 2021
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 5
ABBREVIATIONS ........................................................................................................................................ 8
INTRODUCTION................................................................................................................................ 10
1.1.
Trial Objectives .............................................................................................................................. 10
1.2.
Trial Design .................................................................................................................................... 10
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 14
1.4.
Sample Size Justification ............................................................................................................... 15
1.5.
Randomization and Blinding .......................................................................................................... 16
1.5.1.
Randomization............................................................................................................................ 16
1.5.2.
Blinding ....................................................................................................................................... 16
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 17
2.1.
Visit Windows................................................................................................................................. 17
2.1.1.
Efficacy ....................................................................................................................................... 17
2.1.2.
Safety.......................................................................................................................................... 18
2.1.3.
Quality of life ............................................................................................................................... 18
2.2.
Analysis Sets.................................................................................................................................. 18
2.2.1.
Enrolled Analysis Set.................................................................................................................. 18
2.2.2.
Full Analysis Set ......................................................................................................................... 18
2.2.3.
Per-Protocol Analysis Set........................................................................................................... 18
2.2.4.
Safety Analysis Set..................................................................................................................... 21
2.2.5.
Pharmacokinetics Analysis Set .................................................................................................. 22
2.2.6.
Usage of the analysis sets.......................................................................................................... 22
2.3.
Definition of Subgroups.................................................................................................................. 22
2.4.
Study Day and Relative Day .......................................................................................................... 23
2.5.
Baseline, Relevant Time-points and Analyses Periods ................................................................. 23
2.5.1.
Baseline ...................................................................................................................................... 23
2.5.2.
Study treatment start date .......................................................................................................... 24
2.5.3.
Study treatment end date / End of Treatment (EOT) ................................................................. 24
2.5.4.
End of Study (EOS) .................................................................................................................... 24
2.6.
Imputation Rules for Missing/Incomplete dates and times fields................................................... 24
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 26
SUBJECT INFORMATION................................................................................................................ 27
4.1.
Demographics and Baseline Characteristics ................................................................................. 27
4.1.1.
Demographics............................................................................................................................. 27
4.1.2.
Baseline Disease Characteristics ............................................................................................... 28
4.2.
Medical history ............................................................................................................................... 29
4.3.
Disposition Information................................................................................................................... 30
4.3.1.
Screened Subjects and Screening Failures ............................................................................... 30
4.3.2.
Study and Study Treatment Disposition ..................................................................................... 31
4.3.2.1.
Study Treatment Discontinuation ............................................................................................ 31
4.3.2.2.
Study Discontinuation.............................................................................................................. 32
4.4.
Treatment Compliance................................................................................................................... 32
4.4.1.
Overall Compliance (up to EOT) ................................................................................................ 32
4.4.2.
Compliance (up to the Week 16) ................................................................................................ 33
4.5.
Extent of Exposure......................................................................................................................... 33
4.5.1.
Study Treatment Interruptions .................................................................................................... 33
4.5.2.
Study Treatment Duration and Exposure ................................................................................... 33
4.6.
Protocol Deviations ........................................................................................................................ 34
4.7.
Prior and Concomitant Medications ............................................................................................... 35


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4.7.1.
Prior Medications ........................................................................................................................ 35
4.7.2.
Study treatment concomitant medications.................................................................................. 35
EFFICACY ......................................................................................................................................... 36
5.1.
Analysis Specifications................................................................................................................... 36
5.1.1.
Level of Significance................................................................................................................... 36
5.1.2.
Data Handling Rules................................................................................................................... 39
5.2.
Primary Efficacy Endpoint(s).......................................................................................................... 39
5.2.1.
Definition..................................................................................................................................... 39
5.2.2.
Estimand..................................................................................................................................... 39
5.2.3.
Analysis Methods.......................................................................................................................... 40
5.2.3.1.
Hypotheses and statistical model............................................................................................ 40
5.2.3.2.
Handling of missing data for the main analysis....................................................................... 40
5.2.3.3.
Main analysis........................................................................................................................... 41
5.2.3.4.
Supportive/sensitivity analyses................................................................................................ 42
5.2.3.5.
Subgroups analyses ................................................................................................................ 46
5.3.
Secondary Efficacy Endpoints ....................................................................................................... 47
5.3.1.
Change from baseline over 52 weeks in peak VO2.................................................................... 47
5.3.1.1.
Definition.................................................................................................................................. 47
5.3.1.2.
Estimand.................................................................................................................................. 47
5.3.1.3.
Hypotheses and statistical model............................................................................................ 49
5.3.1.4.
Handling of missing data for the main analysis....................................................................... 49
5.3.1.5.
Main analysis........................................................................................................................... 50
5.3.1.6.
Supportive/sensitivity analyses................................................................................................ 50
5.3.1.7.
Subgroups analyses ................................................................................................................ 54
5.3.2.
Change from baseline to Week 16 in mean count per minute of daily PA-Ac............................ 54
5.3.2.1.
Definition.................................................................................................................................. 55
5.3.2.2.
Estimand.................................................................................................................................. 55
5.3.2.3.
Hypotheses and statistical model............................................................................................ 56
5.3.2.4.
Handling of missing data for the main analysis....................................................................... 56
5.3.2.5.
Main analysis........................................................................................................................... 56
5.3.2.6.
Supportive/sensitivity analyses................................................................................................ 57
5.3.2.7.
Subgroups analyses ................................................................................................................ 60
5.4.
Other Efficacy Endpoint(s) ............................................................................................................. 60
5.4.1.
Endpoints related to exercise capacity....................................................................................... 60
5.4.1.1.
Definition.................................................................................................................................. 60
5.4.1.2.
Statistical methods .................................................................................................................. 60
5.4.2.
NT-proBNP ................................................................................................................................. 61
5.4.2.1.
Definition.................................................................................................................................. 62
5.4.2.2.
Statistical methods .................................................................................................................. 62
5.4.3.
Time to clinical events ................................................................................................................ 63
5.4.3.1.
Definition.................................................................................................................................. 63
5.4.3.2.
Statistical methods .................................................................................................................. 64
5.4.4.
Overall Survival (OS).................................................................................................................. 64
5.4.4.1.
Definition.................................................................................................................................. 65
5.4.4.2.
Statistical methods .................................................................................................................. 65
5.4.5.
Physical activity .......................................................................................................................... 66
5.4.5.1.
Definition.................................................................................................................................. 66
5.4.5.2.
Statistical methods .................................................................................................................. 66
SAFETY............................................................................................................................................. 66
6.1.
Adverse Events .............................................................................................................................. 67
6.2.
Clinical Laboratory Tests................................................................................................................ 70
6.2.1.
Laboratory parameters ............................................................................................................... 70
6.2.1.1.
Marked Laboratory Abnormalities............................................................................................ 72
6.2.1.2.
Additional Liver Function Test and Hemoglobin Abnormalities............................................... 75
6.2.1.3.
Estimated glomerular filtration rate (eGFR) and Protein Losing Enteropathy (PLE)............... 75
6.3.
Vital Signs and Physical Examination Findings ............................................................................. 76


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6.4.
Electrocardiogram.......................................................................................................................... 77
6.5.
Other Safety Parameters ............................................................................................................... 77
6.5.1.
Echocardiography....................................................................................................................... 77
6.5.2.
Pregnancy Test........................................................................................................................... 78
QUALITY OF LIFE............................................................................................................................. 78
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 79
8.1.
Pharmacokinetics........................................................................................................................... 79
HEALTH ECONOMICS ..................................................................................................................... 80
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE STUDY 
PROTOCOL....................................................................................................................................... 81
10.1.
Changes to the Statistical Analysis Plan for Special Protocol Submission ................................... 81
10.2.
Changes to the analyses planned in the study protocol ................................................................ 82
10.3.
Clarifications concerning endpoint definitions and related variables or statistical methods .......... 82
REFERENCES............................................................................................................................................ 84
ATTACHMENTS......................................................................................................................................... 85
ATTACHMENT 1 - BMI-FOR-AGE REFERENCE ..................................................................................... 85
ATTACHMENT 2 - ADVERSE EVENTS OF SPECIAL INTEREST .......................................................... 88
I.
Hepatic events of special interest................................................................................................. 88
II.
Edema and fluid retention ........................................................................................................... 88
III.
Anemia / hemoglobin decrease.................................................................................................... 88
IV.
Hypotension .............................................................................................................................. 88
ATTACHMENT 3 - PROTOCOL DEVIATIONS CLASSIFICATION FROM THE INDEPENDENT 
TEAM ................................................................................................................................................. 89


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Status: Approved, Date: 23 August 2021
VERSION HISTORY
Table 1:
SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
Final Version 1 (D-
16.427)
24 Aug 2016
Not applicable
Initial release for special protocol 
assessment to the Food and Drug
Administration Agency.
Final version 1 (D-
19.382)
13 Dec 2019
Janssen SAP template
Introduction of the Interim 
Analysis for sample size re-
estimation
Special protocol assessment re-
submission of protocol version 8 
to the Food and Drug 
Administration Agency.
Final version 2 (D-
20.077)
20 Feb 2020
Section 3.2.3
Appendix 1
To incorporate comments from 
Food and Drug Administration 
Agency received by email on 13 
Feb 2020 .
Final version 3
25 Feb 2021
Development of all analyses as 
detailed in Section 10.1 of this 
document
Clinical Study Report.
Final version 4
12 July 2021
Sections 4.4.1 and 4.4.2 
Clarification of derivation for 
compliance
With the introduction of the 
COVID-19 protocol appendix, 
on-site visits could be performed 
remotely or delayed, and while 
study treatment may have been 
dispensed via direct-to-patient 
shipments, subjects were asked to 
return empty bottles/unused 
tablets only at their next on-site 
visit. The overall compliance and 
the compliance up to Week 16 
will be calculated only for 
selected subjects as detailed in 
Sections 4.4.1 and 4.4.2.
Sections 4.5.2, 4.6, and 9
Minor clarification for 
implementation.
Section 5.2.3.4 Removal of the 
estimator based on different 
model 1 (by adding treatment-by-
geographical region interaction)
In order to assess the consistency 
of the treatment effect across 
regions, the subgroup analysis is 
already planned in section 5.2.3.5 
where the treatment-by-region 
interaction is investigated.
Sections 5.2.3.4, 5.3.1.6, and 
5.3.2.6 Addition of sensitivity 
analyses for primary and 
secondary efficacy endpoints
To explore the robustness of the 
main analysis treatment effect 
estimates to missing data, 
multiple imputation sensitivity 
analyses will be added.
Section 5.4.4
Vital Status Follow Up (VSFU) 
not assessed for subjects 
randomized in site 1101 
VSFU could not be assessed in 
site 1101. Therefore, randomized 
subjects in these sites are 
assumed with unknown vital 
status and censored at their EOS, 
unless they died prior to EOS.
Final version 5
23 August 2021
Section 2.3 Addition of 
subgroups: BMI at baseline, SpO2
at baseline, Peak respiratory 
exchange ratio at baseline
After consultation with the Study 
Results Committee constituted of 
external clinicians with expertise 
in subjects with Functional Single 
Ventricle Heart Disease on 


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SAP Version
Approval Date
Change
Rationale
13-Aug-2021, additional 
subgroups have been added based 
on clinical consideration and 
blinded aggregated baseline 
characteristics at baseline, to 
assess the consistency of the 
treatment effect on the primary 
and secondary efficacy endpoints.
Section 4.1.2 Addition of 
‘sildenafil citrate’ as preferred 
term to qualify PAH specific 
therapies
The preferred term ‘sildenafil 
citrate’ was erroneously not 
included in the definition of PAH 
specific therapies.
Sections 5.2.3.4 and 5.3.1.6 
Minor clarification on the 
exclusion of invalid baseline peak 
VO2 from the sensitivity multiple 
imputation analyses. This 
clarification complies with the 
general estimand language and 
does not impact the planned 
efficacy analyses provided in the 
previous SAP version and as 
agreed with FDA.
Sections 5.2.3.4, 5.3.1.6, and 
5.3.2.6 Additional sensitivity 
analysis for primary and 
secondary efficacy enpdoints
After consultation with the Study 
Results Committee constituted of 
external clinicians with expertise 
in subjects with Functional Single 
Ventricle Heart Disease on 13-
Aug-2021, an additional estimand 
excluding subjects with cardiac 
heterotaxy defects (isomerism) 
will be added to assess the 
robustness of results (for each 
primary and secondary efficacy 
endpoint) excluding subjects with 
extra-cardiac defects.
Section 5.4.4 Vital Status Follow 
up for those subjects with the End 
of Study within 4 weeks of the 
Study Closure announcement.
Minor clarification for 
implementation.
Sections 6.2.1 Additional analysis 
for total bilirubin, ALT, AST
After consultation with the Study 
Results Committee constituted of 
external clinicians with expertise 
in subjects with Functional Single 
Ventricle Heart Disease on 13-
Aug-2021, additional analyses on 
total bilirubin, ALT and AST will 
be added to characterize the 
pattern over time of these 
parameters.
Subjects who have undergone 
Fontan surgery and have a 
Functional Single Ventricle will 
sometimes experience hepatic 
congestion as a consequence of 
volume overload. As a result of 


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Status: Approved, Date: 23 August 2021
SAP Version
Approval Date
Change
Rationale
this, bilirubin may be raised 
with/without corresponding rises 
in AST and ALT reflective of 
hepatocellular damage. Given 
macitentan’s potential to cause 
vasodilation, there is the 
possibility that a beneficial effect 
may be seen on both bilirubin and 
transaminases. These analyses 
will explore this clinical 
consideration.


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Status: Approved, Date: 23 August 2021
ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
AV
Atrioventricular
BMI
Body Mass Index
BP
Blood Pressure
CGI-C
Clinician Global Impression of Change
CGI-S
Clinician Global Impression of Severity
CDISC
Clinical Data Interchange Standards Consortium
CL
Confidence Limit
CPET
Cardiopulmonary Exercise Testing
CRO
Contract Research Organization
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria For Adverse Events
CV
Coefficient of Variation
CYP3A4
Cytochrome P450 3A4
DTS
Data Transfer Specifications
EC
Extra Cardiac
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EC-TCPC
Extra Cardiac Total Cavopulmonary Connection
ENR
Enrolled Analysis Set
EOP
End-of-Post-treatment observation period
EOS
End-of-Study
EOT
End-of-Treatment
EQ-5D-5L
Euro Quality of Life 5D (dimensions)
ERA
Endothelin Receptor Antagonist
FAS
Full Analysis Set
FC
Functional Class
FDA
Food and Drug Administration
FU
Follow-up
GDRA
Global Drug Regulatory Affairs
HR
Heart Rate
ICF
Informed Consent Form
IDMC
Independent Data Monitoring Committee
IRT
Interactive Response Technology
KM
Kaplan-Meier
LLOQ
Lower Limit of Quantification
LT-TCPC
Lateral Tunnel Total Cavopulmonary Connection
LV
Left Ventricle
MAR
Missing at Random
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple Imputation
MMRM
Mixed Model Repeated Measures
NT-proBNP
N-terminal prohormone of Brain Natriuretic Peptide
NYHA FC
New York Heart Association Functional Class
OL
Open Label
OLE
Open Label Extension
PA-Ac
Physical Activity measured by Accelerometer
PGA-S
Patient Global Assessment of Disease Severity
PGI-C
Patient Global Impression of Change
PD
Protocol Deviation
PK
Pharmacokinetic


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Status: Approved, Date: 23 August 2021
PKS
Pharmacokinetic Analysis Set
PLE
Protein-Losing Enteropathy
PP
Per-Protocol Analysis Set
PTOP
Post-Treatment Observation Period
Q-Q
Quantile-Quantile
QoL
Quality of life
RV
Right Ventricle
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCL
Study Closure
SD
Standard Deviation
SDTM
Study Data Tabulation Model
S-FU
Safety Follow-Up
SI
International System of Units
SMQ
Standardised MedDRA Query
SOC
System Organ Class
SpO2
Peripheral Oxygen Saturation
SS
Safety Analysis Set
SSRE
Sample Size Re-Estimation 
TCPC
Total Cavo-Pulmonary Connection
TEMPO
Treatment with endothelin receptor antagonist in fontan patients, a randomized, placebo-
controlled, double-blind study measuring peak oxygen consumption
ULN
Upper Limit of Normal
VAS
Visual Analogue Scale
VCO2
Carbon dioxide production 
[V̇ CO2 is a flow = a ratio of Volume of Carbon Dioxide by unit of time]
VE
Pulmonary ventilation. 
[Respiratory minute volume, the total Volume of gas Expired per minute. (V̇ E is a flow = a 
ratio of a volume by unit of time)]
VO2
Oxygen uptake/consumption 
[V̇ O2 is a flow = a ratio of Volume of Oxygen by unit of time]
VSFU
Vital Status Follow-Up
WHO
World Health Organization
WU
Wood Unit


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INTRODUCTION
This Statistical Analysis Plan (SAP) describes the planned statistical data analyses of the double-
blind study AC-055H301 (RUBATO) for the purpose of the Clinical Study Report (CSR).
This SAP refers to the documents listed in Table 2. 
Table 2:
Study Documents
Document
Version
Study Protocol AC-055H301 (RUBATO)
Final version 10 (D-20.425)
SAP for Special Protocol Assessment 
Final version 2 (D-20.077)
SAP for Independent Data Monitoring Committee 
Final version 2.1 (D-18.337)
eCRF specifications
Final version 008 (or latest implemented version)
IDMC Charter 
Final version 5.0
Source data for the analyses are provided as Statistical Analysis Software (SAS®) data sets 
according to Clinical Data Interchange Standards Consortium Study Data Tabulation Model 
(SDTM). Source data are provided according to the Database Release Plan document. 
All descriptive or formal statistical analyses will be performed using SAS statistical software 
(Version 9.4), unless otherwise specified.
1.1.
Trial Objectives
The primary objective of the study is to assess the effect of macitentan on exercise capacity 
(measured by peak oxygen uptake VO2) in comparison with placebo in Fontan-palliated subjects.
The secondary objectives are:

To assess the effect of macitentan on long-term exercise capacity (measured by peak VO2 over 
52 weeks).

To assess the effect of macitentan on daily physical activity measured by accelerometer (PA-
Ac).

To evaluate the safety and tolerability of macitentan. 
Other objectives are:

To assess the efficacy of macitentan on endpoints related to exercise capacity.

To assess the effect of macitentan on NT-proBNP.

To assess the effect of macitentan on clinical worsening.

To assess the effect of macitentan on Quality of life (QoL).

To assess the effect of macitentan on pharmacoeconomic endpoints.

To assess the plasma concentration of macitentan and its metabolite (ACT-132577) at trough.
1.2.
Trial Design
This is a prospective, multi-center, double-blind, randomized, placebo-controlled, parallel-group 
Phase 3 study with an adaptive sample size re-assessment.


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At least 134 subjects will be randomized in a 1:1 ratio to either macitentan or placebo. 
Randomization will be stratified by geographical region (America, Europe, Asia, Oceania). The 
study will be conducted in approximately 31 investigational sites in 11 countries.
Given the uncertainty about both the true treatment effect and variability of the primary efficacy 
endpoint variable, the Sponsor made the decision on 24 January 2019 (based on an internal
meeting) to implement an interim analysis (IA) for unblinded sample size re-estimation
(introduced from protocol version 8). This IA is performed by an Independent Statistical Analysis 
Center (ISAC) / Statistical Support Group (SSG) for the Independent Data Monitoring Committee 
(IDMC). Only the IDMC and the ISAC/SSG are unblinded to the data. This sample size 
re-estimation allows the sample size to be potentially increased up to a total sample size of 268
subjects. Full details about the IA are presented in Section 3.
The study comprises the following consecutive periods:
Screening period: Starts with the signature of the informed consent (Visit 1) and ends with the 
subject’s Randomization (Visit 2).
Treatment period: Starts with the administration of the first dose of study treatment (Visit 2 / 
Randomization) and ends on the day of the last dose of study treatment, expected to be at 52 weeks.
Subjects who prematurely and permanently discontinue study treatment before Week 52 (Visit 6) 
must have a premature End-of-Treatment (EOT) visit as soon as possible but not later than 7 days 
after last dose of study drug. 
Safety follow-up (S-FU) period: After permanent study treatment discontinuation, subjects will 
be followed up for a minimum of 30 days (S-FU). 
Subjects eligible to enter the AC 055H302 open-label (OL) extension study may do so as soon as 
their eligibility has been confirmed, even prior to completion of the full S-FU period. The period 
ends with administration of first study drug in the OL extension study.
Post-treatment observation period (PTOP):
Subjects who prematurely and permanently discontinue study treatment will enter the PTOP after 
their S-FU period is completed. The PTOP lasts until the planned study EOT (at most 52 weeks 
after Randomization) for each individual subject. This last visit of the PTOP is called 
End-of-PTOP (EOP). The PTOP consists of an abbreviated schedule of assessments at 90-day 
intervals.
End-of-Study (EOS):
EOS is reached by an individual subject:

When the S-FU period has been completed (for those subjects who do not discontinue study 
treatment prematurely), or


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
When the S-FU period and PTOP have been completed (for those subjects who discontinue 
study treatment prematurely), or

If subjects enter the AC-055H302 RUBATO OL extension study, with first administration of 
OL study drug.
For all subjects, EOS corresponds to the last visit performed in this AC-055H301 RUBATO 
double-blind study. 
Study closure (SCL) will be announced by the sponsor when all subjects have reached their EOS 
in AC-055H301 RUBATO.
Vital status follow-up (VSFU):
A VSFU will be performed within 8 weeks after the SCL announcement to determine vital status 
of all subjects randomized in AC-055H301 RUBATO, irrespective of whether the subject is 
included in the AC-055H302 OL extension study.
SCL:
The SCL applies to all randomized subjects and will occur:

When all subjects have had their individual VSFU, and

No later than 8 weeks after SCL announcement.
The visit schedule and protocol-mandated procedures are performed according to the table of 
assessments in the protocol.
The overall study design is depicted in Figure 1. An example of premature discontinuation and 
PTOP is depicted in Figure 2. 
Figure 3 depicts the design for a subject who enters the AC-055H302 OL extension study at 
Week 52.


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Figure 1:
Study design
EOS = End-of-Study; EOT = End-of-Treatment; SCL = Study Closure; V = visit; VSFU = Vital Status Follow-Up;
= Telephone call (for visit).
Figure 2:
PTOP (example of discontinuation after Visit 4)
EOS = End-of-Study; EOP = End-of-PTOP; EOT = End-of-Treatment; P = PTOP visit; PTOP = Post-treatment observation 
period; SCL = Study Closure; V = visit; VSFU = Vital Status Follow-Up; = Telephone call (for visit).


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Figure 3:
OL extension study (entry at Visit 6)
DB = Double-blind; EOS = End-of-Study; EOT = End-of-Treatment; OL = Open-label (extension); SCL = Study Closure; V = 
visit; VSFU = Vital Status Follow-Up; = Telephone call (for visit).
No S-FU will be performed in subjects entering the AC-055H302 RUBATO-OL extension study 
at individual subject’s EOT/EOS for the AC-055H301 RUBATO study.
In instances where administration of AC-055H302 OL study drug does not immediately follow 
EOT in the AC-055H301 RUBATO study, the subject will enter the normal S-FU period until 
administration of the first dose of the OL study drug occurs.
1.3.
Statistical Hypotheses for Trial Objectives
The primary efficacy endpoint is the change in peak VO2 from baseline to Week 16. The primary 
null hypothesis to be tested is that macitentan 10 mg has no impact on exercise capacity, as 
assessed by the mean change in peak VO2 from baseline to Week 16 compared to placebo. 
Rejection of the null hypothesis confirms the effects of macitentan 10 mg on exercise capacity; 
see Section 5.2.3.1 for further details.
The primary null hypothesis will be tested at a two-sided 1% alpha level, and if rejected the study 
will be declared to show ‘conclusive’ evidence of efficacy on the primary efficacy endpoint. If the 
primary null hypothesis can only be rejected at a two-sided 5% alpha level, the study will be 
declared ‘positive’.
Conditional to conclusive or positive outcome of the primary efficacy endpoint at final analysis, 
the secondary efficacy endpoints will be formally evaluated at the same significance level as the 
primary efficacy endpoint according to the testing hierarchy following the order of the endpoints 
as listed in Section 5.3. 
Statistical hypotheses for secondary endpoints are also addressed in Sections 5.3.1.3 and 5.3.2.3.


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1.4.
Sample Size Justification
The sample size is based on the primary efficacy endpoint, the 16-week change from baseline in 
peak VO2. The aim of the trial is to reject the statistical hypothesis of no treatment difference.
Assuming that the macitentan versus placebo difference is not worse than the bosentan versus 
placebo difference in TEMPO study, a 2.4 mL/kg/min difference of macitentan to placebo on the 
change in peak VO2 is hypothesized. The variability of the treatment effect of macitentan vs 
placebo is assumed to be greater than that observed in the TEMPO study of bosentan versus 
placebo in subjects with Fontan-palliated circulation (Hebert 2013, Hebert 2014), namely a 
standard deviation of 4.0 mL/kg/min yielding a standardized effect size of 0.6.
It is further assumed that all randomized subjects are evaluable. The family-wise two-sided Type
I error is set to 1% (ie, the level of significance), and the targeted statistical power is 80% (ie, Type
II error of 20%).
The sample size is determined under the assumption of normal distribution of the primary efficacy 
endpoint (based on a two-sample t-test with equal unknown variances). 
Based on the above assumptions and with a 1:1 randomization ratio, a total of 134 subjects, i.e. 
67 per treatment group, are required to establish superiority of macitentan 10 mg over placebo at 
two sided α=1%. 
Alternative sample size scenarios for the primary endpoint are given in Table 3, i.e., for different 
effect sizes from 0.4 to 0.8, and standard deviation from 3.0 to 6.0 mL/kg/min and treatment 
difference of 2.4 mL/kg/min.
Table 3:
Sample size with treatment effect of 2.4 mL/kg/min and statistical power 1-β of 80% in a 1:1 
randomization ratio by level of significance α and effect size (with selected sample size in bold 
face)

Standardized 
Effect size
SD
n per arm
Total N
1%
0.4
6.0
148
296
0.5
4.8
96
192
0.6*
4.0
67
134
0.8
3.0
39
78
5%
0.4
6.0
100
200
0.5
4.8
64
128
0.6
4.0
45
90
0.8
3.0
26
52
Standard deviation (SD) with a treatment difference of 2.4 mL/kg/min; n: sample size per treatment group
(macitentan 10 mg or placebo) with a 1:1 ratio; N: total number of randomized subjects.
*Selected assumptions and sample size.
All calculations were performed using the East software version 6.3.


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Initially (up to protocol version 7), the study contained a blinded sample size re-estimation, which 
would allow for an increase in the pre-planned sample size of 134 subjects in case of higher than 
expected variability for the primary efficacy endpoint. As described in Section 1.2, the IA for 
unblinded sample size re-estimation has since replaced the blinded sample size re-estimation, and 
was introduced in protocol version 8.
1.5.
Randomization and Blinding
1.5.1. Randomization 
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 Visit 2 to 
randomize the subject. The IRT assigns a randomization number to the subject and assigns the 
treatment kit number, which matches the treatment group assigned by the randomization list to the 
randomization number.
Subjects are assigned to the two treatment groups in a 1:1 ratio based on a permutated-block 
randomization stratified by the geographical region (America, Europe, Asia, Oceania) in order to 
balance treatment groups throughout the conduct of the trial.
The randomization list is generated by an independent Contract Research Organization (CRO),
Almac Clinical Technologies, using SAS® v9.3 and details regarding requirements for the 
generation of the Subject Randomization List(s) for this study are highlighted in the Biostatistics 
Addendum for the Subject Randomization List.
1.5.2. Blinding
This study will be performed in a double-blind fashion. The investigator and study personnel, the 
subjects, the clinical research associates (CRAs), Sponsor personnel, and CRO personnel involved 
in the conduct of the study will remain blinded to the study treatment until study completion. 
Sponsor personnel responsible for clinical study supply distribution will need to be unblinded to 
ensure adequate supply of study treatment. These persons will be clearly identified, their 
unblinding will be documented in the trial master file and they will not take part in any clinical 
trial team (CTT) meetings after study set-up has been completed.
Until the time of unblinding for final data analysis, the randomization list is kept strictly 
confidential and accessible only to authorized persons, e.g., the ISAC/SSG, who are not involved 
in the conduct of the study.
During the conduct of the study (in June 2020), the unblinding documents (i.e., randomization and 
material lists) were transferred from Actelion legacy Global Quality Management to the Secure 
Data Office according to the Janssen process.


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GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
As subjects do not always adhere to the protocol visit schedule, the following rules are applied to 
assign actual visits (including unscheduled ones) to analysis visits. Listed below are the visit 
windows and the target days for each visit. The reference day is Study Day 1 (see Section 2.4 for 
definition). If a subject has 2 or more actual visits with an available value in the same visit window
the visit closest to the target day will be used as the protocol visit for that visit window. For peak 
VO2, if a subject has 2 or more actual visits in the same visit window, the visit with the valid value 
closest to the target day will be used as the protocol visit for that visit window. The other additional 
visit(s) will not be used in the summaries or analyses by visit, but they can be used for 
determination of other endpoints (e.g., time to event endpoints, marked laboratory abnormalities). 
If 2 actual visits are equidistant from the target day within a visit window, the later visit is used.
Except otherwise specified, if more than one assessment falls on the same day then the worst 
assessment (i.e., lowest for peak VO2) is used.
All assignments will be made in chronological order. Once a visit date is assigned to a visit 
window, it will no longer be used for a later time point except for the endpoint. Listed below 
(Table 4) are the visit windows and the target days for each visit defined in the protocol.
Assessments which fall outside of any planned window will not be included in summary tables but 
will be included into individual subject listings.
Table 4:
Visit Windows
Parameter
Scheduled Visit 
Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point (Day)
Efficacy 
parameters
2
Baseline
<=1
1
4
Week 16
99 to 168
113
5
Week 32**
169 to 293
225
6
Week 52
294 to 420
365
Premature End-of-
Treatment 
remapping for 
safety parameters 
and Quality of Life
2
Baseline***
<=1
1
3
Week 8**
2 to 98
57
4
Week 16
99 to 168
113
5
Week 32**
169 to 293
225
6
Week 52
294 to open end
365
*Relative to Study Day 1; ** on-site visits performed until protocol version 7, then converted to remote visits (phone 
call); *** Safety assessments (e.g., laboratory, vital signs) on Day 1 are considered baseline. Safety signals (i.e., adverse 
events) occurring/starting on Day 1 are considered treatment-emergent while safety events (i.e., laboratory marked 
abnormalities, vital signs abnormalities) occurring/starting on Day 1 are not considered treatment-emergent.
2.1.1. Efficacy
For the efficacy visit windows, all the assessment after the treatment start date will be considered, 
unless otherwise specified.
For subjects who prematurely discontinue study treatment, the End-of-Treatment visit (if 
available) will be re-assigned to a scheduled visit in the respective time window as defined above 
(including any assessment after treatment start date).   


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2.1.2. Safety
For safety, only assessments measured during the treatment period (i.e., from study treatment start 
up to 30 days after study treatment discontinuation, limits included) will be considered at the 
scheduled visit up to Visit 6/Week 52. 
For subjects who prematurely discontinue study treatment, the End-of-Treatment visit (if 
available) will be re-assigned to a scheduled visit in the respective time window as defined above 
(including any assessment from study treatment start up to 30 days after study treatment 
discontinuation, limits included). In addition, the following assessments are derived:

“Last on-treatment assessment” will be derived as last assessment prior to or on End-of-
Treatment + 1 day (limits included)

“Last follow-up assessment” will be derived as last assessment between End-of-Treatment + 
1 day (limit excluded) and End-of-Treatment + 35 days (limit included). 
2.1.3. Quality of life 
For the quality of life, all the assessment after the treatment start date are considered at the 
scheduled visit up to Visit 6/Week 52. For subjects who prematurely discontinue study treatment, 
the End-of-Treatment visit (if available) will be re-assigned to a scheduled visit in the respective 
time window as defined above (including any assessment after treatment start date).   
2.2.
Analysis Sets
The following analysis sets are described in protocol Section 10.1.
2.2.1. Enrolled Analysis Set
The Enrolled Analysis Set (ENR) includes all subjects who are screened and have a subject 
identification number.
2.2.2. Full Analysis Set
The Full Analysis Set (FAS) includes all subjects assigned (i.e., randomized) to a study treatment. 
In order to adhere to the intention-to-treat principle as much as possible:

Subjects are evaluated according to the study treatment they have been assigned to (which may 
be different from the study treatment they have received);

All available data are included.
The FAS is part of the population definition for Estimand for the main analysis of primary and 
secondary efficacy endpoints. 
2.2.3. Per-Protocol Analysis Set
The Per-Protocol Set (PP) is defined as part of the population definition for Estimand for the 
sensitivity analyses of primary and secondary efficacy endpoints.

Definition of Population for Estimand - primary efficacy endpoint (PP1)


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This estimand population (PP1) will comprise all subjects who received actual study treatment 
assigned by IRT and who complied with the protocol sufficiently up to and including Week 16 for 
the primary efficacy endpoint (refer to Table 5 to identify those protocol deviations that lead to the 
exclusion from PP1).

Definition of Population for Estimand (PP2 and PP3) - secondary efficacy endpoints - (PP2 
and PP3)
This estimand population (PP2 or PP3) will comprise all subjects who received actual study 
treatment assigned by IRT and who complied with the protocol sufficiently up to and including 
the timepoint of evaluation for the secondary efficacy endpoints (refer to Table 5 to identify those 
protocol deviations that lead to the exclusion from PP2 and PP3 respectively).
The identification of protocol deviations leading to exclusion of subjects/data from PP1, PP2, and 
PP3 has been conducted by an independent team before database lock as documented in
ATTACHMENT 3.


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Table 5:
Protocol Deviations leading to exclusion of subjects / data from PP1/PP2/PP3
PD Condition
PD 
Identifier
Categorization of 
PD 
Primary 
endpoint (Peak 
VO2 at Week 
16 -PP1
Secondary 
endpoint (Peak 
VO2 over Week 
52) - PP2
Secondary 
endpoint 
(mean count 
per minute of 
daily PA-Ac at 
Week 16) - PP3
Unable to understand and comply with the 
instructions, and to physically perform the CPET.
PD_MM.140
Entered but did 
not satisfy criteria
X
X
Known severely reduced single ventricle ejection 
fraction (< 30%)
PD_MM.144
Entered but did 
not satisfy criteria
X
X
X
Known Fontan circulation stenosis, affected area > 
50% of the diameter
PD_MM.145
Entered but did 
not satisfy criteria
X
X
X
Known valvular defects (severe atrioventricular [AV] 
valve regurgitation, outflow obstruction)
PD_MM.146
Entered but did 
not satisfy criteria
X
X
X
Known pulmonary-venous pathway obstruction
PD_MM.147
Entered but did 
not satisfy criteria
X
X
X
Clinical worsening leading to medical interventions 
including reoperation of Fontan circulation within 3 
months of screening
PD_MM.149
Entered but did 
not satisfy criteria
X
X
X
Unscheduled hospitalization due to deterioration of the 
Fontan palliated condition within 3 months of 
screening
PD_MM.150
Entered but did 
not satisfy criteria
X
X
X
Signs and symptoms of HF requiring change in 
diuretic therapy within 3 months of screening
PD_MM.151
Entered but did 
not satisfy criteria
X
X
X
Ventricular tachyarrhythmia or supraventricular 
tachyarrhythmia within 3 months of screening
PD_MM.152
Entered but did 
not satisfy criteria
X
X
X
Plastic bronchitis/chyloptysis within 3 months of 
screening
PD_MM.156
Entered but did 
not satisfy criteria
X
X
X
Signs and symptoms requiring the addition of a new 
class of cardiovascular medication (e.g., nitrates, 
alpha-blockers, or ERAs) within 3 months of screening
PD_MM.157
Entered but did 
not satisfy criteria
X
X
X
History of syncope during exercise
PD_MM.158
Entered but did 
not satisfy criteria
X
X
X
Symptomatic coronary artery disease at Screening
PD_MM.159
Entered but did 
not satisfy criteria
X
X
X
Exercise training program for cardiopulmonary 
rehabilitation in the 3-month period prior to Screening
PD_MM.161
Entered but did 
not satisfy criteria
X
X
X
Treatment with nitrates, alpha-blockers, or ERAs in 
the 3-month period prior to Screening
PD_MM.171
Entered but did 
not satisfy criteria
X
X
X
Introduction or change of dose of PH specific drugs 
(other than ERAs) in the 3-month period prior to 
Screening
PD_MM.172
Entered but did 
not satisfy criteria
X
X
X
Male or female < 12 years old  
PD_PM.351
Entered but did 
not satisfy criteria
X
X
X
Not a Fontan-palliated subject with either LT-TCPC, 
or EC-TCPC surgery > 1 year before Screening
PD_PM.352
Entered but did 
not satisfy criteria
X
X
X
Subject not in NYHA FC II or III (assessed by the 
investigator using the Specific Activity Scale
PD_PM.353
Entered but did 
not satisfy criteria
X
X
X
Peripheral oxygen saturation (SpO2) of < 88% at rest at 
Screening
PD_PM.354
Entered but did 
not satisfy criteria
X
X
X
Respiratory limitation with a breathing reserve of < 
10%
PD_PM.355
Entered but did 
not satisfy criteria
X
X
X
Iron deficiency defined as ferritin < 10 µg/L at 
Screening
PD_PM.356
Entered but did 
not satisfy criteria
X
X
X
Body mass index (BMI) for age reference (z scored) 
equivalent to BMI > 35 kg/m2 (for adults) at Screening
PD_PM.357
Entered but did 
not satisfy criteria
X
X
X
Peak VO2 < 15 mL/kg/min at Baseline
PD_PM.362
Entered but did 
not satisfy criteria
X
X
X
Initiation of forbidden therapy up to the week 16 visit 
PD_PM.324
Received a 
disallowed 
concomitant 
treatment
X
X
X
Initiation of forbidden therapy after the week 16 visit
PD_PM.341
Received a 
disallowed 
concomitant 
treatment
X
Study medication not stored correctly but subject 
continued to use it. 
PD_MM.124
Received wrong 
treatment or 
incorrect dose
X
X
X


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Note: If the PD date is available, exclude from PP1 
and PP3 if the PD date is prior to the Visit 4 CPET 
assessment, and from PP2 if the PD date is prior to the 
Visit 6 PA-Ac assessment
Administration of incorrect study treatment (i.e. 
Subject did not get medication bottle assigned by IRT).
Note: This PD leads to exclusion if, after unblinding, 
the allocated bottle did not contain the planned study 
treatment (i.e.,if the PD_PM.333 has been classified as 
“Important”). Thereafter, if the PD leads to exclusion 
and the PD date is available (either date of first intake 
from an incorrect bottle of - if this data is not 
available, use the date when wrong bottle was 
dispensed), only exclude if occurred prior to 
corresponding efficacy assessment date.
PD_PM.333
Received wrong 
treatment or 
incorrect dose
X
X
X
Study treatment compliance for the whole treatment 
period < 80% or > 120% 
PD_PM.335
Received wrong 
treatment or 
incorrect dose
X
Study treatment compliance up to the Week 16 visit < 
80% or > 120%  
PD_PM.336
Received wrong 
treatment or 
incorrect dose
X
X
Treatment interruption of > 4 consecutive weeks up to 
Week 16
PD_PM.367
Received wrong 
treatment or 
incorrect dose 
X
X
X
Treatment interruption of > 4 consecutive weeks after 
Week 16
PD_PM.368
Received wrong 
treatment or 
incorrect dose 
X
Informed consent not personally signed and dated by 
subject /legal representative
PD_MM.101
Other
X
X
X
Non-justified treatment code was break before 
unblinding of the study
PD_MM.111
Other
X
X
X
Subject has developed a condition that interferes with 
CPET assessment
PD_MM.112
Other
X 
Note: if the PD
is linked to 
Visit 4
X
Note: if the PD
is linked to Visit 
6
CPET at Visit 4 conducted under different conditions 
than at baseline
PD_MM.114
Other
X
CPET at Visit 4 done, but not valid/questionable on 
review by central reading facility
PD_MM.115
Other
X
CPET at Visit 6 conducted under different conditions 
than at baseline
PD_MM.121
Other
X
CPET at Visit 6 done, but not valid/questionable on 
review by central reading facility
PD_MM.318
Other
X
Subject does not have sufficient PA-Ac baseline data
PD_PM.303
Other
X
Randomization CPET done, but not valid/questionable 
on review by central reading facility
PD_PM.304
Other
X
X
Subject does not have sufficient PA-Ac data at Visit 4
PD_PM.313
Other
X
Subject not Randomized but received study drug
PD_PP.245
Other
X
X
X
CPET at Visit 4 not done
PD_PP.251
Other
X
CPET at Visit 6 not done
PD_PP.253
Other
X
Peak VO2 measurements at Week 16 (Visit 4) not 
available
PD_PP.260
Other
X
2.2.4. Safety Analysis Set
The Safety Set (SS) includes all subjects who received at least one dose of study treatment. 
Subjects will be analyzed according to the study treatment they actually received.
The treatment received will be considered different from the treatment assigned at randomization 
(randomized treatment) only in the case of a dispensing error sustained throughout the entire 
double-blind study. Other dispensing errors will not qualify for a change from the randomized 
treatment group.


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2.2.5. Pharmacokinetics Analysis Set
The Pharmacokinetic Analysis Set (PKS) includes all randomized and treated subjects, for whom 
a PK blood sample at trough has been collected and who do not deviate from the protocol in a way 
that might affect the evaluation of the trough concentrations.
A subject will be excluded from the PKS if he/she meets the following criteria/events for all visits 
(Week 4/Week 8 and Week 16/EOT):
o
PD_PP.250 Subject has no PK assessment
o
PD_PM.364 PK sampling taken after the morning dose of study treatment
2.2.6. Usage of the analysis sets
The main analyses of the primary, secondary and other efficacy endpoints will be performed on 
the FAS, as per population definitions for estimands in the corresponding sections.
Safety and pharmacokinetic analyses will be performed on the SS and PKS, respectively.
Listings will be prepared on the FAS, unless otherwise specified.
2.3.
Definition of Subgroups
In order to assess the consistency of the treatment effect across different subject subgroups, 
analyses will be performed on the primary efficacy endpoint and the secondary efficacy endpoints 
for the subgroups described in Table 6 and Table 7.
Table 6:
Subgroups definition
Subgroup
Definition
Age Group
Adolescents: 12-<18 yrs
Adults: >= 18 yrs
Geographical region
America
Europe 
Asia
Oceania
Region
US
Non-US
Ventricular dominance
Left ventricle
Right ventricle / Mixed
Countries will be assigned to geographical region based on the Standard Country or Area Codes 
for Statistical Use (M49) standard (https://unstats.un.org/unsd/methodology/m49/).
After consultation with the Study Results Committee constituted of external clinicians with 
expertise in subjects with Functional Single Ventricle Heart Disease on 13-Aug-2021, the 
following subgroups have been added based on clinical consideration and blinded aggregated 
baseline characteristics at baseline, to assess the consistency of the treatment effect on the primary 
and secondary efficacy endpoints:


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Table 7:
Additional subgroups definition
Subgroup
Definition
BMI at baseline
Underweight/Normal 
Overweight/Obese (including obese class I, II, III)
SpO2 at baseline
< 92 %
>= 92%
Peak respiratory exchange ratio
at baseline 
< 1.1
>= 1.1
2.4.
Study Day and Relative Day
Study Day 1 or Day 1 refers to the start date of the first study treatment administration (see 
Section 2.5.2 for definition). All efficacy and safety assessments at all visits will be assigned a day 
relative to this date.
Study day or relative day for a visit is defined as:

Visit date − (date of Study Day 1) +1, if visit date is ≥ date of Day 1

Visit date − date of Day 1, if visit date < date of Day 1
There is no ‘Day 0’.
2.5.
Baseline, Relevant Time-points and Analyses Periods
2.5.1. Baseline
Except where otherwise specified, the baseline is defined as the last non-missing assessment 
obtained before or on the day of the start of study treatment. If unscheduled/re-test visits are 
performed on the day of study treatment start, the non-missing assessment of the last 
unscheduled/re-test visit on study treatment start date is considered as baseline. 
If more than one assessment falls on the same day then the worst assessment (i.e., lowest for peak 
VO2) is used, unless otherwise specified.
Missing values for peak VO2 at baseline are not allowed by protocol, but in case a subject has been 
randomized with a non-missing baseline value that has subsequently been evaluated as “invalid”
by the independent central reading facility, it will be imputed for the main analysis of the primary 
efficacy endpoint as detailed in Section 5.2.3.2. In case of re-screening, the value from the first 
screening attempt will not be used for determining the baseline.
For the physical activity measured by accelerometer, the 9-day time period is selected by taking 
the first (in chronological order) interval of 9 consecutive days of daily daytime data with at least 
4 complete daily time periods, starting from the day after or on the Screening visit (or Re-Screening 
as appropriate) up to treatment start date (i.e. the 9-day time period should fall entirely before or 
on treatment start date). To be considered evaluable, physical activity should have been measured 
for at least 4 complete daily daytime periods (out of 9 consecutive days) at baseline. A complete 
day is defined as a record of at least 7 hours of daily daytime data.


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2.5.2. Study treatment start date
This is the “Treatment start date” (defined as the date of the first dose of study treatment intake) 
from the first interval, in chronological order, recorded in the “Study Drug Log” eCRF module. If 
missing, the randomization date will be used.
2.5.3. Study treatment end date / End of Treatment (EOT)
This is the “Treatment end date” (defined as the date of the last dose of study treatment intake)
from the last interval, in chronological order, recorded in the “Study Drug Log” eCRF module. It 
is also called End of Treatment or permanent study treatment discontinuation. 
EOT is the date of the last dose of double-blind study treatment in AC-055H301 RUBATO study.
2.5.4. End of Study (EOS)
The EOS corresponds to the last visit in this AC-055H301 RUBATO study as described in 
Section 1.2 and directly available in the SDTM. The EOS visit date does not include the Vital 
Status Follow up. 
2.6.
Imputation Rules for Missing/Incomplete dates and times fields
All dates and times used in the analyses are supposed to be complete, apart from the types included 
in Table 8.
In the following, ‘lower limit’ and ‘upper limit’ refer to the minimum or maximum, respectively, 
of a possible date. For example, if the day is missing, the lowest limit is the first day of the given 
month and the upper limit is the last day of the given month. If the day and month are missing, the 
lower limit refers to the first day of the given year and the upper limit to the last day of the given 
year. The earliest and the latest of different dates refer to the first or last date, respectively, when 
ordered in sequence.
Table 8:
Imputation Rules for Missing/Incomplete dates and times fields
Type of date 
Date is incomplete
Date is missing
Adverse Events
AE resolution date
The upper limit.
No replacement, the AE is 
considered as ongoing in the 
analysis.
AE onset date
If the end date of the AE is not 
before the study treatment start date 
and if the study treatment start date 
falls in the range of possible dates, 
the study treatment start date is 
used. In all the other cases, the 
lower limit is used.
The earliest between the 
resolution date and the study 
treatment start date.


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Type of date 
Date is incomplete
Date is missing
Fontan surgery completion and Medical History
Date of last Fontan 
surgery completion
Day missing: 15th of the month
Day and month missing: 30th of 
June
No replacement.
Medical history end date
The upper limit.
No replacement.
Medical history start date
The lower limit.
No replacement.
Medications
Previous/Concomitant 
medication end date
The 
upper 
limit 
unless 
the 
medication started prior to study 
treatment start (or start date is 
missing) and ‘Ongoing at start of 
treatment?’ is ticked ‘No’, and the 
upper limit is after the study 
treatment start (DB) and the study 
treatment start falls in the range of 
possible dates then it is replaced 
with treatment start date - 1.
If the medication started 
prior to study treatment start 
and ‘Ongoing at start of 
treatment?’ is ticked ‘No’, 
then it is considered a 
previous medication and it is 
imputed with treatment start 
date -1.
Previous/Concomitant 
medication start date
The lower limit except when:
not tagged as ongoing at start of 
treatment 
AND
the therapy end date is not collected 
or with the upper limit after the 
study treatment start date or the end 
date is after the study treatment 
start date
AND 
the study treatment start date falls 
in the range of possible dates
in which case it is the study 
treatment start date.
No 
replacement, 
the 
medication is considered to 
have started before the date 
of consent.
For determining treatment duration and emergent periods


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Type of date 
Date is incomplete
Date is missing
Treatment start date
- Day is missing: replaced by the 
day of the randomization date. In 
the 
case 
the 
day 
of 
the 
randomization is in the previous 
month, replace the day by the lower 
limit.
- Day and month are missing: 
replace 
entirely 
by 
the 
randomization date.
Replace entirely by the 
randomization date. 
Treatment end date (EOT)
Use the earliest date among:
upper limit
EOS
date of death.
Use the earliest date among:
EOS
date of last contact
date of death.
EOS
The upper limit.
Raw extraction date.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
This study implemented one IA for unblinded sample size re-estimation. There is no early stopping 
for efficacy or early stopping for futility at the IA. The full type I error rate of 1% (two-sided) is 
spent only at final analysis.
The IA was conducted by an ISAC/SSG for the IDMC to allow unblinded sample size 
re-estimation. The IA took place when the first 95 randomized subjects had completed their Week 
16 Cardiopulmonary Exercise Testing (CPET) assessment or withdrew from the study without a 
Week 16 CPET assessment (this corresponds to a 16-week information fraction for the primary 
efficacy endpoint of approximately 70% of the pre-planned sample size of 134 subjects). The data
cut off applied for the IA was 11-Feb-2020.
Detailed guidelines for interim decision-making are described in the SAP, dated 25 February 2020 
(D-20.077) for the purpose of the Special Protocol Assessment (SPA) submission of protocol 
Version 8 to the US Food and Drug Administration (FDA). The SAP for SPA outlines the 
statistical methods and analyses to be applied for the primary efficacy endpoint for the sample size 
re-estimation and it was used as reference by the ISAC/SSG.
The ISAC/SGG made unblinded results available to the IDMC. The IDMC reviewed the interim 
results and made corresponding recommendations in line with the IDMC charter. The 
recommendation related to the IA was provided to the Sponsor Committee only after all approvals 
(both IRBs/IECs and Health Authorities) of the relevant protocol for subjects contributing to the 
IA had been received. Based on the IDMC meeting of 7 April 2020, the IDMC recommended to 
keep the target sample size at 134 subjects, without sample size adjustment. When the IDMC 
recommendation related to the IA was received (i.e., 23 June 2020), a total of 141 subjects were 


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randomized into the study. The recruitment was closed with no possibility of new screening 
activities. Those subjects in screening were continued to be evaluated for eligibility into the study 
if all criteria were met. A total of 142 subjects were randomized into the study.
Furthermore, periodic IDMC meetings are scheduled to review safety and efficacy data according 
to the IDMC charter. Separate IDMC SAPs (D-18.337 9 March 2020 for AC-055H301/RUBATO 
and D-20.079 9 March 2020 for AC-055H302/RUBATO-OL) are provided for data monitoring 
committee review. The IDMC SAPs describe in detail the statistical analyses and presentation of 
the data for the open session of the IDMC meetings. These outputs provide support to the 
ISAC/SSG to ensure the studies are conducted to high scientific and ethical standards.
SUBJECT INFORMATION
The number of subjects in the ENR will be presented overall while the number of subjects in each 
analysis set (i.e., FAS, PP1, PP2, PP3, SS, and PKS) will be summarized and listed by treatment 
group and overall. 
Listings will be provided displaying the following information:

Subject membership in the different analysis sets (PP1, PP2, PP3, SS, PKS). Subjects in 
the ENR and not randomized will not be displayed. This listing will be run on FAS.

Reasons for exclusion from the population definitions for estimand (i.e., PP1, PP2, PP3). 
Reasons for exclusion from PP1, PP2, and PP3 will be summarized by treatment group on the 
FAS. Reasons for exclusion from PKS will be covered in Section 8.
In addition, the distribution of subjects by geographical region, country, and site ID by treatment
group and overall will be presented.
4.1.
Demographics and Baseline Characteristics
For re-screened subjects, the data assessed during the last screening attempt (i.e., re-screening 
visit) will be included in the analysis of demographic and baseline characteristics. The data coming 
from the first screening attempt will be included, if not available at re-screening.
4.1.1. Demographics
Table 9 presents a list of the demographic variables that will be summarized by treatment group
and overall for the FAS. Demographics will also be summarized by subgroups as defined in 
Section 2.3, using the FAS.
Table 9:
Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum], and IQ range).
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2)
Categorical Variables
Age (12– <18, 18– <30, 30–<40, 40-<65, = 65)
Sex (male, female)


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Race (, American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander White, Other, Not 
Applicable)
Frequency distribution with the 
number and percentage of subjects 
in each category.
Ethnicity (Hispanic or Latino, not Hispanic or Latino, Unknown)
Geographical region (America, Europe, Asia, Oceania)a
Region (US, Non-US)
BMI ([underweight <18.5 kg/m2, normal 18.5-<25 kg/m2, overweight 25-
<30 kg/m2, obese class I 30-<35 kg/m2, obese class II 35-<40 kg/m2, obese
class III ≥40 kg/m2]) b
a Countries will be assigned to geographical region based on the Standard Country or Area Codes for Statistical Use 
(M49) standard.
b For adolescents (boys or girls) between 12 and 18 years, BMI-for-age reference equivalent to BMI cutoffs 
for adults are calculated as provided in Attachment 1.
Individual subject’s listing will be provided on the FAS.
4.1.2. Baseline Disease Characteristics
Table 10 presents a list of the baseline disease characteristics that will be summarized by treatment 
group and overall for the FAS. Baseline characteristics will also be summarized by subgroups as 
defined in Section 2.3, using the FAS.
Table 10:
Baseline Disease Characteristics Variables
Continuous Variables:
Summary Type
SpO2 (%) at baseline
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum], and IQ range).
NT-proBNP (pmol/L) at baseline
Peak VO2 (mL/kg/min) at baseline
Mean count per minute of daily Physical Activity at baseline 
Daily mean activity time in min (sedentary, light, moderate, vigorous)
Time since Fontan palliation completion (years)
Categorical Variables
NYHA FC
PAH specific therapies concomitant at start of study treatment
% of the daily mean total activity time spent in sedentary, light, moderate, 
or vigorous (including very vigorous for adults) at baseline
Congenital heart defect leading to Fontan-palliation
Frequency distribution with the 
number and percentage of subjects 
in each category.
Dominant ventricular morphology (left and right/mixed)
Staged reconstructive surgeries performed before completion of the Fontan 
circulation
Type of primary TCPC Fontan completion
Type of secondary TCPC Fontan completion (TCPC=total cavopulmonary 
connection)
Fenestration Status
Below the details for the derivation of the variables in the table above, as needed.
Fontan History and Fontan completion / TCPC surgery

Congenital heart defect leading to Fontan-palliation (i.e. information collected in the eCRF 
“Fontan history” module, “Cardiac malformation” section) and associated dominant 
ventricular morphology (i.e., left and right/mixed),


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
Staged reconstructive surgeries performed before completion of the Fontan circulation 
(Norwood, Glenn, etc.) [i.e. information collected in the eCRF module “Fontan history”, 
“Single Ventricle: Surgery” section],

Type of current total cavopulmonary connection TCPC (LT-TCPC, EC-TCPC) and whether 
TCPC is primary or secondary [i.e., information collected in the eCRF form for “Fontan 
completion / TCPC surgery”],

Fenestration status (no never had; no initially yes, now closed; yes is open; yes initially no, 
now open) [i.e., information collected in the eCRF form for “Fontan completion / TCPC 
surgery”],

Time since Fontan palliation completion (years), defined as the time from the last Fontan 
surgery to screening (or re-screening as appropriate). It is calculated by firstly taking the 
difference between the date of screening and the date of the last Fontan surgery completion 
and secondly by dividing the result by 365.25.
PAH specific therapies concomitant at start of study treatment

PAH specific medications concomitant at start of study treatment (see Section 4.7.2 for 
definition). Pulmonary hypertension specific medications include: sildenafil, sildenafil 
citrate, tadalafil, vardenafil, udenafil, iloprost, beraprost, epoprostenol, treprostinil, 
selexipag, bosentan, ambrisentan, riociguat (as qualified by the corresponding preferred 
term).
Physical Activity measured by Accelerometer (PA-Ac) at baseline

Mean count per minute of daily PA-Ac at baseline,

Daily mean time spent in sedentary, light, moderate, or vigorous (including very vigorous for 
adults) at baseline.
% of the daily mean total activity time spent in sedentary, light, moderate, or vigorous (including 
very vigorous for adults) at baseline. The accelerometry central reading facility will read daily 
counts/min and will analyze duration of daily activity and time (minutes) spent in sedentary, 
light, moderate, and vigorous physical activity based on the (Freedson 1998) and (Evenson 2008)
cut-points for adults and adolescents, respectively. These data will be transferred to the Sponsor.
Mean counts per minute of daily PA-Ac are calculated by dividing the sum of all activity counts 
collected during wear time for a complete day by the number of minutes of wear time in that day 
across all complete days (at least 4 days out of 9 days). A complete day is defined as a record of 
at least 7 hours of daily daytime data i.e. a complete day if “WearMinutes” >=7*60, (after 
excluding the periods when the device was apparently not worn). In summary, to compute the 
mean counts per minute of daily PA-Ac, it is necessary to identify all complete days; if less than 
4 complete days out of 9 are identified then the baseline is missing, otherwise, if at least 4 
complete days out of 9 are identified, then calculate the baseline on the complete days only.
Individual subject’s listings will be provided on the FAS.
4.2.
Medical history
Includes relevant medical history / current medical conditions/findings based on investigator’s 
judgment present before and/or at the time of signing informed consent as collected during the 
screening visit on the “Medical history” eCRF module.


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The original terms used by the investigators are assigned preferred terms for classification and 
tabulation using the latest implemented version of Medical Dictionary for Regulatory Activities 
(MedDRA).
Medical history is summarized, by treatment group and overall, displaying counts and percentages 
of subjects having been diagnosed with at least one disease. Counts and percentages of subjects 
having been diagnosed with at least one disease are presented by system organ class (SOC) and 
PT within each SOC as well as by PT. The summary tables are presented in descending order 
according to the incidence in the macitentan treatment group (e.g., SOC and PT within each SOC 
with the highest number of occurrences appears first). Equal frequency of different SOC/PTs is 
sorted in alphabetical order of the SOC/PT. Subjects with two or more occurrences of the same 
disease (as qualified by the same PT) are counted only once.
The summary tables will be provided on the FAS.
The medical history is also reported in a subject listing on the FAS.
4.3.
Disposition Information
The following definitions are relevant to provide the disposition information:
4.3.1. Screened Subjects and Screening Failures
It is permitted to re-screen subjects once, if the reason for non-eligibility was transient (e.g., 
abnormal laboratory test, insufficient wash-out period of a forbidden medication). All screening 
assessments should then be repeated at the time of re-screening.
If a subject is screened twice and not randomized, the reason associated with the second screening 
attempt is considered in this analysis. If a subject is screened twice and then randomized, the first 
screening attempt is not considered in the evaluation of screening failures. 
A subject is considered a screening failure if he/she signed the informed consent (i.e., available 
date of informed consent) but was eventually not randomized as identified from the answer to the 
eCRF question “Was the subject randomized?”. If the answer to this question is “No”, the reason 
provided in the eCRF (‘Subject withdrew consent’, ‘Not eligible as per inclusion/exclusion 
criteria’, ‘Lost to follow-up’ or ‘Other’) is used as the primary reason for screening failure. 
The number and percentage of subjects in the following disposition categories will be summarized
overall on the ENR, to display the following information:

Screened subjects (i.e., ENR analysis set)

Screen failures and reasons for discontinuation during screening.
A subject listing (including the inclusion criteria not met or the exclusion criteria met as collected 
in the “Eligibility Criteria” eCRF module) will be also provided for screening failures. 


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4.3.2. Study and Study Treatment Disposition
The number and percentage of subjects in the following disposition categories will be summarized
by treatment group and overall on the FAS, to display the following information:

Subjects randomized 

Subjects receiving study treatment 

Subjects completing the double-blind study treatment up to Week 52

Subjects completing the study participation

Subjects who terminated the study prematurely and reasons for premature termination of the 
study (see Section 4.3.2.2)

Subjects who entered the PTOP (i.e., subjects with PTOP or End-of-post-treatment 
observation period [EOP] visit performed)
The number and percentage of subjects in the following disposition categories will be summarized
by treatment group and overall on the SS, to display the following information:

Subjects who discontinued the study treatment prematurely and reasons for premature 
discontinuation of study treatment (see Section 4.3.2.1).
4.3.2.1.
Study Treatment Discontinuation
Premature study treatment discontinuation (before Week 52) are collected in the “Study Drug Log”
eCRF module and identified as those with a treatment end date and associated reason (‘What was 
the reason for treatment end?’) answered ‘Premature Discontinuation’. Reasons for study 
treatment discontinuation are collected in the “Premature Discontinuation of Study Treatment’
eCRF module. The full list of reasons is the following:

Death

Lost to follow-up

Pre-specified study treatment discontinuation criteria

Subject decision (AE, Lack of Efficacy, No reason provided, Other [medical/non-medical 
reasons])

Physician decision (AE, Other [medical/non-medical reasons])

Sponsor decision (Study termination, Other).
The distribution of the time to premature study treatment discontinuation will be displayed with 
Kaplan-Meier curves for the SS. Subjects who terminate treatment prematurely at any time will be 
considered an ‘Event’ and their date of study treatment discontinuation will be used in the time to 
event calculation. Subjects who complete the study treatment will be censored and the date of end 
of treatment will serve as the time of censoring. 


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4.3.2.2.
Study Discontinuation
Subjects who withdrew from the study are those with any withdrawal reason entered in the “Study 
Discontinuation” eCRF module. Possible reasons for study withdrawal are as follows:

Death

Lost to follow-up

Subject decision/withdrawal of consent (AE, Lack of Efficacy, No reason provided, Other 
[medical/non-medical reasons])

Physician decision (AE, Lack of efficacy, Other [medical/non-medical reasons])

Sponsor decision (Study termination, Other).
A subject who completed the study participation would have no data entered in the eCRF form
“Study Discontinuation” The EOS visit date is entered in the disposition SDTM domain as 
appropriate. 
The distribution of the time to study discontinuation will be displayed with Kaplan-Meier curves 
for the FAS. Subjects who prematurely discontinue from the study at any time will be considered 
an ‘Event’ and their date of study discontinuation will be used in the time to event calculation. 
Subjects who complete the study as per protocol will be censored and the date of end of study will 
serve as the time of censoring.
Listings of subjects will be provided for the following categories:

Randomization scheme and codes, including the stratification factor

Subjects who discontinued study treatment prematurely and related reason(s)

Subjects who terminated study prematurely and related reason(s)

Subjects who were unblinded during the study.
4.4.
Treatment Compliance
Study treatment compliance (%) is based on the study drug dispensing and accountability data 
recorded in the eCRF “Study Drug Dispensing & Accountability” module. 
Compliance assessed at each visit by site personnel is calculated and entered in the eCRF and is 
not (re-) calculated. The reasons for non-compliance since last visit are also collected.
4.4.1. Overall Compliance (up to EOT)
Overall compliance (up to EOT) = [(total number of tablets dispensed at any time total number 
of tablets returned )/ Total number of tablets that should have been taken during the treatment 
period] 100.
With the introduction of the COVID-19 protocol appendix, on-site visits could be performed 
remotely or delayed, and while study treatment may have been dispensed via direct-to-patient 
shipments, subjects were asked to return empty bottles/unused tablets only at their next on-site 
visit. For the compliance up to EOT, irrespective of whether a bottle is returned before, at, or after 


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EOT, corresponding tablets are considered as having been taken prior to EOT. The overall 
compliance will not be calculated for those subjects with any dispensed bottles that were never 
returned.
4.4.2. Compliance (up to the Week 16)
Compliance (up to the week 16 Visit) = [(total number of tablets dispensed at any time from Visit 
2 to the day before the Visit 4/Week 16 total number of tablets returned after Visit 2 and up to 
the Visit 4/Week 16)/ Total number of tablets that should have been taken up to the Visit 4/Week 
16] 100.
For the same reason as above, the compliance up to Week 16 will be calculated if all bottles 
dispensed to a subject between Visit 2 and the day before Visit 4/Week 16 are returned up to Visit
4.
Analysis of study treatment compliance data will be performed on the SS, by treatment group.
Compliance with study treatment will be displayed for two periods, from treatment start to Week 
16 and from treatment start to EOT (i.e., for the whole treatment period). 
Treatment compliance categorized as < 80%, 80–120%, and > 120% will be summarized on the 
SS for both periods.
Drug accountability data are provided in a subject listing on the SS.
4.5.
Extent of Exposure
4.5.1. Study Treatment Interruptions
Analysis of study treatment exposure will be performed on the SS.
A subject is considered to have had a study treatment interruption if the reason for treatment end 
is either ‘Temporarily interrupted due to an AE’ or ‘Temporarily interrupted not due to an AE’
(“Study Drug Log” eCRF form). 
4.5.2. Study Treatment Duration and Exposure
The study treatment duration (in weeks) is defined as the time interval between study treatment 
start date (see Section 2.5.2) and treatment end date (see Section 2.5.3) inclusive, regardless of 
treatment interruptions, calculated as:
	 	
 
 −	  
 + 1
7
Study treatment exposure (in weeks) by excluding treatment interruptions is derived as the [study 
treatment duration (days) - the sum of all treatment interruptions (days)]/7.
For the calculation of study treatment exposure: if the treatment end day is missing in case of a 
study treatment interruption, it is replaced by day 15th of the respective month. In the case that day 


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is before the treatment start of the same interval as reported in the “Study Drug Log” eCRF form, 
it is replaced by the treatment start day of that interval.
Descriptive statistics for duration of study treatment and study treatment exposure (N, mean, 
standard deviation [SD], median and range [minimum and maximum], and IQ range) will be 
presented by treatment group. 
In addition, the cumulative distribution of treatment duration by different class intervals (i.e., at 
least 4 weeks, at least 8 weeks, at least 16 weeks, at least 24 weeks, at least 32 weeks, and at least 
52 weeks) will be summarized to show counts and percentages of subjects in each class interval. 
Study treatment duration will be summarized in the following duration categories: <4 weeks, 4-<8 
weeks, 8-<12 weeks, 12-<16 weeks, 16-<24 weeks, 24-<32 weeks , 32-<52 weeks, ≥52 weeks by 
treatment group and presented graphically in a histogram.
Subjects-year of treatment are calculated as [sum of study treatment duration (in days) for each
subject/365.25]. “Total study treatment duration (subjects-year)” will be displayed by treatment
group.
Exposure data will be provided in a subject listing on the SS.
4.6.
Protocol Deviations
All PDs have been categorized into the following category levels prior to database lock by an 
independent team (as documented in ATTACHMENT 3):

Developed withdrawal/interruption criteria but not withdrawn/interrupted

Entered but did not satisfy criteria

Received a disallowed concomitant treatment

Received wrong treatment or incorrect dose

Other
The analyses of PDs will be based on the FAS.
Subjects with important (i.e., major) PDs will be summarized by displaying the counts and 
percentages of subjects with at least an important PD by treatment group and overall. The summary 
table will be sorted by category. A separate similar summary of important PDs will be provided 
by geographical region and site.
A summary of subjects who did not meet inclusion criteria or who met exclusion criteria will be 
presented by treatment group and overall on the FAS.
All reported PDs will be described in a subject listing. Important PDs will be flagged accordingly.
A listing of subjects who received incorrect study treatment (if applicable) will be provided as 
well.


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4.7.
Prior and Concomitant Medications
All therapies as collected in the “Previous/Concomitant Medication” eCRF module.
The original terms used by the investigators to describe therapies are assigned preferred terms for 
classification and tabulation using the latest version of the World Health Organization (WHO)
Drug code and Anatomic Therapeutic Chemical (ATC) class code dictionaries.
4.7.1. Prior Medications
Previous therapy is defined as any therapy with an end date on or prior to the date of informed 
consent.
If the end date is missing and the start date is prior to the date of informed consent, then the therapy 
is considered as previous if the checkbox for the questions ‘Ongoing at start of treatment?’ and 
“Ongoing at End of Study?” are ticked ‘No’ by the investigator in the eCRF. 
4.7.2. Study treatment concomitant medications
Study treatment concomitant therapy is any treatment that is either ongoing at the start of study 
treatment or is initiated during the double-blind treatment period, identified as:

‘Ongoing at start of treatment? = Yes’ ticked by the investigator in the eCRF,
or

Start date before treatment start date and end date on or after treatment start date,
or

Start date before treatment start date and end date missing with ‘Ongoing at start of treatment?’
≠ No’, 
or

Start date on or after treatment start date and before study treatment end.
Concomitant therapies at start of treatment is any treatment that is either ongoing at the start of 
study treatment or is initiated at the start date of study treatment, identified as:

‘Ongoing at start of treatment? = Yes’ ticked by the investigator in the eCRF,
or

Start date before or on treatment start date and end date on or after treatment start date,
or

Start date before or on treatment start date and end date missing with ‘Ongoing at start of 
treatment?’ ≠ No’.
Counts and percentages of subjects having taken at least a study-treatment concomitant therapy
will be presented, separately, by ATC class and PT within each ATC class as well as by PT. The 
summary table will present therapies in descending order according to the incidence in the 
macitentan treatment group (e.g., ATC and PT within each ATC with the highest number of 
occurrences appear first). Equal frequency of different ATC/PTs will be sorted in alphabetical 


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order of the ATC/PT. Subjects who took more than once the same therapy (as qualified by the 
same PT) will be counted only once.
Previous therapies will be summarized by ATC class and PT within each ATC class.
Individual subject’s listing will be provided. Previous and study treatment concomitant therapies 
are flagged accordingly.
EFFICACY
The hierarchical testing will be applied to the primary and secondary efficacy endpoints as 
represented in Figure 4 below. 
Conditional to conclusive or positive outcome of the primary efficacy endpoint results at final 
analysis (i.e., if the primary endpoint is statistically significant at a significance level α=1% or 5%
two-sided), the secondary efficacy endpoints will be formally evaluated at the same significance 
level as the primary efficacy endpoint according to the testing hierarchy following the order of the 
endpoints as listed in Section 5.3. For example, if the test of the first secondary efficacy endpoint 
is statistically significant at 1% two-sided, then the test of the other secondary endpoint in the 
hierarchy can be formally performed at the same significance level. The formal testing process 
will stop when a test is not statistically significant at 1% two-sided level. 
The stratification factor (i.e. geographical region) coming from the randomization assignment will 
be included in the analysis/model of the efficacy endpoints (when appropriate).
The number of missing data for primary and secondary efficacy endpoints will be monitored on a 
blinded fashion during the dry run review process. Additional sensitivity analyses may be added 
and justified, if deemed appropriate.
5.1.
Analysis Specifications
5.1.1. Level of Significance
The overall type I error rate is 1% two-sided, fully spent at final analysis. 
The study will be declared to show conclusive evidence of efficacy if the test of the primary 
efficacy endpoint is statistically significant at a significance level α = 1% two-sided. Otherwise, if 
the test is statistically significant at a significance level α = 5% two-sided, the study will be 
declared to show ‘positive’ evidence of efficacy. Secondary efficacy endpoints will be analyzed at 
the same significance level as the primary efficacy endpoint using a hierarchical testing procedure 
following the order of the endpoints as listed in Figure 4.


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Figure 4:
Testing strategy for primary and secondary efficacy endpoint at final analysis (2-sided type I 
error rate, α=1% or 5%)
To control the type I error against the unblinded sample size re-estimation at the interim timepoint, 
the final analysis of the primary and secondary efficacy endpoints will be conducted using the 
inverse normal combination method with pre-specified weights to combine first and second stage 
p-values (Lehmacher 1999).
Table 11 presents an overview of the set of subjects in each stage and the pre-defined weights for
the inverse normal method at each stage used at the final analysis of primary and secondary 
efficacy endpoints. The pre-specified weights used for the main analysis are proportional to the 
pre-planned sample size of 134 subjects.  
Peak VO2 at Week 16
Peak VO2 over 52
weeks
Mean count per minute 
of daily PA-Ac at 
Week 16


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Table 11:
Significance level, set of subjects and weights for inverse normal combination method at final analysis
Endpoint
Analysis time 
point
Significance level
Inverse normal combination method
,
α
Stage 1
Stage 2
Subjs
Weight
Subjs
Weight
Primary 
endpoint: Peak 
VO2 at Week 
16
Final
cfinal=2.576*
1%   2-
sided*
	1 = 95
√ with 1: =
!"
!#
1 = 95
134
& = 0.841994789
Remaining 	* = 
	∗−	 =
142 −95 = 47
&1 − := 
-1 −
95
134
= 0.539485659
Secondary 
endpoint: Peak 
VO2 over 52 
weeks
Secondary 
endpoint: mean 
count 
per 
minute of daily 
PA-Ac 
at 
Week 16
/0123,45!67: Weighted inverse-normal combination (WINC) test statistic at final analysis. 845!67= 2.575829
	:= 95 Actual number of subjects who have completed Week 16 CPET assessment (or withdrew from the study without a Week 16 CPET assessment) before the data cutoff (i.e. 11-Feb-
2020) for the interim analysis (i.e., analysis time point 1).
 =
!"
!# =
9:
;< : 16-week information fraction for the evaluation of the primary efficacy endpoint with 	= = 134 >?@8 (pre −planned total sample size)
	*: 	∗−	 = 142 - 95 = 47 subjects where 	∗is the actual total sample size after the IA results.
* The secondary efficacy endpoints will be formally evaluated at the same significance level as the primary efficacy endpoint according to the testing hierarchy, and 
conditional to conclusive/positive outcome of the primary efficacy endpoint results at final analysis.


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5.1.2. Data Handling Rules
For both the primary and secondary endpoints, the corresponding estimand section describes data 
handling rules.
Baseline definitions are provided in Section 2.5.1.
5.2.
Primary Efficacy Endpoint(s)
5.2.1. Definition
The primary efficacy endpoint is the change in peak VO2 (mL/kg/min) from baseline to Week 16, 
defined as:
peak VO2 (mL/kg/min) at Week 16 - peak VO2 (mL/kg/min) at baseline
Peak VO2 is measured during CPET. The values used for peak VO2 at baseline and at Week 16 
will be included based on a blinded data evaluation by the independent central reading facility, as 
reported in the eCRF.
For Week 16, the assessments (including the unscheduled ones) will be mapped to the Week 16 
time window based on the Study Day (see Section 2.1). Any assessment in the Week 16 time 
window, irrespective of premature study treatment discontinuation before Week 16, will be 
included in the main analysis based on a ‘treatment-policy’ estimand strategy. 
5.2.2. Estimand
The primary objective is to assess the effect of macitentan 10 mg on exercise capacity (as assessed 
by peak VO2) in comparison with placebo in Fontan-palliated subjects.
Hence the primary estimand is defined as: 
A. Population: All randomized Fontan-palliated adult and adolescent subjects defined through 
protocol inclusion/exclusion criteria (ie, FAS).
B. Variable: peak VO2 as change from baseline to Week 16.
C. Intercurrent events:

Death occurring before Week 16.
A composite strategy will be applied: in case of death prior to Week 16, the change from 
baseline to Week 16 will be replaced with the lowest observed change in peak VO2 from 
baseline to Week 16 across both treatment groups (i.e., worst-case imputation).

Non-missing peak VO2 value at Week 16 assessed as ‘invalid’ by the central reading 
facility.
A composite strategy will be applied: in case an assessment at Week 16 has been evaluated as 
“invalid” by the independent central reading facility, it will not be included in the analysis and 
the change from baseline to Week 16 will be imputed with the 25th percentile of the observed 


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changes in peak VO2 from baseline to Week 16 (across both treatment groups). If this leads to 
an improvement (a positive change), a change of 0 (no change) will be imputed.

Premature study treatment discontinuation before Week 16
Premature study treatment discontinuation prior to Week 16 will be addressed by a 
“treatment-policy” strategy by including any assessment in the Week 16 time window, 
irrespective of premature study treatment discontinuation, in the main analysis.
D. Population-level summary measure: difference in mean change in peak VO2 from baseline 
to Week 16 between macitentan 10 mg and placebo, as estimated from the ANCOVA model. 
5.2.3. Analysis Methods
5.2.3.1.
Hypotheses and statistical model
The statistical hypotheses for the primary endpoint are formulated in terms of the arithmetic means 
(M) of change in peak VO2 in subjects treated with either placebo or macitentan 10 mg from 
baseline to Week 16.
H0: M macitentan 10 mg = M placebo versus
HA: M macitentan 10 mg ≠ M placebo
The null hypothesis will be tested on the primary variable at a two-sided Type I error rate of 1% 
for conclusiveness based on the inverse normal combination method.
Assuming normal distribution of the primary variable, the ANCOVA model on the change in peak
VO2 will be applied to derive the first-stage and second-stage p-values for the final analysis (see 
Section 5.2.3.3). Model covariates will include randomized treatment group, stratification factor 
(ie, geographical region) and peak VO2 at baseline. 
It is expected to have a negligible incorrect stratification assigned during the randomization
therefore the analysis is based on the stratification factors coming from the randomization 
assignment.
Assumptions of normality will be assessed with graphical diagnostics tools for the fit (i.e., fitted 
normal distribution function displayed on cumulative distribution function of the change from 
baseline to Week 16 [after applying imputation rules for handling of intercurrent events or missing 
data] by treatment group).
Assumptions of normality of residuals and homogeneity of variance (assessment of ANCOVA 
model assumptions) will be investigated and graphically presented (eg, Q-Q and residual plots). 
5.2.3.2.
Handling of missing data for the main analysis
Missing values for peak VO2 at baseline are not allowed by protocol, but in case a subject has been 
randomized with a non-missing baseline value that has subsequently been evaluated as “invalid”
by the independent central reading facility, it will be imputed with the median peak VO2 value 
observed at baseline from the remaining subjects (across treatment groups).


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During the conduct of the study, all efforts will be made to avoid missing values in peak VO2 at 
Week 16. If a subject discontinues treatment prematurely, a CPET will be conducted within 7 days 
of EOT. Furthermore, if treatment is discontinued prior to Visit 4/Week 16, and the subject enters 
the PTOP, it is requested that the subject returns for a CPET assessment at Week 16 (in addition 
to the EOT assessment).
Intercurrent events will be handled as defined in Section 5.2.2. Any missing values which may 
occur in peak VO2 at Week 16 will be handled as in the table below.
Reason
Strategy in handling the change from baseline to Week 16
Other*
Imputed with the 25th percentile of the observed changes in peak VO2 from 
baseline to Week 16 (across both treatment groups). If this leads to an 
improvement (a positive change), a change of 0 (no change) will be imputed.
   *Other could include: premature study treatment discontinuation because of an adverse event, lack of efficacy, or 
lost-to follow up and without a CPET assessment at Week 16.
CPET=Cardiopulmonary Exercise Testing, VO2=Oxygen uptake/consumption. 
5.2.3.3.
Main analysis
The main analysis of the primary efficacy endpoint will be conducted using the inverse normal 
combination method with pre-specified weights to combine first and second stage p-values (see
details in Section 3.2.3 of the SAP for SPA).
The separate first-stage analysis will be based on the first-stage set of subjects contributing to the 
IA. The first-stage p-value from the analysis of covariance (ANCOVA) model including 
randomized treatment, stratification factor (i.e., geographical region), and peak VO2 at baseline as 
covariates in the model will be used to construct the first stage p-value as used in the final analysis 
in the weighted inverse-normal combination (WINC) test statistic at final analysis.
The separate second-stage analysis will be based on the remaining number of subjects required to 
reach the total sample size based on the IA results. Due to the population-wise splitting, no subjects 
contributing to the separate first-stage test statistics are included into the separate second-stage 
analysis. The second-stage p-values will be calculated in the same way as the first-stage p-value.
The primary and secondary endpoints will be tested by combining p-values from the separate first 
and second stage analyses using the inverse-normal combination function with prefixed weights 
(i.e., see Table 11 in Section 5.1.1).
Final interpretation of the results will then be based on the final adjusted p-value, median unbiased 
estimator for the overall treatment effect and corresponding RCIs obtained by ADDPLAN™6.1 
(ADDPLAN Inc. an Aptiv Solutions Co. 2014). Practically, the analysis will be conducted using 
ADDPLAN BASE module, “Adaptive Analysis” menu, “Test of means” functionality with the 
computation options specified in Section 3.2.3 of the SAP for SPA.
The number of subjects with intercurrent events or missing data will be presented by treatment 
group. Absolute values at baseline and at Week 16 as well as absolute change in peak VO2 from 


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baseline to Week 16 (after handling of intercurrent events or applying imputation rules for missing 
data) will also be summarized using descriptive statistics by treatment group.
To graphically display changes in peak VO2, results are visualized by means of a scatter plot of 
peak VO2 values at baseline versus Week 16 (after handling of intercurrent events or applying 
imputation rules for missing data) for each treatment group. Subjects with imputed values for peak 
VO2 are highlighted with different colors/symbols in the graph. The scatter plot is displayed with 
the reference line y = x.
5.2.3.4.
Supportive/sensitivity analyses
Absolute values at baseline and at Week 16 as well as absolute change in peak VO2 from baseline 
to Week 16 will also be summarized using descriptive statistics, for each supportive and sensitivity 
analysis where applicable.
i.
Additional estimands
Additional estimands will be assessed as defined in the tables below. The same ANCOVA model 
as the one described for the primary estimand (see Section 5.2.2) will be applied, based on the 
population wise splitting as applied for the main analysis. 
Table a
Additional Estimand 1 (PP1)
A.
Population: All subjects who received study treatment as assigned by IRT and who complied with the protocol 
sufficiently up to and including the Week 16 for the primary efficacy endpoint (ie, PP1). Protocol deviations 
are defined in Section 2.2.3.
B.
Variable: same as for primary estimand (see Section 5.2.2)
C.
Intercurrent events and strategies: same as primary estimand (see Section 5.2.2)
D.
Population-level summary measure:. same as the ANCOVA model of the primary estimand (see Section
5.2.2)
ANCOVA=Analysis of covariance, IRT=Interactive Response Technology, =PP1=Estimand Population for primary 
efficacy endpoint, VO2 = Oxygen uptake/consumption.
Table b
Additional Estimand 2 (excluding subjects with invalid peak VO2 at baseline)
A.
Population: same as primary estimand (FAS) but excluding subjects with invalid peak VO2 at baseline (see 
Section 5.2.2).
B.
Variable: same as for primary estimand (see Section 5.2.2).
C.
Intercurrent events and strategies: same as primary estimand (see Section 5.2.2).
D.
Population-level summary measure:. same as the ANCOVA model of the primary estimand (see Section
5.2.2).
ANCOVA=Analysis of covariance, FAS=Full Analysis Set, VO2 = Oxygen uptake/consumption.
Table c
Additional Estimand 3 (“while on treatment”)
A.
Population: same as primary estimand (FAS) 
B.
Variable: same as for primary estimand (see Section 5.2.2) except that the assessments in the Week 16 time 
window will only be included in the analysis if they are performed while ‘on-treatment’, defined as up to 7 days 
after last dose of study treatment. 
C.
Intercurrent events and strategies: same as primary estimand (see Section 5.2.2) except that death up to Week 
16 will be considered if occurred up to 7 days after last dose of study treatment. In addition, premature study 
treatment discontinuation before Week 16 are captured through the variable definition.
D.
Population-level summary measure: same as the ANCOVA model of the primary estimand [see Section 5.2.2]
ANCOVA=Analysis of covariance, FAS=Full Analysis Set, VO2 = Oxygen uptake/consumption.


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ii.
Sensitivity analyses of the primary estimand
1. Estimator based on the inverse normal combination method with weights proportional to the 
final actual sample size (i.e., 142 subjects) - to assess the robustness of result when the weights 
are proportional to the actual sample size of 142 subjects.

Same population, same variable, same intercurrent events, and same handling of missing 
data as defined for the primary estimand (Section 5.2.2). 

Same ANCOVA model as defined for the primary estimand (Section 5.2.2) with pre-
specified weights proportional to the actual sample size of 142 subjects (i.e., 
√ = -
95
142 = 0.817932812 for the 1st stage and &1 − = -1 −
95
142 = 0.575313754
for the 2nd stage.
For the primary estimand, the following sensitivity estimators (sensitivity analysis) or additional 
estimand will be evaluated, not controlling for the adaptive design and not based on the population 
wise splitting approach as applied for the main analysis. 
Where applicable, the resulting LS means and corresponding 95% and 99% CLs obtained in each 
treatment group, and the LS means differences (95% and 99% CLs) for macitentan 10 mg vs 
placebo will be provided for the following analyses.
2. Estimator based on standard ANCOVA (pooled) – to test statistical hypothesis disregarding 
the adaptive design for the primary estimand on FAS and for Estimand 1, 2, and 3 as specified 
above in Table a, Table b, and Table c, respectively.

Same population, same variable, same intercurrent events, and same handling of missing 
data as defined for the primary estimand (Section 5.2.2). 

Same ANCOVA model as defined for the primary estimand (Section 5.2.2) carried out on 
the total sample size (without the population wise splitting approach for the control of the 
adaptive design).
3. Additional Estimand based on observed cases – to assess the robustness of results without 
imputation for missing values

Same population, same variable as defined for the primary estimand (Section 5.2.2). 
Intercurrent events will not be considered. Missing (or invalid) peak VO2 at baseline and 
at Week 16 will not be imputed.  

Same ANCOVA model as defined for the primary estimand (Section 5.2.2).
4. Estimator based on ranks (a) – non-parametric analysis to address possible deviations from the 
normality assumptions 

Same population, same variable, same handling of intercurrent events, same imputation 
rules for missing data as defined for the primary estimand (Section 5.2)

ANCOVA based on ranks. Ranking will be performed on the primary variable (change in 
peak VO2 from baseline to Week 16) and the baseline peak VO2 after addressing
intercurrent events or applying rules for missing data as defined (Section 5.2)


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The non-parametric ANCOVA procedure incorporates three steps:
a) Transformation of changes from baseline to Week 16 and baseline values for all 
subjects (regardless of treatment groups) to standardized ranks (i.e., ranks divided by 
the number of subjects ranked plus 1, mean ranks in case of ties).
b) Determination of residuals from the linear regression of the response variable 
standardized ranks on baseline variable standardized ranks. 
c) Application of the one-sided Wilcoxon-Mann-Whitney test to these residuals. The 
standardized test statistic with a continuity correction of 0.5 is asymptotically standard 
normally distributed under the null hypothesis. Two-sided significance level of 0.05 is 
used.
5. Estimator based on ranks (b) non-parametric analysis to address possible deviations from the 
normality assumptions

Same population, same variable as the primary estimand (as defined in Section 5.2.2)

ANCOVA based on ranks. Ranking will be performed as follows:
o
Missing Week 16 values due to subject’s death prior to Week 16 will receive a rank 
score corresponding to a value of the measurement that is worse than any actually 
observed value.
o
Missing Week 16 values for any other reason will receive a rank score corresponding 
to a value of the measurement that is worse than any actually observed value but better 
than subjects who have died prior to Week 16. Adjustments on ranking will be applied 
in order that:
rank (subjects who die) < rank (subjects with missing values) < rank (subjects without missing values).
To guarantee the above condition the ranking will be performed as follows:
o
For subjects who died prior to their Week 16 assessment, missing Week 16 values will 
be imputed with an arbitrary value of -10000
o
For invalid peak VO2 at Week 16 or other conditions causing a missing Week 16 value
(see Section 5.2.3.2), the Week 16 value will be imputed with an arbitrary value of -
5000
o
Changes from baseline will then be calculated using the observed Week 16 values if 
available or the imputed value (i.e., -10000 or -5000 as defined above) 
o
Ranking will be performed on the baseline peak VO2 variable and on the changes from 
baseline to Week 16 in peak VO2.
Same non-parametric ANCOVA procedure as applied above will be incorporated.
6. Estimator based on different model 2 (by adding NYHA functional class at baseline)

Same population, same variable, same handling of intercurrent events, same imputation 
rules for missing data as defined for the primary estimand (Section 5.2.2)


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
Same ANCOVA model as defined for the primary estimand (Section 5.2.2) by adding the 
NYHA functional class at baseline in the model.
7. Estimator based on the number of subjects with available Week 16 data pre- and post-Sponsor 
decision (ie, 24 January 2019) to implement the IA.
To show that the Sponsor has not been influenced by the acquired data to introduce the IA, the 
estimator is based on 2 sub-populations: subjects randomized at least 16 weeks before 
24 January 2019 (pre internal meeting) and all other remaining subjects (post internal meeting).

Same population divided in pre- and post-24-Jan-2019 sub-populations as described above, 
same variable, same intercurrent events, and same handling of missing data as defined for 
the primary estimand (Section 5.2.2). 
To explore the robustness of the main analysis treatment effect estimate to missing data, the 
following multiple imputation (MI) sensitivity analyses will be performed on FAS (not controlling
for the adaptive design) and applying the main model. Baseline peak VO2 values considered 
invalid by the central reading facility (eg, improper gas calibration, lack of physiological response) 
are assumed missing completely at random and these subjects will be excluded from the following 
MI sensitivity analyses (#8, #9).
8. Sensitivity analysis assuming subjects with missing data, due to premature study treatment 
discontinuation, have worsened, otherwise missing data are assumed to be missing at random 
(MAR).
The intercurrent events of death and premature study treatment discontinuation before week 
16 are handled as for the main analysis (Section 5.2.2). Otherwise:
-
Missing/invalid peak VO2 at Week 16 for subjects with premature study treatment 
discontinuation before Week 16 (if not addressed by a “treatment-policy” strategy): the 
change from baseline to Week 16 will be imputed with the 25th percentile of the 
observed changes from baseline across both treatment groups (or with 0, if the 25th
percentile would lead to an improvement).
-
Missing/invalid peak VO2 at Week 16 for subjects without premature study treatment 
discontinuation before Week 16 are assumed MAR. Changes from baseline to Week 
16 will be multiply imputed based on the distribution in the group to which subjects
were randomized.
Rationale: Per International Council for Harmonisation (ICH) E9 (R1) addendum, similar 
assumptions on missing data for participants with and without intercurrent events such as 
premature study treatment discontinuation may often be considered implausible. This sensitivity 
analysis explores the treatment effect under the assumption that following premature study 
treatment discontinuation, a different treatment effect would have been observed compared with 
participants on study treatment. Specifically, this analysis relaxes the MNAR assumption of 
worsening in subjects who have missing Week 16 data but have completed at least 16 weeks of 
DB treatment as compared with the main analysis.
9. Sensitivity analysis assuming missing data are MAR. 


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The intercurrent events of death and premature study treatment discontinuation before Week 
16 are handled as for the main analysis (Section 5.2.2). Otherwise:
-
Missing/invalid Week 16 data are assumed MAR and changes from baseline to Week 
16 will be multiply imputed based on the distribution in the group to which subjects 
were randomized. This may include missing/invalid data following premature study 
treatment discontinuation before Week 16 not addressed by a “treatment-policy”
strategy.
Rationale: Even if subjects have not completed 16 weeks of DB study treatment, they may still 
experience a treatment benefit. Under the MAR assumption, the treatment effect is assumed to be 
as large as in subjects with observed data. This sensitivity analysis relaxes the MNAR assumption 
of worsening in all subjects with missing data. 
10. Sensitivity analysis adding a random error (normal distributed, variance equal to the residual 
variance estimated from the respective main model), to the single imputation values (worse 
case, 25th percentile, or 0 change) planned as main analysis. 
Rationale: To evaluate the impact of a potential under-estimation of the variability with the single-
value imputation approach.
After consultation with the Study Results Committee constituted of external clinicians with 
expertise in subjects with Functional Single Ventricle Heart Disease on 13-Aug-2021, the 
following additional estimand will be added.
11. Additional estimand excluding subjects with cardiac heterotaxy defects (isomerism) – to assess 
the robustness of results excluding subjects with extra-cardiac defects

Population: All randomized Fontan-palliated adult and adolescent subjects defined through 
protocol inclusion/exclusion criteria (ie, FAS) excluding subjects with ‘cardiac heterotaxy 
defects (isomerism)’ as identified in Congenital heart defect leading to Fontan-palliation 
(ie, information collected in the eCRF “Fontan history” module, “Cardiac malformation”
section).

Same variable, same intercurrent events, and same handling of missing data as defined for 
the primary estimand (Section 5.2.2). 

Same ANCOVA model as defined for the primary estimand (Section 5.2.2) carried out on 
the total sample size (without the population wise splitting approach for the control of the 
adaptive design).
5.2.3.5.
Subgroups analyses
Analyses will be carried out the same way as on the entire population as described in Section 
5.2.3.1, after addressing intercurrent events or applying the rules for imputing missing data 
described in Section 5.2.3.2, without controlling for the adaptive design and hence not based on 
the population wise split as applied for the main analysis. For consistency and model performance, 
a common model is applied for each subgroup as defined in Section 2.3. First, the model is run 
including randomized treatment, the subgroup variable, and baseline value as covariates, and the 
interaction treatment-by-subgroup variable. By adding the subgroup variable and treatment-by-
subgroup variable interaction terms to the statistical model, interaction tests are performed to check 
consistency of results accounting for ‘number of subgroup categories minus 1’ degrees of freedom 


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at the 0.01 significance level. If the interaction is statistically significant (i.e., p-value < 0.01), least 
square means estimates for each treatment group as well as treatment effect estimates are derived 
as contrasts from the extended model (i.e., with the treatment-by-subgroup interaction). Otherwise, 
least square means for each treatment group as well as treatment effect estimates are taken from 
the model ran on each subgroup level without the subgroup variable and the interaction term. Least 
square (LS) means estimates, 99% confidence limits (CLs), and corresponding p-values for the 
different levels of each subgroup are tabulated by treatment group. Similarly, treatment effect LS 
means estimates are tabulated and also presented in a forest plot (Cuzick 2005) with a vertical 
reference line displayed at the level of the overall treatment effect macitentan versus placebo. An 
additional forest plot will be produced displaying 95% CLs instead of 99% CLs. In addition, to test 
heterogeneity of treatment effect across pre-defined subgroups, the p-value of the interaction test 
(treatment-by-subgroup) will be displayed on the plot. 
5.3.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are listed here according to the hierarchical order in which they 
will be statistically tested at the same significance level as the primary efficacy endpoint:

Change from baseline over 52 weeks in peak VO2

Change from baseline to Week 16 in mean count per minute of daily PA-Ac.
5.3.1. Change from baseline over 52 weeks in peak VO2
5.3.1.1.
Definition
The first secondary efficacy endpoint is the change from baseline over Week 52 in peak VO2
(mL/kg/min).
Peak VO2 is measured during CPET. The values used for peak VO2 at baseline, at Week 16, and 
at Week 52 (within the pre-defined corresponding time windows, see Section 2.1) will be based 
on a blinded data evaluation by the independent central reading facility, as reported in the eCRF. 
For Week 16 and Week 52, the assessments (including the unscheduled ones) will be mapped to 
the corresponding time windows based on the Study Day (see Section 2.1), irrespective of 
premature study treatment discontinuation before the assessment.
5.3.1.2.
Estimand
The primary estimand for this secondary efficacy endpoint follow the same ‘treatment-policy’
strategy as the primary efficacy endpoint estimand.
The corresponding estimand defining the treatment effect on this endpoint has the following 
attributes:
A. Population: All randomized Fontan-palliated adult and adolescent subjects defined through 
protocol inclusion/exclusion criteria (ie, FAS).
B. Variable: peak VO2 as average change from baseline to Week 16 and Week 52.


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C. Intercurrent events:

Death occurring before Week 52: composite strategy (worst-case). 
In case of death prior to Week 52, all scheduled assessments following the date of death will 
be imputed by a worst-case imputation (ie, lowest observed change in peak VO2 from baseline 
value across both treatment groups and over all assessments).

Non-missing peak VO2 value at Week 16 or Week 52 assessed as ‘invalid’ by the central 
reading facility: composite strategy (minimum of 25th percentile and no change)
In case an assessment at Week 16 or Week 52 has been evaluated as “invalid” by the 
independent central reading facility, it will be ignored. This will result in imputing the change 
from baseline to Week 16 or Week 52 with the 25th percentile of the observed changes in peak 
VO2 from baseline value (across both treatment groups and over all assessments up to study 
day 420). If this leads to an improvement (change >0), a change of 0 (no change) will be 
imputed.

Premature study treatment discontinuation before Week 52.
According to the protocol, if treatment is discontinued prior to Week 16, and the subject enters 
the PTOP, it is requested that the subject returns for a CPET assessment at Week 16 but not at 
Week 52. Therefore, the premature study treatment discontinuation has been added as an 
intercurrent event for the evaluation of peak VO2 at Week 52. Any assessment in the Week 52 
time window (including the unscheduled ones), irrespective of premature study treatment 
discontinuation, will be included in the main analysis if available. In this way, there is 
consistency of strategy for the evaluation of peak VO2 in the short-term (i.e., at Week 16) and 
in the long-term (i.e, over 52 weeks).
If the premature study treatment discontinuation occurs prior to Week 16:

If a valid assessment is available within the time window of Week 16, this will 
result in imputing only the change from baseline to Week 52 with the 25th percentile 
of the observed changes in peak VO2 from baseline value (across both treatment 
groups and over all assessments up to study day 420). If this leads to an 
improvement, a change of 0 (no change) will be imputed.

If no valid assessment is available within the time window of Week 16, all 
scheduled assessments following the date of event will be imputed by applying the 
25th percentile of the observed changes in peak VO2 from baseline value (across 
both treatment groups and over all assessments up to study day 420). If this leads 
to an improvement (change>0), a change of 0 (no change) will be imputed. This is 
consistent with the primary estimand for the primary efficacy endpoint.
From protocol version 7 onwards, Visit 5/Week 32 was converted from a site visit to a 
telephone call, therefore the CPET at Week 32 is not anymore conducted. It is expected that 
approximately 40 subjects will have a CPET assessment at Week 32. In order to limit the 
amount of missing values, in case of missing data at Week 52 following premature study 
treatment discontinuation between Week 16 and Week 52, peak VO2 at Week 52 will be 
replaced with a valid value within the Week 32 time window (see Section 2.1), if available.


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If the premature study treatment discontinuation occurs after Week 16 and before Week 52 
(and no valid assessment is available within the time window of Week 32 or Week 52), this 
will result in imputing the change from baseline to Week 52 with the 25th percentile of the 
observed changes in peak VO2 from baseline value (across both treatment groups and over all 
assessments up to study day 420). If this leads to an improvement (change>0), a change of 0 
(no change) will be imputed. 
D. Population-level summary measure: difference in mean change in peak VO2 from baseline 
over Week 52 (i.e., average of Week 16 and Week 52) between macitentan 10 mg and placebo, 
as estimated from the MMRM. 
5.3.1.3.
Hypotheses and statistical model
The statistical hypotheses for this secondary efficacy endpoint are formulated in terms of the M of 
change from baseline over 52 weeks (i.e., average of Week 16 and Week 52) in peak VO2 in 
subjects treated with either placebo or macitentan 10 mg.
H0: M macitentan 10 mg = M placebo versus
HA: M macitentan 10 mg ≠ M placebo
The null hypothesis will be tested at the same significance level of the primary efficacy endpoint 
ie, 1% two-sided) based on the inverse normal combination method.
The null hypothesis will be tested by means of a MMRM utilizing the post-baseline assessments 
at Week 16 and Week 52. 
5.3.1.4.
Handling of missing data for the main analysis
Missing values for peak VO2 at baseline are not allowed by protocol, but in case a subject has 
been randomized with a non-missing baseline value that has subsequently been evaluated as 
“invalid” by the independent central reading facility, it will be imputed with the median peak VO2
value observed at baseline from the remaining subjects (across treatment groups).
Handling of intercurrent events of death, invalid peak VO2, and premature study treatment 
discontinuation are described under the attribute ‘C. Intercurrent events” of the estimand in 
Section 5.3.1.2. 
Missing data at Week 52 arising from any other reason (e.g., administrative reason) are assumed 
to be missing at random, and as such, will require no further imputation, since the MMRM 
approach will implicitly impute these values under a missing at random assumption.
Any assessment in the Week 16 time window (including the unscheduled ones), irrespective of 
premature study treatment discontinuation before Week 16, will be included in the main analysis. 
Missing values at Week 16 will be implicitly imputed by the MMRM approach, if not addressed 
under the attribute ‘C. Intercurrent events” of the estimand in Section 5.3.1.2.


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5.3.1.5.
Main analysis
The final analysis of this secondary efficacy endpoint will be conducted using the inverse normal 
combination method with pre-specified weights to combine first and second stage p-values (see
Section 3.2.3 of the SAP for SPA).
The difference between macitentan 10 mg and placebo over Week 52 (i.e., average of Week 16 
and Week 52) and corresponding p-value will be estimated at each stage separately (first-stage and 
second-stage) from the MMRM, using a population-wise splitting of data approach. The model 
will include randomized treatment group, time (via a categorical variable for visit), treatment-by-
time interaction, baseline-by-time interaction, and peak VO2 at baseline as fixed effects. An 
unstructured variance-covariance matrix will be specified.
Similarly to the primary efficacy endpoint, the first-stage p-value from the MMRM will be based 
on the actual number of subjects who contributed to the IA and have performed the Week 52 
assessment. The separate second-stage analysis will be based on the remaining number of subjects 
required to reach the total sample size based on the IA results. Due to the population-wise splitting, 
no subjects contributing to the separate first-stage test statistics are included into the separate 
second-stage analysis. The second-stage p-values will be calculated in the same way as the first-
stage p-values.
The separate first and second p-values will be combined using the inverse-normal combination 
function with prefixed weights (i.e., see Table 11 in Section 5.1.1). Final interpretation of the 
results will then be based on the final adjusted p-value, median unbiased estimator for the overall 
treatment effect and corresponding RCIs obtained by ADDPLAN™6.1 (ADDPLAN Inc. an Aptiv 
Solutions Co. 2014). 
The number of subjects with intercurrent events or missing data will be presented by treatment 
group and the change in peak VO2 from baseline overWeek 52 (i.e., average change from baseline 
to Week 16 and Week 52 after handling of intercurrent events or applying imputation rules for 
missing data) will also be summarized using descriptive statistics by treatment group.
To explore the treatment course over time, a plot of the LS mean changes (±SE) in peak VO2 from 
baseline over time will be displayed by treatment group based on a MMRM analysis disregarding 
the adaptive design. The baseline is added to the time axis to visualize an initial change from 0.
The normality and equal variance assumptions underlying the MMRM model will be assessed 
graphically for the change from baseline over 52 weeks in peak VO2.
5.3.1.6.
Supportive/sensitivity analyses
Absolute values at baseline and at Week 52 as well as absolute change in peak VO2 from baseline 
to Week 52 will also be summarized using descriptive statistics, for each supportive and sensitivity 
analysis where applicable.


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i.
Additional estimands
Additional estimands will be assessed as defined in the tables below. The same MMRM model
as the one described for the primary estimand (see Section 5.3.1.2) will be applied, based on the
population wise splitting as applied for the main analysis. 
Table d
Additional Estimand 1 (PP2)
A.
Population: All subjects who received study treatment as assigned by IRT and who complied with the protocol 
sufficiently up to and including the Week 52 for this secondary efficacy endpoint (ie, PP2). Protocol deviations 
are defined in Section 2.2.3.
B.
Variable: same as for primary estimand (see Section 5.3.1.2)
C.
Intercurrent events and strategies: same as primary estimand (see Section 5.3.1.2)
D.
Population-level summary measure:. Same as the MMRM model of the primary estimand (see Section 
5.3.1.2)
IRT=Interactive Response Technology, MMRM=Mixed Model Repeated Measures, PP2= Estimand Population for 
secondary efficacy endpoint.
Table e
Additional Estimand 2 (excluding subjects with invalid peak VO2 at baseline)
A.
Population: same as primary estimand (FAS) but excluding subjects with invalid peak VO2 at baseline (see 
Section 5.3.1.2)
B.
Variable: same as for primary estimand (see Section 5.3.1.2)
C.
Intercurrent events and strategies: same as primary estimand (see Section 5.3.1.2)
D.
Population-level summary measure:. same as the MMRM model of the primary estimand (see Section 
5.3.1.2)
FAS=Full Analysis Set, MMRM= Mixed Model Repeated Measures, VO2= Oxygen uptake/consumption.
Table f
Additional Estimand 3 (“while on treatment”)
A.
Population: same as primary estimand (FAS) 
B.
Variable: same as for primary estimand (see Section 5.3.1.2) except that the assessments in the Week 16 or 
Week 52 time windows will be included in the analysis if ‘on-treatment’, defined as up to 7 days after last dose 
of study treatment. 
C.
Intercurrent events and strategies: same as primary estimand (see Section 5.3.1.2) except that death will be 
considered up to 7 days after last dose of study treatment. Premature study treatment discontinuation are 
captured through the variable definition.
D.
Population-level summary measure: same as the MMRM model of the primary estimand (see Section 5.3.1.2)
FAS=Full Analysis Set, MMRM= Mixed Model Repeated Measures.
ii.
Sensitivity analyses of the primary estimand
1. Estimator based on the inverse normal combination method with weights proportional to the 
final actual sample size (i.e., 142 subjects) - to assess the robustness of result when the weights 
are proportional to the actual sample size of 142 subjects.

Same population, same variable, same intercurrent events, and same handling of missing 
data as defined for the primary estimand (Section 5.3.1.2). 

Same MMRM model as defined for the primary estimand (Section 5.3.1.2) with pre-
specified weights proportional to the actual sample size of 142 subjects (i.e., 
√ = - 9:
<* = 0.817932812 for the 1st stage and &1 − = -1 −
9:
<* = 0.575313754
for the 2nd stage.


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For the primary estimand, the following sensitivity estimator (sensitivity analysis) will be 
evaluated. Sensitivity estimators will not control for the adaptive design and will not be based on 
the population wise splitting as applied for the main analysis.
2. Estimator based on standard MMRM (pooled) to test statistical hypothesis disregarding the 
adaptive design for the primary estimand on FAS and for Estimand 1, 2, and 3 as specified in 
Table d, Table e, and Table f above respectively

Same population, same variable, same intercurrent events, and same handling of missing 
data as defined for the primary estimand (Section 5.3.1.2). 

Same MMRM model as defined for the primary estimand (Section 5.3.1.2) carried out on 
the total sample size (without the population wise splitting approach for the control of the 
adaptive design).
At Week 52, the resulting LS means and corresponding 95% and 99% CLs obtained in each 
treatment group, and the LS means differences (95% and 99% CLs) for macitentan 10 mg vs 
placebo will be provided.
3. Estimator based on ANCOVA
A.
Population: same as primary estimand (FAS).
B.
Variable: change from baseline to Week 52. 
C.
Intercurrent events and strategies: 

Death before Week 52: worst-case imputation (ie, lowest observed change in peak VO2 from baseline to 
Week 52 (across both treatment groups)

Non-missing peak VO2 at Week 52 assessed as ‘invalid’ by the central reading facility: the change from 
baseline to Week 52 will be imputed with the 25th percentile of the observed changes in peak VO2 from 
baseline to Week 52 (across both treatment groups). If this leads to an improvement, a change of 0 (no 
change) will be imputed.

Premature study treatment discontinuation before Week 52: peak VO2 at Week 52 (if not available within 
the corresponding time window) will be replaced with a valid value within the Week 32 time window 
(see Section 2.1), if available. Otherwise, it will be imputed with the 25th percentile of the observed 
changes in peak VO2 from baseline to Week 52 (across both treatment groups). If this leads to an 
improvement, a change of 0 (no change) will be imputed.
D.
Population-level summary measure: difference in change in peak VO2 from baseline to Week 52 between 
macitentan 10 mg and placebo, as estimated from the ANCOVA model including randomized treatment 
group, geographical region and baseline peak VO2 as covariates in the model.
Any missing values which may occur in peak VO2 at Week 52 will be handled as follows: the change from baseline
to Week 52 will be imputed with the 25th percentile of the observed changes in peak VO2 from baseline to Week 
52 (across both treatment groups). If this leads to an improvement, a change of 0 (no change) will be imputed.
ANCOVA=Analysis of covariance, FAS=Full Analysis Set, VO2= Oxygen uptake/consumption.
Similarly to the primary efficacy endpoint, to explore the robustness of the main analysis treatment 
effect estimate to missing data, the following MI sensitivity analyses will be performed on FAS
(not controlling for the adaptive design) and applying the main model. Baseline peak VO2 values 
considered invalid by the central reading facility (eg, improper gas calibration, lack of 
physiological response) are assumed missing completely at random and these subjects will be
excluded from the following MI sensitivity analyses (#4, #5, #6):


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4. Sensitivity analysis assuming subjects with missing Week 52 data, due to premature study 
treatment discontinuation, have worsened (irrespective of Week 32 results being available). 
Otherwise, missing data are assumed to be missing at random (MAR).
The intercurrent events of death are handled as for the main analysis (Section 5.3.1.2). The 
intercurrent events of premature study treatment discontinuation are handled as detailed below.
Missing/invalid peak VO2 for subjects with premature study treatment discontinuation:
If the premature study treatment discontinuation occurs prior to Week 16:

If a valid assessment is available within the time window of Week 16, this will 
result in imputing only the change from baseline to Week 52 with the 25th percentile 
of the observed changes in peak VO2 from baseline value (across both treatment 
groups and over all assessments up to study day 420). If this leads to an 
improvement, a change of 0 (no change) will be imputed.

If no valid assessment is available within the time window of Week 16, all 
scheduled assessments following the date of event will be imputed by applying the 
25th percentile of the observed changes in peak VO2 from baseline value (across 
both treatment groups and over all assessments up to study day 420). If this leads 
to an improvement (change>0), a change of 0 (no change) will be imputed. 
If the premature study treatment discontinuation occurs after Week 16:

If no valid assessment is available within the time window of Week 52, this will 
result in imputing the change from baseline to Week 52 with the 25th percentile of 
the observed changes in peak VO2 from baseline value (across both treatment 
groups and over all assessments up to study day 420). If this leads to an 
improvement (change>0), a change of 0 (no change) will be imputed
Missing/invalid Week 16 or Week 52 peak VO2 for subjects without premature study treatment 
discontinuation are assumed MAR. Changes from baseline to Week 16 or Week 52 will be multiply 
imputed based on the distribution in the group to which subjects were randomized.
5. Sensitivity analysis assuming missing data are MAR:  
The intercurrent events of death are handled as for the main analysis (Section 5.3.1.2).
Otherwise:
-
Missing/invalid Week 16 or Week 52 peak VO2 are assumed MAR and changes from 
baseline to Week 16 or Week 52 will be multiply imputed based on the distribution in 
the group to which subjects were randomized.
6. Sensitivity analysis assuming subjects with missing data would have worsened and 
experienced no treatment effect, irrespective of completing treatment. 
The intercurrent events of death are handled as for the main analysis (Section 5.3.1.2).
Otherwise: 
-
If no valid assessment is available within the time window of Week 16 or Week 52, the 
corresponding change from baseline to Week 16 or Week 52 will be imputed by 
applying the 25th percentile of the observed changes in peak VO2 from baseline value 


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(across both treatment groups and over all assessments up to study day 420). If this 
leads to an improvement (change>0), a change of 0 (no change) will be imputed. 
7. Sensitivity analysis adding a random error (normal distributed, variance equal to the residual 
variance estimated from the respective main model), to the single imputation values (worse 
case, 25th percentile, or 0 change) planned as main analysis. 
After consultation with the Study Results Committee constituted of external clinicians with 
expertise in subjects with Functional Single Ventricle Heart Disease on 13-Aug-2021, the 
following additional estimand will be added.
8. Additional Estimand excluding subjects with cardiac heterotaxy defects (isomerism) – to 
assess the robustness of results excluding subjects with extra-cardiac defects

Population: All randomized Fontan-palliated adult and adolescent subjects defined through 
protocol inclusion/exclusion criteria (ie, FAS) excluding subjects with ‘cardiac heterotaxy 
defects (isomerism)’ as identified in Congenital heart defect leading to Fontan-palliation 
(ie, information collected in the eCRF “Fontan history” module, “Cardiac malformation”
section).

Same variable, same intercurrent events, and same handling of missing data as defined for 
the primary estimand (Section 5.3.1.2). 

Same MMRM model as defined for the primary estimand (Section 5.3.1.2) carried out on 
the total sample size (without the population wise splitting approach for the control of the 
adaptive design).
5.3.1.7.
Subgroups analyses
Analyses will be carried out the same way as on the entire population as described in Section 
5.3.1.3, applying the rules for imputing missing data described in Section 5.3.1.4. Subgroup 
analyses will be displayed as described for the primary efficacy endpoint in Section 5.2.3.5.
5.3.2. Change from baseline to Week 16 in mean count per minute of daily PA-Ac
The daily physical activity (counts/min) of the subject is assessed via accelerometer during the 
daytime. The accelerometer is given to the subject at Visit 1 (Screening visit), and data are
collected for 9 consecutive daily daytime periods after Visit 1, Visit 4 (Week 16) and before Visit 
6 (Week 52). 
The accelerometry central reading facility will read daily counts/min and will analyze duration of 
daily activity and time (minutes) which will be transferred to the Sponsor.
For Week 16 and Week 52, the 9-day time period is selected by taking the first (in chronological 
order) interval of 9 consecutive days of daily daytime data with at least 4 complete daily time 
periods within the corresponding time window (i.e. the 9-day time period should not necessarily 
fall entirely in the corresponding time window, but it should overlap with the time window for at 
least 1 day). All assessments (including the unscheduled ones) will be mapped based on the Study 
Day (see Section 2.1), irrespective of premature study treatment discontinuation before the 


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assessment. To be considered evaluable, physical activity should have been measured for at least 
4 complete daily daytime periods (out of 9 consecutive days) at a specific time point of assessment. 
5.3.2.1.
Definition
Mean counts per minute of daily PA-Ac are calculated by dividing the sum of all activity counts 
(Y axis) collected during wear time for a complete day by the number of minutes of wear time in 
that day across all valid days (at least 4 days out of 9 days). 
The activity counts collected during wear time is identifiable with “WearFilteredAxisYcounts” in 
Data Transfer Specifications (DTS); the number of minutes of wear time corresponds to the 
“WearMinutes “ variable in DTS.
A complete day is defined as a record of at least 7 hours of daily daytime data, ie, a complete day 
if “WearMinutes” >=7*60, (after excluding the periods when the device was apparently not worn
(Troiano 2008). 
In summary, to compute the mean counts per minute of daily PA-Ac, it is necessary to identify all 
complete days; if less than 4 complete days out of 9 are identified then value is missing, otherwise, 
if at least 4 complete days out of 9 are identified, then the value is calculated on the complete days 
only. 
The secondary efficacy endpoint is the change from baseline to Week 16 in mean count per minute 
of daily PA-Ac, defined as:
mean count per minute of daily PA-Ac during 9 consecutive daily daytime periods after Visit 
4/Week 16 − baseline value.
5.3.2.2.
Estimand
The primary estimand defining the treatment effect on this secondary efficacy endpoint has the 
following attributes:
A. Population: All randomized Fontan-palliated adult and adolescent subjects defined through 
protocol inclusion/exclusion criteria (ie,. FAS) with evaluable 9-day time period for the daily 
physical activity at baseline.
B. Variable: Mean count per minute of daily PA-Ac as change from baseline to Week 16.
C. Intercurrent event:

Death occurring before Week 16.
A composite strategy will be applied: in case of death prior to Week 16, the change from baseline 
to Week 16 will be replaced with the lowest observed change from baseline to Week 16 across 
both treatment groups (i.e., worst-case imputation).

Premature study treatment discontinuation before Week 16


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Premature study treatment discontinuation prior to Week 16 will be addressed by a 
“treatment-policy” strategy by including any assessment in the Week 16 time window, 
irrespective of premature study treatment discontinuation, in the main analysis.
D. Population-level summary measure: Difference in change from baseline to Week 16 in mean 
count per minute of daily PA-Ac between macitentan 10 mg and placebo, as estimated from 
the ANCOVA model including randomized treatment group and the mean count per minute of 
daily PA-AC at baseline as covariates in the model.
5.3.2.3.
Hypotheses and statistical model
The statistical hypotheses for this secondary efficacy endpoint are formulated in terms of the M of 
change in mean count per minute of daily PA-Ac in subjects treated with either placebo or 
macitentan 10 mg from baseline to Week 16.
H0: M macitentan 10 mg = M placebo versus
HA: M macitentan 10 mg ≠ M placebo
The null hypothesis will be tested at the same significance level of the primary efficacy endpoint 
ie, 1% two-sided) based on the inverse normal combination method.
Assuming normal distribution of the primary variable, the null hypothesis will be tested by means 
of an ANCOVA model on the change in mean count per minute of daily PA-Ac. Model covariates 
will include randomized treatment group and the mean count per minute of daily PA-AC at 
baseline as covariates. 
5.3.2.4.
Handling of missing data for the main analysis
Intercurrent events will be handled as defined in Section 5.3.2.2. 
If the baseline is available, in case of missing values in mean count per minute of daily PA-Ac at 
Week 16, the following approach for imputation will be applied:
Reason
Strategy in handling the missing change from baseline to Week 16
Other
A change of 0 (no change) will be imputed.
5.3.2.5.
Main analysis
The final analysis of this secondary efficacy endpoint will be conducted using the inverse normal 
combination method with pre-specified weights to combine first and second stage p-values (see 
Section 3.2.3 of the SAP for SPA).
The difference between macitentan 10 mg and placebo and corresponding p-value will be 
estimated at each stage separately (first-stage and second-stage) from the ANCOVA model, using 
a population-wise splitting of data approach. Model covariates will include randomized treatment 
group and mean count per minute of daily PA-Ac at baseline. 


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The separate first-stage analysis will be based on the first-stage set of subjects contributing to the 
IA. The separate second-stage analysis will be based on the remaining number of subjects required 
to reach the total sample size based on the IA results. Due to the population-wise splitting, no 
subjects contributing to the separate first-stage test statistics are included into the separate second-
stage analysis. The second-stage p-values will be calculated in the same way as the first-stage p-
values. 
The separate first and second p-values will be combined using the inverse-normal combination 
function with prefixed weights (i.e., see Table 11 in Section 5.1.1). Final interpretation of the 
results will then be based on the final adjusted p-value, median unbiased estimator for the overall 
treatment effect and corresponding RCIs obtained by ADDPLAN™6.1 (ADDPLAN Inc. an Aptiv 
Solutions Co. 2014).
Absolute values at baseline and at Week 16 as well as absolute change from baseline to Week 16 
in mean count per minute of daily PA-Ac after handling of intercurrent events or applying 
imputation rules for missing data will also be summarized using descriptive statistics by treatment 
group.
5.3.2.6.
Supportive/sensitivity analyses
Absolute values at baseline and at Week 16 as well as absolute change in mean count per minute 
of daily PA-Ac from baseline to Week 16 will also be summarized using descriptive statistics, for 
each supportive and sensitivity analysis where applicable.
i.
Additional estimands
Additional estimands will be assessed as defined in the tables below. The same ANCOVA model 
as the one described for the primary estimand (see Section 5.3.2.2) will be applied, based on the 
population wise splitting as applied for the main analysis. 
Table g Additional Estimand 1 (PP3)
A.
Population: All subjects who received study treatment as assigned by IRT and who complied with the protocol 
sufficiently up to and including the Week 16 for this secondary efficacy endpoint (ie, PP3). Protocol deviations 
are defined in Section 2.2.3.
B.
Variable: Same as for primary estimand (see Section 5.3.2.2)
C.
Intercurrent events and strategies: same as primary estimand (see Section 5.3.2.2)
D.
Population-level summary measure: Same as the ANCOVA model of the primary estimand (see Section 
5.3.2.2)
ANCOVA=analysis of Covariance, IRT=Interactive Response Technology, PP3= Estimand Population for secondary 
efficacy endpoint.
ii.
Sensitivity analyses of the primary estimand
1. Estimator based on the inverse normal combination method with weights proportional to the 
final actual sample size (i.e., 142 subjects) - to assess the robustness of result when the weights 
are proportional to the actual sample size of 142 subjects.

Same population, same variable, same intercurrent events, and same handling of missing 
data as defined for the primary estimand (Section 5.3.2.2). 


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
Same ANCOVA model as defined for the primary estimand (Section 5.3.2.2) with pre-
specified weights proportional to the actual sample size of 142 subjects (i.e., 
√ = -
95
142 = 0.817932812 for the 1st stage and &1 − = -1 −
95
142 = 0.575313754
for the 2nd stage.
For the primary estimand, the following sensitivity estimator (sensitivity analysis) or additional 
estimand will be evaluated, not controlling for the adaptive design and not based on the population 
wise splitting approach as applied for the main analysis.
Where applicable, the resulting LS means and corresponding 95% and 99% CLs obtained in each 
treatment group, and the LS means differences (95% and 99% CLs) for macitentan 10 mg vs 
placebo will be provided for the following analyses.
2. Estimator based on standard ANCOVA (pooled) - to test statistical hypothesis disregarding the 
adaptive design for the primary estimand on FAS and on PP (i.e., Estimand 1 in Table g above)

Same population, same variable, same intercurrent events, and same handling of missing 
data as defined for the primary estimand (Section 5.3.2.2). 

Same ANCOVA model as defined for the primary estimand (Section 5.3.2.2) carried out
on the total sample size (without the population wise splitting approach for the control of 
the adaptive design).
3. Additional Estimand based on observed cases

Same population, same variable as defined for the primary estimand (Section 5.3.2.2). 
Intercurrent events will not be considered. Missing mean count per minute of daily PA-Ac 
at Week 16 will not be imputed.

Same ANCOVA model as defined for the primary estimand (Section 5.3.2.2).
4. Estimator based on the number of subjects with available Week 16 data pre- and post-Sponsor 
decision (ie, 24 January 2019) to implement the IA.
As for the primary efficacy endpoint, the estimator is based on 2 sub-populations: subjects 
randomized at least 16 weeks before 24 January 2019 (pre internal meeting) and all other 
remaining subjects (post internal meeting).

Same population divided in pre- and post-24-Jan-2019 sub-populations as described above, 
same variable, same intercurrent events, and same handling of missing data as defined for 
the primary estimand (Section 5.3.2.2). 
Similarly to the primary efficacy endpoint, to explore the robustness of the main analysis treatment 
effect estimate to missing data, the following multiple imputation sensitivity analyses will be 
performed on FAS (not controlling for the adaptive design) and applying the main model. Missing 
baseline data are assumed missing completely at random and therefore are not included in the 
following analyses. To investigate the plausibility of this assumption, peak VO2 at baseline and 
other key baseline characteristics will be summarized by PA-Ac data available at baseline, to 


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explore if subjects with missing baseline for PA-Ac do not have systematically lower or higher 
maximum exercise capacity.
5. Sensitivity analysis assuming subjects with premature study treatment discontinuation before 
Week 16 have experienced no treatment effect, otherwise missing data are assumed to be 
MAR. 
The intercurrent event of death and premature study treatment discontinuation before Week 16 
are handled as for the main analysis (Section 5.3.2.2).
-
Missing mean count per minute of daily PA-Ac at Week 16 for subjects with premature 
study treatment discontinuation before Week 16 (in case not addressed by treatment-
policy strategy): the change from baseline to Week 16 will be imputed with a change 
of 0.
-
Missing mean count per minute of daily PA-Ac at Week 16 for subjects without
premature study treatment discontinuation before Week 16 are assumed MAR. 
Changes from baseline to Week 16 will be multiply imputed based on the distribution 
in the group to which subjects were randomized.
6. Sensitivity analysis assuming missing data are MAR:  
The intercurrent events of death and premature study treatment discontinuation before Week 
16 are handled as for the main analysis (Section 5.3.2.2). Otherwise:
-
Missing mean count per minute of daily PA-Ac data at Week 16 are assumed MAR and 
changes from baseline to Week 16 will be multiply imputed based on the distribution in 
the group to which subjects were randomized. This may include missing/invalid data 
following premature study treatment discontinuation before Week 16 not addressed by a 
“treatment-policy” strategy.
7. Sensitivity analysis adding a random error (normal distributed, variance equal to the residual 
variance estimated from the respective main model), to the single imputation values (worse 
case or 0 change) planned as main analysis. 
After consultation with the Study Results Committee constituted of external clinicians with 
expertise in subjects with Functional Single Ventricle Heart Disease on 13-Aug-2021, the 
following additional estimand will be added.
8. Additional Estimand excluding subjects with cardiac heterotaxy defects (isomerism) – to 
assess the robustness of results excluding subjects with extra-cardiac defects

Population: All randomized Fontan-palliated adult and adolescent subjects defined through 
protocol inclusion/exclusion criteria (ie, FAS) excluding subjects with ‘cardiac heterotaxy 
defects (isomerism)’ as identified in Congenital heart defect leading to Fontan-palliation 
(ie, information collected in the eCRF “Fontan history” module, “Cardiac malformation”
section).

Same variable, same intercurrent events, and same handling of missing data as defined for 
the primary estimand (Section 5.3.2.2). 

Same ANCOVA model as defined for the primary estimand (Section 5.3.2.2) carried out 
on the total sample size (without the population wise splitting approach for the control of 
the adaptive design).


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5.3.2.7.
Subgroups analyses
Analyses will be carried out the same way as on the entire population as described in 5.3.2.3, 
applying the rules for imputing missing data described in Section 5.3.2.4. Subgroup analyses will 
be displayed as described for the primary efficacy endpoint in Section 5.2.3.5.
5.4.
Other Efficacy Endpoint(s)
All other efficacy endpoints are evaluated in an exploratory and descriptive manner on the FAS.
The estimators will not control for the adaptive design and will not be based on the population 
wise splitting as applied for the main analysis of the primary and secondary efficacy endpoints.
For Week 16 and Week 52, the assessments (including the unscheduled ones) will be mapped to 
the corresponding time windows based on the Study Day (see Section 2.1), irrespective of 
premature study treatment discontinuation before the assessment.
Missing values will not be imputed, unless otherwise specified.
5.4.1. Endpoints related to exercise capacity
Endpoints related to exercise capacity are collected at baseline, Week 16 (Visit 4) and Week 52 
(Visit 6) with CPET. 
5.4.1.1.
Definition
Other efficacy variables related to exercise capacity are:

change in peak VO2 (mL/kg/min) from baseline to Week 52,
This variable is different from the secondary efficacy endpoint ‘Change from baseline over 52 
weeks in peak VO2’ as it does not account for the intermediate timepoint at Week 16.

change from baseline to Week 16 in: VO2 at ventilatory anaerobic threshold (VAT) in 
mL/kg/min, oxygen pulse expressed as VO2/HR (mL O2/beat), oxygen uptake efficiency 
slope (OUES), % predicted peak VO2, VE/VCO2 slope

change from baseline over 52 weeks in: VO2 at ventilatory anaerobic threshold (VAT) in 
mL/kg/min, oxygen pulse expressed as VO2/HR (mL O2/beat), oxygen uptake efficiency 
slope (OUES), % predicted peak VO2, VE/VCO2 slope.
5.4.1.2.
Statistical methods

The change in peak VO2 from baseline to Week 52 will be analyzed by means of an ANCOVA, 
including randomized treatment group and baseline peak VO2 as covariates in the model. This 
analysis is different from the sensitivity analysis of the secondary efficacy endpoint (i.e., 
Estimator based on ANCOVA) which includes randomized treatment group, geographical 
region, and baseline peak VO2 as covariates in the ANCOVA model. The same handling of 
intercurrent events and missing data will be applied as the Estimator based on ANCOVA for 
the secondary efficacy endpoint.


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
The change from baseline to Week 16 in VO2 at VAT, OUES, and % predicted peak VO2 will 
be analyzed similarly with an ANCOVA, including randomized treatment group and 
corresponding baseline value as covariates in the model.

The change from baseline over 52 weeks (i.e., average of Week 16 and Week 52) in VO2 at 
VAT, OUES, and % predicted peak VO2 will be analyzed by means of MMRM model. The 
model will include randomized treatment group, time (via a categorical variable for visit), 
treatment-by-time interaction, baseline-by-time interaction and the value at baseline as fixed 
effects. An unstructured variance-covariance matrix will be specified.

The change from baseline to Week 16 and Week 52 in VO2/HR and VE/VCO2 slope will be 
analyzed using descriptive statistics.

VE/VCO2 slope and peak VO2 at baseline will be analyzed as categorical variables displaying 
for each treatment group the number and proportion of subjects with any clinical event up to 
End-of-Study as defined in Section 5.4.3 in each category.
The categories for VE/VCO2 slope and peak VO2 at baseline:
VE/VCO2: VC I (≤29.9), VC II (30.0-35.9), VC III (36.0-44.9), VC IV (≥45.0);
peak VO2 (<25, 25-<40, 40-<55, ≥55 mL/kg/min).
Receiver operating characteristic (ROC) curve analysis will be performed in order to confirm the 
categorizations for VE/VCO2 slope and peak VO2 variables for predicting the first occurrence of 
any of the clinical events.
Clinical Events are considered as binary (whether or not a composite clinical event has occurred), 
predicted by VE/VCO2 and VO2 at baseline which will be included in the model as continuous 
variables to identify the best cut-offs. From this analysis, optimal cut-offs for VE/VCO2 and peak 
VO2 variables will be derived based on the sensitivity and specificity values. The optimal cut-off 
is the point closest in distance to the upper left hand corner of the ROC curve where sensitivity 
and specificity are equal to 1, it is easily identifiable taking the cut-off that minimizes the square 
root of the sum of squares of 1-sensitivity and 1-specificity, i.e. min{sqrt[(1-sensitivity)2+(1-
specificity)2]}. In addition, the Area Under the Curve (AUC) will be provided for a better 
characterization of the accuracy of the prediction.
Absolute values (at baseline and at each post-baseline visit) as well as the absolute change from 
baseline to each visit for the efficacy variables related to exercise capacity (i.e., peak VO2, VO2 at 
VAT, oxygen pulse expressed as VO2/HR, OUES, % predicted peak VO2, and VE/VCO2 slope)
will be summarized using descriptive statistics by treatment group on the FAS.
Individual subject’s listings will be provided on the FAS.
5.4.2. NT-proBNP
NT-pro-BNP is measured at Visits 2 (Randomization), 4 (Week 16), and 6 (Week 52), according 
to central laboratory working procedures. NT-pro-BNP (pmol/L) samples are processed through 


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the central laboratory and the results will be sent electronically to the Sponsor after database lock 
and unblinding of the study treatment code. The results will be available in SDTM for the analysis.
5.4.2.1.
Definition
The percent of baseline in NT-proBNP at Week 16 (defined as 100 times the post-baseline value 
divided by the baseline value, see formula below) will be evaluated.
PQR −STUQV  WX 16
QR −STUQV  ?YZ	 [ × 100
Similarly, the percent of baseline in NT-proBNP at Week 52 (defined as 100 times the post-
baseline value divided by the baseline value, see formula below) will be evaluated.
PQR −STUQV  WX 52
QR −STUQV  ?YZ	 [ × 100
5.4.2.2.
Statistical methods
NT-proBNP is assumed to follow a log-normal distribution. Therefore, data are log transformed 
before analysis. 
An ANCOVA is carried out on log transformed data (i.e., natural log scale) first for Week 16 and 
then for Week 52. The model for log transformed ratio Week 16 (or Week 52)/baseline includes 
randomized study treatment, the stratification factor (i.e. geographical region) and baseline NT-
proBNP (in natural log scale). 
For Week 16 and Week 52 separately, after fitting the ANCOVA model, the resulting adjusted 
least square means and 2-sided 95% CLs are inversely transformed using the exponential function 
and multiplied by 100 to display the geometric mean and corresponding 2-sided 95% CLs, 
expressed in percent, for each treatment group. Similarly the placebo-corrected treatment effect, 
presented as ratio of geometric means (macitentan over placebo) together with its 2-sided 95% 
CLs is provided.
Values at baseline and at each post-baseline visit (Week 16 and Week 52) as well as the absolute 
change from baseline to each visit will be summarized displaying, for each treatment group, 
descriptive statistics for continuous variables. The percent of baseline will also be summarized at 
each post-baseline visit using geometric means and two-sided 95% confidence intervals of the 
geometric means.
To graphically display changes in NT-proBNP over time, a plot of the geometric mean (and 95% 
CLs) for the percent of baseline at each post-baseline visits will be displayed by treatment group.
A reference line is included at 100% (zero change) and baseline is added to the time axis to 
visualize an initial change from 100%.
Individual subject’s listing will be provided on the FAS.


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5.4.3. Time to clinical events
5.4.3.1.
Definition
The individual components of the following two clinical events endpoints are defined below: 

Composite endpoint of events related to Fontan-palliated clinical worsening and, 

Composite endpoint of events related to Fontan-palliated morbidity.
The dates of occurrence of each component of the above two clinical events endpoints are reported 
in the eCRF. 
For each composite endpoint, a subject is considered as having an event if the investigator reports 
the occurrence of any of the individual component in the eCRF. Subjects who did not experience 
an event will be right-censored at EOS.
The times to clinical events are expressed in weeks and calculated as:

For subjects with an event: the earliest date of occurrence of any of the individual components 
minus date of randomization plus 1 divided by 7,

For censored subjects: the EOS date minus date of randomization plus 1 divided by 7.
Time to event endpoint definition

Composite endpoint of events related to Fontan-palliated clinical worsening 
The components of the composite endpoint of events related to Fontan-palliated clinical worsening
are the following (these are all assessed by the investigator and recorded in the eCRF):

Unscheduled hospitalization for Fontan-palliated morbidity event.

Signs and symptoms of heart failure, requiring change in diuretic therapy.

Clinical worsening leading to interventions related to the Fontan-palliated condition.

Worsening to NYHA FC III, investigator assessed using the Specific Activity Scale [Appendix 
4 of protocol].

Signs and symptoms requiring the addition of a new class of cardiovascular medication (e.g., 
nitrates, alpha-blockers, or Endothelin receptor antagonists (ERAs)), or insertion of a 
pacemaker.

Failing-Fontan defined as one or more of the following:
-
Enlisted on the active list for heart transplantation or effective heart transplantation,
-
Reoperation (e.g., mechanical circulatory support, Fontan take down, Fontan 
revision / conversion, AV valve repair/replacement),
-
Worsening to NYHA FC IV, investigator assessed using the Specific Activity Scale 
[Appendix 4 of protocol],
-
Protein-losing enteropathy (PLE),


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-
Plastic bronchitis/chyloptysis,
-
Peritoneal, pleural, mediastinal, or pericardial effusions,
-
Severe hepatic impairment (as described in exclusion criterion 6.3),
-
Severe renal impairment (as described in exclusion criterion 6.5),
-
Death related to Failing-Fontan.
Clinical events are reported in “Clinical worsening events” section of the eCRF.

Composite endpoint of events related to Fontan-palliated morbidity.
The components of the composite endpoint of events related to Fontan-palliated morbidity are the 
following: 
-
Ventricular tachyarrhythmia or supraventricular tachyarrhythmia, 
-
Thrombotic or hemorrhagic complications (including thromboembolism and 
hemoptysis). 
Clinical events are reported in “Other Fontan-palliated morbidity events” section of the eCRF.
5.4.3.2.
Statistical methods
For each of the two composite endpoints listed above the time to the clinical event will be analyzed, 
separately, using the Kaplan-Meier (KM) product limit method, providing estimates for each 
treatment group and corresponding 95% two-sided CLs at weeks 8, 16, 32, 52, and EOS. The CLs 
are constructed using Greenwood’s formula (Collett 2003) for the standard error of the Kaplan-
Meier estimate and are added to the plot, as well as the p-vale from the logrank test. The number 
of subjects at risk, censored, and with events will be computed and displayed at each time point 
for each group.
Hazard ratios and corresponding 95% confidence intervals will be estimated by means of a Cox 
regression model.
Data will be summarized in tables or figures, including: number of events, number of censored 
observations, number of subjects at risk, and KM estimates of the survival function for time-to-
event variables. 
The graph of the estimated survival function of the time to first composite clinical endpoint for 
each treatment group obtained from the Kaplan-Meier product-limit method will be displayed up 
to the time at which at least 10% of all subjects remain at risk of an event. The graphical 
presentation follows the recommendations from (Pocock 2002).
Individual subject’s listings will be provided for both composite endpoints separately.
5.4.4. Overall Survival (OS)
This endpoint will not be analyzed if no death has occurred. The following estimates will be 
provided if at least one death per treatment group has occurred.


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5.4.4.1.
Definition
The vital status (alive, dead, or unknown) will be reported in the eCRF within 8 weeks of study 
closure announcement at the VSFU visit (“Vital Status Follow-up” eCRF form), or in the death 
form if the subject died prior to EOS. 
Subjects who are known to be alive at the time of VSFU will be censored at the date of VSFU
(date of contact). Subjects with ‘unknown’ vital status at VSFU Visit as collected in the “Vital
Status Follow-up” form (or VSFU Visit not performed) will be censored at EOS.
For those subjects with the EOS within 4 weeks of the SCL announcement (ie, 30-Jun-2021), the 
Vital Status Follow up does not need to be performed. Therefore, these subjects are assumed to be 
alive at VSFU and will be censored at their EOS, which is their VSFU.
The VSFU could not be assessed for those subjects randomized in site 1101 due to rejection from
Human Genetics Resources Administration of China to continue the study at this site. Therefore,
these subjects are assumed with ‘unknown’ vital status and will be censored at their EOS unless 
the subject died prior to EOS.
Time to death is expressed in weeks and calculated as the date of death minus date of 
randomization plus 1, divided by 7 or, for censored subjects, as censoring date minus date of 
randomization plus 1, divided by 7.
5.4.4.2.
Statistical methods
Time to death will be analyzed using the Kaplan-Meier (KM) product limit method, providing
estimates for each treatment group and corresponding 95% two-sided CLs at weeks 8, 16, 32, 52, 
and EOS. The CLs are constructed using Greenwood’s formula (Collett 2003) for the standard 
error of the Kaplan-Meier estimate and are added to the plot, as well as the p-vale from the logrank 
test. The number of subjects at risk, censored, and with events will be computed and displayed at 
each time point for each group.
Hazard ratios and corresponding 95% confidence intervals will be estimated by means of a Cox 
regression model.
Data are listed and summarized in tables or figures, including: number of events, number of 
censored observations, number of subjects at risk, and KM estimates of the survival function for 
time-to-event variables. 
The graph of the estimated survival function of the time to first composite clinical endpoint for 
each treatment group obtained from the Kaplan-Meier product-limit method will be displayed up 
to the time at which at least 10% of all subjects remain at risk of an event. The graphical 
presentation follows the recommendations from (Pocock 2002).
Hazard ratios and corresponding 95% confidence intervals obtained using Cox regression model 
will be summarized.


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5.4.5. Physical activity
5.4.5.1.
Definition
Physical activity efficacy variables include:

change from baseline over 52 weeks in mean count per minute of daily activity.

change from baseline to Week 16 and Week 52 in daily mean time in minutes spent in 
sedentary, light, moderate, or vigorous (including very vigorous for adults).
5.4.5.2.
Statistical methods
The change from baseline over 52 weeks (i.e., average of Week 16 and Week 52) in mean count 
per minute will be analyzed by means of a MMRM model. The model will include randomized 
treatment group, time (via a categorical variable for visit), treatment-by-time interaction, baseline-
by-time interaction and mean count per minute at baseline as fixed effects. An unstructured 
variance-covariance matrix will be specified. Absolute values (at baseline and at each post-
baseline visit) as well as absolute changes from baseline will also be summarized using descriptive 
statistics.
To explore the treatment course over time, a plot of the LS mean changes (±SE) in mean count per 
minute from baseline over time will be displayed by treatment group based on the MMRM 
analysis. The baseline is added to the time axis to visualize an initial change from 0
The daily mean time in minutes spent in:

sedentary physical activity,

light physical activity,

moderate physical activity, 

vigorous (including very vigorous for adults) physical activity
will be summarized as a continuous variable by displaying, for each treatment group, descriptive 
statistics for the absolute values at baseline, at each post-baseline visit as well as for the absolute 
change from baseline. Furthermore, the percent of daily mean total activity time spent in each 
category will be summarized similarly (as continuous variable) including the graphical display
(i.e. bar plot) at each time point of assessment.
In addition, the number of complete days of wearing the accelerometer at baseline, Week 16 and 
Week 52 will also be summarized descriptively.
SAFETY
The following safety endpoints are defined in the protocol (see protocol Section 6.2):

Treatment-emergent adverse events (AEs) and serious AEs up to 30 days after study treatment 
discontinuation, or until initiation of study drug in the AC-055H302 OL extension study, 
whichever occurs first

AEs leading to premature discontinuation of study treatment


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
Change in vital signs (systolic and diastolic arterial BP and pulse rate), including SpO2 and 
body weight from baseline to all assessed time points during the study.

Treatment-emergent marked laboratory abnormalities up to 30 days after study treatment 
discontinuation or until initiation of study drug in the AC-055H302 OL extension study, 
whichever occurs first

Change in laboratory parameters from baseline to all assessed time points during the study.
All safety analyses will be based on the safety analysis set (SS) based on actual treatment received, 
unless otherwise specified. Listings will be provided on the FAS.
Unless otherwise specified, the treatment-emergent period is defined from study treatment start up 
to 30 days after study treatment discontinuation, limits included.
Safety assessments (e.g., laboratory, vital signs) on Day 1 are considered baseline. Safety events 
(i.e., adverse events) occurring/starting on Day 1 are considered treatment-emergent while safety 
signals (i.e., laboratory marked abnormalities, vital signs abnormalities) occurring/starting on Day 
1 are not considered treatment-emergent.
For those subjects who entered the AC-055H302 / RUBATO OL extension study immediately 
after the last dose of study treatment in this AC-055H301 RUBATO study, AEs/SAEs or marked 
laboratory abnormalities after initiation of OL study treatment are reported and followed up in the 
OL extension study, and are not included in the analysis of the DB study.
For all continuous safety variables, descriptive statistics will include the N, mean, standard 
deviation [SD], median and range [minimum, and maximum], and IQ range. Categorical variables 
will be summarized using frequency counts and percentages.
6.1.
Adverse Events
The original terms used by the investigators to describe AEs are assigned preferred terms (PT) and 
system organ class (SOC) for classification and tabulation using the latest implemented MedDRA 
version dictionary.
The following definitions are relevant for the analysis of the adverse events.

Frequency of the adverse events
AEs reported more than once for a subject (as qualified by the same preferred term(s)) are counted 
in the frequency table once. If the reported AE is assigned to several preferred terms, subjects are 
counted for each individual preferred term.

Intensity of the adverse events
For AEs reported more than once for a subject (as qualified by the same preferred term(s)), the 
worst outcome is considered. The categories of intensity are defined as follows: mild, moderate, 
severe, If the intensity is missing, the event is considered severe.


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
Relationship of the adverse events
Relationship to study treatment is defined as ‘related’ or ‘not related’. For AEs reported more than 
once for the same subject (as qualified by the same preferred term(s)), the worst relationship is 
considered. Adverse events with missing relationship are considered in any analysis as related.

Serious adverse events
For the analysis, an AE is considered serious if the tick box ‘Yes’ for ‘Serious?’ is checked on the 
AE eCRF module. If the information on seriousness is missing, the adverse event is considered 
serious.

Adverse Events of Special Interest
AEs of special interest (AESIs) are defined using a selection of preferred terms (Internal MedDRA 
Query). The full definition is included in Attachment 2:
The following groups of AEs of special interest will be summarized:

Hepatic adverse events of special interest,

Edema and fluid retention, 

Anemia / hemoglobin decrease, 

Hypotension.
Overall summary tables of AEs will be provided, containing number and percentages of subjects 
having experienced at least 1 occurrence for the following categories of AEs:

Treatment-emergent AEs

Severe treatment-emergent AEs 

Treatment-emergent AEs related to study treatment

AEs with fatal outcome

Treatment-emergent serious AEs (SAEs)

Treatment-emergent SAEs related to study treatment

AEs leading to premature discontinuation of study treatment
For each category of AEs of special interest, a similar overall summary table will be provided, 
containing number and percentages of subjects having experienced at least 1 occurrence for the 
above categories. In order to account for differences in the time of observation among subjects,
this table will also present the subject-years of observation (SYO) and the incidence rate per 100 
subject-years. 
The subject-observation time will be calculated, for each subject, as follows:


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i.
For subjects without AESI: by considering the study treatment duration as (study treatment 
end date – study treatment start date + 1); 
ii.
For subjects with AESI: by considering the treatment duration up to the start date of first 
event (min [date of first event, study treatment end date] – study treatment start date + 1) 
SYO will be calculated by first summing the subject-observation time for all subjects and then 
dividing the results by 365.25 days.
The incidence rate for an AESI category, per 100 subject-years. will be calculated by dividing the 
number of subjects with treatment-emergent AESI by the SYO and multiplying by 100.
Adjusted Incidence Rate = 100 × (Number of subjects with at least one AE/SYO)
Separate summary tables will be provided by SOC and PT within each SOC for the categories of 
AEs specified above (except for severe treatment-emergent AEs). The summary tables are 
presented in descending order according to the incidence in macitentan 10 mg treatment group 
(e.g., SOC and PT within each SOC with the highest number of occurrences appears first). Equal 
frequency of different SOC/PTs is sorted in alphabetical order of the SOC/PT.
Similarly, separate summary tables will be provided by PT, in descending order of incidence in 
the macitentan 10 mg treatment group for the categories of AEs specified above (except for severe 
treatment-emergent AEs) with the addition of:

Treatment-emergent AEs by maximum intensity

AEs of special interest.
A summary table will be provided, containing number and percentages of subjects who died on 
the SS. Frequencies for the following parameters will be included in the summary table:

Number of subjects who died

Primary cause of death
The summary will be based on the “Death” eCRF module. 
The summary will be provided if at least 3 deaths have occurred overall. The summary table is
presented by descending order of PT according to the incidence of deaths in the macitentan 10 mg 
treatment group.
In addition to the summary tables, separate listings will be provided for subjects who:

Had AEs 

Had SAEs 

Had AEs leading to discontinuation of study treatment. 

Had AEs of special interest.

Had died.
Treatment-emergent AEs (or deaths) are flagged accordingly.


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6.2.
Clinical Laboratory Tests
The analysis of the changes from baseline will be based on the laboratory test results provided by 
central laboratory at scheduled visits. For each post-baseline scheduled visit, only assessments
performed after study treatment start date up to 30 days after study treatment discontinuation will 
be included. End-Of-Treatment visit is mapped to a scheduled visit (see Section 2.1.2). Values 
from unscheduled visits are not included in the summaries by visits but are included in the analysis 
for marked laboratory abnormalities (including additional liver and hemoglobin abnormalities, 
estimated Glomerular Filtration Rate and Protein Losing Enteropathy). Data are evaluated in 
Standard International System of Units (SI). In case of local laboratory, values (incl. reference 
ranges) are converted in SI units according to the Sponsor’s internal guidelines. The tests converted 
in SI units are available in SDTM for the analysis. Local laboratory values will be included, 
together with central laboratory values, in the analyses of marked abnormalities only.
All values reported as below or above the limit of quantification (e.g., ‘< 3’, ‘> 100’) are substituted 
with the limit of quantification (e.g., ‘< 3’, is substituted by ‘3’) for the purpose of the analysis. 
The values are listed including the < or > sign.
If more than one value for a laboratory parameter is assessed on the same day, from central and 
local laboratory, the value from the central laboratory is considered for the analysis. If more than 
one value falls on the same time point (date and time) then the one with the last sequential number 
in SDTM will be used.
6.2.1. Laboratory parameters
Below the list of laboratory parameters with corresponding SI units.
Hematology

Hemoglobin (g/L)

Hematocrit (L/L)

Erythrocyte count (reticulocyte count) (1012/L)

Leukocyte count with differential (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils) counts (109/L).

Platelet count (109/L).
Clinical chemistry

Alanine aminotransferase (ALT) (U/L)

Aspartate aminotransferase (AST) (U/L)

Alkaline phosphatase (U/L)

Total and direct bilirubin (μmol/L)

Gamma glutamyl transpeptidase (U/L)

Creatinine (μmol/L)

Blood urea nitrogen (mmol/L)


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
Uric acid (μmol/L)

Glucose (mmol/L)

Cholesterol (mmol/L)

Triglycerides (mmol/L)

Sodium, potassium, chloride, calcium (mmol/L)

Serum albumin (g/L)

Total protein (g/L)

Alpha-fetoprotein (ug/L)

Cystatin-C (mg/L).
Coagulation tests

Prothrombin time and/or international normalized ratio.
All laboratory parameters (defined above) provided by the central and local laboratory will be 
listed together, including those from unscheduled visits. Marked laboratory abnormalities (MLAs) 
are flagged accordingly.
Changes from baseline to all scheduled visits will be summarized by treatment group, displaying 
descriptive statistics for hematology (including coagulation tests) and clinical chemistry. 
Similarly, changes from baseline to the ‘last on-treatment assessment” and to the “last follow-up
assessment” (see Section 2.1.2) will be summarized as well.
For selected laboratory tests (see list below), results will be visualized by means of scatter plots of 
values at baseline versus last-on treatment assessment. The scatter plot is displayed with the 
reference line y = x.

Hematology: hemoglobin, hematocrit, leukocytes, platelets

Clinical chemistry: ALT, AST, Alkaline phosphatase, total bilirubin, creatinine.
After consultation with the Study Results Committee constituted of external clinicians with 
expertise in subjects with Functional Single Ventricle Heart Disease on 13-Aug-2021, the 
following analyses of change from baseline in total bilirubin, ALT, and AST will be performed 
considering all observed values (from scheduled or unscheduled assessments) and the actual 
assessment day to assess and characterize the pattern of total bilirubin, ALT, and AST (separately) 
over time. 
Gilbert’s syndrome is a common inherited disease caused by a gene mutation whereby the liver is 
unable to properly process bilirubin, a byproduct of the breakdown of red blood cells. It results in 
elevated bilirubin levels. Given that subjects with Gilbert’s Syndrome will have bilirubin 
elevations that are not necessarily caused by hepatic congestion, these subjects (as qualified by the 
preferred term ‘Gilbert’s syndrome’ in the “Medical history” eCRF module) will be removed from 
the analyses of change in bilirubin, ALT and AST over time.


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
Spaghetti plots will be presented by treatment group to explore the longitudinal pattern of 
observed values.

A parametric longitudinal mixed-effects model, with a (fixed-effects) mean structure that is 
quadratic over time (with time corresponding to the actual assessment day) and with a random 
intercept and a random slope will be considered for changes from baseline to each post-
baseline assessment. The model will include time, time-by-treatment interaction term, time-
by-time-by- treatment quadratic interaction term, an indicator variable and the baseline value. 
Random intercept and slope at the level of the subject will be considered. Estimates by 
treatment groups at analysis visits Week 16 and Week 52, will be presented along with their 
95% confidence intervals from the model. Graphical presentation of model estimates along 
with 95% confidence regions will be overlayed to the observed values of the change from 
baseline.
6.2.1.1.
Marked Laboratory Abnormalities
A laboratory test abnormality is defined as any value outside the normal range as provided by the 
central and local laboratory. The direction of the abnormality (below or above the normal range) 
is indicated using ‘H’ and ‘L’. 
A marked laboratory abnormality (MLA) is defined as any value that fulfills the applicable 
condition for LL / HH, as provided in Table 12. More severe marked abnormalities are indicated 
by LLL / HHH, where applicable.
The definitions of marked abnormal values are based mainly on the Common Terminology Criteria 
for Adverse Events (CTCAE) (CTCAE 2010) grading system and, in specific cases (e.g., 
lymphocyte levels), are adjusted based on the known pharmacodynamic effect of the study drugs 
(e.g., LLL threshold for lymphocytes).
Treatment-emergent MLAs, including liver function test, hemoglobin, estimated glomerular 
filtration rate and protein losing enteropathy abnormalities, are those occurring after the study 
treatment start and up to 30 days after study treatment discontinuation, that were not present at 
baseline in the same or worse category (considering the direction of worsening). In other words, 
the MLAs are evaluated independently by direction of worsening (e.g., a post-baseline MLA of 
“HH” is considered treatment-emergent if the baseline is “L” or “LL” or “LLL” (where applicable) 
or “H”, or within normal limits or missing. On the other hand, it is not considered as treatment-
emergent if the baseline is “HH” or “HHH” when applicable).


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Table 12:
Threshold for Marked Laboratory Abnormalities
Parameter (SI unit)
LL
LLL
HH
HHH
Hemoglobin (g/L)
< 100
ALERT: 
< 100 (re-
test) 
< 80
ALERT: 
< 80 (re-
test) 
Increase in > 20 
g/L above ULN or 
above baseline (if 
baseline is above 
ULN)
Increase in > 40 g/L above ULN or 
above baseline (if baseline is above 
ULN)
Hematocrit (L/L)
< 0.28 
(female)
< 0.32 (male)
< 0.20
> 0.55 (female)
> 0.60 (male)
> 0.65
Platelet count (109 /L)
< 75 
< 50
> 600
> 999
Eythrocyte count 
(1012 /L)
ND
ND
ND
ND
Leukocyte count (109
/L)
NA
< 1.9
> 20.0
> 100.0
Lymphocyte (109 /L)
ND
< 0.2
> 4.0
>20
Neutrophils (109 /L) 
< 1.5 
< 1.0
ND
ND
Eosinophils (109 /L) 
ND
ND
> 5.0
ND
AST (U/L)*
ND
ND
≥ 3 ULN
ALERT: 
≥ 3 ULN 
(exclusion at 
baseline or re-test)
≥ 5 ULN
ALERT: 
≥ 5 ULN (re-test)
≥ 8 ULN (discontinuation) **
ALT (U/L)*
ND
ND
≥ 3 ULN
ALERT: 
≥ 3 ULN 
(exclusion at 
baseline or re-test)
≥ 5 ULN
ALERT: 
≥ 5 ULN (re-test)
≥ 8 ULN (discontinuation) **
Total bilirubin 
(umol/L)
ND
ND
≥ 2 ULN 
ALERT: 
≥ 2 ULN 
combined with 
ALT or AST ≥ 3 
ULN
(discontinuation)
≥ 5 ULN
Alkaline Phosphatase 
(U/L)
ND
ND
> 2.5 ULN
> 5 ULN
INR*
ND
ND
≥ 1.5 ULN or
≥ 1.5 above 
baseline if on 
anticoagulation
≥ 2.5 ULN or
≥ 2.5 above baseline if on 
anticoagulation
Creatinine (umol/L)*
ND
ND
>1.5 ULN or 
>1.5 baseline (if 
baseline > ULN)
> 3 ULN or 
>3 baseline (if baseline > ULN)


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Parameter (SI unit)
LL
LLL
HH
HHH
eGFR (mL/min/1.73 
m2)
< 60 
< 30 
ALERT:  
<30 
(exclusion 
at 
baseline)
ND
ND
Blood Urea Nitrogen
(mmol/L)
ND
ND
> 2.5 ULN
> 5 ULN
Albumin (g/L)
< 30 
ALERT: < 30 
combined with 
total protein < 
50 (exclusion at 
baseline) 
< 20
ND
ND
Glucose (mmol/L)
< 3.0
< 2.2
> 8.9
>13.9
Potassium (mmol/L)
< 3.2
< 3.0
> 5.5
> 6.0
Sodium (mmol/L)
ND
< 130
> 150 
> 155 
Calcium (mmol/L)
< 2.0 
< 1.75
> 2.9
> 3.1
Triglyceride (mmol/L)
ND
ND
> 3.42
> 11.4
Cholesterol (mmol/L)*
ND
ND
> 7.75
> 12.92
Serum pregnancy test
ND
ND
ND
Positive
ALERT: 
Positive
The above values come from the protocol Table 5 in Appendix 1 of the protocol.
* HH and HHH based on CTCAE 2010 v4.03 (CTCAE 2010)
**** Also HHHH as > 8 x ULN
For INR, a subject is considered to be on anticoagulation if the subject took antithrombotic agent (ATC codes B01A) and date of 
INR assessment is on or after start of anticoagulation therapy.
ALERT = study-specific alerts that trigger specific actions by the investigator [see Protocol Section 5.1.11; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; INR = International Normalized Ratio; MCH = mean corpuscular 
hemoglobin; MCV = mean corpuscular volume; may be complemented by definitions provided by the central laboratory (see central 
laboratory manual); NA = not applicable; ND = not defined; SI = international system of units; ULN = upper limit of normal.
For each category (i.e., LL, LLL, HH, HHH, HHHH), treatment-emergent MLAs (separately for 
hematology and clinical chemistry) will be summarized by treatment group, displaying counts and 
percentages of subjects with at least a treatment-emergent marked laboratory abnormality for each 
parameter for which the marked abnormality is defined (except for serum pregnancy test). MLAs 
related to coagulation tests will be included in the summary of hematology MLAs.
In addition, for each parameter for which the abnormalities are defined, the distribution of subjects 
at baseline versus the following categories will be displayed:

worst low value up to 30 days after study treatment discontinuation, 

worst high value up to 30 days after study treatment discontinuation, 

“last on-treatment assessment” (see definition in Section 2.1.2).
If LL/LLL or HH/HHH are not defined for a parameter “NA” will appear in the table for the
corresponding parameter/category. 


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All laboratory tests for subjects with at least one treatment-emergent MLAs are provided in a 
separate subject listing.
6.2.1.2.
Additional Liver Function Test and Hemoglobin Abnormalities
The following elevated liver test abnormalities are considered:
–
ALT or AST ≥ 3 × ULN; 
–
ALT or AST ≥ 3 × ULN and < 5 × ULN; 
–
ALT or AST ≥ 5 × ULN and < 8 × ULN; 
–
ALT or AST ≥ 8 × ULN.
–
ALT or AST ≥ 3 × ULN in combination (i.e., at the same visit) with total bilirubin 
≥2 × ULN
The following hemoglobin abnormalities are considered:
–
Hemoglobin < 80 g/L 
–
Hemoglobin ≥ 80 g/L and < 100 g/L
–
Hemoglobin < 100 g/L 
The highest ALT or AST value at any post-baseline time point of assessment up to 30 days after 
study treatment discontinuation is considered for classification in the categories above.
The lowest hemoglobin value at any post-baseline time point of assessment up to 30 days after 
study treatment discontinuation is considered, as defined above.
Treatment-emergent liver/hemoglobin abnormalities are summarized by treatment group,
displaying counts and percentages of subjects with at least a treatment-emergent abnormality for 
each predefined abnormality.
Using the “evaluation of drug-induced serious hepatotoxicity” (eDISH) plots, graphical 
representations of maximum treatment-emergent ALT (in multiples of ULN) by maximum 
treatment-emergent total bilirubin (in multiples of ULN) will be produced, to identify potential
Hy’s Law cases for each subject. The graph will be on a log10 scale for all subjects having 
assessments > 0.0625 ULN for both peaks. Two reference lines will be plotted identifying the 2 
× ULN for total bilirubin and 3 × ULN for ALT. The normal subjects are on the left lower quadrant, 
the possible Hy’s Law cases appear on the right upper quadrant. The peak is defined as the 
maximum value from study treatment start up to 30 days after study treatment discontinuation (for 
the same subjects, not necessarily the peak of ALT occurs at the same time of the peak of total 
bilirubin).
6.2.1.3.
Estimated glomerular filtration rate (eGFR) and Protein Losing 
Enteropathy (PLE)
The abnormality associated to the estimated creatinine clearance for determining glomerular 
filtration rate reflecting severe renal function is defined as eGFR < 30 mL/min/1.73m2. 


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If creatinine clearance is estimated, the Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) equation (Levey 2009) will be used for adults and the Bedside Schwartz equation 
(Schwartz 2009) for adolescents, for determining glomerular filtration rate (GFR) according to the 
formula in the protocol Section 7.2.4.2. The derived GFR is available in the SDTM.
The distribution of subjects in the following categories will be displayed by treatment group:
o
G1 (Normal or high): ≥ 90 mL/min/1.73m2
o
G2 (Mildly decreased): 60-89 mL/min/1.73m2
o
G3a (Mildly to moderately decreased): 45-59 mL/min/1.73m2
o
G3b (Moderately to severely decreased): 30-44 mL/min/1.73m2
o
G4 (Severely decreased): 15-29 mL/min/1.73m2
o
G5 (Kidney failure): < 15 mL/min/1.73m2
The lowest eGFR value at any post-baseline time point of assessment up to 30 days after study 
treatment discontinuation (that was not present at baseline) is considered.
The protein losing enteropathy is defined as:

Albumin < 30 g/L in combination (i.e., at the same visit) with total protein < 50 g/L. 
Treatment-emergent eGFR or PLE abnormalities are summarized by treatment group, displaying 
counts and percentages of subjects with at least one abnormality.
6.3.
Vital Signs and Physical Examination Findings
Vital signs parameters include: systolic and diastolic blood pressure (mmHg), pulse rate (bpm), 
SpO2 (%), height (cm), and body weight (kg). 
The analysis of the changes from baseline will be based on results at scheduled visits. For each 
post-baseline scheduled visit, only assessments performed after study treatment start date up to 30 
days after study treatment discontinuation will be included. End-of-Treatment (if any) visit is 
mapped to a scheduled visit (see Section 2.1.2). Values from unscheduled visits are not included 
in the summaries by visits but are included in the analysis for abnormality.
Changes from baseline to all scheduled visits will be summarized by treatment group, displaying 
descriptive statistics for systolic and diastolic blood pressure (mmHg), pulse rate (bpm), SpO2 (%),
and body weight (kg). Similarly, changes from baseline to the ‘last on-treatment assessment” and 
to the “last follow-up assessment” (see Section 2.1.2) will be summarized as well. Height will be 
summarized only at baseline together with the demographic characteristics.
Box plots will be presented to graphically display the distribution of the change from baseline in 
vital signs (BP, pulse rate, SPO2, and body weight) over time (i.e., at each scheduled visit from 
Week 1 to Week 52). 
The number and percentages of subjects with the following abnormality for the systolic blood 
pressure: < 90 mmHg for adults (or < 85 mmHg for adolescents (<18 years old) who are < 150 cm 


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in height) at any post-baseline assessment (scheduled or unscheduled) after the study treatment 
start up to 30 days after study treatment discontinuation (that were not present at baseline), will be 
presented by treatment group. 
A listing of all vital sign measurements will be provided. Position (supine or sitting) and location 
(left or right arm) for vital signs will be included as well as the flag for abnormal systolic blood 
pressure.
Physical examinations performed during the course of the study are reported in a subject listing, 
with associated general assessment. If an abnormality is found, further details describing the signs 
and symptoms related to the abnormality are specified.
6.4.
Electrocardiogram
No direct reporting of ECG results is planned.
An ECG result is reported as an AE in the case of an abnormal assessment representing a clinically 
significant finding that was either not present at baseline, or worsened after the start of study 
treatment.
6.5.
Other Safety Parameters
6.5.1. Echocardiography
Single ventricle ejection fraction (%), Fontan circulation stenosis value (%), ventricular outflow 
to aorta doppler velocity (m/s) and valvular defects [vena contracta diameter (mm) and regurgitant 
orifice (cm2)] are measured at screening and End of Treatment (EOT) visit and reported in the 
eCRF. 
Severe AV valve regurgitation is present where the vena contracta is 7 mm or the effective 
regurgitant orifice is 0.4 cm2. In the eCRF, up to two valve regurgitation values may be collected. 
If both are present in the eCRF, the largest will be considered for the analysis.
Presence of left ventricular outflow obstruction is confirmed by a pulsed-wave Doppler velocity 
2.5 m/s.
The analysis of echocardiography will be based on results at scheduled visits. 
Changes from baseline (i.e.,screening) to Week 52/EOT in Fontan circulation stenosis (%) and 
ejection fraction (%) will be summarized by treatment group, displaying descriptive statistics for
continuous variables.
Valvular defects (identified by severe AV valve regurgitation and presence of left ventricular 
outflow obstruction) will be summarized at baseline (i.e.screening) and Week 52/EOT by 
treatment group using frequency counts and percentages.
Individual listing of echocardiographic parameters will be provided.


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6.5.2. Pregnancy Test
For females of childbearing potential, a serum pregnancy test is performed at Screening (Visit 1), 
and urine pregnancy tests at Randomization (Visit 2), and every 4 weeks (+/−7 days) thereafter up 
to EOS. In addition, a serum pregnancy test is performed at any time if pregnancy is suspected 
during the study.
Pregnancies must be entered in the AE page of the eCRF. Methods of contraception are collected 
in the Contraceptive Methods Log page of the eCRF. Change in childbearing potential status is 
collected in the Childbearing Potential Status Change page of the eCRF.
Childbearing potential status, contraception and pregnancy test data are reported in subject’s 
listings.
QUALITY OF LIFE 
Quality of life (QoL) parameters will be assessed for all subjects by 2 sets of QoL questionnaires 
including the EQ-5D-5L and the patient/clinician assessment of severity and assessment of change 
(PGA-S, PGI-C and CGI-S, CGI-C, respectively). These will be completed on paper, and site staff 
will enter the corresponding values in the eCRF. 
The PGA-S and PGI-C are completed by subjects, while the CGI-S and CGI-C are completed by 
clinicians (a physician, either an investigator or sub-investigator). Completion should occur at the 
beginning of the visit.    
Disease Severity (PGA-S and CGI-S) is assessed at Randomization (Visit 2), Week 16 (Visit 4), 
and Week 52 (Visit 6), or EOT in case it occurs prior to Week 52. 
Impression of Change (PGI-C and CGI-C) is assessed at Week 16 (Visit 4), and Week 52 (Visit 
6), or EOT in case it occurs prior to Week 52. 
The EQ-5D-5L questionnaires are completed by subjects at Randomization (Visit 2), Week 16 
(Visit 4), Week 52 (Visit 6), or EOT in case it occurs prior to Week 52. If subjects enter the PTOP, 
the questionnaire will be also be completed using designated scripts.
The following QoL endpoints are considered:

Patient Global Assessment of Disease Severity (PGA-S) and Clinician Global Impression of 
Severity (CGI-S) at each scheduled visit (baseline, Visit 4/Week 16, and Visit 6/Week 52),

Patient Global Impression of Change (PGI-C) and Clinician Global Impression of Change 
(CGI-C) questionnaire at each post-baseline scheduled visit (Visit 4/Week 16, and Visit 
6/Week 52) ,

Proportion of subjects within each response category for each dimension (i.e., mobility, self-
care, usual activities, pain/discomfort, anxiety/depression) of the Euro QoL 5D (EQ-5D-5L) 
questionnaire at baseline and post-baseline scheduled visit (Visit 4/Week 16 and Visit 6/Week 
52),


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
Change from baseline to each post-baseline scheduled visit (Visit 4/Week 16 and Visit 6/Week 
52) in self-rated health status score assessed by the EQ-5D-5L questionnaire.
The QoL endpoints will be analyzed descriptively on the FAS by randomized treatment group . 
The analysis of the quality of life endpoints will be based on results at scheduled visits. For each 
post-baseline scheduled visit, only assessments performed after study treatment start date will be 
included. End-of-Treatment (if any) visit is mapped to a scheduled visit (see Section 2.1.2). Values 
from unscheduled visits are not included in the summaries by visits.
For PGA-S, CGI-S, and each dimension of EQ-5D-5L the proportion of subjects within each 
response category will be summarized at baseline and at each post-baseline visit. 
Each dimension of EQ-5D-5L questionnaire is divided into 5 levels of perceived problems: Level 
1 indicating no problems, Level 2 indicating slight problems, Level 3 indicating moderate 
problems, Level 4 indicating severe problems, and Level 5 indicating extreme problems. The 
frequency distribution of subject’s responses over time will be provided in a graphical 
representation (i.e. bar plot) for ach treatment group. The percentages of subjects reporting 
problems will be summarized by grouping responses from Level 2 to Level 5 for each dimension 
of EQ-5D-5L questionnaire.
For PGI-C and CGI-C, the proportion of subjects within each response category will be 
summarized at each post-baseline visit. 
The self-rated health status score assessed by the EQ-5D-5L questionnaire will be summarized at 
baseline, at each post-baseline visit as well as for the absolute change from baseline to each post-
baseline visit. 
Individual subject listings will be provided for each QoL questionnaire.
PHARMACOKINETICS/PHARMACODYNAMICS
8.1.
Pharmacokinetics
Trough (pre-dose) plasma concentrations of macitentan and its metabolite ACT-132577, are 
obtained via blood samples taken at Week 4 (Visit 2, during the regular corresponding monthly 
blood draw) and Week 16 (Visit 4), or at EOT in the case of premature study treatment
discontinuation prior to Week 16.
PK analyses will be performed on the PKS. Reasons for exclusion from PKS will be summarized 
by treatment group on the FAS.
Trough macitentan and ACT-132577 analyte concentrations will be summarized by visit 
(i.e., Week 4, Week 16/EOT) by descriptive statistics (i.e., N, mean, standard deviation [SD], 
range [minimum and maximum], coefficient of variation (%), and geometric mean). A subject will 
be included in the analysis at each visit if the corresponding plasma concentration value is flagged 


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at “steady-state”, as reported in the SDTM, and if the corresponding sample is not taken after the 
morning dose of study treatment (i.e., without PD_PM.364 for the visit under consideration).
Up to protocol version 6, PK sampling were taken at Visit 3/Week 8. With protocol version 7, 
Week 8 was converted to a telephone call therefore PK sampling is taken during Visit 2/Week 4. 
For the evaluation at Week 4, the value at Week 8 (if available) will replace the value at Week 4 
(if not available). 
In case of premature treatment discontinuation prior to Visit 4/Week 16, the value at EOT will 
replace the value at Week 16 (if not available).
Similarly, trough macitentan and ACT-132577 analyte concentrations will be summarized by age 
group (i.e., adolescents: 12-18 yrs vs adults: ≥18 yrs), by sex (i.e., male vs female), by body weight 
at baseline (< 50 kg, >=50kg) as well as by age group * body weight at baseline.
Individual subject listing will be provided.
HEALTH ECONOMICS
The following pharmacoeconomic endpoints are considered:

Number per year of all-cause and Fontan-related hospitalizations from baseline up to EOT.

Number per year of in-patient hospital days for all causes and Fontan-related causes from 
baseline up to EOT.
The number of all-cause and Fontan-related hospitalizations will be calculated during the double-
blind treatment period (defined as the period between the treatment start date, see Section 2.5.2, 
and the EOT, see Section 2.5.3, limits included). The number per year of hospitalizations will be 
calculated as follows:

at group-level: total number of hospitalizations across subjects divided by the total study 
treatment duration (subjects-year)

at subject-level: (number of hospitalizations for each subject / individual treatment duration 
in days) * 365.25.
The number per year of hospital days (all-cause and Fontan-related) will be calculated (at subject-
level) as: 
(total number of hospital days for each subject / individual treatment duration in days) * 365.25.
For each hospitalization, the number of hospital days is calculated as discharge date minus
admission date plus 1. For each subject, the number of days spent in hospital is the sum of the 
number of days in hospital for all his/her hospitalizations up to EOT. 
Number per year of all-cause and Fontan-related hospitalizations and hospital days will be 
summarized descriptively on the FAS by randomized treatment group. 
Individual subject listing will be provided.


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CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE STUDY 
PROTOCOL 
10.1.
Changes to the Statistical Analysis Plan for Special Protocol Submission
SAP version 3 finalized on 25-Feb-2021 has been developed based on the document that was 
finalized and sent to FDA Agency for the SPA re-submission of protocol version 8 (SAP for SPA 
Final version 2 (D-20.077)).
The analyses for the primary and secondary efficacy endpoints were already described in Section 
4 of the SAP for SPA, which are currently under Section 5 of this document.
All the analyses which will be performed for the CSR purpose have been added in this document
and outlined below. Any change, addition or clarification compared to the SAP for SPA for the 
primary and secondary efficacy endpoints are detailed below.

Section 4: Subject Information (i.e., demographics and baseline disease characteristics, 
medical history, screening failures, study and study treatment disposition, treatment 
compliance, extent of exposure, protocol deviations, and prior and concomitant 
medications)

Section 5: Analyses of primary and secondary efficacy endpoints as in the SAP for SPA 
(see changes below) with the addition of the analysis of other efficacy variables
o
Primary and secondary efficacy endpoints: 

the estimators based on the inverse normal combination method with 
weights proportional to the final actual sample size (i.e., 142 subjects) have 
been added in this document (Section 5.2.3.4, Section 5.3.1.6, and 5.3.2.6
for primary and secondary endpoint respectively) to assess the robustness 
of result when the weights are proportional to the actual sample size of 142 
subjects.

the estimator based on different model 1 (Section 5.2.3.4), by adding 
treatment-by-geographical region interaction to the main model, has been 
deleted as the treatment-by-geographical region interaction is already 
investigated in the subgroup analysis as described in Section 5.2.3.5.
o
Secondary efficacy endpoint: Change from baseline over 52 weeks in peak VO2
The estimator based on ANCOVA has been clarified for the handling of 
intercurrent events (i.e., premature study treatment discontinuation was not spelled
out clearly as an event in the SAP for SPA) and the rules for missing data were 
added in line with the primary estimand of this endpoint.
The estimator based on the number of subjects with available Week 52 data pre-
and post- Sponsor decision (i.e., 24 January 2019) to implement the IA as present 
in the SAP for SPA (Section 4.3.1.6) has been deleted as almost no subject would 
have Week 52 data before January 2019, being the first subject randomized in 
December 2017.


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
Section 6: Safety

Section 7: Quality of life

Section 8: Pharmacokinetic

Section 9: Health Economics
10.2.
Changes to the analyses planned in the study protocol
Efficacy

The estimator based on different model 1 (Section 5.2.3.4), by adding treatment-by-
geographical region interaction to the main model, has been deleted as the treatment-
by-geographical region interaction is already investigated in the subgroup analysis 
as described in Section 5.2.3.5.
Safety

Adverse events: The analysis of treatment-emergent non-serious AEs (protocol 
Section 10.3.4.1) will not be part of this document. The list of results to be posted to 
the clinical registry will be detailed in the Data Presentation Specification Part 1 
(Section 1.3).

Treatment-emergent marked laboratory abnormalities (protocol Section 10.3.4.2): 
shift tables of categories of MLAs at baseline versus post-baseline visits, worst low, 
worst high and last post-baseline have been clarified to be with shift tables of 
categories of MLAs at baseline vs worst low value (up to 30 days after study 
treatment discontinuation), worst high value (up to 30 days after study treatment 
discontinuation), “last on-treatment assessment” value. 
Reason: In order to have a consistent overview of LMAs, the shift tables are aligned 
to the evaluation of treatment-emergent LMAs during the treatment period up to 30 
days after study treatment discontinuation for the worst low and worst high value, 
without the need to look at each intermediate post-baseline visits. The evaluation on 
last on treatment assessment has been added.
10.3.
Clarifications concerning endpoint definitions and related variables or 
statistical methods
Analysis sets
The protocol Section 10.1 namely calls “Screened Analysis set (SCR)”, “Per-Protocol Set 
(PPS)”. These analysis sets are renamed “All Enrolled Set (ENR)”, “Per-Protocol Set (PP), 
respectively [refer to Section 2.2] in accordance with current terminology/standards in 
Janssen. 
The definition of SCR remains unchanged.
The definition of the PP has been detailed for each primary and secondary efficacy endpoint 
in line with the estimand language of each endpoint. This will allow to assess the robustness 
of results on a different population (therefore additional estimand) compared to the main 


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estimand. Therefore the PP has been replaced with PP1, PP2, PP3 for the primary and two 
secondary efficacy endpoints, respectively.
Other efficacy endpoints
Physical activity
The analysis of the mean time spent in minutes in each of the category of physical activity 
have been clarified as compared to protocol Section 10.3.5.3. The mean time will be 
summarized as a continuous variable by displaying, for each treatment group, descriptive 
statistics for the absolute values at baseline, Week 16, and Week 52 as well as for the 
absolute change from baseline. Furthermore, the percentage of daily time spent in each 
category will be summarized similarly including the graphical display (i.e. bar plot) at each 
time point of assessment.
The number of subjects who spent time in physical activity categories will not be 
summarized in shift tables (categories at baseline vs categories at post-baseline visits) as 
indeed it is stated in protocol Section 10.3.5.3. Each subject spends the daily time in one 
or more categories therefore the shift tables should make assumption for the selection of 
which category should be compared at baseline vs post-baseline. It is indeed of interest to 
summarize the percentage of daily time spent in each category as continuous variable at 
baseline and at each timepoint of assessment, including the changes from baseline.
Safety
To monitor liver function test and hemoglobin abnormalities, specific categories of 
abnormalities have been better defined in Section 6.2.1.2 of this document as well as in 
Section 6.2.1.3 for eGFR and PLE.


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REFERENCES
ADDPLAN Inc. an Aptiv Solutions Co. (2014). ADDPLAN BASE version 6.1 User Manual. Aptiv 
Solutions, Cologne, Germany. 2014.
Collett D (2003) Modelling Survival Data in Medical Research, 2nd Edition. Chapman & Hall; 2003.
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 
main Health National Cancer Institute.
Cuzick J (2005). Forest plots and the interpretation of subgroups. Lancet 2005;365:1308.
Evenson KR (2008), Catellier DJ, Gill K, Ondrak KS, McMurray RG. Calibration of two objective 
measures of physical activity for children, Journal of Sports Sciences, 2008;26:14,1557-1565.
Freedson PS (1998), Melanson E, Sirard J. Calibration of the Computer Science and Pallications, Inc. 
accelerometer. Official Journal of the American College of Sports Medicine 1998;777-781.
Hebert A (2013), Jensen AS, Idorn A et al. The effect of bosentan on exercise capacity in fontan patients; 
rationale and design for the TEMPO study. BMC Cardiovascular Disorders 2013; 13: 36-42.
Hebert A (2014), Mikkelsen UR, Thilen U et al. Bosentan Improves Exercise Capacity in Adolescents 
and Adults After Fontan Operation - The TEMPO (Treatment With Endothelin Receptor Antagonist in 
Fontan Patients, a Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen 
Consumption Study. Circulation 2014; 130: 2021-30.
Lehmacher W (1999), Wassmer G. 1999. Adaptive sample size calculations in group sequential trials. 
Biometrics 55(4):1286–90. 
Levey AS (2009), Stevens LA, Schmid CH, et al. CKD-EPI (Chronic Kidney Disease Epidemiology 
Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 
5;150(9):604-12.
Pocock SJ (2002), Clayton TC, Altman DG. Survival plots of time-to-event outcomes in clinical trials: 
good practice and pitfalls, Lancet. 2002;359:1686 89.
Schwartz GJ (2009), Work DF. Measurement and estimation of GFR in children and adolescents. Clin 
J Am Soc Nephrol. 2009 Nov;4(11):1832-43.
Troiano RP (2008), Berrigan D, Dodd KW, Mâsse LC, Tilert T, McDowell M. Phyisical activity in the 
United States measured by accelerometer. Med Sci Sports Exerc. 2008 Jan;40 (1):181-8.


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ATTACHMENTS
ATTACHMENT 1 - BMI-FOR-AGE REFERENCE
BMI-for-age cutoffs for adolescents were calculated based on the WHO Child Growth Standards 
(2007) developed using data collected in the WHO Multicentre Growth Reference study. 
According to WHO classification an adult is classified underweight, normal weight, overweight, 
obese class I, obese class II, obese class III according to BMI cutoffs below:
BMI (kg/m2)
Classification
< 18.5
Underweight
18.5 - 25
Normal weight
25 - 30
Overweight
30 - 35
Class I obese
35 - 40
Class II obese
≥ 40
Class III obese
The z-score value associated with a BMI of 18.5, 25, 30, 35, and 40 for a 18 year subject was used 
as the reference for the calculation of the equivalent BMI in adolescents. 
Therefore an adolescent (boy or girl) between 12 and 18 years is classified underweight, normal 
weight, overweight, obese class I, obese class II, obese class III according to BMI cutoffs below:
Sex
Age (years)
Classification
BMI (kg/m2)
Boy
12
Underweight
<15.41
13
Underweight
<15.98
14
Underweight
<16.58
15
Underweight
<17.16
16
Underweight
<17.68
17
Underweight
<18.13
18
Underweight
<18.50
Girl
12
Underweight
<16.18
13
Underweight
<16.83
14
Underweight
<17.40
15
Underweight
<17.86
16
Underweight
<18.17
17
Underweight
<18.37
18
Underweight
<18.50
Sex
Age (years)
Classification
BMI (kg/m2)
Boy
12
Normal weight
≥ 15.41 and < 20.22
13
Normal weight
≥ 15.98 and < 21.13
14
Normal weight
≥ 16.58 and < 22.06
15
Normal weight
≥ 17.16 and < 22.93
16
Normal weight
≥ 17.68 and < 23.72
17
Normal weight
≥ 18.13 and < 24.41
18
Normal weight
≥ 18.50 and < 25
Girl
12
Normal weight
≥ 16.18 and < 21.41


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13
Normal weight
≥ 16.83 and < 22.39
14
Normal weight
≥ 17.40 and < 23.27
15
Normal weight
≥ 17.86 and < 23.96
16
Normal weight
≥ 18.17 and < 24.45
17
Normal weight
≥ 18.37 and < 24.78
18
Normal weight
≥ 18.50 and < 25
Sex
Age (years)
Classification
BMI (kg/m2)
Boy
12
Overweight
≥ 20.22 and < 24.65
13
Overweight
≥ 21.13 and < 25.87
14
Overweight
≥ 22.06 and < 27.0
15
Overweight
≥ 22.93 and < 27.98
16
Overweight
≥ 23.72 and < 28.81
17
Overweight
≥ 24.41 and < 29.48
18
Overweight
≥ 25 and < 30
Girl
12
Overweight
≥ 21.41 and < 25.98
13
Overweight
≥ 22.39 and < 27.19
14
Overweight
≥ 23.27 and < 28.22
15
Overweight
≥ 23.96 and < 28.99
16
Overweight
≥ 24.45 and < 29.52
17
Overweight
≥ 24.78 and < 29.82
18
Overweight
≥ 25 and < 30
Sex
Age (years)
Classification
BMI (kg/m2)
Boy
12
Obese class I
≥ 24.65 and < 30.22
13
Obese class I
≥ 25.87 and < 31.77
14
Obese class I
≥ 27.0 and < 32.97
15
Obese class I
≥ 27.98 and < 33.82
16
Obese class I
≥ 28.81 and < 34.41
17
Obese class I
≥ 29.48 and < 34.79
18
Obese class I
≥ 30 and < 35
Girl
12
Obese class I
≥ 25.98 and < 31.26
13
Obese class I
≥ 27.19 and < 32.62
14
Obese class I
≥ 28.22 and < 33.69
15
Obese class I
≥ 28.99 and < 34.43
16
Obese class I
≥ 29.52 and < 34.85
17
Obese class I
≥ 29.82 and < 35
18
Obese class I
≥ 30 and < 35
Sex
Age (years)
Classification
BMI (kg/m2)
Boy
12
Obese class II
≥ 30.22 and < 37.79
13
Obese class II
≥ 31.77 and < 39.67
14
Obese class II
≥ 32.97 and < 40.58
15
Obese class II
≥ 33.82 and < 40.81
16
Obese class II
≥ 34.41 and < 40.70
17
Obese class II
≥ 34.79 and < 40.41
18
Obese class II
≥ 35 and < 40
Girl
12
Obese class II
≥ 31.26 and < 37.56


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13
Obese class II
≥ 32.62 and < 38.94
14
Obese class II
≥ 33.69 and < 39.85
15
Obese class II
≥ 34.43 and < 40.35
16
Obese class II
≥ 34.85 and < 40.48
17
Obese class II
≥ 35 and < 40.32
18
Obese class II
≥ 35 and < 40
Sex
Age (years)
Classification
BMI (kg/m2)
Boy
12
Obese class III
≥ 37.79
13
Obese class III
≥ 39.67
14
Obese class III
≥ 40.58
15
Obese class III
≥ 40.81
16
Obese class III
≥ 40.70
17
Obese class III
≥ 40.41
18
Obese class III
≥ 40
Girl
12
Obese class III
≥ 37.56
13
Obese class III
≥ 38.94
14
Obese class III
≥ 39.85
15
Obese class III
≥ 40.35
16
Obese class III
≥ 40.48
17
Obese class III
≥ 40.32
18
Obese class III
≥ 40


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ATTACHMENT 2 - ADVERSE EVENTS OF SPECIAL INTEREST
Adverse events of special interest are defined as follows:
I.
Hepatic events of special interest
AEs are included in this grouping if their coded PTs are included in the “Hepatic disorders” SQM 
with including all its sub-SMQ with the exception of “Liver-related coagulation and bleeding 
disturbances (SMQ)”.
II.
Edema and fluid retention
AEs are included in this subgroup if their coded PTs is “Pulmonary congestion” or if within the 
SMQ “Haemodynamic oedema, effusions and fluid overload (SMQ)” with the exception of PTs 
containing “site”.
III.
Anemia / hemoglobin decrease
AEs are included in this grouping if their coded PTs are included in the SMQs “Haematopoietic 
erythropenia” OR “Haematopoietic cytopenias affecting more than one type of blood cell (SMQ)”
(with the exception of two unspecific PTs: “blood disorder”, “blood count abnormal”) OR an event 
with any MedDRA PT containing the text “anaemia”.
IV.
Hypotension
AEs are included in this grouping if their coded PTs are: Blood pressure ambulatory decreased, 
Blood pressure decreased, Blood pressure diastolic decreased, Blood pressure immeasurable, 
Blood pressure orthostatic decreased, Blood pressure systolic decreased, Blood pressure systolic 
inspiratory decreased, CT hypotension complex, Diastolic hypotension, Hypotension, Mean 
arterial pressure decreased, Neonatal hypotension, Orthostatic hypotension, Postoperative 
hypotension, Procedural hypotension.


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ATTACHMENT 3 - PROTOCOL DEVIATIONS CLASSIFICATION FROM THE 
INDEPENDENT TEAM
PPD
PPD
PPD
PPD
PPD
PPD


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Actelion Pharmaceuticals Ltd.
Statistical Analysis Plan for COVID-19 Impact Assessment
Prospective, multi-center, double-blind, randomized, placebo-controlled, parallel-group 
study assessing the efficacy and safety of macitentan in Fontan-palliated adult and 
adolescent subjects
Protocol AC-055H301; Phase 3
JNJ-67896062 / ACT-064992 (macitentan)
Status:
Approved
Date:
23 August 2021
Prepared by:
Actelion Pharmaceuticals Ltd., a Janssen Pharmaceutical Company of Johnson &
Johnson
Document No.: EDMS-307892, 2.0
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.
NCT03153137


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 3
1.
INTRODUCTION.................................................................................................................................. 4
1.1.
Objectives ........................................................................................................................................ 4
1.2.
Study Design.................................................................................................................................... 4
2.
STATISTICAL HYPOTHESES............................................................................................................ 4
3.
SAMPLE SIZE DETERMINATION...................................................................................................... 5
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS....................................................................... 5
5.
STATISTICAL ANALYSES................................................................................................................. 5
5.1.
General Definitions........................................................................................................................... 5
5.1.1.
COVID-19 periods of the pandemic.............................................................................................. 5
5.1.2.
Visit mapping ................................................................................................................................ 6
5.2.
Subject information .......................................................................................................................... 7
5.2.1.
Subject Disposition ....................................................................................................................... 7
5.2.1.1.
Study and Study Treatment Disposition.................................................................................... 7
5.2.2.
Medical History ............................................................................................................................. 7
5.2.3.
Compliance................................................................................................................................... 7
5.2.3.1.
Treatment Compliance .............................................................................................................. 7
5.2.3.2.
Study Assessment Compliance................................................................................................. 7
5.2.4.
Extent of Exposure ....................................................................................................................... 9
5.2.5.
Protocol Deviations....................................................................................................................... 9
5.2.6.
Prior and Concomitant Medications.............................................................................................. 9
5.3.
Efficacy Analyses ............................................................................................................................. 9
5.3.1.
Primary Efficacy Endpoint........................................................................................................... 10
5.3.2.
Secondary Efficacy Endpoint(s) ................................................................................................. 12
5.3.2.1.
Change from baseline over 52 weeks in peak VO2................................................................. 12
5.3.2.2.
Change from baseline to Week 16 in mean count per minute of daily PA-Ac ........................ 13
5.4.
Safety Analyses ............................................................................................................................. 15
5.4.1.
Adverse Events........................................................................................................................... 15
5.4.2.
Clinical laboratory test ................................................................................................................ 16
6.
SUPPORTING DOCUMENTATION .................................................................................................. 16
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 16
6.2.
Appendix 2 List of COVID-19 related AEs ..................................................................................... 16
LIST OF IN-TEXT TABLES
Table 1:
SAP Version History Summary................................................................................................... 3
Table 2:
Study Documents........................................................................................................................ 4
Table 3:
COVID-19 periods of the pandemic............................................................................................ 5
Table 4:
Mapping of premature End-of-Treatment visit or unscheduled visits ......................................... 6


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VERSION HISTORY
Table 1:
SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1.0
8 April 2021
Not Applicable
Initial release
2.0
23 August 2021
Sections 5.1.2
Clarification of visit mapping in 
case of missing or invalid 
assessments.
Section 5.3.2.1
1. Addition of “Pre/During 
COVID-19” as Week 16 
assessment may fall in Pre-
COVID19 period while 
Week 52 in “During COVID-
19” period.
2. After consultation with the 
Study Results Committee 
constituted of external 
clinicians with expertise in 
subjects with Functional 
Single Ventricle Heart 
Disease on 13-Aug-2021, an 
additional analysis will be 
performed excluding subjects 
who had reported COVID-19 
infection.
Section 5.3.2.2
Clarification for the derivation of 
the 9-day time window


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Status: Approved, Date: 23 August 2021
1.
INTRODUCTION
This Statistical Analysis Plan (SAP) describes the analyses to assess the impact of the COVID-19 
pandemic in the double-blind study AC-055H301 (RUBATO), following the guidance within the 
COVID-19 Standard Reporting Guideline Principles. This document is a separate Appendix of the 
Clinical Study Report (CSR) SAP of this study.
This SAP refers to the documents listed in Table 2. 
Table 2:
Study Documents
Document
Date, Version
Study Protocol AC-055H301 (RUBATO)
Final version 10
Study Protocol AC-055H301 COVID-19 Appendix
Approved version, 17 June 2020 (D-20.158)
SAP for CSR AC-055H301 (RUBATO)
Final approved version (EDMS-RIM-264216)
Data Presentation Specifications Part 1 AC-055H301 
(RUBATO)
Final version
Source data for the analyses will be Analysis Data Model (ADaM) data sets derived for the 
AC-055H301 (RUBATO) CSR SAP.
Except where otherwise specified, all definitions and conventions used in the CSR SAP of this 
study will be applied.
1.1.
Objectives
To assess the impact of COVID-19 pandemic on:
1. disposition information 
2. compliance
3. extent of exposure
4. protocol deviations
5. prior and concomitant medications
6. efficacy (ie, primary and secondary efficacy endpoints)
7. selected safety.
1.2.
Study Design
The study design is described in section 3.1 of the study protocol.
2.
STATISTICAL HYPOTHESES
Not applicable for the scope of this document.
The statistical hypotheses for the trial objectives are described in the CSR SAP (section 1.3 for 
general consideration and sections 5.2.3.1, 5.3.1.3, and 5.3.2.3 for primary and secondary efficacy 
endpoints, respectively). 


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Status: Approved, Date: 23 August 2021
3.
SAMPLE SIZE DETERMINATION
Not applicable for the scope of this document. 
The sample size of this study AC-055H301/RUBATO is based on the justification provided in 
section 1.4 of the CSR SAP.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
The same analysis sets provided in section 2.2 of the CSR SAP will be used.
5.
STATISTICAL ANALYSES
5.1.
General Definitions
5.1.1.
COVID-19 periods of the pandemic
World Health Organization Director-General’s opening remarks at the media briefing on 
COVID-19 on 11 March 2020 declared that the assessment of COVID-19 can be characterized as 
a pandemic. Therefore, the COVID-19 periods related to the pandemic could be identified as
follows:
Table 3:
COVID-19 periods of the pandemic
Period
Definition
Pre COVID-19
Defined as the period before 11 March 2020 unless there is prior evidence of 
COVID-19 by the data collection. In that case, 11 March 2020 is replaced by 
the date of the first evidence of COVID-19 (see definition below).
During COVID-19*
Defined as the period between 11 March 2020 (or earlier in case of prior 
evidence of COVID-19) and the end date of the pandemic (limits included). 
Post COVID-19*
Defined as the period starting immediately after the end date of pandemic
onwards.
* Given that the pandemic still ongoing at the time of this document, no end date of the pandemic is available. 
Therefore, an open end is set for the ‘During COVID-19’ period and the ‘Post COVID-19’ period cannot be considered 
for the analysis.
Prior evidence of COVID-19 (ie, before 11 March 2020) can be identified as follows:

Date of premature study treatment discontinuation / study withdrawal: reasons for 
premature study treatment discontinuation / study withdrawal are identified in the 
corresponding eCRF modules prefixed with the text “COVID-19 related”, as appropriate
(ie, either for AE, or medical or non-medical reason, whether subject or physician decision). 

Onset date of adverse events (AEs): COVID-19 related AEs are identified if the 
corresponding preferred terms (PTs) are included in the list as provided in Appendix 2 List of 
COVID-19 related AEs.

Date of death: if the death is COVID-19 related, the primary cause of death should contain 
the text “COVID-19” in the “Death” eCRF module. (Note: “COVID-19” should then also be 
reported in the corresponding (S)AE).

Protocol deviations (PDs): if a PD is linked to COVID-19, the PD term should be prefixed 
with the text “COVID-19 related”.


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Each assessment/visit will be associated to the COVID-19 periods of the pandemic as defined 
above considering their date respect to the cut-off date of 11 March 2020 (or earlier, as applicable). 
For example, if the peak VO2 assessment at Week 16 was performed before the cut-off date of 
11 March 2020, and there is no prior evidence of COVID-19, that assessment is associated to the 
“Pre COVID-19” period, otherwise it is associated to the “During COVID-19” period. 
Note that it is possible that ‘COVID-19 related” data occurred in the “Pre COVID-19” period, due 
to the fact that the study is running since late 2017 and the pandemic start date selected for the 
analyses (11 March 2020) does not necessarily coincide with the COVID-19 virus circulation start 
date in all countries. 
5.1.2.
Visit mapping
To minimize the amount of missing data and the possibility to delay the assessments until the on-
site visits can be resumed according to the COVID-19 protocol appendix, the efficacy analysis will 
be based on scheduled visits, considering all scheduled assessments after the treatment start date.
In case of missing or invalid assessment at scheduled visit, extended time windows for Week 16 
and Week 52 will be considered as follows:

for subjects who prematurely discontinue study treatment, the End-of-Treatment visit (if 
available) will be re-assigned to a scheduled visit if conducted during the time window 
specified in the table below. 

unscheduled visits (if available) or Visit 5/Week 32 (if available) will be also re-assigned
to a scheduled visit if conducted during the time window specified in the table below.
The following rules are applied to assign End-of-Treatment or unscheduled visits (including 
Visit 5/Week 32) to analysis visits. If a subject has 2 or more actual visits with an available value 
in the same visit window the visit closest to the target day will be used as the protocol visit for that 
visit window. For peak VO2, if a subject has 2 or more actual visits in the same visit window, the 
visit with the valid value closest to the target day will be used as the protocol visit for that visit 
window. The other additional visit(s) will not be used in the summaries or analyses by visit, but 
they can be used for determination of other endpoints (eg, time to event endpoints, marked 
laboratory abnormalities). If 2 actual visits are equidistant from the target day within a visit 
window, the later visit is used. Except otherwise specified, if more than one assessment falls on 
the same day then the worst assessment (ie, lowest for peak VO2) is used.
Table 4:
Mapping of premature End-of-Treatment visit or unscheduled visits
Parameter
Scheduled Visit 
Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point (Day)
Premature End-of-
Treatment or 
unscheduled visits   
re-mapping 
2
Baseline
<=1
1
4
Week 16
2 to 224
113
6
Week 52
225 to open end
365
*Relative to Study Day 1.


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5.2.
Subject information
The last subject was randomized in RUBATO in 30 June 2020 with the screening activities 
announced to close on 23 June 2020. In total there are 8 subjects randomized after or on 11 March
2020.
5.2.1.
Subject Disposition
No subject was reported to fail the screening because of COVID-19, therefore the impact of 
COVID-19 in the screening activities will not be evaluated in the different pandemic periods.
5.2.1.1.
Study and Study Treatment Disposition
Reasons for premature termination of the study due to COVID-19 are captured in the “Study 
discontinuation” eCRF module.
Reasons for premature study treatment discontinuation due to COVID-19 are captured in the 
“Premature Discontinuation of Study Treatment” eCRF module.
The corresponding summaries for study and study treatment disposition as planned in the CSR 
SAP section 4.3.2 will show details for subjects who reported reasons for discontinuation due to 
COVID-19. Therefore, no specific summary will be provided.
Listings of subjects will be provided for the following categories:

Subjects who terminated study prematurely due to COVID-19 

Subjects who discontinued study treatment prematurely due to COVID-19.
5.2.2.
Medical History
The impact of COVID-19 in the medical history will not be evaluated as there are only 8 subjects 
randomized after or on 11 March 2020.
5.2.3.
Compliance
5.2.3.1.
Treatment Compliance
The analysis of treatment compliance defined in the main CSR SAP (overall up to EOT, and up to 
Week 16) is further performed in the subgroup of subjects impacted by COVID-19 (ie, for those 
subjects who experienced at least a COVID-19 related AE). A subject listing of study treatment 
compliance will be provided.
5.2.3.2.
Study Assessment Compliance
The number and percentage of subjects in the following categories will be summarized by 
treatment group and overall on the FAS, to display the following information:

Number and % of subjects who missed at least one post-baseline scheduled assessment
identified by the reporting of at least one of the following protocol deviations PD_PM.309 
(Visit 3 assessment not done/missing), PD_PM.311 (Visit 4 assessment not done/missing), 


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PD_PM.315 (Visit 5 assessment not done/missing), PD_PM.319 (Visit 6 assessment not 
done/missing), PD_PM.322 (Visit 7 assessment not done/missing)
o
Number and % of subjects who missed at least one post-baseline scheduled 
assessment due to COVID-19, identified by the reporting of at least one of the 
above protocol deviations with the prefix “COVID-19 related”

Number and % subjects who missed scheduled Visit 4/Week 16 assessment, identified by 
the reporting of the protocol deviation PD_PM.311 (Visit 4 assessment not done/missing)
o
Number and % of subjects who missed scheduled Visit 4/Week 16 assessment due 
to COVID-19, identified by the reporting of the protocol deviation PD_PM.311 
with the prefix “COVID-19 related”

Number and % of subjects who missed CPET at scheduled Visit 4/Week 16, identified by
the reporting of the protocol deviation PD_PP.251 (CPET at Visit 4 not done)
o
Number and % of subjects who missed CPET at scheduled Visit 4/Week 16 due to 
COVID-19, identified by the reporting of the protocol deviation PD_PP.251 with 
the prefix “COVID-19 related”

Number and % of subjects with insufficient PA-Ac data at scheduled Visit 4/Week 16, 
identified by the reporting of the protocol deviation PD_PM.313 (Subject does not have 
sufficient PA-Ac data at Visit 4)
o
Number and % of subjects with insufficient PA-Ac data at scheduled Visit 4/Week 
16 due to COVID-19, identified by the reporting of the protocol deviation 
PD_PM.313 with the prefix “COVID-19 related”

Number and % subjects who missed scheduled Visit 6/Week 52, identified by the reporting 
of the protocol deviation PD_PM.319 (Visit 6 assessment not done/missing)
o
Number and % of subjects who missed scheduled Visit 6/Week 52 due to COVID-
19, identified by the reporting of the protocol deviation PD_PM.319 with the prefix 
“COVID-19 related”

Number and % of subjects who missed CPET at scheduled Visit 6/Week 52, identified by 
the reporting of the protocol deviation PD_PP.253 (CPET at Visit 6 not done)
o
Number and % of subjects who missed CPET at scheduled Visit 6/Week 52 due to 
COVID-19, identified by the reporting of the protocol deviation PD_PP.253 with 
the prefix “COVID-19 related”

Number of remote visits per subject, identified by the reporting of the protocol deviation 
PD_MM.190 (Visit was performed remotely/partly remotely)


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o
Number of remote visits per subject due to COVID-19, identified by the reporting 
of the protocol deviation PD_MM.190 with the prefix “COVID-19 related”
A subject listing of study assessment compliance will be provided based on the PDs reporting.
5.2.4.
Extent of Exposure
A subject is considered to have a dose not administered if he/she has a study treatment interruption
(ie, if a reason associated with a study treatment end is ‘Temporarily interrupted due to an AE’ or 
‘Temporarily interrupted not due to an AE’ in the “Study Drug Log” eCRF module). 
Due to data collection (eg, no direct link between study treatment interruption and AEs), a dose 
not administered because of COVID-19 cannot be derived from the “Study Drug Log”, therefore 
no summary will be provided. 
A listing of subjects with any temporary study treatment interruptions (ie, as reported in the “Study 
Drug Log” eCRF module) will be reported as well as a separate listing of subjects who reported a 
COVID-19 related AEs with action taken with study treatment=“Drug interrupted”.
5.2.5.
Protocol Deviations 
Protocol deviations COVID-19 related are identified with the text “COVID-19 related” as a prefix
of the PD description.
Subjects with important (ie, major) “COVID-19 related” PDs will be summarized by displaying 
counts and percentages of subjects with at least an important “COVID-19 related” PD within each 
category (as defined in the CSR SAP) by treatment group and overall. A separate similar summary 
of important “COVID-19 related” PDs will be provided by geographical region and site.
All reported “COVID-19 related” PDs will be described in a subject listing. Important PDs will be 
flagged accordingly.
5.2.6.
Prior and Concomitant Medications 
Previous and study treatment concomitant therapy are defined in the CSR SAP (sections 4.7.1 and 
4.7.2, respectively).
Individual subject’s listing of all concomitant medications for all subjects who experienced at least 
a COVID-19 related AE will be provided. Previous and study treatment concomitant therapies are 
flagged accordingly.
5.3.
Efficacy Analyses
All efficacy analyses will be based on the full analysis set (FAS), not controlling for the adaptive 
design and not based on the population wise splitting approach as applied for the main analyses of 
primary and secondary efficacy endpoints. 
For both the primary and secondary endpoints, the corresponding estimand section describes data
handling rules. Baseline definitions follows section 2.5.1 of the CSR SAP. To minimize the 


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amount of missing data and the possibility to delay the assessments until the on-site visits can be 
resumed according to the COVID-19 protocol appendix, the assessments at Week 16 and Week 52 
will be based on scheduled Visit 4 and Visit 6, respectively. In case of missing scheduled 
visit/assessment, premature End-of Treatment and unscheduled visits (including Visit 5/Week 32 
if available) will be re-mapped to a scheduled visit as described in Section 5.1.2 (unless otherwise 
specified).
An overview of visits/assessments not performed because of COVID-19 will be provided by 
treatment group and overall for primary and secondary efficacy endpoints.
5.3.1.
Primary Efficacy Endpoint
Absolute values at baseline and at Week 16 as well as absolute change in peak VO2 from baseline 
to Week 16 will be summarized using descriptive statistics, where appropriate.
1. Additional Estimand (based on scheduled visits).
A.
Population: FAS 
B.
Variable: peak VO2 as change from baseline to scheduled Week 16 visit (see Section 5.1.2 of this document).
C.
Intercurrent events and strategies: same as primary estimand (see section 5.2.2 of the CSR SAP).
D.
Population-level summary measure: same as the ANCOVA model of the primary estimand (see section 5.2.2 
of the CSR SAP) carried out on the total sample size (without the population wise splitting approach for the 
control of the adaptive design).
2. To account for the pandemic and to assess the robustness of the results in the presence of 
the changes made during the pandemic, a Mixed Model Repeated Measures (MMRM) will 
use all data available to estimate the effect at Week 16. 
A. Population: All randomized Fontan-palliated adult and adolescent subjects defined through 
protocol inclusion/exclusion criteria (ie, FAS).
B. Variable: peak VO2 as change from baseline to Week 16.
C. Intercurrent events:

Death occurring before Week 52: composite strategy (worst-case). 
In case of death prior to Week 52, all scheduled assessments following the date of death will 
be imputed by a worst-case imputation (ie, lowest observed change in peak VO2 from baseline 
value across both treatment groups and over all assessments).

Non-missing peak VO2 value at Week 16 or Week 52 assessed as ‘invalid’ by the central 
reading facility: composite strategy (minimum of 25th percentile and no change)
In case an assessment at Week 16 or Week 52 has been evaluated as “invalid” by the 
independent central reading facility, it will be ignored. This will result in imputing the change 
from baseline to Week 16 or Week 52 with the 25th percentile of the observed changes in peak 
VO2 from baseline value (across both treatment groups and over all assessments). If this leads 
to an improvement (change >0), a change of 0 (no change) will be imputed.

Premature study treatment discontinuation before Week 52 not “COVID-19” related.


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According to the protocol, if treatment is discontinued prior to Week 16, and the subject enters 
the Post-Treatment Observation Period (PTOP), it is requested that the subject returns for a 
CPET assessment at Week 16 but not at Week 52. 
If the premature study treatment discontinuation occurs prior to Week 16 and it is not “COVID-
19” related:
-
If a valid assessment is available at Week 16 (see Section 5.1.2), this will result in 
imputing only the change from baseline to Week 52 with the 25th percentile of the 
observed changes in peak VO2 from baseline value (across both treatment groups 
and over all assessments). If this leads to an improvement (change>0), a change of 
0 (no change) will be imputed.
-
If no valid assessment is available at Week 16 (see Section 5.1.2), all scheduled 
assessments following the date of event will be imputed by applying the 25th
percentile of the observed changes in peak VO2 from baseline value (across both 
treatment groups and over all assessments). If this leads to an improvement, a 
change of 0 (no change) will be imputed.
If the premature study treatment discontinuation occurs after Week 16 and before Week 52 and 
it is not “COVID-19” related (and no valid assessment is available at Week 52 based on the 
definition in Section 5.1.2), this will result in imputing the change from baseline to Week 52 
with the 25th percentile of the observed changes in peak VO2 from baseline value (across both 
treatment groups and over all assessments). If this leads to an improvement (change>0), a 
change of 0 (no change) will be imputed. 
D. Population-level summary measure: difference in mean change in peak VO2 from baseline 
to Week 16 between macitentan 10 mg and placebo, as estimated from the MMRM. 
Missing data at Week 16 and Week 52 arising from any other reason (eg, premature study 
treatment discontinuation due to COVID-19, missed visits because of COVID-19) are assumed to 
be missing at random, and as such, will require no further imputation, since the MMRM approach 
will implicitly impute these values under a missing at random assumption.
The model will include randomized treatment group, time (via a categorical variable for visit), 
treatment-by-time interaction, baseline-by-time interaction, and peak VO2 at baseline as fixed 
effects. An unstructured variance-covariance matrix will be specified.
At Week 16, the resulting LS means and corresponding 95% and 99% CLs obtained in each 
treatment group, and the LS means differences (95% and 99% CLs) for macitentan 10 mg vs 
placebo will be provided.
3. Subgroup analysis based on the COVID-19 periods of the pandemic.


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In order to assess the consistency of the treatment effect across the COVID-19 periods of the 
pandemic, the subgroup “COVID-19 periods” will be added, categorizing the assessments as 
follows:

“Pre COVID-19 period” if Week 16 peak VO2 assessment falls in the “Pre COVID-19”
period

“During COVID-19 period” if Week 16 peak VO2 assessment falls in the “During COVID-
19” period
The COVID-19 periods of the pandemic are defined in Table 3 of Section 5.1.1.
The subgroup analysis will be carried out the same way as the other subgroup analyses as described 
in section 5.2.3.5 of the CSR SAP, based on scheduled visits.
5.3.2.
Secondary Efficacy Endpoint(s)
5.3.2.1.
Change from baseline over 52 weeks in peak VO2
Absolute values at baseline and over Week 52 as well as absolute change in peak VO2 from 
baseline over Week 52 will be summarized using descriptive statistics, where appropriate.
1. Additional Estimand (based on scheduled visits).
A.
Population: FAS.
B.
Variable: peak VO2 as average change from baseline to scheduled Week 16 and scheduled Week 52 (see 
Section 5.1.2 of this document)
C.
Intercurrent events and strategies: same as main estimand (see section 5.3.1.2 of the CSR SAP)
D.
Population-level summary measure: Same as the MMRM model of the main estimand (see section 5.3.1.2 of 
the CSR SAP), carried out on the total sample size (without the population wise splitting approach for the 
control of the adaptive design).
2. To account for the pandemic and to assess the robustness of the results in the presence of 
the changes made during the pandemic, a Mixed Model Repeated Measures (MMRM) will 
use all data available to estimate the effect at Week 52 as done for the primary efficacy 
endpoint. 

Same population, variable peak VO2 as change from baseline to Week 52 (scheduled 
visit), same intercurrent events, and same handling of missing data as defined for the 
primary efficacy endpoint (Section 5.3.1 of this document). 

Same MMRM model as defined for primary efficacy endpoint (Section 5.3.1) carried 
out on the total sample size (without the population wise splitting approach for the 
control of the adaptive design).
At Week 52, the resulting LS means and corresponding 95% and 99% CLs obtained in each 
treatment group, and the LS means differences (95% and 99% CLs) for macitentan 10 mg vs 
placebo will be provided.
3. Subgroup analysis based on the COVID-19 periods of the pandemic.


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Subgroup analyses will be carried out similarly as described for the primary efficacy endpoint in 
Section 5.3.1 above, by applying the MMRM. The assessments will be categorized as follows:

“Pre COVID-19 period” if both Week 16 and Week 52 peak VO2 assessment falls in the 
“Pre COVID-19” period

“Pre/During COVID-19” if peak VO2 assessment at Week 16 falls in the “Pre COVID-19”
period and the one at Week 52 falls in the “During COVID-19” period

“During COVID-19 period” if both Week 16 and Week 52 peak VO2 assessment falls in 
the “During COVID-19” period
The COVID-19 periods of the pandemic are defined in Table 3 of Section 5.1.1.
After consultation with the Study Results Committee constituted of external clinicians with 
expertise in subjects with Functional Single Ventricle Heart Disease on 13-Aug-2021, an 
additional analysis will be performed excluding subjects who had reported a COVID-19 infection 
during the course of the study and consequently could have compromising assessments impacted 
by the prior infection. These subjects are identified based on the reporting of the AEs containing
the text “COVID-19” (as qualified by the preferred term) and with the corresponding AE onset 
date before Week 16 or Week 52 assessments. This analysis will be performed only for this 
secondary efficacy endpoint over 52 weeks as COVID-19 infections were reported towards the 
end of the subject’s treatment period, much later the evaluation of Week 16. The analysis will be 
performed based on the estimand at analysis point #1 (with a different population based on FAS 
excluding subjects described above).
5.3.2.2.
Change from baseline to Week 16 in mean count per minute of daily 
PA-Ac
Absolute values at baseline and at Week 16 as well as absolute change in mean count per minute 
of daily PA-Ac from baseline to Week 16 will also be summarized using descriptive statistics,
where appropriate.
For Week 16, the 9-day time period is first selected as described in CSR SAP section 5.3.2. In case 
the 9-day time period is not available, an extended time window as described in Section 5.1.2 is 
considered. 
1. Additional Estimand (based on extended time window for Week 16).
A.
Population: FAS.
B.
Variable: Mean count per minute of daily PA-Ac as change from baseline to extended Week 16 time window
(see Section 5.1.2 of this document)
C.
Intercurrent events and strategies: same as main estimand (see section 5.3.2.2 of the CSR SAP)
D.
Population-level summary measure: Same as the ANCOVA model of the main estimand (see section 5.3.2.2 
of the CSR SAP) carried out on the total sample size (without the population wise splitting approach for the 
control of the adaptive design).


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2. To account for the pandemic and to assess the robustness of the results in the presence of 
the changes made during the pandemic, a Mixed Model Repeated Measures (MMRM) will 
use all data available to estimate the effect at Week 16. 
A. Population: All randomized Fontan-palliated adult and adolescent subjects defined through 
protocol inclusion/exclusion criteria (ie, FAS).
B. Variable: mean count per minute of daily PA-Ac as change from baseline to Week 16.
C. Intercurrent events:

Death occurring before Week 52: composite strategy (worst-case). 
In case of death prior to Week 52, all scheduled assessments following the date of death will 
be imputed by a worst-case imputation (ie, lowest observed change from baseline value across 
both treatment groups and over all assessments).

Premature study treatment discontinuation before Week 52 not “COVID-19” related.
If the premature study treatment discontinuation occurs prior to Week 16 and it is not 
“COVID-19” related:
-
If a valid assessment is available at Week 16 (see Section 5.1.2), this will result in 
imputing only the change from baseline to Week 52 with a change of 0 (no change).
-
If no valid assessment is available at Week 16 (see Section 5.1.2), all scheduled 
assessments following the date of event will be imputed by applying a change of 
0 (no change).
If the premature study treatment discontinuation occurs after Week 16 and before Week 52 
and it is not “COVID-19” related (and no valid assessment is available at Week 52 based on 
the definition in Section 5.1.2), this will result in imputing the change from baseline to Week 
52 with a change of 0 (no change). 
D. Population-level summary measure: difference in mean change mean count per minute from 
baseline to Week 16 between macitentan 10 mg and placebo, as estimated from the MMRM. 
Missing data at Week 16 and Week 52 arising from any other reason (eg, premature study 
treatment discontinuation due to COVID-19, missed visits because of COVID-19) are assumed to 
be missing at random, and as such, will require no further imputation, since the MMRM approach 
will implicitly impute these values under a missing at random assumption.
The model will include randomized treatment group, time (via a categorical variable for visit), 
treatment-by-time interaction, baseline-by-time interaction, and mean count per minute at baseline 
as fixed effects. An unstructured variance-covariance matrix will be specified.
At Week 16, the resulting LS means and corresponding 95% and 99% CLs obtained in each 
treatment group, and the LS means differences (95% and 99% CLs) for macitentan 10 mg vs 
placebo will be provided.
3. Subgroup analysis based on the COVID-19 periods of the pandemic.


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Subgroup analyses will be carried out similarly as described for the primary efficacy endpoint in 
Section 5.3.1 above.
5.4.
Safety Analyses
All safety analyses will be based on the safety analysis set (SS) based on actual treatment received, 
unless otherwise specified. Listings will be provided on the FAS.
All definitions and conventions used in the CSR SAP section 6 of this study 
(AC-055H301/RUBATO) will be applied, unless otherwise specified.
5.4.1.
Adverse Events
COVID-19 related AEs are identified if the corresponding PTs are included in the list as provided 
in Appendix 2 List of COVID-19 related AEs.
Overall summary table of COVID-19 related AEs will be provided, containing number and 
percentages of subjects having experienced at least 1 occurrence for the following categories of 
AEs:

Treatment-emergent COVID-19 related AEs

Severe treatment-emergent COVID-19 related AEs 

COVID-19 related AEs with fatal outcome 

Treatment-emergent serious COVID-19 related AEs (SAEs)

COVID-19 related AEs leading to premature discontinuation of study treatment
A separate summary table will be provided by Special Interest Category (ie, COVID-19 related
AEs) and PT for the following categories of AEs:

Treatment-emergent COVID-19 related AEs

COVID-19 related AEs with fatal outcome 

Treatment-emergent serious COVID-19 related AEs (SAEs)

COVID-19 related AEs leading to premature discontinuation of study treatment.
A summary table will be provided, containing number and percentages of subjects who died on 
the SS. Frequencies for the following parameters will be included in the summary table:

Number of subjects who died

Cause of death (eg, cause term 1, cause term 2, COVID-19 cause term etc)
The summary will be based on the “Death” eCRF module. The summary will be provided if at 
least 3 deaths have occurred overall. The summary table is presented by descending order of PT
according to the incidence of deaths in the macitentan 10 mg treatment group. An individual 
subject listing will be provided as well.


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In addition to the summary tables, a listing will be provided for subjects who had experienced 
COVID-19 related AEs.
5.4.2.
Clinical laboratory test
The results from COVID-19 testing will be captured as COVID-19 related AEs and reported as 
described in Section 5.4.1 of this document.
Options for the conduct of safety laboratory assessments are described in protocol section 7.2.4.1 
and include laboratory samples taken at study site, at a satellite laboratory, collected via home 
healthcare visits service, or taken and analyzed locally. These alternatives continue to be valid also 
during the COVID-19 periods of the pandemic (ie, “Pre COVID-19” and “During COVID-19” as 
defined in Table 3 of Section 5.1.1).  
A summary display will show the percentage of laboratory data (considering all parameters) that 
were conducted at central and local laboratory during the COVID-19 periods by treatment group 
and overall. This summary output will be presented for all assessments conducted during the 
course of the study and for key scheduled assessments (ie, Week 16 and Week 52).
6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AE
Adverse Event
ANCOVA
Analysis of Covariance
COVID
Corona Virus Disease
CSR
Clinical Study Report
DPS
Data Presentation Specifications
eCRF
electronic Case Report Form
FAS
Full Analysis Set
FDA
Food and Drug Administration
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Measures Repeated Model
PD
Protocol Deviation
PT
Preferred Term
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SS
Safety Analysis Set
WHO
World Health Organization
6.2.
Appendix 2 List of COVID-19 related AEs
AEs are considered as COVID-19 related if their coded PTs are: Asymptomatic COVID-19, 
Congenital COVID-19, Coronavirus infection, Coronavirus test positive, COVID-19, COVID-19 
immunisation, COVID-19 pneumonia, COVID-19 prophylaxis, COVID-19 treatment, Exposure 
to SARS-CoV-2, Multisystem inflammatory syndrome in children, Occupational exposure to 
SARS-CoV-2, Post-acute COVID-19 syndrome, SARS-CoV-2 antibody test positive, SARS-
CoV-2 carrier, SARS-CoV-2 RNA decreased, SARS-CoV-2 RNA fluctuation, SARS-CoV-2 
RNA increased, SARS-CoV-2 sepsis, SARS-CoV-2 test false negative, SARS-CoV-2 test 
positive, SARS-CoV-2 viraemia, Suspected COVID-19, Vaccine derived SARS-CoV-2 infection, 


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Status: Approved, Date: 23 August 2021
Antiviral prophylaxis, Antiviral treatment, Coronavirus test, Coronavirus test negative, COVID-
19 screening, Exposure to communicable disease, Pneumonia viral, SARS-CoV-2 antibody test, 
SARS-CoV-2 antibody test negative, SARS-CoV-2 RNA, SARS-CoV-2 RNA undetectable, 
SARS-CoV-2 test, SARS-CoV-2 test false positive, SARS-CoV-2 test negative.