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
Phase: PHASE3
Conditions: Congenital Heart Disease
Sponsor: Actelion

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 
19 November 2020, page 2/171 
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 
19 November 2020, page 5/171 
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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 
 
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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 
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 
 
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. 

Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H301, RUBATO 
Final Version 10 
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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 
Final Version 10 
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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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Protocol AC-055H301, RUBATO 
Final Version 10 
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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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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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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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Protocol AC-055H301, RUBATO 
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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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Final Version 10 
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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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Protocol AC-055H301, RUBATO 
Final Version 10 
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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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13 REFERENCES 
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[Fernandes 2010] Fernandes SM, McElhinney DB, Khairy P, Graham DA, Landzberg 
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MS, Radojewski EA, Maunsell E, Mital S, Menon SC, Schumacher KR, Payne RM, 
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Fontan Palliation. Circulation;132/Suppl_3/A14024. 
[Goldberg 2019] Goldberg DJ, Zak V, Goldstein BH, Schumacher KR, Rhodes J, Penny 
DJ. Results of the Fontan Udenafil Exercise Longitudinal (FUEL) Trial. 
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R, Fletcher GF, Forman DE, Kitzman DW, Lavie CJ, Myers J,. EACPR/AHA 
Scientific Statement. Clinical recommendations for cardiopulmonary exercise 
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Circulation. 2012 Oct 30;126(18):2261-74. 
[Guazzi 2016a] Guazzi M, Arena R, Halle M, Piepoli MF, Myers J, Lavie CJ. 2016 
focused update: clinical recommendations for cardiopulmonary exercise testing 
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[Hebert 2013] Hebert A, 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 2014] Hebert A, Mikkelsen UR, Thilen U et al.: Bosentan Improves Exercis 
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 
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[ICH E9 (R1)] Statistical Principles for Clinical Trials: Addendum: Estimands and 
Sensitivity Analysis in Clinical Trials. 18 October 2019. [Accessed on 
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trials-addendum-estimands-and-sensitivity-analysis-clinical. 
 [Kempny 2012] Kempny A, Dimopoulos K, Uebing A, Moceri P, Swan L, Gatzoulis 
MA, Diller GP. Reference values for exercise limitations among adults with 
congenital heart disease. Relation to activities of daily life--single centre 
experience and review of published data. Eur Heart J. 2012 Jun;33(11):1386-96. 
[Khairy 2008] Khairy P, Fernandes SM, Mayer JE Jr, Triedman JK, Walsh EP, Lock JE, 
Landzberg MJ. Long-term survival, modes of death, and predictors of mortality in 
patients with Fontan surgery. Circulation. 2008;117:85–92. 
[Leeson 2012] Leeson P, Augustine D, Mitchell A, Becher H. Oxford Specialist 
Handbooks in Cardiology - Echocardiography. 2e. Oxford: Oxford University Press; 
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[Levey 2009] Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman 
HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J, 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. 
[Macitentan IB] Investigator’s Brochure for macitentan, version 16. Actelion 
Pharmaceuticals Ltd, December 2018. 
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and heart rate during elliptical and treadmill exercise. J Sport Rehabil. 2001;10:48-
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et al. ATS/ERS Task Force. General considerations for lung function testing. Eur 
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[Miller 2005b] Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, 
et al; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005 
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[Pocock 2002] Pocock SJ, Clayton TC, G Altman DG. Survival plots of time-to-event 
outcomes in clinical trials: good practice and pitfalls. Lancet 2002;359:1686–89. 
[Pulido 2013] Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and 
mortality in pulmonary arterial hypertension. New Engl J Med 2013; 369:809–18. 
SERAPHIN Study.  
[Pundi 2015] Pundi KN, Johnson JN, Dearani JA, Pundi KN, Li Z, Hinck CA, Dahl SH, 
Cannon BC, O’Leary PW, Driscoll DJ, Cetta F. 40-Year Follow-Up After the 
Fontan Operation: Long-Term Outcomes of 1,052 Patients. J Am Coll Cardiol. 
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[Rasmussen 2015] Rasmussen AR, Wohlfahrt-Veje C, Tefre de Renzy-Martin K, Hagen 
CP, Tinggaard, J, Mouritsen A, et al. Validity of Serlf-Assesment of Pubertal 
Maturation. Pediatrics. 2015 Jan;135(1):86-93. 
[Sajan 2011] Sajan I, Manlhiot C, Reyes J, McCrindle BW, Humpl T, Friedberg MK. 
Pulmonary arterial capacitance in children with idiopathic pulmonary arterial 
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disease: relation to pulmonary vascular resistance, exercise capacity, and survival. 
Am Heart J. 2011 Sep;162(3):562-8. pii: S0002-8703(11)00484-4.  
[Schwartz 2009] Schwartz GJ, Work DF. Measurement and estimation of GFR in 
children and adolescents. Clin J Am Soc Nephrol. 2009 Nov;4(11):1832-43. 
[Shang 2013] Shang XK, Li YP, Liu M, et al. Efficacy of endothelin receptor antagonist 
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Cardiovascular Society 2009 Consensus Conference on the management of adults 
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[Troiano 2008] Troiano RP, Berrigan D, Dodd KW, Mâsse LC, Tilert T, McDowell M. 
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[Udholm 2018] Udholm S, Aldweib N, Hjortdal VE, Veldtman GR. Prognostic power of 
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[Wasserman 2005] Wasserman K, Hansen JE, Sue DY, Whipp BJ. Principles of Exercise 
Testing and Interpretation, 4th ed. 2005; Philadelphia: Lea and Febiger. 
 

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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. 

Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H301, RUBATO 
Final Version 10 
19 November 2020, page 149/171 
Confidential 
EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
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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Protocol AC-055H301, RUBATO 
Final Version 10 
19 November 2020, page 150/171 
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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 
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 

Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H301, RUBATO 
Final Version 10 
19 November 2020, page 151/171 
Confidential 
EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
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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Protocol AC-055H301, RUBATO 
Final Version 10 
19 November 2020, page 152/171 
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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 
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.  

Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H301, RUBATO 
Final Version 10 
19 November 2020, page 153/171 
Confidential 
EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
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. 
 
 
 

Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H301, RUBATO 
Final Version 10 
19 November 2020, page 154/171 
Confidential 
EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
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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Protocol AC-055H301, RUBATO 
Final Version 10 
19 November 2020, page 155/171 
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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 
 
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). 

Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H301, RUBATO 
Final Version 10 
19 November 2020, page 156/171 
Confidential 
EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
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. 

Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H301, RUBATO 
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. 
 
 
 

Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
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 
  

Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H301, RUBATO 
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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Protocol AC-055H301, RUBATO 
Final Version 10 
19 November 2020, page 160/171 
Confidential 
EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO procedures 
Burden  
Risk 
Conclusion 
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; 

Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H301, RUBATO 
Final Version 10 
19 November 2020, page 161/171 
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 
 
 
 

Macitentan / ACT-064992 
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Final Version 10 
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Doc No D-20.425 
 
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 
 
 
 

Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H301, RUBATO 
Final Version 10 
19 November 2020, page 164/171 
Confidential 
EudraCT 2016-003320-23 
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 
 
 

Macitentan / ACT-064992 
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Protocol AC-055H301, RUBATO 
Final Version 10 
19 November 2020, page 165/171 
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 
 
 

Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
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. 
 

Macitentan / ACT-064992 
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Protocol AC-055H301, RUBATO 
Final Version 10 
19 November 2020, page 167/171 
Confidential 
EudraCT 2016-003320-23 
Doc No D-20.425 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 

Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H301, RUBATO 
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 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H301, RUBATO 
Final Version 10 
19 November 2020, page 169/171 
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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Final Version 10 
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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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Final Version 10 
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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  
 
JNJ-67896062/ACT-064992 Macitentan  
Clinical Protocol AC-055H301  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
3 
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  
 
JNJ-67896062/ACT-064992 Macitentan  
Clinical Protocol AC-055H301  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
4 
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  
 
JNJ-67896062/ACT-064992 Macitentan  
Clinical Protocol AC-055H301  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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  
 
JNJ-67896062/ACT-064992 Macitentan  
Clinical Protocol AC-055H301  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
6 
Status: Approved, Date: 17 June 2020 
INVESTIGATOR AGREEMENT 
 
PPD
PPD