Clinical trial NCT03775421
Conditions: Congenital Heart Disease With Fontan Circulation
Keywords: Congenital Heart Failure macitentan Univentricular Heart Cavopulmonary Anastomosis Fontan circulation
Sponsor: Actelion
Start date: 2019-04-11; Completion date: 2022-01-18
Enrollment: 112 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The aim of this open-label (OL) trial is to study the long-term use of macitentan for up to 2 years in Fontan-palliated adult and adolescent patients beyond the 52 weeks of treatment in the parent RUBATO double-blind (DB) study (AC-055H301, NCT03153137). This OL trial studies the long-term effect of macitentan in Fontan-palliated patients as it is not known if the effect of macitentan is sustained beyond 52 weeks (end of the parent RUBATO DB study). In addition, the trial also studies the long-term safety of macitentan as this is also unknown. Furthermore, the opportunity will be given to patients who were on placebo in the parent RUBATO DB study to receive macitentan 10 mg and benefit from a potentially active treatment.

Detailed description:

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

Protocol documents:
SAP_002.pdf: 
Janssen Research & Development
Statistical Analysis Plan
Prospective, multi-center, single-arm, open-label long-term study assessing the safety, 
tolerability, and effectiveness of macitentan in Fontan-palliated adult and adolescent 
subjects
AC-055H302/RUBATO-OL; Phase 3
ACT-064992 / JNJ-67896062 (macitentan)
Status:
Approved
Date:
17 December 2021
Prepared by:
Actelion Pharmaceuticals Ltd., a Janssen Pharmaceutical Company of Johnson & 
Johnson
Document No.: EDMS-RIM-265704, 1.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential. The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT03775421


ACT-064992 / JNJ-67896062 (macitentan)
Statistical Analysis Plan AC-055H302/RUBATO-OL; Phase 3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 17 December 2021
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF TABLES ......................................................................................................................................... 3
LIST OF FIGURES ....................................................................................................................................... 3
VERSION HISTORY..................................................................................................................................... 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Objectives and Endpoints ................................................................................................................ 5
1.2.
Study Designs .................................................................................................................................. 6
2.
STATISTICAL HYPOTHESES............................................................................................................ 8
3.
SAMPLE SIZE DETERMINATION...................................................................................................... 8
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS....................................................................... 8
5.
STATISTICAL ANALYSES............................................................................................................... 10
5.1.
General Considerations ................................................................................................................. 10
5.1.1.
Visit Windows ............................................................................................................................. 10
5.1.2.
Definition of Baseline, Periods and Dates/Days......................................................................... 11
5.1.2.1.
Baseline................................................................................................................................... 11
5.1.2.2.
Treatment Start Date (Day 1) and Day Numbering in Analysis Sets ...................................... 11
5.1.2.3.
End of Treatment (EOT) Date ................................................................................................. 12
5.1.2.4.
End of Study (EOS) Date ........................................................................................................ 13
5.1.2.5.
DB Period ................................................................................................................................ 13
5.1.2.6.
OL Period................................................................................................................................. 13
5.2.
Participant Dispositions.................................................................................................................. 13
5.2.1.
Study Treatment Discontinuation ............................................................................................... 13
5.2.2.
Study Discontinuation................................................................................................................. 14
5.2.3.
Other Disposition Information ..................................................................................................... 15
5.3.
Extent of Exposure and Compliance.............................................................................................. 15
5.4.
Safety Analysis............................................................................................................................... 17
5.4.1.
Adverse Events........................................................................................................................... 17
5.4.2.
Deaths......................................................................................................................................... 21
5.4.3.
Vital Signs................................................................................................................................... 22
5.4.4.
Laboratory................................................................................................................................... 23
5.4.4.1.
Marked Laboratory Abnormalities............................................................................................ 25
5.4.4.2.
Additional Liver Function Test and Hemoglobin Abnormalities............................................... 27
5.4.5.
Echocardiography....................................................................................................................... 28
5.5.
Efficacy Analysis ............................................................................................................................ 29
5.5.1.
Cardiopulmonary Exercise Testing (CPET)................................................................................30
5.5.2.
Physical Activity Measure by Accelerometer..............................................................................32
5.5.3.
Fontan-palliated Clinical Worsening and Morbidity Events ........................................................34
5.6.
Other Analyses............................................................................................................................... 36
5.6.1.
Definition of Subgroups and subgroup analyses........................................................................ 36
6.
SUPPORTING DOCUMENTATION ..................................................................................................37
6.1.
Appendix 1: List of Abbreviations................................................................................................... 37
6.2.
Appendix 2: Changes to Protocol-Planned Analyses .................................................................... 39
6.3.
Appendix 3: Demographic and Baseline Characteristics...............................................................39
6.3.1.
Demographics............................................................................................................................. 39
6.3.2.
Baseline Disease Characteristics ............................................................................................... 40
6.4.
Appendix 4: Protocol Deviations and Quality Tolerance Limits (QTL)........................................... 42


ACT-064992 / JNJ-67896062 (macitentan)
Statistical Analysis Plan AC-055H302/RUBATO-OL; Phase 3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 17 December 2021
6.5.
Appendix 5: Prior and Concomitant Medications........................................................................... 49
6.5.1.
Prior Medications ........................................................................................................................ 49
6.5.2.
Concomitant Medications ........................................................................................................... 49
6.5.3.
Concomitant Medications at Start of Study Treatment in Analysis Set ...................................... 50
6.6.
Appendix 6: Intervention Compliance ............................................................................................ 51
6.7.
Appendix 7: Adverse Events of Special Interest and COVID-19 related AEs ............................... 52
7.
REFERENCES................................................................................................................................... 53
LIST OF TABLES
Table 1:
SAP Version History Summary................................................................................................... 4
Table 2:
Study Documents........................................................................................................................ 5
Table 3:
Analysis Set Definitions .............................................................................................................. 8
Table 4:
Usage of Analysis Sets............................................................................................................... 9
Table 5:
Time Windows for the OL Period and Day 30 FU .................................................................... 11
Table 6:
Thresholds for Marked Laboratory Abnormalities..................................................................... 26
Table 7:
Table of Subgroups for Analyses.............................................................................................. 36
Table 8:
Demographic Variables............................................................................................................. 39
Table 9:
Baseline Disease Characteristics ............................................................................................. 40
Table 10:
PD Classification Based on AC-055H302 (RUBATO OL) ........................................................ 42
Table 11:
Quality Tolerance Limits as per Integrated Analytical Risk-Based Monitoring Plan................. 48
LIST OF FIGURES
Figure 1:
RUBATO OL Study Design......................................................................................................... 6
Figure 2:
RUBATO OL Study Design (with S-FU in the AC-055H301 RUBATO DB Study) ..................... 7


ACT-064992 / JNJ-67896062 (macitentan)
Statistical Analysis Plan AC-055H302/RUBATO-OL; Phase 3
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Status: Approved, Date: 17 December 2021
VERSION HISTORY
Table 1:
SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
17 December 2021
Not Applicable
Initial release


ACT-064992 / JNJ-67896062 (macitentan)
Statistical Analysis Plan AC-055H302/RUBATO-OL; Phase 3
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Status: Approved, Date: 17 December 2021
1.
INTRODUCTION
This Statistical Analysis Plan (SAP) describes in detail the methods, conduct and content of the 
data analysis of AC-055H302/RUBATO open-label extension study (hereafter referred to as the 
RUBATO OL study) for the purpose of the abbreviated Clinical Study Report (CSR). As planned 
in the protocol, some of the analyses are based on data pooled with data from the corresponding 
core study, AC-055H301/RUBATO (hereafter referred to as the RUBATO DB study). 
Following the evaluation of the study results from the RUBATO DB study, a sponsor decision was 
taken to terminate the RUBATO OL study early. For this reason, an abbreviated CSR is planned.
All safety data and selected non-safety data obtained will be summarized in the abbreviated CSR.
All analyses are exploratory in nature and therefore no multiplicity issues are foreseen.
This SAP refers to the documents listed in Table 2.
Table 2:
Study Documents
Document
Date, Version
Study Protocol AC-055H302 (RUBATO OL)
Final Version 4 (D-20.426)
Study Protocol AC-055H301 (RUBATO)
Final Version 10 (D-20.425)
AC-055H301 SAP for clinical study report (CSR)
Final Version 5 (EDMS-RIM-264216, 3.0)
AC-055H301 SDTM annotated eCRF specifications
Version 1.0, 8 September 2021, or latest 
implemented version
AC-055H302 SDTM annotated eCRF specifications
Version 11.0 (draft 19 October 2021), or latest 
implemented version
Study Protocol AC-055H302 (RUBATO OL) COVID-19 
Appendix
Approved version, 17 June 2020 (D-20.159)
Study Protocol AC-055H301 (RUBATO) COVID-19 Appendix
Approved version, 17 June 2020 (D-20.158)
Source data for the AC-055H301/RUBATO DB will be Analysis Data Model (ADaM) data sets 
derived for the AC-055H301/RUBATO CSR SAP. Except where otherwise specified, all 
definitions and conventions used in the CSR SAP of this study will be applied, as applicable.
Source data for the RUBATO OL study are provided as Statistical Analysis Software (SAS®) data 
sets according to Clinical Data Interchange Standards Consortium Study Data Tabulation Model 
(SDTM). Source data are provided according to the Database Release Plan document.
The pooling of RUBATO DB and RUBATO OL means that the data from the same subjects 
randomized in RUBATO DB will be concatenated with their data from the OL study. The 
concatenation of data from the same subject is referred to as ‘pooling’ in this document.
1.1.
Objectives and Endpoints
The primary objective of the study is to assess the long-term safety and tolerability of macitentan 
in Fontan-palliated adult and adolescent subjects. This SAP describes how safety and selected 


ACT-064992 / JNJ-67896062 (macitentan)
Statistical Analysis Plan AC-055H302/RUBATO-OL; Phase 3
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Status: Approved, Date: 17 December 2021
efficacy will be analyzed and summarized in order to support the abbreviated RUBATO OL CSR. 
This includes the concatenation of data from studies RUBATO DB and RUBATO OL.
1.2.
Study Designs
RUBATO DB is a prospective, multi-center, double-blind, randomized, placebo controlled, 
parallel-group Phase 3 study assessing the efficacy and safety of macitentan in Fontan-palliated 
adult and adolescent subjects.
At least 134 subjects were to be randomized in a 1:1 ratio to receive 52 weeks of treatment with 
either macitentan or placebo. Randomization was stratified by geographical region (America, 
Europe, Asia, Oceania). The study was to be conducted in approximately 31 investigational sites 
in 11 countries.
The study is completed, database was locked on 02-Sep-2021.
RUBATO OL is a prospective, multi-center, single-arm, open-label, long-term, Phase 3 study
assessing the safety, tolerability, and effectiveness of macitentan in Fontan-palliated adult and 
adolescent subjects. The overall study design of RUBATO OL is depicted in Figure 1.
Figure 1:
RUBATO OL Study Design
DB = Double-blind (study); EOS = End-of-Study; EOT = End-of-Treatment; OL = Open-label (extension); V = visit
= Telephone call (for visit).


ACT-064992 / JNJ-67896062 (macitentan)
Statistical Analysis Plan AC-055H302/RUBATO-OL; Phase 3
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Status: Approved, Date: 17 December 2021
In instances where administration of RUBATO OL study treatment does not immediately follow 
End-of-Treatment (EOT) in the RUBATO DB study, the subject will enter the DB S-FU period 
per protocol until administration of the first dose of the OL study treatment occurs (Figure 2).
Figure 2:
RUBATO OL Study Design (with S-FU in the AC-055H301 RUBATO DB Study)
DB = Double-blind (study); EOS = End-of-Study; EOT = End-of-Treatment; OL = Open-label (extension); 
S-FU = Safety Follow-up; V = visit; = Telephone call (for visit).
No S-FU will be performed for subjects entering a post-trial access program at individual subject’s 
EOT for the RUBATO OL study.
Visit and assessment schedules of the RUBATO DB and the RUBATO OL studies can be found 
in the corresponding protocols.
As it was recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an 
impact on the conduct of the clinical studies, the sponsor issued Study Protocol COVID-19 
Appendices to provide options for study related subject management in the event of disruption to 
the conduct of the study. Discontinuations of study interventions and withdrawal from the study 
were to be documented with the prefix “COVID-19-related” in the electronic case report form 
(eCRF). Also, protocol deviations (PDs) linked to COVID-19, were to be prefixed with the text 
“COVID-19 related” in the clinical database.
The RUBATO DB results showed no clinically meaningful difference favoring macitentan 10 mg 
that would provide treatment benefit to Fontan-palliated patients, and therefore, the sponsor has 
decided that the RUBATO OL study will be terminated early.


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Statistical Analysis Plan AC-055H302/RUBATO-OL; Phase 3
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Status: Approved, Date: 17 December 2021
2.
STATISTICAL HYPOTHESES
No formal hypothesis testing is performed. All efficacy analyses are purely descriptive. 
3.
SAMPLE SIZE DETERMINATION
Not applicable. RUBATO OL is an extension study of the RUBATO DB study, hence the sample 
size of the pools will be up to the number of randomized subjects in the RUBATO DB study, with 
no sample size statistical considerations.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Table 3 below describes analysis sets, periods and treatment arms used.
Table 3:
Analysis Set Definitions
Analysis Set
Period definition 
Treatment Arms
RUBATO Open-label 
Extension Set (OLES)
The RUBATO Open-label Extension Set (OLES) includes 
all subjects treated with macitentan in RUBATO OL study. 
Only data from the OL period (as defined in Section 5.1.2.6) 
are considered with the exception of baseline data 
(including demographic data, medical and disease history 
data, prior medication) which may origin from the DB 
period. Treatment arms “DB-Macitentan 10 mg” and “DB-
Placebo” follow the treatment arm from RUBATO DB 
safety set (SS), i.e., are based on actual treatment received 
in study RUBATO DB.
DB-Placebo 
DB-Macitentan 10 
mg
OL Macitentan 10 
mg (All OLES 
subjects)
RUBATO pool (FAS and 
SS)
Pool of all RUBATO DB and RUBATO OL data. Data 
from the same subjects randomized in DB are concatenated 
with their data from the OL extension study. Baseline is 
defined relative to first intake of study medication in the 
RUBATO DB study, as defined in the RUBATO DB study 
SAP. Treatment arms for FAS follow the treatment arm 
assignment from RUBATO DB FAS analyses, i.e.,
treatment as randomized. 
Treatment arms for SS follow the treatment arm assignment 
from RUBATO DB SS analyses, i.e., are based on actual 
treatment received in study RUBATO DB.
Placebo/Macitentan 
10 mg (Plc/Maci)
Macitentan 10 mg 
/Macitentan 10 mg 
(Maci/Maci)
RUBATO Total 
Macitentan Analysis Set 
(TMAS) (SS)
Only subjects receiving at least one dose of macitentan 
(either in RUBATO DB or RUBATO OL) are included. 
Only subjects from the macitentan arm in the RUBATO DB 
SS analyses are considered to have received macitentan in 
the RUBATO DB, their data are concatenated with their 
data from the OL extension. For subjects from the DB study 
SS placebo arm, only data with assessment dates during the 
OL period (as defined in in Section 5.1.2.6) are considered, 
with the exception of baseline data (including demographic 
data, medical and disease history data, prior medication) 
which may origin from the DB period. Baseline is defined 
relative to first intake of macitentan study treatment (either 
in RUBATO DB or RUBATO OL).
Macitentan 10 mg 
Pool
FAS – Full analysis set, SS – Safety Set.


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Table 4 describes usage of analysis sets.
Table 4:
Usage of Analysis Sets
Analysis Set
Endpoint
RUBATO 
OLES
RUBATO pool
RUBATO 
TMAS (SS)
Efficacy
CPET (peak VO2, VO2 at VAT)
Yes 
Yes (FAS)
PA-Ac (Mean count per minute) 
Yes 
Yes (FAS)
Fontan-palliated clinical worsening
Yes (FAS) 
Fontan-palliated morbidity
Yes (FAS) 
Safety
AEs (incl SAEs, AESI, AE by intensity, by relationship, AE 
leading to study treatment discontinuation, fatal AEs)
Yes 
Yes (SS) for 
Maci/Maci Arm 
only
Yes
Death
Yes (SS)
Vital signs (BP, pulse) including peripheral oxygen 
saturation (SpO2) and body weight, over time
Yes
Yes (SS)
Systolic blood pressure outlier analyses
Yes
Yes (SS) for 
Maci/Maci Arm 
only
Yes
Laboratory results, over time 
Yes
Yes (SS)
Marked laboratory abnormalities/laboratory outlier analyses
Yes
Yes (SS) for 
Maci/Maci Arm 
only
Yes
Echocardiography numerical results, over time
Yes
Yes (SS)
Echocardiography valvular defects
Yes
Yes (SS)
Yes
Exposure/Compliance
Yes
Yes (SS) 
Yes
Demographics
Yes
Yes
Baseline Disease Characteristics
Yes
Yes
Disposition
Yes
Yes 
Protocol Deviations 
Yes
Concomitant Medications 
Yes
Yes


ACT-064992 / JNJ-67896062 (macitentan)
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Status: Approved, Date: 17 December 2021
5.
STATISTICAL ANALYSES
5.1.
General Considerations
SAS (Statistical Analysis System®) version 9.4 is used for all the statistical analyses, except if 
otherwise specified.
Data will be listed and summarized by appropriate descriptive statistics (tables or figures).
General rules for data presentations as described below are followed unless otherwise specified:
!
All listings will be sorted by treatment arm, site ID, subject ID and when appropriate by visit 
/ date of assessment. All data collected will be displayed, including unscheduled visits (if any).
!
In summary tables, treatment arms will be presented in columns from left to right following 
the order shown in Table 3.
!
If on a table or figure a visit/timepoint is empty (i.e., zero subjects across all treatment arms), 
this visit/timepoint is not displayed. 
5.1.1.
Visit Windows
As subjects do not always adhere to the protocol visit schedule, the following rules are applied to
assign actual visits to analysis visits. 
Visit-based analyses are planned to be conducted based on the RUBATO OLES and on the 
RUBATO pool. Analysis visits for the RUBATO DB period within the RUBATO pool follow the 
RUBATO DB SAP, visits labelled “Baseline” or “Week xx” in the RUBATO DB CSR SAP are 
re-labelled to “DB Baseline” or “DB Week xx”. For the RUBATO OL period, analyses visits are 
assigned according to Table 5.
Safety assessments are generally reported based on the nominal visit, i.e., according to the visit 
reported in the database, however for subjects who discontinued OL study treatment prematurely 
with available premature EOT visit, the EOT assessments may be re-assigned to a scheduled visit 
according to the windows specified in Table 5 in case the premature EOT visit assessment is 
treatment emergent (i.e., within 30 days after study treatment discontinuation).
All efficacy assessments (including unscheduled ones) are assigned to analysis visits as follows: 
If a subject has two or more assessments in one visit window, the assessment closest to the target 
day will be used as the analysis visit for that visit window. The other additional assessment(s) will 
not be used in by-visit summaries or analyses, but they can be used for determination of other 
endpoints (e.g., time to event endpoints). If two assessments are equidistant from the target day 
within a visit window, the later visit is used. If more than one value falls on the same timepoint 
then the one with the worst assessment (i.e., lowest peak VO2, VO2 at VAT, PA-Ac mean count 
per minute) is used. All assignments will be made in chronological order. Once an assessment is 
assigned to a visit window, it will no longer be used for a later time point. 


ACT-064992 / JNJ-67896062 (macitentan)
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Status: Approved, Date: 17 December 2021
Assessments which fall outside of any planned window will not be included in by-visit summary 
tables and graphs but will be included in outlier tables and into individual subject listings.
Table 5:
Time Windows for the OL Period and Day 30 FU
Parameter
Analysis Visit
(label on output)
Time Interval
(OL Day)*
Target Time 
Point
(OL Day)
PA-Ac
OL Baseline
1 to 30
2-10
Efficacy parameters.
Safety parameters (for EOT 
visit remapping only)
OL Week 26
92 to 273
183
OL Week 52
274 to 455
365
OL Week 78
456 to 637
547
OL Week 104
638 to 819
729
OL Week 130
820 to 1001
911
OL Week 156
1002 to 1183
1093
Laboratory (aminotransferases 
and hemoglobin only)
Day 30 FU
≥ Analysis 
Set EOT + 28
Analysis Set EOT + 
30
* Relative to OL Day 1 (defined in Section 5.1.2.2)
5.1.2.
Definition of Baseline, Periods and Dates/Days
5.1.2.1.
Baseline
The DB baseline is used as derived in the core DB study (i.e., not re-derived). Except where 
otherwise specified in the RUBATO DB CSR SAP, DB baseline is defined as the last non-missing 
assessment obtained before or on the day of the start of study treatment.
The macitentan baseline is defined as the last value assessed prior or on the macitentan treatment 
start date (either in the core RUBATO DB study or in the RUBATO OL extension) defined in 
Section 5.1.2.2.
Baseline in OLES is generally defined as the last non-missing assessment obtained prior or on the 
RUBATO OL treatment start date defined in Section 5.1.2.2. For PA-Ac, OLES baseline is based 
on assessments recorded after RUBATO OL treatment start date, details are given in Section 5.5.2.
Baseline in RUBATO pool and RUBATO DB set corresponds to DB baseline.
Baseline in TMAS set corresponds to macitentan baseline.
5.1.2.2.
Treatment Start Date (Day 1) and Day Numbering in Analysis Sets
The DB treatment start date (DB Day 1) is used as derived in the RUBATO DB study (i.e., not 
re-derived).  
The OL treatment start date (OL Day 1) is the date of first dose of macitentan treatment in the 
RUBATO OL study. This is the “Treatment start date” (defined as the date the first dose of study 
treatment intake) from the first interval, in chronological order, recorded in the “Study Drug Log”
eCRF module of RUBATO OL. 
The macitentan treatment start date (macitentan Day 1), is defined to be the date of first dose 
of macitentan either in the core RUBATO DB study or in the extension RUBATO OL. For subjects 


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from the macitentan group according to the SS in RUBATO DB, it is the DB treatment start date 
(as defined above), for subjects from the placebo group according to the SS in RUBATO DB it is 
the OL treatment start (as defined above).
OLES Day 1 corresponds to OL treatment start date (OL Day 1).
RUBATO pool Day 1 and RUBATO DB Day 1 set correspond to DB treatment start date (DB 
Day 1).
TMAS Day 1 corresponds to macitentan treatment start date (macitentan Day 1).
All safety and efficacy assessments/events (with the exception of Fontan-palliated clinical 
worsening and Fontan-palliated morbidity) at all visits will be assigned a day relative to analysis 
set Day 1.
Day or relative day for a visit/ assessments/event is defined as:
!
Visit/assessment/event date − Date of analysis set Day 1 + 1, if visit/assessment/event date is 
≥ date of analysis set Day 1
!
Visit date/assessment/event − Date of analysis set Day 1, if visit/assessment/event date < date 
of analysis set Day 1
There is no ‘Day 0’.
Day of Fontan-palliated clinical worsening and Fontan-palliated morbidity in the RUBATO pool 
is calculated relative to the randomization date:
!
Date of Fontan-palliated clinical worsening / morbidity – Randomization Date + 1
5.1.2.3.
End of Treatment (EOT) Date
DB EOT corresponds to study treatment end date as defined in the RUBATO DB CSR SAP.
OL EOT is only defined for subjects treated with OL treatment and corresponds to “Treatment 
end date” from the last interval, in chronological order, recorded in the “Study Drug Log” eCRF
form.
Macitentan EOT is defined to be the date of last dose of macitentan either in the RUBATO DB 
study or in the extension RUBATO OL. For subjects from the macitentan group according to the 
SS RUBATO DB who did not enter the RUBATO OL study, this is the DB EOT (as defined in
above), otherwise it is the OL EOT as defined above.
EOT in OLES corresponds to OL EOT.
EOT in RUBATO pool corresponds to OL EOT for subjects treated with OL treatment, and to 
DB EOT for subjects not treated with OL treatment.
EOT in TMAS corresponds to macitentan EOT.


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5.1.2.4.
End of Study (EOS) Date
DB EOS corresponds to EOS date as defined in the RUBATO DB CSR SAP.
OL EOS is only defined for subjects treated with OL treatment and corresponds to the date entered 
on the ‘Visit Summary-EOS’ eCRF Form. For subjects who died, EOS corresponds to the date of 
death. If a subject is lost to follow-up, EOS corresponds to the date of last successful contact from 
the 'Study Discontinuation' eCRF form.
EOS in OLES corresponds to OL EOS.
EOS in RUBATO pool and in TMAS corresponds to OL EOS for subjects treated with OL 
treatment, and to DB EOS for subjects not treated with OL treatment.
5.1.2.5.
DB Period
All visits, assessments and events dated prior to the OL treatment start date (as defined in 
Section 5.1.2.2) are considered to belong to the DB period. For subjects not in the OLES (i.e., those 
not dosed with OL treatment), all data collected in RUBATO DB database is included and assigned 
to DB period.   
5.1.2.6.
OL Period
It is the period between OL treatment start date (as defined in Section 5.1.2.2) and OL EOS (as 
defined in Section 5.1.2.4), limits included.
5.2.
Participant Dispositions
As per protocol amendment 3 (protocol version 4), RUBATO OL was planned to continue for each 
subject until the last subject has globally completed 104 weeks (2 years) of treatment. Subjects 
who enrolled the into RUBATO OL (i.e., were treated with OL treatment) and who did not consent 
to protocol version 4, but completed 104 weeks of OL treatment and the corresponding S-FU 
period under protocol version 3, are considered treatment and study completers in the OL period.
The following definitions are relevant to provide the disposition information. 
5.2.1.
Study Treatment Discontinuation
The number and percentage of subjects who discontinued study treatment (incl discontinuation 
reasons) in the analysis set are presented for the RUBATO OLES and the RUBATO TMAS. 
In both studies, study treatment discontinuations are collected in the “Study Drug Log” eCRF form 
and identified as those with a treatment end date and associated reason (‘What was the reason for 
treatment end?’) answered ‘Premature Discontinuation’. Reasons for study treatment 
discontinuation are collected in the “Premature Discontinuation of Study Treatment’ eCRF form. 
The following reasons for permanent treatment discontinuation are displayed (including if 
documented to be “COVID-19 related” as per prefix in database):
!
Death


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!
Lost to follow-up
!
Pre-specified study treatment discontinuation criteria
!
Adverse Event (this combines reports of subject and physician decision)
!
Lack of Efficacy (this combines reports of subject and physician decision)
!
Other 
∀
Other medical reasons (this combines reports of subject and physician decision)
∀
Other non-medical reasons (this combines reports of subject and physician decision)
∀
No reason provided (Subject decision)
∀
Sponsor decision - Study termination
∀
Sponsor decision - Other
For analyses based on the RUBATO TMAS an additional Study Treatment Discontinuation reason 
is defined as
!
Completed treatment in RUBATO DB study but not enrolled into RUBATO OL study
For the RUBATO OLES, only RUBATO OL eCRF forms are considered whereas for the 
RUBATO TMAS, information is concatenated from both study eCRFs. For subjects who 
prematurely discontinued study treatment in the DB study and who entered the OL study after 
completing the week 52 PTOP visit in the DB study, the study treatment discontinuation reason in 
DB is not considered for treatment disposition in RUBATO TMAS.
An individual listing of subjects who discontinued study treatment prematurely and related 
reason(s) will be provided for the RUBATO OLES and the RUBATO TMAS.
5.2.2.
Study Discontinuation
The number and percentage of subjects who prematurely discontinued study (including
discontinuation reasons) in the analysis set is presented for the RUBATO OLES and the RUBATO 
TMAS. 
In both studies, study treatment discontinuations are collected in the “Study Discontinuation”
eCRF page.
Subjects who withdrew from the study are those with any withdrawal reason entered in the “Study 
Discontinuation” eCRF module. The following reasons for study discontinuation are displayed
(including if documented to be “COVID-19 related” as per prefix in database):
!
Death
!
Lost to follow-up
!
Adverse Event (this combines reports of subject and physician decision)


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!
Lack of Efficacy (this combines reports of subject and physician decision)
!
Other 
∀
Other medical reasons (this combines reports of subject and physician decision)
∀
Other non-medical reasons (this combines reports of subject and physician decision)
∀
No reason provided (Subject decision)
∀
Sponsor decision - Study termination
∀
Sponsor decision - Other
For analyses based on the RUBATO TMAS an additional Study Discontinuation reason is defined 
as:
!
Completed DB study but not enrolled into RUBATO OL study
For the RUBATO OLES, only RUBATO OL eCRF forms are considered whereas for the 
RUBATO TMAS, information is concatenated from both study eCRF and OL disposition 
overwrites DB disposition.
An individual listing of subjects who discontinued study prematurely and related reason(s) will be 
provided for the RUBATO OLES and the RUBATO TMAS.
5.2.3.
Other Disposition Information
For the RUBATO OLES, the study and treatment disposition as defined in the RUBATO DB SAP 
will be presented to inform on the number of subjects seamlessly entering the RUBATO OL study 
versus subjects enrolling into OL after entering the DB study PTOP.
In addition, the distribution (number and percentage of subjects) by geographical region, country, 
and site ID will be presented for the RUBATO OLES and the RUBATO TMAS.
The number of subjects in the different analysis sets will be tabulated and a listing of subject 
membership in the different analysis sets is provided.
5.3.
Extent of Exposure and Compliance
Exposure and compliance variables are derived and summarized for the RUBATO OLES, 
RUBATO pool (SS), and the RUBATO TMAS.
The exposure within an analysis set is evaluated first in terms of study treatment duration, 
including study treatment interruptions. The study treatment exposure (in days) in analysis set is 
calculated as:
	 	
 
 	 	  −	  
 	 	  + 1
In addition, the study treatment exposure is evaluated in terms of actual days exposed to study 
treatment, excluding any temporary interruptions. A subject is considered to have had a study 


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treatment interruption if the reason for treatment end is either ‘Temporarily interrupted due to an 
AE’ or ‘Temporarily interrupted not due to an AE’ (“Study Drug Log” eCRF form), corresponding 
treatment end dates, and treatment restart dates are taken from the “Study Drug Log” eCRF form. 
For the RUBATO pool and the RUBATO TMAS, also gaps between DB EOT (defined in
Section 5.1.2.3) and OL treatment start date (defined in Section 5.1.2.2) are considered as 
interruption. Treatment interruptions and gaps between DB EOT and OL treatment start of more 
than 30 days are flagged.
The study treatment exposure, excluding any temporary interruptions, is calculated as:

 	  	 	  −
 
	  		 	 	 .
Where the total duration of interruptions is the sum of all treatment interruptions. The duration of 
each treatment interruption is calculated as:
	  
 (   
) −
	 	
 
 (  	 	
 
) −1.
Compliance is assessed as a percentage based on exposure as defined above from the study drug 
log, calculated for each pool as follows:

 	  	 	  
	 		 × 100

 	  	 	 
Note: Compliance below 100% must not be indicative of a deviation from the protocol since there 
are protocol mandated reasons for interruptions and a protocol allowed gap in transition from DB 
to OL study.
Corresponding categorical variables (not mutually exclusive) are derived for compliance in the 
categories:
!
< 80 %
!
≥ 80 %
The study treatment exposure (i.e., duration of treatment including interruptions) and study 
treatment exposure excluding any interruptions will be expressed in weeks for summary tables 
(i.e., calculated days of exposure are divided by 7), and corresponding categorical variables (not 
mutually exclusive) are derived (i.e., ≥24, ≥48, ≥72, ≥96, ≥120, ≥144 weeks). The number and 
percent of subjects with 0, 1 or >1 treatment interruptions of >30 days are presented in the exposure 
table.
Exposure and compliance variables are summarized for the RUBATO OLES, RUBATO pool (SS)
(Maci/Maci arm only), and the RUBATO TMAS by means of descriptive statistics (N, mean, 
standard deviation [SD], median and range [minimum and maximum], and IQ range) for the 
continuous variables and by means of number and percentage of subjects for categorical variables.


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Study drug log data and derived exposure and compliance data will be also listed for the RUBATO 
OLES and the RUBATO TMAS.
5.4.
Safety Analysis
The following safety endpoints are defined for analysis:
!
Treatment-emergent AEs and SAEs up to 30 days after study treatment discontinuation;
!
AEs leading to death;
!
AEs leading to premature discontinuation of study treatment;
!
AEs of special interest (anemia/hemoglobin decrease, hepatic adverse events of special 
interest, hypotension, edema and fluid retention) and COVID-19 related AEs. AEs of special 
interest (AESI) and COVID-19 related AEs are defined using a selection of preferred terms 
(Internal MedDRA Query). The full definition is included in Section 6.7 Appendix 7; 
!
(Change in) vital signs (systolic and diastolic arterial BP and pulse rate), including peripheral 
oxygen saturation (SpO2) and body weight over time;
!
Treatment-emergent decrease in systolic blood pressure (SBP) up to 30 days after study 
treatment discontinuation;
!
Treatment-emergent marked laboratory abnormalities up to 30 days after study treatment 
discontinuation;
!
(Change in) laboratory parameters over time; 
!
(Change in) echocardiography parameters over time;
!
Treatment-emergent echocardiography abnormalities (valvular defects) up to 30 days after 
study treatment discontinuation.
For all continuous safety variables, descriptive statistics will include the N, mean, standard 
deviation [SD], median and range [minimum and maximum] and IQ range. Categorical variables
will be summarized using frequency counts and percentages. Unless otherwise specified, data are 
summarized by the treatment arms defined in Table 3 for the corresponding analysis set.
5.4.1.
Adverse Events
An adverse event (AE) is defined as any term reported by the Investigator in the “Adverse Event”
eCRF form. The original terms used by the Investigators to describe AEs are assigned preferred 
terms (PT) and system organ class (SOC) for classification and tabulation using the latest 
implemented MedDRA version dictionary.
Any AE occurring at or after the study treatment start within the analysis set up to 30 days after 
the analysis set EOT (limits included) is considered to be treatment-emergent. 
The following definitions are relevant for the analysis of the adverse events.
!
Frequency of the adverse events


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All AEs reported more than once within a subject (as qualified by the same preferred term(s)) are 
counted once in the frequency table. In the event that the reported AE is assigned to several 
preferred terms, subjects are counted for each individual preferred term.
!
Intensity of the adverse events
For AEs reported more than once for a subject (as qualified by the same preferred term(s)) but 
with different intensities, the worst intensity is considered. The categories of intensity are defined 
as follows: mild, moderate and severe. If intensity is missing, the event is considered severe.
!
Relationship of the adverse events
Relationship to study treatment is defined as ‘related’ (yes) or ‘not related’ (no). For AEs reported 
more than once within a subject (as qualified by the same preferred term(s)), the strongest 
relationship reported (i.e., ‘related’) is considered. Adverse events with missing relationship are 
considered in any analysis as related.
!
Adverse events leading to discontinuation of study treatment
An AE is defined as leading to discontinuation of study treatment if the corresponding ‘Action 
taken with study treatment’ field in the eCRF “AE” form is ‘Drug withdrawn’.
!
Serious adverse events
A SAE is an AE for which the corresponding ‘Serious?’ field in the eCRF AE form is ticked ‘Yes’.
If the information on seriousness is missing, the adverse event is considered serious.
!
AEs with fatal outcome
An AE is considered having fatal outcome if the tick box “Fatal” for “Outcome” on the eCRF 
Adverse Event page is checked. 
!
Adverse events of special interest (AESIs) and COVID-19 related AEs
AEs of special interest are defined using a selection of preferred terms (Internal MedDRA Query)
as detailed in Section 6.7 Appendix 7 Adverse Events of Special Interest and COVID-19 related 
AEs.
!
Incidence rate per 100 subject-years of observation (SYO)
In order to account for differences in the time of observation among subjects, for some event types, 
tables will present the subject-years of observation (SYO) and the incidence rates per 
100 subject-years. The subject-observation time will be calculated, for each subject, as follows:
1.
For subjects without event of interest: by considering the treatment duration as (EOT date –
treatment start date + 1);


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2.
For subjects with event of interest: by considering the treatment duration up to the start date 
of first event (min [date of first event, EOT date] – treatment start date + 1)
SYO will be calculated by first summing the subject-observation time for all subjects and then 
dividing the results by 365.25 days.
The incidence rate for the event of interest, per 100 subject-years, will be calculated by dividing 
the number of subjects with event of interest by the SYO and multiplying by 100:
Adjusted Incidence Rate = 100 × (Number of subjects with at least one event of interest / SYO)
!
Pooling of AEs
For the RUBATO TMAS and RUBATO pool, AEs from DB and OL study are pooled. AEs that 
started in the DB study and were still ongoing on Day 1 of the OL study are reported in the 
‘Ongoing Adverse Events from AC-055H301’ OL eCRF form. AEs included in the OL eCRF as 
‘ongoing’ from the DB study and the original AEs included in the DB eCRF will be merged using 
a dedicated ID linking variable included in the related SDTM datasets. If the event worsened in 
intensity/seriousness after start of study treatment in the OL study, such an event was reported in 
the usual Adverse Event OL eCRF Form. 
The following rules will be used by merging the SDTM datasets:
o The outcome as entered in OL study will be used for the analysis (even if not yet entered 
due to AE still ongoing)
o If the action taken for an ongoing AE is given as temporarily interrupted in the DB study 
database, and the action taken is missing, none, not applicable, or unknown in the OL 
study database, then the value from the DB will be retained. For all the other cases the 
action taken as entered in OL study will be used for the analysis
If an event with (partially) missing onset date in the DB study is also entered on the form “Ongoing 
adverse events from AC-055H301” eCRF page in the OL, this AE will not be considered as 
treatment-emergent with respect to the OL period (i.e., in subjects of the RUBATO TMAS 
receiving placebo during DB study), and no dates or other variables will be imputed if missing or 
partial. Such events will appear in listings only and flagged as DB period event.
All adverse event summary tables described below will be provided for the RUBATO OLES, the 
RUBATO TMAS, and for the Macitentan 10 mg/Macitentan 10 mg arm of the RUBATO pool 
(SS), if not otherwise specified.
An overall summary table of AEs will be provided, containing number and percentages of subjects 
having experienced at least 1 occurrence for the following categories of AEs:
!
Treatment-emergent AE
!
Treatment-emergent AE related to study treatment


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!
Treatment-emergent serious AE (SAE)
!
Treatment-emergent SAE related to study treatment
!
AEs leading to premature discontinuation of study treatment
!
Treatment-emergent Fatal (leading to death) AE
!
Severe treatment-emergent AE 
In order to account for differences in the time of observation among subjects in the RUBATO 
TMAS, and for the Macitentan 10 mg/Macitentan 10 mg arm of the RUBATO pool (SS), the
subject-years of observation (SYO) and the incidence rate per 100 subject-years will be presented 
for the following categories of AEs:
!
Treatment-emergent serious AE (SAE)
!
AEs leading to premature discontinuation of study treatment
Separate summary tables (containing number and percentages of subjects) will be provided by 
SOC and PT within each SOC for the following categories of AEs:
!
Treatment-emergent AEs
!
Treatment-emergent SAEs 
!
AEs leading to discontinuation of study treatment
!
Treatment-emergent AEs related to study treatment
!
Treatment-emergent SAEs related to study treatment
!
Treatment-emergent SAEs leading to discontinuation of study treatment
!
Treatment-emergent Fatal AEs.
The summary tables are presented in descending order (e.g., SOC and PT within each SOC with 
the highest number of occurrences appears first). For the summaries on the RUBATO OLES, 
sorting is done considering the treatment arms in the following sequence: OL Macitentan 10 mg, 
DB-Macitentan 10 mg, DB-Placebo. In case of equal frequency of different SOC/PTs, alphabetical 
order is used.
Similarly, separate summary tables (containing number and percentages of subjects) will be 
provided by PT for the following categories of AEs:
!
Treatment-emergent AEs
!
Treatment-emergent SAEs 
!
AEs leading to discontinuation of study treatment
!
Treatment-emergent AEs related to study treatment
!
Treatment-emergent SAEs related to study treatment


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!
Treatment-emergent SAEs leading to discontinuation of study treatment
!
Treatment-emergent AEs by maximum intensity
!
Treatment-emergent AESI, serious AESI, AESI leading to discontinuation of study treatment, 
AESI with fatal outcome
!
Treatment-emergent COVID-19 related AEs, serious COVID-19 related AEs, COVID-19 
related AEs leading to discontinuation of study treatment, COVID-19 related AEs with a fatal 
outcome
For each category of AESI, and for COVID-19 related AEs, an overall summary table will be 
provided, containing number and percentages of subjects having experienced at least 1 occurrence 
for the following categories: Any AE (plus worst severity of any AE), Any related AE, Any fatal 
AE, Any SAE, Any related SAE, Any AE leading to discontinuation of study treatment. For the 
incidence of subjects with any AESI/COVID-19 related AE, this table will also present 95% 
Clopper-Pearson CL, and the subject-years of observation (SYO) plus incidence rate per 100 
subject-years. 
In addition to the summary tables, listings will be provided based on the RUBATO pool (SS), 
displaying:
!
AEs 
!
SAEs 
!
AEs leading to discontinuation of study treatment
!
AEs of special interest
!
All AEs in subjects who had any COVID-19 related AE
!
All AEs in subjects who had at least one treatment interruption of >30 days. In this listing, 
AEs with onset date during the interruption(s) are flagged along with the “Day of AE onset 
relative to last intake prior to treatment interruption” derived as AE start date – treatment end 
date prior to interruption + 1. Only events with a start date during an interruption of >30 days 
are flagged this way.
For each AE it will be flagged if started in OL or DB period and whether considered treatment-
emergent.
5.4.2.
Deaths
A summary table will be provided, containing number and percentages of subjects who died on 
RUBATO pool (SS). Frequencies for the following parameters will be included in the summary 
table:
!
Number of subjects who died
!
Primary cause of death


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The summary will be based on the “Death” eCRF modules from the DB and the OL eCRF. The 
summary table is presented by descending order of PT according to the incidence of deaths in the 
maci/maci treatment arm. The summary will be provided if at least 3 deaths have occurred overall. 
A corresponding listing is provided and for each death it will be flagged if started in OL or DB 
period.
5.4.3.
Vital Signs
Vital signs parameters include systolic and diastolic blood pressure (mmHg), pulse rate (bpm) 
SpO2 (%), and body weight (kg) and are summarized by displaying descriptive statistics for the 
observed values at baseline, for the observed post-baseline assessments, and for the absolute 
changes from analysis set baseline to each post-baseline visits/timepoint. Except for baseline, only 
treatment-emergent assessments will be included. Assessments dated after the study treatment start 
up to 30 days after analysis set EOT (limits included) are considered to be treatment-emergent.
The following nominal visits/timepoints will be displayed for the RUBATO pool (SS):
!
DB Baseline ^ ( ~ analysis set baseline)
!
DB Week 16
!
DB Week 52
!
OL Baseline ^
!
OL Week 26
!
OL Week 52
!
OL Week 78
!
OL Week 104
!
OL Week 130
!
OL Week 156
The following nominal visits/timepoints will be displayed for the OLES:
!
OL Baseline ^ ( ~ analysis set baseline)
!
OL Week 26
!
OL Week 52
!
OL Week 78
!
OL Week 104
!
OL Week 130
!
OL Week 156
^ This is not a nominal visit but the derived baseline. In the RUBATO pool (SS), the same 
assessment may be displayed under 2 timepoints “DB Week 52” and “OL Baseline”.


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Data is included for analysis regardless of the location (left arm, right arm) or the position of 
measurement (supine or sitting).
For the RUBATO pool (SS), change from baseline in systolic and diastolic arterial BP, SpO2 (%)
and pulse rate over time will also be graphically presented based on box plots, on a time axis scaled 
by the target days of nominal visits at DB Week 16, DB Week 52, OL Baseline, OL Week 26, OL 
Week 52, OL Week 78, OL Week 104. The box indicates the interquartile range, a horizontal line 
within the box indicates the median, and a diamond shape indicates the mean. Whiskers denote 
minimum and maximum values within the boundary of +/- 1.5 times the size of the interquartile 
range. Circles indicate outliers from +/- 1.5 times the size of the interquartile range. A reference 
line at zero change is drawn.
A decrease in SBP is considered if a post-treatment SBP measurement (scheduled or unscheduled) 
up to 30 days after analysis set EOT (limits included) is <90 mmHg [or <85 mmHg for adolescents 
(<18 years old) who are < 150 cm in height] and was not present at baseline. The incidence 
(number, percentage, and 95% CL using ClopperPearson formula) of subjects with at least one 
treatment-emergent low systolic blood pressure (SBP) will be summarized for the RUBATO 
OLES, RUBATO pool (SS) (Maci/Maci arm only), and the RUBATO TMAS. Denominator is the 
number of subjects with at least one treatment-emergent SBP measurement available. For the
RUBATO OLES and the RUBATO pool, the number and percentage of subjects with a decrease 
in SBP is also summarized by visit.
Blood pressure, pulse rate, SpO2, height and body weight measurements will be reported in a 
subject listing for the RUBATO pool (SS). Position (supine or sitting) and location (left or right 
arm) for vital signs will be included. Each value will be flagged as assessed during OL or DB 
period and whether considered treatment-emergent.
5.4.4.
Laboratory
Safety laboratory samples are centrally analyzed by Covance and the results are electronically 
transferred into the clinical databases of the two studies. In exceptional cases, the protocols allow 
the utilization of local laboratories. Local laboratory analysis results are entered in the eCRF. 
Quantitative results from local laboratories are not summarized (i.e., not included in summary 
statistics or graphical representations). Qualitative results like (marked) abnormality 
categorization, liver test elevation categories, etc. are derived from local laboratory data and 
summarized together with qualitative results derived from central laboratory data. Values from 
unscheduled visits are not included in by visit/timepoint summaries but are included in the listings 
and in the summaries for marked abnormalities and liver function test abnormalities.
Data are evaluated in Standard International (SI) units as provided by the central laboratory. In 
case of local laboratory, values are converted into SI units. The tests converted in SI are available 
in SDTM for the analysis. All values reported as below or above the limit of detection (e.g., ‘< 3’, 
‘> 100’) are substituted with the limit of detection (e.g., ‘< 3’, is substituted by ‘3’) for the purpose 
of the analysis. The values are listed including the < or > sign.


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Safety laboratory data are summarized by displaying descriptive statistics for the observed values 
at baseline, for the observed post-baseline assessments, and for the absolute changes from analysis 
set baseline to each post-baseline visit/timepoint. Except for baseline and FU visit, only treatment-
emergent assessments will be included. Assessments dated after the study treatment start date up 
to and including 30 days after analysis set EOT are considered to be treatment-emergent.
The following selected parameters (SI unit) are included in the descriptive statistics summary 
tables: 
!
Hematology: Hemoglobin (g/L), Hematocrit (L/L), Leukocyte count (10^9/L), Neutrophils 
(10^9/L), Lymphocytes (10^9/L), Platelet count (10^9/L).
!
Chemistry: Alanine Aminotransferase (U/L), Aspartate Aminotransferase (U/L), Alkaline 
phosphatase (U/L), Bilirubin (umol/L), Direct bilirubin (umol/L), Gamma glutamyl 
transpeptidase (U/L), Creatinine (umol/L), Glomerular Filtration Rate, calculated by central 
laboratory (mL/min/1.73m2).
!
Coagulation tests: Prothrombin Time (sec), Prothrombin Intl. Normalized Ratio (ratio). 
The following visits/timepoints will be displayed for the RUBATO pool (SS):
!
DB Baseline ^ ( ~ analysis set baseline)
!
DB Week 16
!
DB Week 52
!
OL Baseline ^
!
OL Week 26
!
OL Week 52
!
OL Week 78
!
OL Week 104
!
OL Week 130
!
OL Week 156
!
Day 30 FU (aminotransferases and hemoglobin only)
The following visits/timepoints will be displayed for the OLES:
!
OL Baseline ^ ( ~ analysis set baseline)
!
OL Week 26
!
OL Week 52
!
OL Week 78
!
OL Week 104
!
OL Week 130


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!
OL Week 156
!
Day 30 FU (aminotransferases and hemoglobin only)
^ This is not a nominal visit but the derived baseline. In the RUBATO pool (SS), the same 
assessment may be displayed under 2 timepoints “DB Week 52” and “OL Baseline”.
Further analyses as described below will be conducted based on the RUBATO pool (SS), and for 
hematology parameters hemoglobin, hematocrit, leukocytes, platelets and chemistry parameters 
ALT, AST, Alkaline phosphatase, total bilirubin, creatinine. Only treatment emergent 
measurements are included:
!
The change from baseline over time is presented based on box plots, on a time axis scaled by 
the target days of nominal visits at DB Week 16, DB Week 52, OL Week 26, OL Week 52, 
OL Week 78, OL Week 104. The box indicates the interquartile range, a horizontal line within 
the box indicates the median, and a diamond shape indicates the mean. Whiskers denote 
minimum and maximum values within the boundary of +/- 1.5 times the size of the 
interquartile range. Circles indicate outliers from +/- 1.5 times the size of the interquartile 
range.
All laboratory tests provided by the central and local laboratory will be listed together for the 
RUBATO pool (SS), including those from unscheduled visits. Marked laboratory abnormalities 
(MLAs) are flagged accordingly. Each value will be flagged as assessed during OL or DB period 
and whether considered treatment-emergent.
5.4.4.1.
Marked Laboratory Abnormalities
A laboratory test abnormality is defined as any value outside the normal range as provided by the 
central and local laboratory. The direction of the abnormality (below or above the normal range) 
is indicated using ‘H’ and ‘L’. 
A marked laboratory abnormality (MLA) is defined as any value that fulfills the applicable 
condition for LL/HH, as provided in Table 6. The marked laboratory abnormalities (MLA) are 
derived according to the protocol and listed in Table 6 below. More severe marked abnormalities 
are indicated by LLL/HHH/HHHH, where applicable.
The definitions of marked abnormal values are based mainly on the Common Terminology Criteria 
for Adverse Events (CTCAE [CTCAE 2010]) grading system and, in specific cases 
(e.g., lymphocyte levels), are adjusted based on the known pharmacodynamic effect of the study 
treatment (e.g., LLL threshold for lymphocytes).
All laboratory data are taken into account regardless of whether they correspond to scheduled (per 
protocol) or unscheduled assessments, and regardless of whether they were analyzed by local or 
central laboratory.
Treatment-emergent MLAs are all marked laboratory abnormalities occurring after the study 
treatment start in the analysis set and up to 30 days after analysis set EOT, that were not present at 
analysis set baseline (see Section 5.1.2.1 for definition) in the same or worse category (considering 


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the direction of worsening). In other words, the MLAs are evaluated separately for both directions 
of worsening (e.g., a post-baseline MLA of “HH” is considered treatment-emergent if the baseline 
is “L” or “LL” or “LLL” (where applicable) or “H”, or within normal limits or missing. On the 
other hand, it is not considered as treatment-emergent if the baseline is “HH” or “HHH” when 
applicable). In case of missing baseline, an MLA is considered to not have been present at baseline.
Table 6:
Thresholds for Marked Laboratory Abnormalities
Parameter (SI unit)
LL
LLL
HH
HHH
Hemoglobin (g/L)
< 100
< 80
Increase in > 20 
g/L above ULN or 
above baseline (if 
baseline is above 
ULN)
Increase in > 40 g/L above ULN or 
above baseline (if baseline is above 
ULN)
Hematocrit (L/L)
< 0.28 
(female)
< 0.32 (male)
< 0.20
> 0.55 (female)
> 0.60 (male)
> 0.65
Platelet count (109 /L)
< 75 
< 50
> 600
> 999
Eythrocyte count 
(1012 /L)
ND
ND
ND
ND
Leukocyte count (109
/L)
< 3.0
< 1.9
> 20.0
> 100.0
Lymphocyte (109 /L)
ND
< 0.2
> 4.0
>20
Neutrophils (109 /L) 
< 1.5 
< 1.0
ND
ND
Eosinophils (109 /L) 
ND
ND
> 5.0
ND
AST (U/L)*
ND
ND
≥ 3 ULN
≥ 5 ULN
≥ 8 ULN (included as HHHH)
ALT (U/L)*
ND
ND
≥ 3 ULN
≥ 5 ULN
≥ 8 ULN (included as HHHH)
Total bilirubin 
(umol/L)
ND
ND
≥ 2 ULN 
≥ 5 ULN
Alkaline Phosphatase 
(U/L)
ND
ND
> 2.5 ULN
> 5 ULN
INR*
ND
ND
≥ 1.5 ULN or
≥ 1.5 # above 
baseline if on 
anticoagulation
≥ 2.5 ULN or
≥ 2.5 # above baseline if on 
anticoagulation
Creatinine (umol/L)*
ND
ND
>1.5 ULN or 
>1.5 × above 
baseline (if 
baseline > ULN)
> 3 ULN or 
>3 × above baseline (if baseline > 
ULN)
eGFR (mL/min/1.73 
m2)
< 60 
< 30 
ND
ND
Blood Urea Nitrogen 
(mmol/L)
ND
ND
> 2.5 ULN
> 5 ULN
Albumin (g/L)
< 30 
< 20
ND
ND
Glucose (mmol/L)
< 3.0
< 2.2
> 8.9
>13.9
Potassium (mmol/L)
< 3.2
< 3.0
> 5.5
> 6.0
Sodium (mmol/L)
ND
< 130
> 150 
> 155 
Calcium (mmol/L)
< 2.0 
< 1.75
> 2.9
> 3.1
Triglyceride (mmol/L)
ND
ND
> 3.42
> 11.4
Cholesterol (mmol/L)*
ND
ND
> 7.75
> 12.92
The above values come from the protocol Table 4 of the protocol.


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* HH and HHH based on CTCAE 2010 v4.03 (CTCAE 2010)
ALT = alanine aminotransferase; AST = aspartate aminotransferase; eGFR = estimated glomerular filtration rate; INR = 
International Normalized Ratio; NA = not applicable; ND = not defined; SI = international system of units; ULN = upper 
limit of normal.
For INR, a subject is considered to be on anticoagulation if the subject took antithrombotic agent (ATC codes B01A) and date of 
INR assessment is on or after start of anticoagulation therapy.
For each category (i.e., LL, LLL, HH, HHH, HHHH), the number and percentage of subjects with 
at least one treatment-emergent MLA will be summarized (separately for hematology/coagulation 
tests and clinical chemistry). Denominator is the number of subjects with at least one treatment-
emergent measurement of the corresponding laboratory parameter available. This summary is 
provided for the RUBATO OLES, RUBATO pool (SS) (Maci/Maci arm only), and the RUBATO 
TMAS.
5.4.4.2.
Additional Liver Function Test and Hemoglobin Abnormalities
The following elevated liver test abnormalities are considered:
!
ALT or AST ≥ 3 × ULN 
!
ALT or AST ≥ 5 × ULN 
!
ALT or AST ≥ 8 × ULN
!
ALT or AST ≥ 3 × ULN and total bilirubin ≥2 × ULN (at the same sample date)
!
ALT or AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN and alkaline phosphatase < 2 × ULN 
(at the same sample date)
!
ALT or AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN (at any post-baseline time point up to 
30 days after EOT)
The following hemoglobin abnormalities are considered:
!
Hemoglobin < 80 g/L 
!
Hemoglobin ≥ 80 g/L and < 100 g/L
!
Hemoglobin < 100 g/L. 
The highest ALT or AST value and the lowest hemoglobin at any post-baseline time point of 
assessment up to 30 days after analysis set EOT (limits included) is considered for classification 
in the categories above. 
For each abnormality category, incidence (number, percentage, and 95% CL using 
Clopper-Pearson formula) of subjects with at least one treatment-emergent abnormality will be 
summarized. Denominator is the number of subjects with at least one treatment-emergent 
measurement of any of the corresponding laboratory parameters available. This summary is 
provided for the RUBATO OLES, RUBATO pool (SS) (Maci/Maci arm only), and the RUBATO 
TMAS.


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Using the “evaluation of drug-induced serious hepatotoxicity” (eDISH) plots, graphical 
representations of maximum treatment-emergent ALT (in multiples of ULN) by maximum 
treatment-emergent total bilirubin (in multiples of ULN) will be produced, to identify potential 
Hy’s Law cases for each subject. The graph will be on a log10 scale for all subjects having 
assessments > 0.0625 # ULN for both peaks. Two reference lines will be plotted identifying the 
2 × ULN for total bilirubin and 3 × ULN for ALT. The normal subjects are on the left lower 
quadrant, the possible Hy’s Law cases appear on the right upper quadrant. The peak is defined as 
the maximum value from study treatment start up to 30 days after study treatment discontinuation 
(for the same subjects, not necessarily the peak of ALT occurs at the same time of the peak of total 
bilirubin). The same plot is provided for parameter AST and both plots are produced for the 
RUBATO OLES, RUBATO pool (SS) (Maci/Maci arm only), and the RUBATO TMAS.
All chemistry tests provided by the central and local laboratory, including those from unscheduled 
visits, will be listed separately for subjects with ALT or AST ≥ 3 × ULN and total bilirubin ≥ 2 × 
ULN (at any post-baseline time point up to 30 days after EOT) for the RUBATO pool (SS). Each 
value will be flagged as assessed during OL or DB period and whether considered treatment-
emergent.
5.4.5.
Echocardiography
Numerical echocardiography parameters include single ventricle ejection fraction (%), Fontan 
circulation stenosis value (%), ventricular outflow to aorta doppler velocity (m/s), vena contracta 
diameter (mm) and regurgitant orifice (cm2). Single ventricle ejection fraction (%) is summarized 
by displaying descriptive statistics for the observed values at baseline, for the observed post-
baseline assessments, and for the absolute changes from analysis set baseline to each post-baseline 
visits/timepoint. Except for baseline, only treatment-emergent assessments will be included. 
Assessments dated after the study treatment start up to 30 days after analysis set EOT (limits 
included) are considered to be treatment-emergent.
The following nominal visits/timepoints will be displayed for the RUBATO pool (SS):
!
DB Baseline ^ ( ~ analysis set baseline)
!
DB Week 52
!
OL Baseline ^
!
OL Week 52
!
OL Week 104
!
OL Week 156
The following nominal visits/timepoints will be displayed for the OLES:
!
OL Baseline ^ ( ~ analysis set baseline)
!
OL Week 52
!
OL Week 104


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!
OL Week 156
^ This is not a nominal visit but the derived baseline. In the RUBATO pool (SS), the same 
assessment may be displayed under 2 timepoints “DB Week 52” and “OL Baseline”.
The following valvular defects are assessed:
!
Severe AV valve regurgitation is present where the vena contracta is ∃7 mm or the 
effective regurgitant orifice is ∃0.4 cm2 in a post-baseline assessment up to 30 days after 
analysis set EOT, and not present at baseline. In the eCRF, up to two valve regurgitation 
values may be collected. If both are present in the eCRF, the largest will be considered for 
the derivation of Severe AV valve regurgitation.  
!
Presence of left ventricular outflow obstruction is confirmed by a pulsed-wave Doppler 
velocity % 2.5 m/s in a post-baseline assessment up to 30 days after analysis set EOT, and 
not present at baseline.
For each of the defects, the incidence (number, percentage, and 95% CL using ClopperPearson 
formula) of subjects with at least one occurrence (scheduled or unscheduled) will be summarized
for the RUBATO OLES, RUBATO pool (SS) (Maci/Maci arm only), and the RUBATO TMAS. 
Denominator is the number of subjects with at least one corresponding treatment-emergent 
echocardiography measurement available. For the RUBATO OLES and the RUBATO pool, the 
number and percentage of subjects with valvular defects is also summarized by visit. 
Echocardiographic parameters (all numerical and valvular defects) will be reported in a subject 
listing for the RUBATO pool (SS). Each value will be flagged as assessed during OL or DB period 
and whether considered treatment-emergent.
5.5.
Efficacy Analysis
The following efficacy endpoints are assessed:
Cardiopulmonary exercise testing (CPET)
!
The change from analysis set baseline to each scheduled time point in peak VO2. 
!
The change from analysis set baseline to each scheduled time point in VO2 at VAT. 
Physical activity measure by Accelerometer (PA-Ac)
!
Change from analysis set baseline to each scheduled time point in mean count per minute of 
daily PA-Ac. 
Other endpoints
!
Composite endpoint of event related to Fontan-palliated clinical worsening (time to first 
occurrence of clinical worsening up to analysis set EOS).


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!
Composite endpoint of events related to Fontan-palliated morbidity (time to first occurrence 
of morbidity up to analysis set EOS).
No formal hypothesis testing will be performed, as all efficacy analyses are considered exploratory 
and no inferential analysis is planned for the efficacy variables. 
All efficacy endpoints will be analyzed descriptively.
!
All assessments (including the unscheduled ones) are considered and re-assigned to the most 
appropriate visit according to the rules described in Section 5.1.1. 
!
Listings of all efficacy variable described below will be provided for the RUBATO pool 
(FAS).
!
To investigate the effect of switching from placebo to macitentan 10 mg, some efficacy 
endpoints are assessed on the RUBATO pool (FAS). Subjects will be analyzed according to 
the treatment they were randomized to in the RUBATO DB. 
!
Following 52 weeks of treatment with either placebo or macitentan 10 mg in the DB study, it 
must be assumed that the two populations will not be similar in terms of baseline 
characteristics at the start of the OL study. With this limitation acknowledged, specific 
efficacy endpoints will be analyzed only for the OL study (i.e., on the OLES), overall and split 
by DB randomized treatment.
5.5.1.
Cardiopulmonary Exercise Testing (CPET)
Measurements from CPET over time will be displayed at the following analysis visits (see 
Section 5.1.1for assignment of assessments to analysis visits, and Section 5.1.2.1 for baseline in 
analysis set definitions):
The following analysis visits/timepoints will be displayed for the RUBATO pool (FAS):
!
DB Baseline ( ~ analysis set baseline)
!
DB Week 16
!
DB Week 52
!
OL Baseline 
!
OL Week 52
!
OL Week 104
!
OL Week 156
The following analysis visits/timepoints will be displayed for the OLES:
!
OL Baseline ( ~ analysis set baseline)
!
OL Week 52
!
OL Week 104


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!
OL Week 156 
In the RUBATO pool (FAS), the same assessment may be displayed under 2 timepoints “DB Week 
52” and “OL Baseline”.
The following endpoints related to CPET are defined: 
!
Change in peak VO2 (mL/kg/min), from analysis set baseline to each scheduled time point.
!
Change in VO2 at VAT, from analysis set baseline to each scheduled time point.
Derived as:
Value at scheduled timepoint – Value at analysis set baseline
The values used for peak VO2 and VO2 at VAT at baseline and at each scheduled time point above 
(including the unscheduled ones, within the pre-defined corresponding analysis visits, see 
Section 5.1.1) will be based on a blinded data evaluation by the independent central reading 
facility. In case an assessment has been evaluated as “invalid” by the independent central reading 
facility, it will be ignored.
Baseline peak VO2 and VO2 at VAT is not re-derived for the RUBATO pool (FAS) but taken from 
the RUBATO DB CSR analysis.  
For the OLES, baseline peak VO2 and VO2 at VAT are derived in a similar manner, i.e., among 
all available measurements evaluated as “valid” by the central reading facility, the latest 
assessment prior or at the OL treatment start date (see Section 5.1.2.2) is considered baseline. If 
no “valid” assessment exists, baseline is imputed with the median value observed at baseline from 
the remaining subjects (within the DB treatment arm, i.e., DB-placebo or DB-Macitentan 10 mg).
No imputation of missing or invalid post-baseline peak VO2 and VO2 at VAT is performed, 
i.e., data summaries will be based on observed measurements (excluding invalid results).
Peak VO2 and VO2 at VAT will be summarized displaying descriptive statistics for the observed 
values at baseline, for the observed value at each post-baseline assessment, and for the absolute 
changes from baseline to each post-baseline assessment in analysis sets RUBATO OLES and 
RUBATO pool (FAS). For the RUBATO pool (FAS), to graphically display changes, a plot of the 
mean changes (±SE) in peak VO2 and in in VO2 at VAT from analysis set baseline over time will 
be displayed by treatment arm. A reference line is included at zero change and baseline is added 
to the time axis to visualize an initial change from zero.
In addition, for the RUBATO pool (FAS), Spaghetti plots will be presented by treatment arm to 
explore the longitudinal pattern of change from baseline in Peak VO2 and VO2 at VAT considering 
all the observed values (from scheduled or unscheduled assessments) and the actual assessment 
day in RUBATO pool.


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Peak VO2 and VO2 at VAT will be reported in a subject listing for the RUBATO pool (FAS). Each 
value will be flagged as assessed during OL or DB period. 
5.5.2.
Physical Activity Measure by Accelerometer
The daily physical activity (counts/min) of the subject is assessed via accelerometer during the 
daytime. In RUBATO DB, data are collected for 9 consecutive daily daytime periods after Visit 1, 
after the week 16 visit and before the week 52 visit (which may be selected as baseline for the 
RUBATO OLES). In RUBATO OL, data are collected for 9 consecutive daily daytime periods 
after the enrollment visit at Day 1 (mapped to analysis visit “OL Baseline”, if available considered 
baseline for the RUBATO OLES), and after the visits at weeks 26, 52, and 78 visit and before the 
week 104 visit.
The accelerometry central reading facility will read daily counts/min and will analyze duration of 
daily activity and time (minutes) which will be transferred to the Sponsor.
For all post baseline assessments during OL period, the 9-day time period is selected by taking the 
first (in chronological order) interval of 9 consecutive days with at least 4 complete daily time 
periods within the corresponding time window (i.e., the 9-day time period should not necessarily 
fall entirely in the corresponding time window, but it should overlap with the time window for at 
least 1 day). All assessments (including the unscheduled ones) will be mapped based on the Study 
Day in analysis set (see Section 5.1.1), irrespective of premature study treatment discontinuation 
before the assessment. To be considered evaluable, physical activity should have been measured 
for at least 4 complete daily daytime periods (out of 9 consecutive days) at a specific time point of 
assessment. For the RUBATO pool (FAS), the mean count per minute at analysis visits “DB 
Baseline”, “DB Week 16”, and “DB Week 52” is taken from the RUBATO DB ADaM.
To derive baseline mean count per minute of daily PA-Ac for the RUBATO OLES, the PA-Ac 
data from the OL visit 1 is considered. The 9-day time period is selected by taking the first (in 
chronological order) interval of 9 consecutive days with at least 4 complete daily time periods, at 
or after OL treatment start date up to 30 days after OL treatment start. To be considered evaluable, 
physical activity should have been measured for at least 4 complete daily daytime periods (out of 
9 consecutive days) at baseline. A complete day is defined as a record of at least 7 hours of daily 
daytime data.
The values used for the PA-Ac at baseline and each post-baseline assessment are based on data 
evaluation by the accelerometry central reading facility.
Mean counts per minute of daily PA-Ac are calculated by dividing the sum of all activity counts 
(Y axis) collected during wear time for a complete day by the number of minutes of wear time in 
that day across all valid days (at least 4 days out of 9 days). 
The activity counts collected during wear time is identifiable with “WearFilteredAxisYcounts” in 
Data Transfer Specifications (DTS); the number of minutes of wear time corresponds to the 
“WearMinutes “ variable in DTS.


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A complete day is defined as a record of at least 7 hours of daily daytime data, i.e., a complete day 
if “WearMinutes” >=7*60, (after excluding the periods when the device was apparently not worn
[Troiano 2008]). 
In summary, to compute the mean counts per minute of daily PA-Ac, it is necessary to identify all 
complete days; if less than 4 complete days out of 9 are identified then value is missing, otherwise, 
if at least 4 complete days out of 9 are identified, then the value is calculated on the complete days 
only. 
The following endpoint related to PA-Ac are defined:
!
change from analysis set baseline to each scheduled time point in mean count per minute of 
daily PA-Ac from analysis, derived as: 
Value at scheduled timepoint – Value at analysis set baseline
Mean count per minute of daily PA-Ac will be summarized displaying descriptive statistics for the 
observed values at baseline, for the observed value at each post-baseline assessment, and for the 
absolute changes from baseline to each post-baseline assessment in analysis sets RUBATO OLES 
and RUBATO pool (FAS). For the RUBATO pool (FAS), to graphically display changes, a plot 
of the mean changes (±SE) in mean count per minute of daily PA-Ac from analysis set baseline 
over time will be displayed by treatment arm. A reference line is included at zero change and 
baseline is added to the time axis to visualize an initial change from zero.
The following analysis visits/timepoints will be displayed for the RUBATO pool (FAS):
!
DB Baseline ( ~ analysis set baseline)
!
DB Week 16
!
DB Week 52
!
OL Baseline 
!
OL Week 26
!
OL Week 52
!
OL Week 78
!
OL Week 104
The following analysis visits/timepoints will be displayed for the OLES:
!
OL Baseline ( ~ analysis set baseline)
!
OL Week 26
!
OL Week 52
!
OL Week 78
!
OL Week 104


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In addition, for the RUBATO pool (FAS), spaghetti plots will be presented by treatment arm to 
explore the longitudinal pattern of change from baseline in mean count per minute of daily PA-Ac 
considering all the observed values (from scheduled or unscheduled assessments) and the actual 
assessment day in RUBATO pool.
PA-Ac data will be reported in a subject listing for the RUBATO pool (FAS). Each value will be 
flagged as assessed during OL or DB period.
5.5.3.
Fontan-palliated Clinical Worsening and Morbidity Events
The following clinical events endpoints are assessed based on the RUBATO pool (FAS) only:
!
Composite endpoint of events related to Fontan-palliated clinical worsening and, 
!
Composite endpoint of events related to Fontan-palliated morbidity.
The dates of occurrence of each component of the above two clinical events endpoints are reported 
in the eCRF. 
For each composite endpoint, a subject is considered as having an event if the investigator reports 
the occurrence of any of the individual component in the eCRF (data from RUBATO DB and 
RUBATO OL are pooled for this purpose), with an event date on or after the date of randomization. 
Subjects who did not experience an event will be right censored at EOS (as defined in 
Section 5.1.2.4).
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.
Composite endpoint of events related to Fontan-palliated clinical worsening 
The components of the composite endpoint of events related to Fontan-palliated clinical worsening
are the following (these are all assessed by the investigator and recorded in the eCRFs):
!
Unscheduled hospitalization for Fontan-palliated morbidity event.
!
Signs and symptoms of heart failure, requiring change in diuretic therapy.
!
Clinical worsening leading to interventions related to the Fontan-palliated condition.
!
Worsening to NYHA FC III, investigator assessed using the Specific Activity Scale.
!
Signs and symptoms requiring the addition of a new class of cardiovascular medication 
(e.g., nitrates, alpha-blockers, or Endothelin receptor antagonists (ERAs)), or insertion of a 
pacemaker.
!
Failing-Fontan defined as one or more of the following:
∀
Enlisted on the active list for heart transplantation or effective heart transplantation,


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∀
Reoperation (e.g., mechanical circulatory support, Fontan take down, Fontan revision / 
conversion, AV valve repair/replacement),
∀
Worsening to NYHA FC IV, investigator assessed using the Specific Activity Scale,
∀
Protein-losing enteropathy (PLE),
∀
Plastic bronchitis/chyloptysis,
∀
Peritoneal, pleural, mediastinal, or pericardial effusions,
∀
Severe hepatic impairment,
∀
Severe renal impairment,
∀
Death related to Failing-Fontan.
Clinical events are reported in “Clinical worsening events” section of the eCRF.
Composite endpoint of events related to Fontan-palliated morbidity.
The components of the composite endpoint of events related to Fontan-palliated morbidity are the 
following: 
!
Ventricular tachyarrhythmia or supraventricular tachyarrhythmia, 
!
Thrombotic or hemorrhagic complications (including thromboembolism and hemoptysis). 
Clinical events are reported in “Other Fontan-palliated morbidity events” section of the eCRFs.
For each of the two composite endpoints listed above the time to the clinical event will be analyzed, 
separately, using the Kaplan-Meier (KM) product limit method, providing estimates for each 
treatment arm and corresponding 95% two-sided CLs at DB weeks 26 and 52, and at OL Weeks 26, 
52, 78, 104, 130, 156. The CLs are constructed using Greenwood’s formula (Collett 2003) for the 
standard error of the Kaplan-Meier estimate and are added to the plot. The number of subjects at 
risk, censored, and with events will be computed and displayed at each time point for each group.
Data will be summarized in tables or figures, including: number of events, number of censored 
observations, number of subjects at risk, and KM estimates of the survival function for time-to-
event variables. 
The graph of the estimated survival function of the time to first composite clinical endpoint for 
each treatment arm obtained from the Kaplan-Meier product-limit method will be displayed up to 
the time at which at least 10% of all subjects remain at risk of an event. The graphical presentation 
follows the recommendations from (Pocock 2002).
Individual subject’s listings based on the RUBATO pool (FAS) will be provided for both 
composite endpoints (including details of all (i.e., not only first) individual component events) 
separately, indicating period (OL or DB period) at time of clinical event.


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5.6.
Other Analyses
5.6.1.
Definition of Subgroups and subgroup analyses
Table 7:
Table of Subgroups for Analyses
Subgroup
Definition
Age (as defined in Section 6.2)
! 12 - <18 years
! ≥18 years
The following analyses are presented by age subgroups in the same way as described above for 
the overall group:
!
Study Disposition (for OLES and TMAS)
!
Treatment Disposition (for OLES and TMAS)
!
Demographic Characteristics (for OLES and TMAS)
!
Baseline Characteristics (for OLES and TMAS)
!
Study Treatment Exposure (for RUBATO pool, OLES and TMAS)
!
Liver and Hemoglobin Abnormalities (for RUBATO pool Maci/Maci Arm, OLES and 
TMAS)
!
Descriptive statistics of vital signs by visit (for RUBATO and OLES)
!
Overall summary table of AEs (Any AE, related AE, SAE, related SAE, AE leading to 
premature discontinuation of study treatment, fatal AE, severe AE) (for RUBATO pool 
Maci/Maci Arm, OLES and TMAS)
!
Treatment-emergent AEs by SOC and PT within each SOC (for RUBATO pool Maci/Maci 
Arm, OLES and TMAS)
!
Treatment-emergent AEs by PT (for RUBATO pool Maci/Maci Arm, OLES and TMAS)
!
Treatment-emergent SAEs by SOC and PT within each SOC (for RUBATO pool Maci/Maci 
Arm, OLES and TMAS)
!
Treatment-emergent SAEs by PT (for RUBATO pool Maci/Maci Arm, OLES and TMAS)
!
AEs leading to premature discontinuation of study treatment by SOC and PT within each SOC
(for RUBATO pool Maci/Maci Arm, OLES and TMAS)
!
AEs leading to premature discontinuation of study treatment PT (for RUBATO pool 
Maci/Maci Arm, OLES and TMAS)
!
Treatment-emergent AESI by PT (for RUBATO pool Maci/Maci Arm, OLES and TMAS)
!
Number of subjects who died and primary cause of death (for RUBATO pool)


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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1: List of Abbreviations
AE
Adverse event
AESI
Adverse Events of Special Interest
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase
ATC
Anatomic Therapeutic Chemical
CPET
Cardiopulmonary Exercise Testing
CL
Confidence Limit
CSR
Clinical study report
DB
Double Blind
DTS
Data Transfer Specifications
eCRF
Electronic case report form
EOS
End-of-Study
EOT
End-of-Treatment
FAS
Full Analysis Set
FC 
Functional class
ICH
International Council on Harmonisation
LV
Left ventricle
MAR
Missing at random
MedDRA
Medical Dictionary for Regulatory Activities
NT-pro-BNP
n-terminal pro-brain natriuretic peptide
NYHA
New York Heart Association 
OL
Open Label
OLES
Open-label Extension analysis set
PA-Ac
Physical Activity measured by Accelerometer
PD
Protocol deviation
PT
Preferred Term
QTL
Quality Tolerance Limit
RV
Right ventricle
SAE
Serious adverse event
SAP
Statistical analysis plan
SE
Standard Error


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SD
Standard Deviation
SDTM
Study Data Tabulation Model 
SI
International system of units
SMQ
Standardised MedDRA Query
SOC
System organ class
SpO2
Peripheral oxygen saturation
SS
Safety Analysis Set
TCPC
Total cavopulmonary connection
TMAS
Total Macitentan analysis set
ULN
Upper limit of normal
VAT
Ventilatory anaerobic threshold
VO2
Oxygen uptake/consumption 
[V̇ O2 is a flow = a ratio of Volume of Oxygen by unit of time]
WHO
World Health Organization


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Status: Approved, Date: 17 December 2021
6.2.
Appendix 2: Changes to Protocol-Planned Analyses
This study was prematurely discontinued by the sponsor. Study results will be presented in an 
abbreviated CSR.  
While all safety data obtained will be summarized, only a subset of the protocol-specified efficacy 
endpoints and none of the protocol-specified pharmacoeconomic endpoints will be summarized. 
Due to the early termination of this long-term study, only key safety data (SAE, AEs leading to 
discontinuation, AESI) are presented adjusted for subject-years of observation. Subgroup analyses 
are limited to analyses by age-group.
6.3.
Appendix 3: Demographic and Baseline Characteristics
6.3.1.
Demographics
Demographic data will be presented for the RUBATO OLES and the RUBATO TMAS.
Weight, Height, Body Mass Index (BMI) will be taken/derived from the analysis set baseline.
Age and sex are collected on the RUBATO OL study Demographics page and used for the 
RUBATO OLES and for RUBATO TMAS subjects from the placebo arm in the RUBATO DB 
SS. For RUBATO TMAS subjects from the macitentan arm in the RUBATO DB SS, the RUBATO 
DB demographics page is used.
All other demographic variables are taken from the RUBATO DB demographics page.
Table 8 presents a list of the demographic variables that will be summarized RUBATO OLES and 
the RUBATO TMAS. Demographics will also be summarized by subgroups as defined in 
Section 5.6.1.
Table 8:
Demographic Variables
Continuous Variables:
Summary Type
Age 
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum], and IQ range).
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2)
Categorical Variables
Age (12– <18, 18– <30, 30–<40, 40-<65, %= 65)
Frequency distribution with the 
number and percentage of subjects 
in each category.
Sex (male, female)
Race (American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander, White, Other, Not 
Applicable)
Ethnicity (Hispanic or Latino, not Hispanic or Latino, Unknown)
Geographical region (America, Europe, Asia, Oceania)
Region (US, Non-US)
BMI ([underweight <18.5 kg/m2, normal 18.5-<25 kg/m2, overweight 25-
<30 kg/m2, obese class I 30-<35 kg/m2, obese class II 35-<40 kg/m2, obese
class III ≥40 kg/m2]) a
a Body Mass index BMI (kg/m2) is calculated in the eCRF for RUBATO DB, for RUBATO OL, it is derived as 
Weight (kg) / [Height (cm) / 100]2, rounded to one decimal as done in DB eCRF. For adolescents (boys or girls) 
between 12 and 18 years, BMI-for-age reference equivalent to BMI cutoffs for adults are calculated as provided 
in Attachment 1 of the RUBATO DB CSR SAP (EDMS-RIM-264216, 1.0).


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Status: Approved, Date: 17 December 2021
All demographic data will be reported in subject listings on the RUBATO OLES and the RUBATO 
TMAS.
6.3.2.
Baseline Disease Characteristics
Table 9 presents a list of baseline disease characteristics variables that will be summarized 
RUBATO OLES and the RUBATO TMAS.
Table 9:
Baseline Disease Characteristics
Continuous Variables:
Summary Type
Time since Fontan palliation completion (years) at treatment start in 
analysis set
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum], and IQ range).
Peak VO2 (mL/kg/min) at baseline at analysis set baseline
VO2 at VAT at baseline at analysis set baseline
Mean count per minute of daily Physical Activity at baseline at analysis set 
baseline
NT-proBNP (pmol/L) at analysis set baseline
Categorical Variables
Congenital heart defect leading to Fontan-palliation as recorded at DB 
study entry
Frequency distribution with the 
number and percentage of subjects 
in each category.
Dominant ventricular morphology (left and right/mixed) as recorded at DB 
study entry
Staged reconstructive surgeries performed before completion of the Fontan 
circulation as recorded at DB study entry
Type of primary TCPC Fontan completion as recorded at DB study entry
Type of secondary TCPC Fontan completion (TCPC=total cavopulmonary 
connection) as recorded at DB study entry
Fenestration Status as recorded at DB study entry
PAH specific therapies concomitant at start of study treatment in analysis 
set
NYHA FC at analysis set baseline
PAH specific therapies concomitant at start of study treatment in analysis set
!
PAH specific medications concomitant at start of study treatment in analysis set (see 
Section 6.5.3 for definition). Pulmonary hypertension specific medications are: sildenafil, 
sildenafil citrate, tadalafil, vardenafil, udenafil, iloprost, beraprost, epoprostenol, treprostinil, 
selexipag, bosentan, ambrisentan, riociguat.
All other variables that are presented, are based on data recorded at entry into study RUBATO DB 
will be derived as described in the RUBATO DB CSR SAP. The remaining variables are re-derived 
in the same manner as described in the RUBATO DB CSR SAP, based on the analysis set baseline 
(as defined in Section 5.1.2.1).


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Status: Approved, Date: 17 December 2021
All baseline disease characteristics variables will be reported in subject listings on the RUBATO 
OLES and the RUBATO TMAS.


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Status: Approved, Date: 17 December 2021
6.4.
Appendix 4: Protocol Deviations and Quality Tolerance Limits (QTL)
The description of each protocol deviation (PD) is agreed in the sponsor protocol deviation code 
list (PD list Version 3, dated 20-Apr-2021). According to this document, each PD is classified as 
important or not important. A further categorization into one of the following categories is 
documented in Table 10: Entered but did not satisfy criteria, Developed withdrawal/interruption 
criteria but not withdrawn/interrupted, Received a disallowed concomitant treatment, Received 
wrong treatment or incorrect dose, Other.
Only important (i.e., major) protocol deviations will be summarized by category, displaying counts 
and percentages of subjects with at least one PD within each category for the RUBATO OLES. A 
separate similar summary of important PDs will be provided by geographical region and site.
These summaries are provided for all important (i.e., major) PDs and separately for all COVID-
19 related important (i.e., major) PDs.
All reported PDs and all reported COVID-19 related PDs will be reported in subject listings. Both 
listings are provided for the RUBATO OLES, with important PDs flagged accordingly.
Table 10:
PD Classification Based on AC-055H302 (RUBATO OL) 
Condition
Identifier
Important
Categorization of PD for 
reporting
Subject not enrolled but received study drug
PD_MM.101
Yes
Received wrong treatment 
or incorrect dose
Informed consent not personally signed and dated by subject 
/legal representative 
PD_MM.102
Yes
Other
Study assessments were performed but no informed consent was 
signed and dated by subject/legal representative.
PD_MM.103
Yes
Other
Informed consent process (including re-consenting) not followed
PD_MM.104
Yes
Other
Subject enrolled but did not complete Week 52 of RUBATO DB
PD_MM.132
Yes
Entered but did not satisfy 
criteria
Woman of childbearing potential who did not have a negative 
serum pregnancy test prior to first intake of OL study drug 
PD_MM.133
Yes
Entered but did not satisfy 
criteria
Other violation before enrollment not listed above
PD_MM.105
No
Other
Woman of childbearing potential who did not agree to perform 
monthly pregnancy tests up to the end of the S-FU period
PD_MM.134
Yes
Entered but did not satisfy 
criteria
Woman of childbearing potential who did not agree to use reliable 
contraception from enrollment and up to at least 30 days after 
study drug discontinuation
PD_MM.135
Yes
Entered but did not satisfy 
criteria
Clinical worsening leading to medical interventions including 
reoperation of Fontan circulation during the enrollment period
PD_MM.136
Yes
Entered but did not satisfy 
criteria
Systolic BP < 90 mmHg (< 85 mmHg for subjects < 18 years old and 
< 150 cm of height) at rest
PD_PM.325
Yes
Entered but did not satisfy 
criteria
Hemoglobin < 75% of the lower limit of normal assessed by 
central laboratory at enrollment
PD_PM.326
Yes
Entered but did not satisfy 
criteria
Known or suspected pulmonary veno-occlusive disease
PD_MM.137
Yes
Entered but did not satisfy 
criteria
Known and documented severe hepatic impairment defined as 
Child-Pugh Score C
PD_MM.138
Yes
Entered but did not satisfy 
criteria
Serum AST and/or ALT > 3 x upper limit of normal range assessed 
by central laboratory at enrollment
PD_PM.327
Yes
Entered but did not satisfy 
criteria
Severe renal impairment (estimated creatinine clearance < 30 
mL/min/1.73m2) assessed by central laboratory at enrollment
PD_PM.328
Yes
Entered but did not satisfy 
criteria


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Condition
Identifier
Important
Categorization of PD for 
reporting
Hypersensitivity to any active substance or excipient of any of the 
study drugs
PD_MM.139
Yes
Entered but did not satisfy 
criteria
Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer 
within 1 month prior to enrollment (Visit 1)
PD_MM.140
Yes
Entered but did not satisfy 
criteria
Treatment with a strong CYP3A4 inhibitor within 1 month prior to 
enrollment (Visit 1)
PD_MM.141
Yes
Entered but did not satisfy 
criteria
Treatment with a moderate dual CYP3A4/CYP2C9 inhibitor (e.g.,
fluconazole, amiodarone) or co-administration of a combination 
of moderate CYP3A4 and moderate CYP2C9 inhibitors within 1 
month prior to enrollment (Visit 1)
PD_MM.142
Yes
Entered but did not satisfy 
criteria
Any factor or condition likely to affect protocol compliance of the 
subject, as judged by the investigator
PD_MM.143
Yes
Entered but did not satisfy 
criteria
Treatment with another investigational therapy during the OL 
study
PD_MM.144
Yes
Entered but did not satisfy 
criteria 
Treatment with ERAs other than macitentan
PD_MM.145
Yes
Entered but did not satisfy 
criteria
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
PD_MM.146
Yes
Entered but did not satisfy 
criteria
Any planned surgical intervention (e.g., organ transplant) during 
the study period, except minor interventions (e.g., tooth 
extraction)
PD_MM.147
Yes
Entered but did not satisfy 
criteria
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.
PD_MM.148
Yes
Entered but did not satisfy 
criteria
PA-Ac device not correctly assigned or initiated at enrollment
PD_MM.149
Yes
Other
Subject not contacted to remind them to wear PA-Ac device
PD_MM.150
No
Other
Enrollment assessment not done/missing
PD_PP.202
Yes
Other
Pregnancy testing at enrollment not done
PD_PM.301
Yes
Other
Entry enrollment labs are > 4 weeks after EOT Visit in AC-055H301 
RUBATO DB
PD_PM.302
Yes
Other
Study drug not withheld prior to assessments at enrollment visit
PD_MM.106
No
Other
CPET at Visit 1 conducted under different conditions than during 
the AC-055H301 RUBATO DB study
PD_MM.107
No
Other
CPET at Visit 1 done, but not valid/questionable on review by 
central reading facility
PD_MM.108
No
Other
CPET at Visit 1 not done according to guidelines and central reader 
manual
PD_MM.109
No
Other
CPET at Visit 1 not done (but required)
PD_MM.151
No
Other
SAE not reported within 24 hours of knowledge, or not reported 
as per protocol
PD_MM.110
Yes
Other
Other violation at enrollment not listed above
PD_MM.111
No
Other
Subject has no post-baseline safety assessment
PD_PM.303
Yes
Other
Subject has no post-baseline efficacy assessment
PD_PM.304
Yes
Other
PA-AC device not returned/device lost/issues with upload
PD_MM.152
No
Other


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Condition
Identifier
Important
Categorization of PD for 
reporting
Subject does not have sufficient PA-Ac baseline data
PD_PM.305
No
Other
Visit 2 assessment not done/missing
PD_PP.203
Yes
Other
Visit 2 vital signs assessed under different conditions than at 
baseline
PD_MM.116
No
Other
Visit 2 labs missing/incomplete
PD_PM.306
Yes
Other
Study drug not withheld prior to assessments at Visit 2
PD_MM.117
No
Other
PA-Ac device not correctly assigned or initiated at Visit 2
PD_MM.153
No
Other
Subject does not have sufficient PA-Ac data at Visit 2
PD_PM.329
No
Other
Subject not contacted to remind them to wear PA-Ac device
PD_MM.154
No
Other
PA-Ac device not returned/lost device/upload problems
PD_MM.155
No
Other
CPET at Visit 3 conducted under different conditions than at 
baseline
PD_PM.307
No
Other
CPET at Visit 3 done, but not valid/questionable on review by 
central reading facility
PD_PM.308
No
Other
CPET at Visit 3 not done according to guidelines and central reader 
manual
PD_MM.118
No
Other
CPET at Visit 3 not done
PD_PP.204
No
Other
Visit 3 assessment not done/missing
PD_PP.205
Yes
Other
Visit 3 vital signs assessed under different conditions than at 
baseline
PD_MM.119
No
Other
Subject does not have sufficient PA-Ac data at Visit 3
PD_PM.309
No
Other
Visit 3 labs missing/incomplete
PD_PM.310
Yes
Other
Study drug not withheld prior to assessments at Visit 3
PD_MM.120
No
Other
Visit 4 assessment not done/missing
PD_PP.206
Yes
Other
Visit 4 vital signs assessed under different conditions than at 
baseline
PD_MM.121
No
Other
Subject does not have sufficient PA-Ac data at Visit 4
PD_PM.311
No
Other
Visit 4 labs missing/incomplete
PD_PM.312
Yes
Other
Study drug not withheld prior to assessments at Visit 4
PD_MM.122
No
Other
Visit 5 assessment not done/missing
PD_PP.207
Yes
Other
CPET at Visit 5 conducted under different conditions than at 
baseline
PD_PM.313
No
Other
CPET at Visit 5 done, but not valid/questionable on review by 
central reading facility
PD_MM.123
No
Other
CPET at Visit 5 not done according to guidelines and central reader 
manual
PD_MM.124
No
Other
CPET at Visit 5 not done
PD_PP.208
No
Other
Visit 5 vital signs assessed under different conditions than at 
baseline
PD_MM.125
No
Other


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Status: Approved, Date: 17 December 2021
Condition
Identifier
Important
Categorization of PD for 
reporting
Subject does not have sufficient PA-Ac data at Visit 5
PD_PM.314
No
Other
Visit 5 labs missing/incomplete
PD_PM.315
Yes
Other
Study drug not withheld prior to assessments at Visit 5 
PD_MM.126
No
Other
Visit 6 assessment not done/missing
PD_PP.214
Yes
Other
Visit 6 vital signs assessed under different conditions than at 
baseline
PD_MM.171
No
Other
Visit 6 labs missing/incomplete
PD_PM.332
Yes
Other
Study drug not withheld prior to assessments at Visit 6
PD_MM.172
No
Other
Visit 7 assessment not done/missing
PD_PP.215
Yes
Other
CPET at Visit 7 conducted under different conditions than at 
baseline
PD_PM.333
No
Other
CPET at Visit 7 done, but not valid/questionable on review by 
central reading facility
PD_MM.173
No
Other
CPET at Visit 7 not done according to guidelines and central reader 
manual
PD_MM.174
No
Other
CPET at Visit 7 not done
PD_PP.216
No
Other
Visit 7 vital signs assessed under different conditions than at 
baseline
PD_MM.175
No
Other
Visit 7 labs missing/incomplete
PD_PM.334
Yes
Other
Study drug not withheld prior to assessments at Visit 7
PD_MM.176
No
Other
Visit 8 assessment not done/missing
PD_PP.217
Yes
Other
Visit 8 vital signs assessed under different conditions than at 
baseline
PD_MM.177
No
Other
Visit 8 labs missing/incomplete
PD_PM.335
Yes
Other
Study drug not withheld prior to assessments at Visit 8
PD_MM.178
No
Other
Visit 9 assessment not done/missing
PD_PP.218
Yes
Other
CPET at Visit 9 conducted under different conditions than at 
baseline
PD_PM.336
No
Other
CPET at Visit 9 done, but not valid/questionable on review by 
central reading facility
PD_MM.179
No
Other
CPET at Visit 9 not done according to guidelines and central reader 
manual
PD_MM.180
No
Other
CPET at Visit 9 not done
PD_PP.219
No
Other
Visit 9 vital signs assessed under different conditions than at 
baseline
PD_MM.181
No
Other
Visit 9 labs missing/incomplete
PD_PM.337
Yes
Other
Study drug not withheld prior to assessments at Visit 9
PD_MM.182
No
Other
Initiation of forbidden medication
PD_PM.338
Yes
Received a disallowed 
concomitant treatment
Aminotransferase elevation ≥ 3 x ULN and study drug not 
interrupted or discontinued
PD_PM.316
Yes
Developed 
withdrawal/interruption 


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Condition
Identifier
Important
Categorization of PD for 
reporting
criteria but not 
withdrawn/interrupted
Aminotransferase elevation ≥ 3 x ULN and retests not done per 
protocol
PD_PM.317
Yes
Other
Hemoglobin < 100 g/L with a decrease from baseline of ≥ 50 g/L 
and retest not done per protocol
PD_PM.318
Yes
Other
Hemoglobin < 80 g/L with no underlying blood loss and study 
treatment not interrupted 
PD_PM.319
Yes
Developed 
withdrawal/interruption 
criteria but not 
withdrawn/interrupted
Re-introduction of treatment before a) Aminotransferases 
returned to pre-treatment or normal range b) Hemoglobin 
returned to pre-treatment or normal range
PD_PM.320
Yes
Developed 
withdrawal/interruption 
criteria but not 
withdrawn/interrupted
Blood pressure dropped < 90 mm Hg (< 85 mm Hg for subjects < 
18 years old and < 150 cm of height and study drug not 
interrupted
PD_PM.321
Yes
Developed 
withdrawal/interruption 
criteria but not 
withdrawn/interrupted
Subject got pregnant during the treatment period or within 30 
days after treatment discontinuation
PD_PM.322
Yes
Other
Subject got pregnant and study drug was not interrupted
PD_PM.330
Yes
Developed 
withdrawal/interruption 
criteria but not 
withdrawn/interrupted
Woman of childbearing potential not using reliable contraception
PD_PM.323
Yes
Other
Pregnancy test was missed
PD_MM.156
Yes
Other
CPET performed out of window of last QA (> 213 days since last 
QA)
PD_MM.127
No
Other
ECHOC not performed according to guidelines
PD_MM.128
No
Other
Subject received treatment which was not approved for use
PD_MM.157
Yes
Other
Study treatment compliance between 2 visits < 80% or > 120% 
PD_PM.324
Yes
Received wrong treatment 
or incorrect dose
Overall study treatment compliance for the whole treatment 
period < 80% or > 120% 
PD_MM.158
Yes
Received wrong treatment 
or incorrect dose
Study treatment compliance based on subject's report
PD_MM.183
No
Received wrong treatment 
or incorrect dose
Study medication not stored correctly but subject continued to 
use it
PD_MM.129
Yes
Received wrong treatment 
or incorrect dose
Study treatment not administered as per protocol (any dose of 
study treatment higher than the planned total daily dose in a 
single day will be considered an overdose)
PD_MM.159
Yes
Received wrong treatment 
or incorrect dose
Subject treatment not discontinued although subject (legally 
acceptable representative) decided not to continue treatment
PD_MM.160
Yes
Developed 
withdrawal/interruption 
criteria but not 
withdrawn/interrupted
Subject medication not discontinued although investigator 
considers that the subject should not continue treatment
PD_MM.161
Yes
Developed 
withdrawal/interruption 
criteria but not 
withdrawn/interrupted
Sponsor decision to withdraw subject or terminate study and 
subject was not discontinued within the time indicated by the 
sponsor
PD_MM.162
Yes
Developed 
withdrawal/interruption 
criteria but not 
withdrawn/interrupted


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Status: Approved, Date: 17 December 2021
Condition
Identifier
Important
Categorization of PD for 
reporting
Visit 2 performed out of window (Day 183 ± 7 days)
PD_PP.209
No
Other
Visit 3 performed out of window (Day 365 ± 7 days)
PD_PP.210
No
Other
Visit 4 performed out of window (Day 547 ± 7 days)
PD_PP.211
No
Other
Visit 5 performed out of window (Day 729 ± 7 days)
PD_PP.212
No
Other
Visit 6 performed out of window (Day 911 ± 7 days)
PD_PP.220
No
Other
Visit 7 performed out of window (Day 1093 ± 7 days)
PD_PP.221
No
Other
Visit 8 performed out of window (Day 1275 ± 7 days)
PD_PP.222
No
Other
Visit 9 performed out of window (Day 1457 ± 7 days)
PD_PP.223
No
Other
Visit EOS performed out of window (EOS + 30-35 days)
PD_PP.213
No
Other
6-monthly visit performed out of window
PD_MM.163
No
Other
FU-visit performed out of window
PD_MM.164
No
Other
Visit was performed remotely/partly remotely
PD_MM.165
No
Other
SAE not reported within 24 hours of knowledge, or not reported 
as per protocol
PD_MM.130
Yes
Other
CPET data not sent to central reading facility within 5 working 
days
PD_MM.166
No
Other
Monthly lab performed out of window
PD_PM.331
No
Other
Monthly lab sample missing 
PD_MM.167
Yes
Other
Consecutive lab samples missing/not available without 
replacement/local labs being done 
PD_MM.168
Yes
Other
Oversampling during lab assessments
PD_MM.169
Yes
Other
Lab report not signed within 5 days of receipt
PD_MM.170
No
Other
Other violation during treatment period and follow-up not listed 
above
PD_MM.131
No
Other


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During the course of this long-term safety study, two quality tolerance criteria were defined as 
shown in table 11 below. Both are related to participants' safety.
Table 11:
Quality Tolerance Limits as per Integrated Analytical Risk-Based Monitoring Plan
Critical to Quality Factor
Parameter
Primary Threshold
Captured in PD/PD 
category
Subjects who meet at least one of 
the study specific discontinuation 
criteria must be permanently 
discontinued.
% subjects not 
discontinued according to 
protocol safety criteria.
10% subjects not discontinued 
according to protocol safety 
criteria. Special attention in the 
first 6 months of treatment 
(because of placebo roll over 
patients)
Developed 
withdrawal/interruption 
criteria but not 
withdrawn/interrupted
Safety laboratory must be done 
per time and events schedule in 
the protocol.
% of subjects with 2 
missing consecutive safety 
lab tests and % of missing 
safety lab test.
10 % of subjects with 2 missing 
consecutive safety lab tests
PD_MM.168


ACT-064992 / JNJ-67896062 (macitentan)
Statistical Analysis Plan AC-055H302/RUBATO-OL; Phase 3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
49
Status: Approved, Date: 17 December 2021
6.5.
Appendix 5: Prior and Concomitant Medications
All therapies as collected in the “Previous/Concomitant Medication” eCRF form of the two studies 
RUBATO DB and RUBATO OL will be pooled for the RUBATO OLES and the RUBATO 
TMAS. 
The original terms used by the investigators to describe therapies are assigned preferred terms for 
classification and tabulation using the latest version of the World Health Organization (WHO)
Drug code and Anatomic Therapeutic Chemical (ATC) class code dictionaries.
6.5.1.
Prior Medications
Prior medications are defined as any therapy with an end date prior to the date of first intake of 
study medication in the analysis set. 
If the end date is missing and the start date is prior to the date of first intake of study medication 
in the analysis set, and 
!
the checkbox for the question ‘Ongoing at start of treatment?’ is ticked ‘No’ on the RUBATO 
DB eCRF form, then the therapy is considered as previous for all subjects in the RUBATO 
OLES and the RUBATO TMAS. 
!
the checkbox for the question ‘Ongoing at start of treatment?’ is ticked ‘No’ on the RUBATO 
OL eCRF form, then the therapy is considered as previous in the RUBATO OLES for all 
subjects and in the RUBATO TMAS for subjects from the placebo arm in the RUBATO DB 
(SS). In the RUBATO TMAS it is considered concomitant for subjects from the macitentan 
arm in the RUBATO DB (SS) unless the same record (i.e., same therapy, same start date, 
missing end date, ‘Ongoing at start of treatment?’ ticked ‘No’) is also documented in the DB 
eCRF. In this case it is also considered previous for the RUBATO TMAS. 
6.5.2.
Concomitant Medications 
Concomitant medications are all therapies that are ongoing at, and/or initiated before date of first 
intake of study medication in the analysis set and terminated after the date of first intake of study 
medication in the analysis set, or initiated on or after the date of first intake of study medication in 
the analysis set up to the date of EOT in the analysis set.
Number and percentages of subjects having taken at least one medication will be presented by 
Anatomic Therapeutic Chemical (ATC) class (level 4) and PT within each ATC class for the 
RUBATO OLES and the RUBATO TMAS. All summaries will be tabulated by ATC class, and 
individual preferred terms within each ATC class. ATC classes will be sorted by descending order. 
For the summaries on the RUBATO OLES, sorting is done considering the arms in the following 
sequence: OL Macitentan 10 mg, DB-Macitentan 10 mg, DB-Placebo. If the frequencies of ATC 
class are the same, alphabetical order will be used. The same rule applies for preferred terms within 
ATC class.


ACT-064992 / JNJ-67896062 (macitentan)
Statistical Analysis Plan AC-055H302/RUBATO-OL; Phase 3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
50
Status: Approved, Date: 17 December 2021
Subjects who took the same medication more than once (as qualified by the same PT(s)) are 
counted only once. In case the reported medication is assigned to several PTs, subjects are counted 
for each individual PT.
All medications will be reported in a subject listing including all subjects with flags to identify 
prior and concomitant medications accordingly, on the RUBATO OLES and the RUBATO 
TMAS. This listing is repeated in the subset of subjects who had any COVID-19 related AE.
6.5.3.
Concomitant Medications at Start of Study Treatment in Analysis Set
Concomitant therapies at start of treatment in analysis set is any treatment that is either ongoing at 
the start of study treatment or is initiated at the start date of study treatment, identified as follows:
!
‘Ongoing at start of treatment? = Yes’ ticked by the investigator in the eCRF*,
or
!
Start date before or on analysis set treatment start date and end date on or after treatment start 
date,
or
!
Start date before or on analysis set treatment start date and end date missing with ‘Ongoing at 
start of treatment?’ ≠ No’ in the eCRF*.
* Based on the RUBATO OL “Previous/Concomitant Medication” eCRF form for OLES and 
for RUBATO TMAS subjects from the placebo arm in the RUBATO DB SS.
Based on the RUBATO DB “Previous/Concomitant Medication” eCRF form for RUBATO 
TMAS subjects from the macitentan arm in the RUBATO DB SS. 


ACT-064992 / JNJ-67896062 (macitentan)
Statistical Analysis Plan AC-055H302/RUBATO-OL; Phase 3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
51
Status: Approved, Date: 17 December 2021
6.6.
Appendix 6: Intervention Compliance
Not applicable. Only percentage of days with study treatment exposure (excluding interruptions) 
of the duration of exposure (including interruptions) are reported as described in Section 5.3.


ACT-064992 / JNJ-67896062 (macitentan)
Statistical Analysis Plan AC-055H302/RUBATO-OL; Phase 3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
52
Status: Approved, Date: 17 December 2021
6.7.
Appendix 7: Adverse Events of Special Interest and COVID-19 related AEs
Adverse events of special interest are defined as follows:
I. 
Hepatic events of special interest
AEs are included in this grouping if their coded PTs are included in the “Hepatic disorders” SMQ 
with including all its sub-SMQ with the exception of “Liver-related coagulation and bleeding 
disturbances (SMQ)”.
II. 
Edema and fluid retention
AEs are included in this subgroup if their coded PTs is “Pulmonary congestion” or if within the 
SMQ “Haemodynamic oedema, effusions and fluid overload (SMQ)” with the exception of PTs 
containing “site”.
III. 
Anemia / hemoglobin decrease
AEs are included in this grouping if their coded PTs are included in the SMQs “Haematopoietic 
erythropenia” OR “Haematopoietic cytopenias affecting more than one type of blood cell (SMQ)”
(with the exception of two unspecific PTs: “blood disorder”, “blood count abnormal”) OR an event 
with any MedDRA PT containing the text “anaemia”.
IV. 
Hypotension
AEs are included in this grouping if their coded PTs are: Blood pressure ambulatory decreased,
Blood pressure decreased, Blood pressure diastolic decreased, Blood pressure immeasurable, 
Blood pressure orthostatic decreased, Blood pressure systolic decreased, Blood pressure systolic 
inspiratory decreased, CT hypotension complex, Diastolic hypotension, Hypotension, Mean 
arterial pressure decreased, Neonatal hypotension, Orthostatic hypotension, Procedural 
hypotension, Dialysis hypotension, Hypotensive crisis, Post procedural hypotension.
List of COVID-19 related AEs
AEs are considered as COVID-19 related if their coded PTs are: Asymptomatic COVID-19, 
Congenital COVID-19, Coronavirus infection, Coronavirus test positive, COVID-19, COVID-19 
immunisation, COVID-19 pneumonia, COVID-19 prophylaxis, COVID-19 treatment, Exposure 
to SARS-CoV-2, Multisystem inflammatory syndrome in children, Occupational exposure to 
SARS-CoV-2, Post-acute COVID-19 syndrome, SARS-CoV-2 antibody test positive, SARS-
CoV-2 carrier, SARS-CoV-2 RNA decreased, SARS-CoV-2 RNA fluctuation, SARS-CoV-2
RNA increased, SARS-CoV-2 sepsis, SARS-CoV-2 test false negative, SARS-CoV-2 test 
positive, SARS-CoV-2 viraemia, Suspected COVID-19, Vaccine derived SARS-CoV-2 infection, 
Antiviral prophylaxis, Antiviral treatment, Coronavirus test, Coronavirus test negative, COVID-
19 screening, Exposure to communicable disease, Pneumonia viral, SARS-CoV-2 antibody test, 
SARS-CoV-2 antibody test negative, SARS-CoV-2 RNA, SARS-CoV-2 RNA undetectable, 
SARS-CoV-2 test, SARS-CoV-2 test false positive, SARS-CoV-2 test negative.


ACT-064992 / JNJ-67896062 (macitentan)
Statistical Analysis Plan AC-055H302/RUBATO-OL; Phase 3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
53
Status: Approved, Date: 17 December 2021
7.
REFERENCES
(CTCAE 2010) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
Published: May 28, 2009 (v4.03: June 14, 2010) U.S. Department of Health And Human 
Services. National Institutes of Health National Cancer Institute. 
(Collett 2003) Modelling Survival Data in Medical Research, 2nd Edition. Chapman & Hall; 2003. 
(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. 
(Troiano 2008) Troiano RP, Berrigan D, Dodd KW, Mâsse LC, Tilert T, McDowell M. Physical 
activity in the United States measured by accelerometer. Med Sci Sports Exerc. 
2008;40(1):181-8.

Prot_000.pdf: 
Actelion Pharmaceuticals Ltd 
(a Janssen Pharmaceutical Company 
of Johnson and Johnson)* 
Confidential – FOIA Exemptions Apply in U.S. 
Macitentan / ACT 064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H302 
RUBATO OL 
Prospective, multi-center, single-arm, open-label long-term study assessing the 
safety, tolerability, and effectiveness of macitentan in Fontan-palliated adult and 
adolescent subjects 
Study Phase: 
3 
EudraCT Number: 
2018-002821-45 
Status and version: 
Final Version 4 
Date: 
19 November 2020 
Document type: 
Amended Global protocol 
Actelion 
document 
number 
(Doc No.): 
D-20.426
*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. 
NCT03775421


Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H302, RUBATO OL 
Version 4 
19 November 2020, page 2/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
SPONSOR CONTACT DETAILS 
Sponsor 
 
Actelion Pharmaceuticals Ltd 
Gewerbestrasse 16 
CH-4123 Allschwil 
Switzerland 
 
+
 
Clinical Trial Physician  
Contact details of the Clinical Trial Physician can 
be found in the Investigator Site File 
Medical Emergency Hotline 
Toll phone number:  
+
 
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 
 
Consultant Cardiologist 
 
Queen Elizabeth Hospital Birmingham 
B15 2TH, UK 
 
 
PPD
PPD
PPD


Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H302, RUBATO OL 
Version 4 
19 November 2020, page 3/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
CONTRACT RESEARCH ORGANIZATION INFORMATION 
 
CENTRAL LABORATORY 
 
Covance, Inc. / 8211 SciCor Drive, 
Indianapolis, IN 46214, USA 
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 
A list of site-specific contact details for Contract Research Organizations (CROs) can 
be found in the Investigator Site File. 
 
 
 




Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H302, RUBATO OL 
Version 4 
19 November 2020, page 5/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
INVESTIGATOR SIGNATURE PAGE 
Treatment name / number:  
Macitentan / ACT 064992 
Indication 
 
 
 
Macitentan in Fontan-palliated subjects 
Protocol number, study acronym, study title 
AC-055H302, RUBATO OL: Prospective, multi-center, single-arm, open-label extension 
study assessing the safety, tolerability, and effectiveness 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 
Town 
Date 
 
Signature 
Principal 
Investigator 
 
 
 
 
 
 
 


Macitentan / ACT-064992 
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Version 4 
19 November 2020, page 6/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment 3, Version 4 
19 November 2020 
Amendment 2, Version 3 
16 July 2020 
Amendment 1, Version 2 
20 February 2019 
Original Protocol, Version 1 
16 July 2018 
 
Amendment 3 (19 November 2020) 
Overall Rationale for the Amendment: The purpose of this amendment is to align the 
study protocol with updates made for the AC-055H301 RUBATO study. Countries who 
did not enroll candidates for RUBATO OL during the RUBATO study were removed from 
the section on acceptable methods of contraception. Study treatment supply and storage 
information was simplified as part of the Actelion and Janssen integration. 
The study duration is being adapted to help ensure treatment with macitentan is available 
after the expected treatment duration of 2 years per patient. Additionally, global safety 
updates were made to align the protocol with Janssen processes as part of the Actelion and 
Janssen integration. Furthermore, based on recent literature [Udholm 2018] on the 
potential prognostic value of cardiopulmonary exercise testing (CPET) in Fontan-palliated 
patients, the Sponsor added two new exploratory efficacy endpoint variables that have not 
been collected thus far but were already part of the CPET assessments evaluated by the 
central reading facility. One of these variables, oxygen update/consumption (VO2) at 
ventilatory anaerobic threshold (VAT), has also been claimed [Goldberg 2019] to be of 
interest in a recently completed study with a phosphodiesterase 5 inhibitor (PDE5i). 
Finally, an appendix was added to facilitate evaluation of exclusion criterion 3.3.  
A Protocol Amendment Summary of Changes Table for the current amendment is provided 
below. 
Section number 
and Name 
Description of Change 
Brief Rationale 
3.1.1 Study periods 
Update of treatment period definition 
to state that 104 weeks of study 
treatment for each subject refers to 
after the last participant has completed 
the AC-055H301 treatment period 
 
The safety follow-up period definition 
was updated to state that subjects 
could enter a post-trial access program 
Updated to clarify treatment 
period definition. 
 
 
Updated to clarity when 
subjects could enter the 
post-trial access program. 


Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H302, RUBATO OL 
Version 4 
19 November 2020, page 7/118 
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Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
Section number 
and Name 
Description of Change 
Brief Rationale 
as soon as their eligibility had been 
confirmed. 
 
Statement added that no S-FU will be 
performed for subjects entering the 
post-trial access program. 
 
 
Updated for clarity. 
3.1.2 Study duration 
Updated to state that the study will 
continue until the last subject has 
completed 104 weeks of treatment and 
their S-FU period. 
Updated for clarity. 
4.4 Exclusion criteria 
Footnote 4 added. 
 
Added for clarity. 
4.5.2.1 Denmark, Germany, and 
UK 
Removal of Germany from the 
subheading. 
No longer applicable to this 
study 
4.5.2.2 Czech Republic, and 
Poland 
Removal of Ireland from the 
subheading. 
No longer applicable to this 
study. 
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.  
5.1.6 Study treatment supply 
Location of study drug manufacture 
sites removed. 
Information removed to 
allow greater flexibility. 
5.1.6.2.2 
Study 
treatment 
storage 
Specific temperature range for study 
drug storage removed. Highly detailed 
information regarding study drug 
storage temperature regulations and 
deviation reporting requirements 
removed. 
Superfluous information 
removed for clarity. 
5.1.10.1 Liver aminotransferase 
abnormalities; 7.2.4.1 Type of 
laboratory; 9.1 Definition of 
adverse events; 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. 
6.1 Efficacy endpoints 
Inclusion of change in VO2 at VAT 
and change in oxygen update 
efficiency slope. 
Added two exploratory 
efficacy endpoint variables 
as an alignment with the 
RUBATO study. 
7.1.1 Enrollment 
Information added regarding re-
consenting of participants. 
Added for clarity. 


Macitentan / ACT-064992 
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Protocol AC-055H302, RUBATO OL 
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19 November 2020, page 8/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
Section number 
and Name 
Description of Change 
Brief Rationale 
7.1.2 Unscheduled visits 
Table 2 updated to add visit 5 and add 
footnote 11. Additional text was 
added to footnotes 3 and 9 for clarity. 
Table updated to state the 
changes in the study 
duration. 
7.2.2.1 
Cardiopulmonary 
exercise testing 
Information about determination of 
VO2 at VAT and OUES is updated 
and corresponding reference is cited. 
Updated as new efficacy 
endpoints were added 
during this amendment. 
7.2.2.3 
NT-proBNP 
measurement 
Assessments at Visits 3 to 5 replaced 
with assessments at every 26 week 
visit. 
Updated to reflect changes 
in study duration. 
7.2.4 Laboratory assessments 
Aminotransferase and hemoglobin 
tests at weeks 39, 65, and 91 replaced 
with assessments every 12 weeks. 
Updated to reflect changes 
in study duration. 
7.2.4.1 Type of laboratory 
"Actelion Pregnancy Form" updated 
to Pregnancy Notification Form". 
Updated to align with 
Janssen processes. 
8.1 Study completion as per 
protocol 
Included that study completion will 
occur after the last subject has had 
2 years of treatment. Additional 
clarifications regarding the S-FU visit 
were added. 
Updated to reflect changes 
in study duration. 
8.2 Premature withdrawal from 
study 
Inclusion of locator agencies. 
Information added for 
clarity. 
9 
Safety 
definitions 
and 
reporting requirements 
Introductory paragraph moved from 
section 9.5 to this location and 
modified to cover all AEs. 
Updated for clarity and 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. 
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 
Text added defining sponsor 
responsibilities relating to AE and 
SUSAR reporting. 
Included 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" 
 
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 


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Protocol AC-055H302, RUBATO OL 
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Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
Section number 
and Name 
Description of Change 
Brief Rationale 
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 added. 
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 moved from 9.5.2 to 9.7. 
Updated to align with 
Janssen processes. 
Synopsis; 
10.2.1 Efficacy variables 
VO2 at VAT, OUES added. 
Updated as these efficacy 
endpoints were added 
during this amendment 
10.2.2 Safety variables; 10.2.2.1 
Adverse events 
Removal of respiratory tract 
infections from AEs of special 
interest. 
Removed as not considered 
an AESI for macitentan. 
10.3.2 Sub-group analyses 
Subgroup analyses based on age (<18; 
≥ 18 and < 65 and ≥ 65 years) and 
race (White, Asian, Other) & 
Ethnicity (Hispanic / Non-Hispanic) 
will not be conducted and hence 
deleted. Race (White, Asian, Other) & 
Ethnicity (Hispanic / Non-Hispanic). 
 
Removed to align with 
RUBATO DB protocol. 
13 References 
References added. 
Added to support reference 
included in the text. 
Appendix 6 
Comparison 
of RUBATO OL procedures 
versus 
standard 
of 
care: 
comparison of burden and risks 
 
Frequency of liver function related 
common blood parameter assessments 
updated from every 3 months until 
Week 104 to every 12 weeks until 
EOT. 
Updated to reflect changes 
in study duration. 
Appendix 
7 
Child-Pugh 
Classification 
Appendix Added. 
Added as an aid to correctly 
evaluate exclusion criterion 
3.3. 
Abbreviations: IMP=investigational medicinal product; PQC=Product quality complaint;  
SUSAR= Suspected unexpected serious adverse reaction. 
 
 
 
 


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Version 4 
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Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
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 ..........................................................16 
PROTOCOL SYNOPSIS AC-055H302 RUBATO OL ....................................................19 
PROTOCOL ......................................................................................................................27 
1 
BACKGROUND .........................................................................................................27 
1.1 
Indication ......................................................................................................27 
1.2 
Study treatment .............................................................................................27 
1.2.1 
Macitentan ........................................................................................27 
1.2.2 
Physico-chemical properties of macitentan ......................................28 
1.3 
Purpose and rationale of the study ................................................................28 
1.4 
Summary of known and potential risks and benefits ....................................29 
2 
STUDY OBJECTIVES ...............................................................................................30 
2.1 
Primary objective ..........................................................................................30 
2.2 
Secondary objectives ....................................................................................31 
2.3 
Other objectives ............................................................................................31 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................31 
3.1 
Study design .................................................................................................31 
3.1.1 
Study periods ....................................................................................31 
3.1.2 
Study duration ...................................................................................34 
3.2 
Study design rationale ..................................................................................34 
3.3 
Study committees .........................................................................................35 
4 
SUBJECT POPULATION ..........................................................................................35 
4.1 
Subject population description .....................................................................35 
4.2 
Rationale for the selection of the study population ......................................36 


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4.3 
Inclusion criteria ...........................................................................................36 
4.4 
Exclusion criteria ..........................................................................................36 
4.5 
Criteria for women of childbearing potential ...............................................38 
4.5.1 
Definition of childbearing potential ..................................................38 
4.5.2 
Acceptable methods of contraception ...............................................38 
4.5.2.1 
Denmark and UK ..................................................................... 39 
4.5.2.2 
Czech Republic and Poland ..................................................... 39 
4.5.2.3 
France ...................................................................................... 40 
4.5.2.5 
Asia and Oceania ..................................................................... 41 
5 
TREATMENTS ..........................................................................................................42 
5.1 
Study treatment .............................................................................................42 
5.1.1 
Investigational treatment: Description and rationale ........................42 
5.1.2 
Comparator: Description and rationale .............................................42 
5.1.3 
Study treatment administration .........................................................42 
5.1.4 
Treatment assignment .......................................................................43 
5.1.5 
Blinding ............................................................................................43 
5.1.6 
Study treatment supply .....................................................................43 
5.1.6.1 
Study treatment packaging and labeling ................................. 43 
5.1.6.2 
Study treatment distribution and storage ................................. 43 
5.1.6.3 
Study treatment dispensing ..................................................... 44 
5.1.6.4 
Study treatment return and destruction ................................... 44 
5.1.7 
Study treatment accountability and compliance with study  
treatment ...........................................................................................45 
5.1.7.1 
Study treatment accountability ................................................ 45 
5.1.7.2 
Study treatment compliance .................................................... 45 
5.1.8 
Study treatment dose adjustments and interruptions ........................46 
5.1.9 
Premature discontinuation of study treatment ..................................46 
5.1.10 
Study-specific criteria for interruption / premature discontinuation  
of study treatment .............................................................................47 
5.1.10.1 
Liver aminotransferase abnormalities ..................................... 47 
5.1.10.2 
Hemoglobin abnormalities ...................................................... 48 
5.1.10.3 
Pregnancy ................................................................................ 49 
5.1.10.4 
Drop in BP ............................................................................... 49 
5.1.10.5 
Initiation of forbidden medication ........................................... 49 
5.1.10.6 
Failing Fontan .......................................................................... 49 
5.2 
Previous and concomitant medications ........................................................50 
5.2.1 
Definitions ........................................................................................50 
5.2.2 
Reporting of previous/concomitant medications / auxiliary  
medicinal products / other therapies in the eCRF .............................50 


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5.2.3 
Allowed concomitant therapy ...........................................................50 
5.2.4 
Forbidden concomitant therapy ........................................................50 
6 
STUDY ENDPOINTS ................................................................................................51 
6.1 
Efficacy endpoints ........................................................................................51 
6.2 
Safety endpoints ...........................................................................................53 
6.3 
Pharmacoeconomic endpoints related to hospitalization ..............................53 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS ................................................53 
7.1 
General information ......................................................................................53 
7.1.1 
Enrollment ........................................................................................53 
7.1.2 
Unscheduled visits ............................................................................54 
7.2 
Study assessments .........................................................................................57 
7.2.1 
Demographics / baseline characteristics ...........................................57 
7.2.2 
Efficacy assessments .........................................................................58 
7.2.2.1 
Cardiopulmonary exercise testing ........................................... 58 
7.2.2.2 
PA-Ac ...................................................................................... 59 
7.2.2.3 
NT-proBNP measurement ....................................................... 60 
7.2.2.4 
Composite endpoint of time to clinical worsening .................. 60 
7.2.3 
Safety assessments ............................................................................60 
7.2.3.1 
Physical examination ............................................................... 61 
7.2.3.2 
Vital signs ................................................................................ 61 
7.2.3.3 
Weight and height ................................................................... 61 
7.2.3.4 
ECG assessment ...................................................................... 62 
7.2.3.5 
Echocardiography .................................................................... 62 
7.2.4 
Laboratory assessments ....................................................................62 
7.2.4.1 
Type of laboratory ................................................................... 62 
7.2.4.2 
Laboratory tests ....................................................................... 64 
7.2.5 
Pharmacoeconomic assessments .......................................................66 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL  
CARE ..........................................................................................................................66 
8.1 
Study completion as per protocol .................................................................66 
8.2 
Premature withdrawal from study ................................................................66 
8.3 
Premature termination or suspension of the study ........................................67 
8.4 
Medical care of subjects after study completion / withdrawal from study ...68 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................68 
9.1 
Adverse events ..............................................................................................68 


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9.1.1 
Definition of adverse events .............................................................68 
9.1.2 
Intensity of adverse events ................................................................69 
9.1.3 
Relationship to study treatment ........................................................70 
9.1.4 
Reporting of adverse events ..............................................................70 
9.1.5 
Follow-up of adverse events .............................................................70 
9.2 
Serious adverse events ..................................................................................71 
9.2.1 
Definitions of serious adverse events ...............................................71 
9.2.2 
Reporting of serious adverse events .................................................71 
9.2.3 
Follow-up of serious adverse events .................................................72 
9.2.4 
After the 30-day follow-up period ....................................................72 
9.2.5 
Reporting procedures ........................................................................72 
9.3 
Pregnancy .....................................................................................................73 
9.3.1 
Reporting of pregnancy ....................................................................73 
9.3.2 
Follow-up of pregnancy ....................................................................73 
9.4 
Study safety monitoring ................................................................................73 
9.5 
Product Quality Complaints .........................................................................74 
9.5.1 
Procedures .........................................................................................74 
9.6 
Special Reporting Situations ........................................................................74 
9.7 
Contacting Sponsor Regarding Product Quality ..........................................75 
10 STATISTICAL METHODS .......................................................................................75 
10.1 
Analysis sets .................................................................................................75 
10.1.1 
Total Macitentan Analysis Set ..........................................................75 
10.1.2 
Long-term Macitentan Analysis Set .................................................75 
10.1.3 
Open-label extension Set (OLES) .....................................................75 
10.1.4 
Per-protocol Analysis Set .................................................................75 
10.2 
Variables .......................................................................................................75 
10.2.1 
Efficacy variable(s) ...........................................................................76 
10.2.2 
Safety variables .................................................................................77 
10.2.2.1 
Adverse events ........................................................................ 77 
10.2.2.2 
Laboratory data ........................................................................ 78 
10.2.2.3 
Vital signs ................................................................................ 78 
10.2.2.4 
Echocardiography .................................................................... 78 
10.2.3 
Other variables ..................................................................................78 
10.2.3.1 
Exposure to study drug ............................................................ 78 
10.2.3.2 
Pharmacoeconomic variables related to hospitalization ......... 78 
10.3 
Description of statistical analyses .................................................................78 
10.3.1 
Overall testing strategy .....................................................................82 
10.3.2 
Sub-group analyses ...........................................................................82 
10.4 
Interim analyses ............................................................................................82 


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10.5 
Sample size ...................................................................................................82 
11 DATA HANDLING ....................................................................................................83 
11.1 
Data collection ..............................................................................................83 
11.2 
Maintenance of data confidentiality .............................................................83 
11.3 
Database management and quality control ...................................................83 
12 PROCEDURES AND GOOD CLINICAL PRACTICE .............................................84 
12.1 
Ethics and Good Clinical Practice ................................................................84 
12.2 
Independent Ethics Committee / Institutional Review Board ......................84 
12.3 
Informed consent ..........................................................................................85 
12.4 
Indemnification, compensation and refund of expenses to subjects and 
investigators ..................................................................................................86 
12.5 
Protocol adherence/compliance ....................................................................86 
12.6 
Protocol amendments ...................................................................................87 
12.7 
Essential documents and retention of documents .........................................87 
12.8 
Monitoring ....................................................................................................88 
12.9 
Investigator Site File .....................................................................................89 
12.10 
Audit .............................................................................................................89 
12.11 
Inspections ....................................................................................................89 
12.12 
Reporting of study results and publication ...................................................90 
13 REFERENCES ............................................................................................................91 
14 APPENDICES .............................................................................................................96 
 
 


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LIST OF TABLES 
 
Table 1 
Dosing scheme ........................................................................................... 43 
Table 2 
Visit and assessment schedule .................................................................... 55 
Table 3 
Usage of Analysis sets ................................................................................ 79 
Table 4 
Thresholds for marked laboratory abnormalities ....................................... 97 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design ............................................................................................... 33 
Figure 2 
Study design (with S-FU in the AC-055H301 RUBATO DB study) ........ 34 
Figure 3 
Acceptable birth-control options ................................................................ 41 
 
 
LIST OF APPENDICES 
 
Appendix 1 
Central laboratory abnormalities and alert flags ........................................ 96 
Appendix 2 
Echocardiography ..................................................................................... 100 
Appendix 3 
Cardiopulmonary exercise testing ............................................................ 103 
Appendix 4 
Specific Activity Scale ............................................................................. 108 
Appendix 5 
Tanner stages (self-assessment) ............................................................... 109 
Appendix 6 
Comparison of RUBATO OL procedures versus standard of care: 
comparison of burden and risks ............................................................... 110 
Appendix 7 
Child-Pugh Score ..................................................................................... 117 
Appendix 8 
Protocol Amendment History ................................................................... 118 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
 
AE  
Adverse event 
ALT  
Alanine aminotransferase 
AP  
Alkaline phosphatase  
AST  
Aspartate aminotransferase 
AV  
Atrioventricular 
BP  
Blood pressure 
BR  
Breathing reserve 
CHD  
Congenital heart disease 
CPET  
Cardiopulmonary exercise testing 
CRA  
Clinical Research Associate 
CRO  
Contract Research Organization 
CSR  
Clinical Study Report 
CTCAE  
Common Terminology Criteria For Adverse Events 
CYP3A4  
Cytochrome P450 3A4 
DB  
Double-blind 
ECG  
Electrocardiogram 
ECHOC  
Echocardiography 
eCRF  
electronic Case Report Form 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
ERA  
Endothelin receptor antagonist 
ET  
Endothelin 
ETA  
Endothelin receptor A 
ETB  
Endothelin receptor B 
EU  
European Union 
FC  
Functional class 
FEV1  
Forced expiratory volume in one second 
GCP  
Good Clinical Practice 
GFR  
Glomerular filtration rate 


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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 
ISF  
Investigator Site File 
KM  
Kaplan-Meier 
LTMAS  
Long-term Macitentan Analysis Set 
MedDRATM  
Medical Dictionary for Regulatory Activities 
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) 
OLES  
Open-label Extension Set 
OUES  
Oxygen uptake efficiency slope 
PA-Ac  
Physical Activity measured by Accelerometer 
PAH  
Pulmonary arterial hypertension 
PI  
Principal Investigator 
PLE  
Protein-losing enteropathy 
PORTICO  
PORtopulmonary Hypertension Treatment wIth maCitentan – a 
randOmized Clinical Trial 
PQC  
Product quality complaint 
QS  
Quality System 
RER  
Respiratory exchange ratio 


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RSI  
Reference safety information  
SAE  
Serious adverse event 
SAP  
Statistical Analysis Plan 
SD  
Standard deviation 
S-FU  
Safety follow-up 
SIV  
Site Initiation Visit 
SpO2  
Peripheral oxygen saturation 
SYE  
Subject-years exposure 
TMAS  
Total Macitentan Analysis Set 
ULN  
Upper limit of normal 
VAT  
Ventilatory anaerobic threshold 
VCO2  
Carbon dioxide production 
VE  
Minute ventilation 
VO2  
Oxygen uptake/consumption (V̇ O2 is a flow = a ratio of a 
volume by unit of time) 
 
 
 


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PROTOCOL SYNOPSIS AC-055H302 RUBATO OL  
TITLE 
Prospective, multi-center, single-arm, open-label, long-term study 
assessing the safety, tolerability, and effectiveness of macitentan in 
Fontan-palliated adult and adolescent subjects 
ACRONYM 
RUBATO OL 
OBJECTIVES 
 
Primary objective(s) 
To assess the long-term safety and tolerability of macitentan in 
Fontan-palliated adult and adolescent subjects.  
Secondary objectives 
• To assess the effect of macitentan on exercise capacity 
(measured by peak oxygen uptake [VO2]). 
• To assess the effect of macitentan on daily Physical Activity 
measured by Accelerometer (PA-Ac)  
 
Other objectives 
Other objectives are described in Section 2.3.  
DESIGN 
A prospective, multi-center, single-arm, open-label, long-term, 
Phase 3 study 
PERIODS 
Enrollment period: 
The enrollment period for a subject begins with the visit at Week 52 
of the double-blind (DB) study, AC-055H301 RUBATO DB and 
signing of the informed consent form (ICF), and lasts until the 
administration of the first dose in the AC-055H302 RUBATO 
open-label (OL) study (Visit 1). 
Treatment period: 
The OL treatment period will start with the administration of the first 
dose of macitentan 10 mg and last until whichever of the following 
occurs first: 
• 104 weeks (2 years) of treatment for each subject after the last 
participant has completed the AC-055H301 RUBATO DB 
treatment period. 
• The subject or the investigator decides to discontinue the study 
drug.  
• The sponsor decides to stop this AC-055H302 RUBATO OL 
study. 


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Safety follow-up (S-FU) period: 
For an individual subject, S-FU starts on the day after the last dose of 
OL study treatment and ends 30 to 35 days thereafter with the 
End-of-Study (EOS) Visit. 
EOS: 
For an individual subject, the study is completed with the EOS Visit.  
For all subjects, EOS corresponds to the last visit performed in this 
AC-055H302 RUBATO OL study.  
PLANNED 
DURATION 
Approximately 225 weeks from first subject, first visit, to last subject, 
last visit. 
SITE(S) 
/ COUNTRY(IES) 
31 sites in 11 countries (planned).  
SUBJECTS 
/ 
GROUPS 
Up to the maximum number of randomized subjects in the double-
blind AC-055H301 RUBATO study, planned to be approximately 134 
subjects* treated with macitentan 10 mg  
* Sample size of the DB part of the study may be increased to a maximum of 268 subjects, 
based on the interim analysis for sample size re-estimation during the double-blind 
AC-055H301 RUBATO DB study.  
 
INCLUSION 
CRITERIA 
1. Written informed consent/assent from the subject and/or a legal 
representative prior to initiation of any study-mandated 
procedures. 
2. Subjects who have completed Week 52 of AC-055H301 
RUBATO DB. 
3. Women of childbearing potential must 
3.1. Have a negative serum pregnancy test prior to first intake of 
OL study drug, and, 
3.2. Agree to perform monthly pregnancy tests up to the end of the 
S-FU period, and, 
3.3. Must use reliable methods of contraception from enrollment 
up to at least 30 days after study treatment discontinuation 
[see Section 4.5.2]. 
EXCLUSION 
CRITERIA 
1. Clinical worsening leading to medical interventions including 
reoperation of Fontan circulation (Fontan take-down) during the 
enrollment period. 
2. Systolic blood pressure (BP) < 90 mmHg (< 85 mmHg for subjects 
< 18 years old and < 150 cm of height) at rest. 


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3. Criteria related to macitentan use: 
3.1. Hemoglobin < 75% of the lower limit of normal assessed by 
central laboratory at enrollment 
3.2. Known or suspected pulmonary veno-occlusive disease 
3.3. Known and documented severe hepatic impairment defined 
as Child Pugh Score C, [Appendix 7] 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 
3.4. Serum 
aspartate 
and/or 
alanine 
aminotransferases  
> 3 × upper limit of normal range assessed by central 
laboratory at enrollment 
3.5. Severe renal impairment (estimated creatinine clearance 
< 30 mL/min/1.73m2) assessed by central laboratory at 
enrollment 
3.6. Pregnancy, breastfeeding, or intention to become pregnant 
during the study, or women of childbearing potential not 
using a reliable method of contraception 
3.7. Hypersensitivity to any active substance or excipient of any 
of the study drugs 
3.8. 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 enrollment (Visit 1) 
3.9. Treatment with a strong CYP3A4 inhibitor such as 
ketoconazole, itraconazole, voriconazole, clarithromycin, 
telithromycin, nefazodone, ritonavir, and saquinavir, within 
1 month prior to enrollment (Visit 1) 
3.10. Criterion modified per Amendment 2 
Treatment with a moderate dual CYP3A4/CYP2C9 inhibitor 
(e.g. fluconazole, amiodarone) or co-administration of a 
combination of moderate CYP3A4 and moderate CYP2C9 
inhibitors within 1 month prior to enrollment (Visit 1) 
4. General exclusion criteria: 
4.1. Any factor or condition likely to affect protocol compliance 
of the subject, as judged by the investigator 
4.2. Treatment with another investigational therapy during the 
OL study 
4.3. Treatment with ERAs other than macitentan 


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4.4. 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 
4.5. Any planned surgical intervention (e.g., organ transplant) 
during the study period, except minor interventions 
(e.g., tooth extraction) 
5. 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. 
 
STUDY 
TREATMENTS 
Investigational treatment 
Macitentan 10 mg, oral tablet, once daily, with or without food 
Comparator 
Not applicable 
ENDPOINTS 
Efficacy endpoints 
• The change in peak VO2, from baseline to each scheduled time 
point. 
• Change in ventilatory efficiency (assessed as minute 
ventilation [VE] / carbon dioxide production [VCO2] slope), 
from baseline to each scheduled time point. 
• Change in VO2 at ventilatory anaerobic threshold (VAT), from 
baseline to each scheduled time point. 
• Change in oxygen uptake efficiency slope (OUES), from 
baseline to each scheduled time point. 
• Change from baseline to each scheduled time point in mean 
count per minute of daily PA-Ac.  
• Change from baseline to each scheduled time point in daily 
mean time in minutes spent in sedentary, light, moderate, or 
vigorous PA-Ac.  
• Percent of baseline at each scheduled time point in N-terminal 
prohormone of brain natriuretic peptide (NT-proBNP).  
• Composite endpoint of event related to Fontan-palliated 
clinical worsening, time to first occurrence of clinical 
worsening up to EOS, defined as one or more of the following: 


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o Unscheduled hospitalization for Fontan-palliated 
morbidity event1 
o Signs and symptoms of heart failure2, requiring 
change in diuretic therapy 
o Clinical worsening leading to interventions related to 
the Fontan-palliated condition 
o Worsening to New York Heart Association functional 
class (NYHA FC) III, investigator assessed using the 
Specific Activity Scale [Appendix 4] 
o Signs and symptoms requiring the addition of a new 
class of cardiovascular medication (e.g., nitrates, 
alpha-blockers, or endothelin receptor antagonists), or 
insertion of a pacemaker. 
o Failing-Fontan defined as one or more of the 
following: 
− Enlisted 
on 
the 
active 
list 
for 
heart 
transplantation 
or 
effective 
heart 
transplantation 
− Reoperation (e.g., mechanical circulatory 
support, Fontan take down, Fontan revision / 
conversion, 
atrioventricular 
valve 
repair/ 
replacement) 
− Worsening to NYHA FC IV, investigator 
assessed using the Specific Activity Scale 
[Appendix 4]. 
− Protein-losing enteropathy (PLE) 
− Plastic bronchitis/chyloptysis 
− Peritoneal, pleural, mediastinal, or pericardial 
effusions 
− Severe hepatic impairment (as described in 
exclusion criterion 3.3) 
− Severe renal impairment (as described in 
exclusion criterion 3.5)  
− Death related to Failing-Fontan  
 
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 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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• Events related to Fontan palliated morbidity, time to first 
occurrence up to EOS of one or more of the following: 
o Ventricular 
tachyarrhythmia 
or 
supraventricular 
tachyarrhythmia3 
o Thrombotic or hemorrhagic complications (including 
thromboembolism and hemoptysis). 
• Time to death (all-cause mortality) up to EOS. 
Safety endpoints 
• Treatment-emergent adverse events (AEs) and serious AEs up 
to 30 days after study treatment discontinuation and AEs 
leading to death. 
• AEs leading to premature discontinuation of study treatment. 
• Change in vital signs (systolic and diastolic arterial BP and 
pulse rate), including peripheral oxygen saturation (SpO2) and 
body weight over time. 
• Treatment-emergent marked laboratory abnormalities up to 
30 days after study treatment discontinuation. 
• Change in laboratory parameters over time. 
Pharmacoeconomic endpoints related to hospitalization 
Pharmacoeconomic endpoints are described in Section 6.3 
 
ASSESSMENTS 
Refer to the schedule of assessments in Table 2. 
 
3 Arrhythmia qualifies as an event only if it requires hospitalization, cardioversion, addition/increase in 
antiarrhythmic treatment, or invasive tests or treatment. 


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STATISTICAL 
METHOD-
OLOGY 
Analysis sets 
There will be three main analysis sets: 
i. 
The Total Macitentan Analysis Set (TMAS) includes all 
subjects who received at least one dose of macitentan 10 mg 
either in the main study (AC-055H301 DB) or in the long-term 
study (AC-055H302 OL). 
ii. 
The Long-term Macitentan Analysis Set (LTMAS) includes 
all subjects randomized to macitentan 10 mg in the main study 
(AC-055H301 DB) regardless of subsequent enrollment into 
the AC-055H302 OL study. 
iii. 
The Open-label extension set (OLES) includes all subjects 
treated with macitentan 10 mg in AC-055H302 RUBATO OL.  
Analyses 
The long-term safety of macitentan will primarily be assessed on the 
TMAS. The long-term efficacy of macitentan will primarily be 
assessed on the LTMAS. Both efficacy and safety will also be 
assessed on the OLES.  
Variables are summarized using appropriate descriptive statistics: 
• For continuous variables (e.g. the change in peak VO2 over 
time, the change in mean count per minute of daily PA-Ac, 
change in ventilatory efficiency, percent of baseline in 
NT-proBNP and absolute change from baseline in 
NT-proBNP, change in laboratory parameters): number of 
non-missing 
observations, 
mean, 
standard 
deviation, 
minimum, Q1, median, Q3 and maximum. 
• For 
dichotomous 
or 
categorical 
variables 
(e.g. 
treatment-emergent AEs, serious AEs (SAEs), AEs leading to 
premature discontinuation of study treatment, AEs leading to 
death, AE of special interest, vital signs abnormalities, 
treatment-emergent marked laboratory abnormalities: number 
of non-missing observations, and frequency with percentage 
per category. Denominators for percentages are the number of 
subjects in corresponding analysis data sets, unless otherwise 
specified. 
• For time-to-event variables (time to death, time to first 
occurrence of composite endpoint of events related to 


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Fontan-palliated clinical worsening, time to first occurrence of 
events related to Fontan-palliated morbidity, number of 
events, number of subjects at risk, number of censored 
observations and Kaplan-Meier estimates with 2 sided 95% 
confidence intervals at relevant time points.  
To account for differences in the duration of treatment exposure 
among subjects, incidence rates of AEs, SAEs, AEs leading to 
discontinuation, AEs of special interest, and deaths will be presented 
as adjusted for subject-years exposure.  
STUDY 
COMMITTEES 
To ensure subjects’ safety, an independent Data Monitoring 
Committee (IDMC) will review the data from the AC-055H302 
RUBATO OL study on a regular basis until the end of the 
AC-055H301 RUBATO DB study (i.e., OL data will be reviewed 
only in combination with the data of the DB study). Once the AC-
055H301 RUBATO DB study has concluded, the IDMC will no 
longer continue to monitor the AC-055H302 RUBATO OL study. 
After that, the sponsor will continue to review the data on an ongoing 
basis. 
 


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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 et al. 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 [Diller 2015].  
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 on the efficacy and tolerability of endothelin (ET) receptor 
blockade in Fontan-palliated patients, after successful surgery [Derk 2015]. Among these 
studies, the placebo-controlled clinical study TEMPO [Hebert 2014] was conducted in 
Denmark and Sweden with bosentan in 75 Fontan-palliated patients. 69 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 (pulmonary vascular resistance [PVR] decrease) and functional 
improvement (NYHA) in adults and adolescents. This small prospective cohort study 
conducted without a control group by Agnoletti et al. [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 *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 treated with 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 [Agnoletti 2017]. 
Systolic blood pressure (BP) diminished in all adolescents (all on bosentan) and adults (all 
on macitentan), significantly so only for adolescents. No significant differences were 
detected in diastolic BP and oxygen saturation. Blood tests of hepatic and renal function 
were unchanged, no hepatic toxicity developed, and anemia never occurred. 
Detailed information on macitentan, is provided in 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 [Macitentan IB].  
1.3 Purpose and rationale of the study 
The purpose of the AC-055H302 RUBATO open-label (OL) study is to assess the 
long-term use of macitentan in Fontan-palliated adult and adolescent subjects beyond the 
52 weeks of treatment in the AC-055H301 RUBATO double-blind (DB) study.  


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The primary objective of this study is to assess the long-term safety and tolerability of 
macitentan in this population.  
The rationale of this study relies on the fact that the long-term safety of macitentan in this 
population is not known. The dynamic of the effect of macitentan over time is also 
unknown, e.g., whether the efficacy of macitentan (if any) is sustained beyond 52 weeks 
(end of the DB study).  
In addition, the opportunity will be given to subjects who were on placebo in the 
AC-055H301 RUBATO DB study to receive macitentan 10 mg and potentially benefit 
from an active treatment. 
1.4 Summary of known and potential risks and benefits 
Macitentan is approved for the treatment of pulmonary arterial hypertension (PAH) based 
on data generated in the SERAPHIN study [Pulido 2013]. In addition, macitentan was 
investigated in another congenital heart disease indication (Eisenmenger Syndrome) in the 
MAESTRO study [Gatzoulis 2019]. Safety and tolerability are well documented in both 
indications in the IB [Macitentan IB]. 
Effects on BP 
Macitentan is a vasodilator. However, in the pivotal study in PAH [Pulido 2013], no 
difference in mean change from baseline in 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 
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. 


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Effect on edema/fluid retention 
Events of edema/fluid retention are frequent symptoms of PAH worsening and associated 
complications such as right ventricular failure. In the pivotal placebo-controlled study in 
PAH (SERAPHIN [Pulido 2013] study) such events were reported with similar incidences 
for macitentan and placebo patients. 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, and 
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 study 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 are provided in the IB [Macitentan IB]. 
Benefit 
It is expected that macitentan treatment in Fontan-palliated patients will positively impact 
exercise capacity and possibly delay disease progression. 
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 to stop subject’s participation 
if, on balance, he/she believes that continuation would be detrimental to the subject’s 
well-being. 
2 
STUDY OBJECTIVES 
2.1 Primary objective 
To assess the long-term safety and tolerability of macitentan in Fontan-palliated adult and 
adolescent subjects. 


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2.2 Secondary objectives 
• To assess the effect of macitentan on exercise capacity (measured by peak VO2).  
• To assess the effect of macitentan on daily Physical Activity measured by 
Accelerometer (PA-Ac). 
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 time to first occurrence of clinical worsening (or 
morbidity) events.  
• To assess the effect of macitentan on pharmacoeconomic endpoints related to 
hospitalization. 
3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
This is a prospective, multi-center, single-arm, open-label, long-term, Phase 3 study. 
Up to the maximum number of randomized subjects in the double-blind AC-055H301 
RUBATO study, planned to be approximately 134 subjects will be enrolled to macitentan 
10 mg once daily (o.d.). Sample size may be increased to a maximum of 268 subjects 
depending on interim analysis for sample size re-estimation during the AC-055H301 
RUBATO DB study. This study will be conducted in approximately 31 sites in 
11 countries. 
3.1.1 Study periods 
The study comprises the following consecutive periods: 
Enrollment period: The enrollment period for a subject begins with the visit at Week 52 
in the DB study, AC-055H301 RUBATO DB and signing of the informed consent form 
(ICF), and lasts until the administration of the first dose in the AC-055H302 RUBATO OL 
study (Visit 1).  
Treatment period: The OL treatment period will start with the administration of the first 
dose of macitentan 10 mg and last until whichever of the following occurs first: 
• 104 weeks (2 years) of study treatment for each subject after the last participant 
has completed the AC-055H301 RUBATO DB treatment period. 
• The subject or the investigator decides to discontinue the study drug.  
• The sponsor decides to stop this AC-055H302 RUBATO OL study. 


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Safety follow-up (S-FU) period: For an individual subject, starts on the day after the last 
dose of OL study treatment and ends 30 to 35 days thereafter with the End-of-Study (EOS) 
Visit. 
Subjects eligible to enter a post-trial access program 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 drug in a post-trial access program. 
EOS: For an individual subject, the study is completed with the EOS Visit.  
For all subjects, EOS corresponds to the last visit performed in this AC-055H302 
RUBATO OL study.  
The visit schedule and protocol-mandated procedures are performed according to the table 
of assessments [Table 2] and are described in Section 7. 


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The overall study design is depicted in Figure 1. 
Figure 1 
Study design  
 
 
DB = Double-blind (study); EOS = End-of-Study; EOT = End-of-Treatment; OL = Open-label (extension); V = visit 
= Telephone call (for visit). 
 
In instances where administration of AC-055H302 RUBATO OL study drug does not 
immediately follow End-of-Treatment (EOT) in the AC-055H301 RUBATO DB study, the 
subject will enter the normal DB S-FU period until administration of the first dose of the 
OL study drug occurs [Figure 2]. 


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Figure 2 
Study design (with S-FU in the AC-055H301 RUBATO DB study) 
 
 
DB = Double-blind (study); EOS = End-of-Study; EOT = End-of-Treatment; OL = Open-label (extension); 
S-FU = Safety Follow-up; V = visit; = Telephone call (for visit). 
 
No S-FU will be performed for subjects entering a post-trial access program at individual 
subject’s EOT for the AC-055H302 RUBATO OL study. 
 
3.1.2 Study duration 
The study starts with the first act of recruitment (i.e., first ICF signed) and ends with the 
last visit / telephone call of the last subject. 
Study AC-055H302 RUBATO OL will continue at each site until the last subject has 
globally completed 104 weeks (2 years) of treatment and their S-FU period, or withdrawal 
from the study, or the sponsor decides to end the study. 
3.2 Study design rationale 
The AC-055H302 RUBATO OL study population consists of subjects who have completed 
Week 52 of AC-055H301 RUBATO DB. Subjects will be rolled over from the DB study to 


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this OL study without knowledge of their previous study treatment (macitentan 10 mg or 
placebo). The eligible subjects are those who fulfilled the inclusion and exclusion criteria 
prior administration of the first dose of macitentan in AC-055H302 RUBATO OL study.  
The selection of subjects who complete the 52-week AC-55H301 RUBATO DB study 
period allows the inclusion only of those subjects who are sufficiently stable on study drug 
and/or on concomitant medications and hence can potentially benefit from further 
treatment. It should be noted that subjects who experience a disease progression during the 
DB study (see AC-055H301 RUBATO study protocol section 6.1.3) can be treated with 
the available standard of care. If they continue into the study up to the Week 52 Visit, they 
are allowed to enter this AC-055H302 OL extension, if they still fulfill the selection 
criteria.  
3.3 Study committees 
An Independent Data Monitoring Committee (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 operational prior to enrollment of the first subject into the study. The 
composition and operation of the IDMC is described in the IDMC charter. This IDMC will 
monitor data from the AC-055H302 RUBATO OL study together with the data from the 
AC-055H301 RUBATO DB study. Once the AC-055H301 RUBATO DB study has 
concluded, the IDMC will no longer continue to monitor the AC-055H302 RUBATO OL 
study. After that, the sponsor will continue to review the data on an ongoing basis. 
An ILSDRB (an external expert committee of hepatologists), has been appointed to provide 
ongoing assessment and advice regarding serious hepatic adverse events (AEs) of special 
interest that require further evaluation during the study as per the ILSDRB charter. 
4 
SUBJECT POPULATION 
4.1 Subject population description 
This study will enroll adolescent (> 12 years) and adult male and female subjects who had 
previously participated in the AC-055H301 RUBATO DB study. 
They must have completed Week 52 of AC-055H301 RUBATO DB. 
Women of childbearing potential must not be pregnant, breastfeeding, or intend to become 
pregnant during the study, and must agree to use reliable contraception throughout the 
study. 
Eligible subjects and/or legal representatives must be able and willing to give informed 
consent/assent for participation in the clinical study. 


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Treatment with ERAs (other than macitentan as study treatment) is not permitted during 
this study. 
4.2 Rationale for the selection of the study population 
The study population includes those subjects who have completed the AC-055H301 
RUBATO DB study and have experienced good tolerability of study drug, with an absence 
of safety concerns that would have led to a premature EOT. 
Therefore, it is ethically acceptable and possibly in their interest to continue on a potentially 
beneficial treatment.  
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. Subjects who have completed Week 52 of AC-055H301 RUBATO DB. 
3. Women of childbearing potential must: 
3.1. Have a negative serum pregnancy test prior to first intake of OL study drug, and, 
3.2. Agree to perform monthly pregnancy tests up to the end of the S-FU period, and, 
3.3. Must use reliable methods of contraception from enrollment up to at least 30 days 
after study treatment discontinuation [Section 4.5.2]. 
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. Clinical worsening leading to medical interventions including reoperation of Fontan 
circulation (Fontan take-down) during the enrollment period. 
2. Systolic BP < 90 mmHg (< 85 mmHg for subjects < 18 years old and < 150 cm of 
height) at rest. 
3. Criteria related to macitentan use: 
3.1. Hemoglobin < 75% of the lower limit of normal assessed by central laboratory at 
enrollment 
3.2. Known or suspected pulmonary veno-occlusive disease 


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3.3. Known and documented severe hepatic impairment defined as Child Pugh Score 
C [Appendix 7]4, 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 
3.4. Serum AST and/or ALT > 3 × upper limit of normal range assessed by central 
laboratory at enrollment 
3.5. Severe renal impairment (estimated creatinine clearance < 30 mL/min/1.73m2) 
assessed by central laboratory at enrollment 
3.6. Pregnancy, breastfeeding, or intention to become pregnant during the study, or 
women of childbearing potential not using a reliable method of contraception 
3.7. Hypersensitivity to any active substance or excipient of any of the study drugs 
3.8. 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 enrollment (Visit 1) 
3.9. Treatment with a strong CYP3A4 inhibitor such as ketoconazole, itraconazole, 
voriconazole, 
clarithromycin, 
telithromycin, 
nefazodone, 
ritonavir, 
and 
saquinavir, within 1 month prior to enrollment (Visit 1) 
3.10. Criterion modified per Amendment 2 
Treatment with a moderate dual CYP3A4/CYP2C9 inhibitor (e.g. fluconazole, 
amiodarone) or co-administration of a combination of moderate CYP3A4 and 
moderate CYP2C9 inhibitors within 1 month prior to enrollment (Visit 1) 
4. General exclusion criteria: 
4.1. Any factor or condition likely to affect protocol compliance of the subject, as 
judged by the investigator 
4.2. Treatment with another investigational therapy during the OL study 
4.3. Treatment with ERAs other than macitentan 
4.4. 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 
4.5. Any planned surgical intervention (e.g., organ transplant) during the study period, 
except minor interventions (e.g., tooth extraction) 
 
4 The assessment for hepatic impairment must be fully documented in the medical notes for subjects that have clinical 
signs and evidence (from central or local labs) of hepatic impairment (Child Pugh Score as per Appendix 7). This 
means that for subjects who have no clinical signs of hepatic impairment, investigators must be requested to 
document in their medical notes that “based on clinical signs and evidence from local or central labs results the 
patient does not have severe hepatic impairment”. 


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5. 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: 
• Tubal sterilization (occlusion or ligation of tubes at least 6 weeks prior to screening), 
• 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 
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 during the enrollment period up to at least 30 days after study treatment 
discontinuation. Reliable contraception must be started at least 30 days prior to Visit 1. 
The methods of birth control used (including non-pharmacological methods) must be 
recorded in the eCRF. 


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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 Denmark and UK 
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 the countries in reference, 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 
• 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). 
4.5.2.2 Czech Republic and Poland 
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. 


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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 3]. If a partner’s vasectomy 
is the chosen method of contraception, a hormone or barrier method must be used along 
with this method.  
In addition to acceptable birth control methods identified in Figure 3, 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. 


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Figure 3 
Acceptable birth-control options 
 
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. 


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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 both sides, 
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. 
5.1.2 Comparator: Description and rationale 
This is an open-label extension study of the AC-055H301 RUBATO DB study, and no 
comparator will be used.  
Nevertheless, the Open Label Extension Set (OLES) will include information where 
subjects previously on placebo and those previously on macitentan in the AC-055H301 
RUBATO DB study are described separately.  
5.1.3 Study treatment administration 
If the subject is eligible, the first intake of study treatment will take place at site, during the 
Enrollment visit (Visit 1), after successful completion of all eligibility assessments. 
The subjects must be instructed not to take study treatment in the morning of study visit 
days. 
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. 
 


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Table 1 
Dosing scheme 
Treatment period 
Duration 
Study treatment 
Dose regimen 
Treatment 
Day 1 to EOT 
Macitentan 
10 mg o.d. 
Follow-up 
30 days after EOT 
NA 
NA 
EOT = End-of-Treatment; NA = not applicable; o.d. = once daily. 
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 1 to enroll the subject. The IRT will allocate medication bottles to the 
subject. All study drug bottle numbers must be assigned through the IRT. 
5.1.5 Blinding 
Blinding is not applicable as the AC-055H302 RUBATO OL study is conducted in an OL 
fashion, where all subjects receive active treatment of macitentan 10 mg o.d.  
Subjects may receive information on the treatment they previously received in the 
AC055H301 DB study once database closure of that study has occurred. 
5.1.6 Study treatment supply 
Manufacture, labeling, packaging, and supply of study treatment will be conducted 
according to Good Manufacturing Practice, Good Clinical Practice (GCP), and any local 
or national regulatory requirements. 
All study treatment supplies are to be used only in accordance with this protocol, and not 
for any other purpose. 
5.1.6.1 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. 
5.1.6.2 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. 
5.1.6.2.1 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 


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study treatment, which will be re-supplied continuously as soon as a predefined minimum 
level of study treatment has been reached.  
5.1.6.2.2 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 drug handling and storage. 
5.1.6.3 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 to / returned 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 5.1.6.2.2].  
5.1.6.4 Study treatment return and destruction 
The protocol-mandated study treatment return procedures may not be altered without prior 
written approval from Actelion. 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. 
5.1.7 Study treatment accountability and compliance with study treatment 
5.1.7.1 Study treatment accountability 
The inventory of study treatment dispensed to and returned by the subject 
(i.e., study-treatment accountability) must be performed by site personnel on the day of the 
visit and before dispensing further study treatment. It is to be recorded by site personnel on 
the Study-Treatment 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.  
5.1.7.2 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 Investigation Medicinal Product 
(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 


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the eCRF by the CRA. Permanent discontinuation of study treatment may be considered 
after consultation with Actelion. 
The investigator must discuss the non-compliance with the subject to clarify the reasons 
and to take appropriate actions to avoid reoccurrence. This discussion and its outcome must 
be documented in the source documents. 
5.1.8 Study treatment dose adjustments and interruptions 
Study treatment dose adjustments are not permitted. 
Study treatment may be temporarily interrupted in response to an AE, a diagnostic or 
therapeutic procedure, a laboratory abnormality, or for administrative reasons. 
Study-specific criteria for interruption of study treatment are described in Section 5.1.10. 
If study treatment is interrupted by the subject for any reason, she/he must immediately 
inform the investigator. 
Interruptions of study treatment must be kept as short as possible. 
Study treatment interruptions as well as reasons for interruptions must be recorded in the 
eCRF. 
5.1.9 Premature discontinuation of study treatment 
The decision to prematurely discontinue study treatment may be made by the subject, the 
investigator, or Actelion personnel. The main reason and whether discontinuation of study 
treatment is the decision of the subject (e.g., 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 (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 5.1.10. 


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A subject who prematurely discontinues study treatment is NOT considered as withdrawn 
from the study and will be followed up until the follow-up period is complete, 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 for a safety follow-up visit 30-35 days after the last intake of study treatment.  
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. 
5.1.10 Study-specific criteria for interruption / premature discontinuation of study 
treatment 
5.1.10.1 Liver aminotransferase abnormalities 
Interruption of study treatment 
Study treatment must be interrupted in the following cases: 
• Aminotransferases (i.e., ALT and/or AST) ≥ 3 and < 8 × 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). 
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 


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• 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.  
5.1.10.2 Hemoglobin abnormalities 
If there is a case of hemoglobin < 100 g/L accompanied by a change from baseline5 of 
≥ 50 g/L during the treatment period, 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: 
• 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. 
 
5 Baseline hemoglobin refers to the last hemoglobin value obtained prior to first intake of study treatment. 


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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. 
5.1.10.3 Pregnancy 
If a female subject becomes pregnant while on study treatment, study treatment must be 
interrupted immediately. For reporting of pregnancies, refer to Section 9.3.1. 
5.1.10.4 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. 
5.1.10.5 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. 
5.1.10.6 Failing Fontan 
Study treatment must be permanently discontinued if the subject in the AC-055H302 
RUBATO OL study has one of the following Failing-Fontan circulation occurrences: 
• Effective heart transplantation 
• Fontan take down 


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• Severe hepatic impairment (as described in exclusion criterion 3.3) 
• Severe renal impairment (as described in exclusion criterion 3.5)  
5.2 Previous and concomitant medications 
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 medications / auxiliary medicinal 
products / other therapies 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/pacemakers 
• Beta blockers 
• Pulmonary hypertension-specific drugs except ERAs 
5.2.4 Forbidden concomitant therapy 
Forbidden therapy includes agents interfering with CPET, or influencing drug exposure. 
• ERAs other than macitentan 
• CYP3A4 and drug-drug-interaction 


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− 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]. 
• 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. 
6 
STUDY ENDPOINTS 
6.1 Efficacy endpoints 
The primary endpoint for this study is safety and tolerability. Efficacy endpoints are 
assessed only as exploratory secondary endpoints.  
• The change in peak VO2, from baseline to each scheduled time point. 
• Change in ventilatory efficiency (assessed as minute ventilation [VE] / carbon dioxide 
production [VCO2] slope), from baseline to each scheduled time point. 
• Change in VO2 at ventilatory anaerobic threshold (VAT), from baseline to each 
scheduled time point. 
• Change in oxygen uptake efficiency slope (OUES), from baseline to each scheduled 
time point. 
• Change from baseline to each scheduled time point in mean count per minute of daily 
PA-Ac.  
• Change from baseline to each scheduled time point in daily mean time in minutes spent 
in sedentary, light, moderate, or vigorous PA-Ac.  
• Percent of baseline at each scheduled time point in NT-proBNP.  
• Composite endpoint of event related to Fontan-palliated clinical worsening time to first 
occurrence of clinical worsening up to EOS, defined as one or more of the following: 


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− Unscheduled hospitalization for Fontan-palliated morbidity event6 
− Signs and symptoms of HF7, 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, atrioventricular (AV) valve repair/replacement) 
o Worsening to NYHA FC IV, investigator assessed using the Specific Activity 
Scale [Appendix 4]. 
o Protein-losing enteropathy (PLE) 
o Plastic bronchitis/chyloptysis 
o Peritoneal, pleural, mediastinal, or pericardial effusions 
o Severe hepatic impairment (as described in exclusion criterion 3.3) 
o Severe renal impairment (as described in exclusion criterion 3.5)  
o Death related to Failing-Fontan  
• Events related to Fontan-palliated morbidity, time to first occurrence up to EOS of 
one or more of the following: 
− Ventricular tachyarrhythmia or supraventricular tachyarrhythmia8 
− Thrombotic or hemorrhagic complications (including thromboembolism and 
hemoptysis) 
• 
Time to death (all-cause mortality) up to EOS. 
 
6 Only applicable as an event if hospitalization / intervention was unscheduled/not related to routine Fontan 
related follow-up, and hospital stay was (≥ 24 hours). 
7 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. 
8 Arrhythmia qualifies as an event only if it requires hospitalization, cardioversion, addition/increase in 
antiarrhythmic treatment, or invasive tests or treatment. 


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6.2 Safety endpoints 
• Treatment-emergent AEs9 and SAEs up to 30 days after study treatment 
discontinuation and AEs leading to death. 
• AEs leading to premature discontinuation of study treatment. 
• Change in vital signs (systolic and diastolic arterial BP and pulse rate), including 
peripheral oxygen saturation (SpO2) and body weight over time.  
• Treatment-emergent marked laboratory abnormalities up to 30 days after study 
treatment discontinuation. 
• Change in laboratory parameters over time.  
6.3 Pharmacoeconomic endpoints related to hospitalization 
• Number per year and overall of all-cause and Fontan-related hospitalizations, from 
enrollment up to EOT. 
• Number per year and overall of in-patient hospital days for all causes and 
Fontan-related causes, from enrollment up to EOT. 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS 
7.1 General information 
The study visits are listed in Table 2. 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. An S-FU visit 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 Enrollment 
Enrollment starts with the signature of the informed consent. The date on which the first 
enrollment assessment is performed corresponds to the date of the Enrollment Visit.  
The assessments are not to be repeated if they were done during the EOT Visit in the 
AC-055H301 RUBATO DB study, and if that visit was performed within 5 weeks of this 
 
9 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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visit. However, entry enrollment labs for AC-055H302 RUBATO OL study must be 
conducted if enrollment is later than 4 weeks after EOT of the AC-055H301 RUBATO DB 
study, or if those are not evaluable.  
It is the responsibility of the investigator/delegate to obtain written informed consent from 
each subject participating in this study after adequate face-to-face explanation of the 
objectives, methods, and potential hazards of the study. The subjects who agree to 
participate in the study and the investigator/delegate must sign the ICF prior to any 
study-related assessment or procedure. 
It is permitted to re-screen subjects during the enrollment period [see Section 3.1.1], if the 
reason for non-eligibility was transient (e.g., abnormal laboratory test). 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 eligibility assessments that were out of the eligibility range 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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AE = adverse event; BP = blood pressure; CPET = cardiopulmonary exercise testing; ECG = electrocardiogram; EOS = End-of-Study; EOT = End-of-Treatment;  
FC = functional class; HR = heart rate; NT-proBNP = N-terminal prohormone of brain natriuretic peptide; NYHA = New York Heart Association; SAE = serious 
adverse event; SpO2 = peripheral oxygen saturation; = Telephone call (for visit). 
*Transferred electronically by an external service provider 
1 The assessments denoted by ‘(X)’ are not to be repeated if they were done during the EOT Visit in the AC-055H301 RUBATO DB study, and if that visit was performed 
within 5 weeks of this visit. Entry enrollment laboratory tests for AC-055H302 RUBATO OL study must be conducted if enrollment is later than 4 weeks after EOT 
of the AC-055H301 RUBATO DB study, or if those are not evaluable. Assessments denoted by ‘X’ must be performed regardless of whether the value was obtained 
in the EOT Visit in the AC-055H301 RUBATO DB study. 
2 Visit may be performed by telephone, as long as laboratory assessments are done with central lab kits. 
3 Laboratory assessments are done for aminotransferases and hemoglobin monthly (28 ± 7 days) until Week 24. Subsequently, aminotransferases and hemoglobin 
are done at every 12 weeks and at EOT + 30 days. Additional liver tests may be performed as clinically indicated, and as recommended per local label. Alpha-
fetoprotein tests are only conducted every 52 weeks. 
4 Scheduled study medication dispensing/return procedures may be adapted according to the site practice. 
5 All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after study treatment discontinuation must be reported [see also Section 9]. 
6 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. 
7 Serum pregnancy test at enrollment 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 phone calls from the site. 
8 A visit may occur over more than one day. 
9 The device is given to the subject at Visit 1 (Enrollment), and data is collected for 9 consecutive daily daytime periods after Visit 1, Visit 2, Visit 3 (Week 52), Visit 4 
(Week 78), and 9 days before Visit 5 (Week 104). No additional assessments are made in case treatment is prolonged for more than 104 weeks. 
10 The CPET assessment only needs to be completed during enrollment if no assessment is available from the AC-55H301 RUBATO DB study at Week 52. 
11 The CPET assessment will only occur every 52 weeks. 
 


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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 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. 
Study assessments performed during unscheduled visits will also be recorded in the eCRF. 
The following order of assessments is recommended:  
1. Physical examination, vital signs and echocardiography 
2. CPET (including electrocardiogram [ECG]) 
3. Blood sampling, 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 for the below-listed 
equipment used to perform study assessments must be available prior to the enrollment of 
the first subject. Calibration certificates of other equipment must be available as per local 
requirements. 
• 
Temperature measurement devices for study treatment storage area and freezer. 
• 
CPET equipment (metabolic cart including ECG device, ergometer). 
Evidence of equipment calibration must be present in the Investigator Site File (ISF). 
7.2.1 Demographics / baseline characteristics 
For subjects enrolled in the AC-055H302 RUBATO OL study, the demographic and 
baseline characteristic data recorded in the database of the AC-055H301 RUBATO DB 
study will include: age, sex, race and ethnicity10, body weight, height, NYHA FC, as well 
 
10 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 CRF only where it is allowed. 


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as the reason why a woman is not considered to be of childbearing potential (if applicable). 
Body weight, height, NYHA FC, as well as the reason why a woman is not considered to 
be of childbearing potential (if applicable) may be re-evaluated at Week 52 of the 
AC-055H301 RUBATO DB study and may serve as baseline for the AC-055H302 
RUBATO OL study. 
For subjects who were not eligible to enter this AC-055H302 RUBATO OL study, the 
following data will be recorded in the eCRF if available: 
• Reason for non-eligibility; 
− subject not eligible as per inclusion/exclusion criteria, 
− subject withdrew consent. 
 
7.2.2 Efficacy assessments 
7.2.2.1 Cardiopulmonary exercise testing 
CPET will be conducted at study sites at visits listed in Table 2. Subjects entering the 
AC-055H302 RUBATO OL study after having prematurely discontinued treatment in the 
AC-055H301 RUBATO DB study, will need to perform a CPET at Visit 1 (Enrollment). 
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 
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]. 


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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. 
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 device is given to the subject at Visit 1 (Enrollment), and data is collected for 
9 consecutive daily daytime periods after Visit 1, Visit 2, Visit 3 (Week 52), Visit 4 
(Week 78), and before Visit 5 (Week 104). The duration of physical activity data collection 
will allow including data during weekdays 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.  


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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. 
Should the AC-055H301 DB study analysis demonstrate no clear trend using PA-Ac, this 
assessment will be discontinued during the AC-055H302 OL study. 
7.2.2.3 NT-proBNP measurement 
NT-proBNP is measured at Visits 2 (Week 26), and at every 26 week visit, according to 
central laboratory working procedures. The baseline is the last assessment done prior to 
entering this AC-055H302 OL study, e.g. data for Visit 6 (Week 52) of the AC-055H301 
DB study.  
Should the AC-055H301 DB study analysis demonstrate no clear trend for NT-proBNP, 
this assessment will be discontinued during the AC-055H302 OL study. 
7.2.2.4 Composite endpoint of time to clinical worsening 
Occurrence of an event component of the 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 OL 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 OL treatment are derived from the 
reported AEs in the eCRF. 


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• Change in vital signs (systolic and diastolic BP and pulse rate), and body weight over 
time. 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 OL treatment 
discontinuation. 
• Change in laboratory parameters over time. 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 enrollment (if necessary) includes the examination of the general 
appearance, 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 for all physical examinations must be included in the source documentation at 
the study site. The observations should be reported according to body system in the eCRF 
as either normal or abnormal. If an abnormality is found it should be specified on the 
corresponding eCRF page (except for abnormalities related to Fontan circulation), 
describing the signs related to the abnormality (e.g., systolic murmur) and not the diagnosis 
(e.g., mitral valve insufficiency). Physical examination findings made after signing of 
informed consent, which meet the definition of an AE [Section 9.1.1], must be recorded on 
the AE page of the eCRF. 
7.2.3.2 Vital signs 
Vital signs (BP, pulse rate) will be measured at all scheduled visits except safety follow-up. 
Systolic and diastolic blood pressure 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), same arm (left/right) 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. 


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7.2.3.4 ECG assessment 
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 
enrollment (if necessary) and at Visits 3 and 5. 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). 
If 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. 
7.2.4 Laboratory assessments 
Laboratory tests are conducted at every visit. Full hematology and clinical chemistry panels 
[see Section 7.2.4.2] are done at enrollment (if necessary) and every visit except for 
Alpha-fetoprotein which is only drawn every 52 weeks. Laboratory assessments are done 
for aminotransferases, hemoglobin, and pregnancy monthly (28 ± 7 days) until Week 24. 
Subsequently, aminotransferases and hemoglobin are done every 12 weeks and at EOT + 
30 days. 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. 
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. 


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A serum pregnancy test (for females of childbearing potential) will be analyzed at Visit 1 
(enrollment) and complemented with monthly 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.  
• 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 


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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. Any clinically relevant laboratory abnormalities (including ALT/AST 
abnormalities ≥ 3 × ULN) detected after administration of the first dose of study treatment 
must be reported as an AE or SAE as appropriate [see Section 9], and must be followed 
until the value returns to within the normal range or is stable, or until the change is no 
longer clinically relevant, except when otherwise specified (e.g., in the case of ALT/AST 
abnormalities [see Section 5.1.10.1]). 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. 
7.2.4.2 Laboratory tests  
Hematology 
• Hemoglobin  
• Hematocrit  
• Erythrocyte count (reticulocyte count)  
• Leukocyte count with differential counts (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils)  
• Platelet count  


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Rules for study treatment interruption in case of hemoglobin abnormalities including 
assessment of additional parameters are provided in Section 5.1.10.2. 
Clinical chemistry 
• ALT  
• AST  
• Alkaline phosphatase  
• Total and direct bilirubin  
• Gamma glutamyl transpeptidase  
• Creatinine  
• Blood urea nitrogen  
• Uric acid  
• Glucose 
• Cholesterol 
• Triglycerides 
• Sodium, potassium, chloride, calcium  
• Total protein  
• Serum albumin  
• Alpha-fetoprotein* 
• NT-proBNP  
*only taken every 52 weeks  
 
Rules for OL treatment interruption / permanent discontinuation and laboratory re-tests in 
case of ALT and/or AST elevation are provided in Section 5.1.10.1. 
Creatinine clearance is estimated the Chronic Kidney Disease using Epidemiology 
Collaboration 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. 
 


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Adolescents: 
GFR (mL/min/1.73m2) = (0.41 × Height in cm) / Creatinine in mg/dL 
Coagulation tests 
• Prothrombin time and/or INR 
Pregnancy test 
A serum pregnancy test for women of childbearing potential will be performed at 
enrollment, 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 Pharmacoeconomic assessments 
Pharmacoeconomic parameters will be assessed as described in Section 6.3. 
Data elements to be collected on the eCRF include: Hospitalization admission date, 
discharge date, reason for admission. 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE 
8.1 Study completion as per protocol 
A subject who completed OL treatment until the last subject has had 2 years of treatment, 
Week 104 and had the S-FU, is considered to have completed the study as per protocol.  
The overall study is considered completed when all subjects have completed their 
individual S-FU, and their status is known: alive or deceased, withdrawn consent or have 
been lost to follow-up. 
Note that the S-FU visit may not be needed for subjects who continue macitentan treatment 
(e.g., special access program, clinical trial) at their individual EOT of AC-055H302; these 
subjects are still considered to have completed the study. 
8.2 Premature withdrawal from study 
Subjects may voluntarily withdraw from the study without justification for any reason at 
any time. Subjects are considered withdrawn if they state an intention to withdraw further 
participation in all components of the study (i.e., withdrawal of consent), die, or are lost to 


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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, 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. 
8.3 Premature termination or suspension of the study 
Actelion reserves the right to terminate the study at any time globally or locally. 
Investigators can terminate the participation of their site in the study at any time. 
If the study is prematurely suspended or terminated, Actelion will promptly inform the 
investigators, the Independent Ethics Committees (IECs) / Institutional Review Boards 
(IRBs), and health authorities, as appropriate, and provide the reasons for the suspension 
or termination. 


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If the study is suspended or prematurely terminated for any reason, the investigator – in 
agreement with Actelion – must promptly inform all enrolled subjects and ensure their 
appropriate treatment and follow-up, as described in Section 8.4. Actelion may inform the 
investigator of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the subjects’ interests. 
In addition, if the investigator suspends or terminates the study without prior agreement 
from Actelion, the investigator must promptly inform Actelion personnel and the IEC/IRB, 
and provide both with a detailed written explanation of the termination or suspension. 
If the IEC/IRB suspends or terminates its approval / favorable opinion of the study, the 
investigator must promptly notify Actelion personnel and provide a detailed written 
explanation of the termination or suspension. 
Any suspension or premature termination of the study must be discussed with the IDMC 
as long as they are active for the AC-055H301 RUBATO DB study. 
8.4 Medical care of subjects after study completion / withdrawal from study 
After the subject’s study completion or premature withdrawal from the study, whichever 
applies, the investigator/delegate will explain to subjects what treatment(s) / medical care 
is necessary and available according to local regulations.  
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
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 
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 OL treatment initiation until 30 days after OL treatment discontinuation) whether or 
not considered by the investigator as related to study treatment. 


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AEs include: 
• Exacerbation of a pre-existing disease. 
• Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 
• Disease or medical condition detected or diagnosed during the course of the study even 
though it may have been present prior to the start of the study. 
• Continuous persistent disease or symptoms present at study start that worsen following 
the signing of informed consent. 
• Abnormal assessments, e.g., change on physical examination, ECG findings, if they 
represent a clinically significant finding that was not present at study start or worsened 
during the course of the study. 
• Laboratory test abnormalities if they represent a clinically significant finding, 
symptomatic or not, which was not present at study start or worsened during the course 
of the study or led to dose reduction, interruption or permanent discontinuation of study 
treatment. 
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].  
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.  
Ongoing AEs from AC-055H301 RUBATO DB will be reported on the ongoing AEs eCRF 
form for the AC-055H302 RUBATO OL, if an increase in intensity occurs for an ongoing 
AE, a new AE will be reported. 
The three categories of intensity are defined as follows: 


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 Mild 
The event may be noticeable to the subject. It does not usually influence daily activities, 
and normally does not require intervention. 
 Moderate 
The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed. 
 Severe 
The event may cause noticeable discomfort and usually interferes with daily activities. The 
subject may not be able to continue in the study, and treatment or intervention is usually 
needed. 
A mild, moderate, or severe AE may or may not be serious [see Section 9.3.1]. These terms 
are used to describe the intensity of a specific event. Medical judgment should be used on 
a case-by-case basis. 
Seriousness, rather than 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. 
9.1.4 Reporting of adverse events 
All AEs with an onset date after signing of informed consent and up to 30 days after study 
treatment discontinuation must be recorded on specific AE pages of the 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. 


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AEs still ongoing more than 30 days after OL study treatment discontinuation must be 
followed up until they are no longer considered clinically relevant or until stabilization. 
The follow-up information obtained after the subject’s EOS Visit / telephone call will not 
be collected by Actelion except for 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. 
• Hospitalization for pre-planned (i.e., planned prior to signing informed consent) 
surgery or standard monitoring of a pre-existing disease or medical condition that did 
not worsen, e.g., hospitalization for coronary angiography in a subject with stable 
angina pectoris. 
However, complications that occur during hospitalization are AEs or SAEs (e.g., if a 
complication prolongs hospitalization). 
9.2.2 Reporting of serious adverse events 
All SAEs, as well as PQCs, occurring after signing of informed consent up to 30 days after 
study treatment discontinuation 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. If the SAE is reported in AC-055H301 RUBATO DB, and 
occurs prior to the first dose of study medication in AC-055H302 RUBATO OL, it does 


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not need to be also reported in AC-055H302 RUBATO OL. However, complications that 
occur during OL treatment are AEs or SAEs (e.g., if a complication prolongs 
hospitalization) and must be reported in RUBATO OL. 
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 Visit / 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 
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 within 24 hours of the 
investigator’s first knowledge of the event. 
All SAEs must be recorded on an SAE form, irrespective of the study treatment received 
by the subject, and whether or not this event is considered by the investigator to be related 
to study treatment. 
The SAE forms must be sent to 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 


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that is assessed as related and unexpected against the RSI is known as a suspected 
unexpected serious adverse reaction (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. 
9.3 Pregnancy 
If a woman becomes pregnant while on study treatment, study treatment must be 
discontinued. The investigator must counsel the subject and discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus. 
9.3.1 Reporting of pregnancy 
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 (see contact details provided on the Pregnancy form), and in the eCRF on an AE 
page. 
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. 
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 9.3.1. 
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 


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(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]. 
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 SAE page of the 
eCRF. 


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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 Contract Research 
Organizations (CROs) supervised by Actelion. 
A Statistical Analysis Plan (SAP) will provide full details of the analyses, data displays, 
and algorithms to be used for data derivations. 
10.1 Analysis sets 
There are three main analysis sets [see also Section 10.3, Table 3].  
10.1.1 Total Macitentan Analysis Set 
The Total Macitentan Analysis Set (TMAS) includes all subjects who received at least one 
dose of macitentan 10 mg either in the main study (AC-055H301) or in the long-term study 
(AC-055H302).  
10.1.2 Long-term Macitentan Analysis Set  
The Long-term Macitentan Analysis Set (LTMAS) includes all subjects randomized to 
macitentan 10 mg in the main study (AC-055H301) regardless of subsequent enrollment 
into the AC-055H302 study.  
10.1.3 Open-label extension Set (OLES)  
The Open-label Extension Set (OLES) includes all subjects treated with macitentan 10 mg 
in AC-055H302 RUBATO OL.  
10.1.4 Per-protocol Analysis Set 
No Per-protocol Analysis Set is defined for AC-055H302 RUBATO OL. However, major 
protocol deviations that may have an impact on the safety or tolerability will be 
summarized by frequency tables. 
10.2 Variables  
All variables described hereafter are related to the endpoints defined in Section 6. As the 
primary objective of AC-055H302 RUBATO OL is long-term safety and tolerability, the 
primary endpoints are related to safety.  


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10.2.1 Efficacy variable(s) 
• Change in peak VO2 to each scheduled time point, i.e., per time point of assessment, 
the change is defined as a time assessment value minus baseline value.  
• Change in ventilatory efficiency from baseline to each scheduled time point 
(VE/VCO2 slope, VO2 / heart rate, VO2 at VAT, OUES and % predicted peak VO2) 
will be also collected at all visits with CPET. Per variable of exercise capacity and per 
post baseline assessment, changes from baseline are defined as post baseline value 
minus baseline value. 
• Change from baseline to each scheduled time point in mean count per minute of 
daily PA-Ac, i.e., per time point of assessment, the change is defined as a time 
assessment mean count per minute of daily PA-Ac minus the mean count per minute 
of baseline daily values. 
• Change from baseline to each scheduled time point in daily mean time in minutes 
spent in sedentary, light, moderate or vigorous PA-Ac, similar definition to above. 
The values used for variables above will be based on data evaluation by the central reading 
facility. 
• Percent of baseline at each scheduled time point in NT-proBNP, i.e., per time point 
of assessment, the percent of baseline in NT-proBNP is defined as 100 times the point 
of assessment value divided by the baseline value. The percent change from baseline 
in NT-proBNP is defined as 100 times the absolute change from baseline divided by 
the baseline value. Also, the absolute change from baseline will be presented and it is 
defined as a post-baseline value minus baseline value. 
The baseline values for above variables are defined as in Section 10.3 Description of 
statistical analyses. 
• Time to clinical events is defined as: 
o Composite endpoint of event related to Fontan-palliated clinical worsening, time 
to first occurrence of clinical worsening up to EOS (where clinical worsening 
events are defined as in Section 6.1),  
o Events related to Fontan-palliated morbidity, time to first occurrence up to EOS 
where events are defined as in Section 6.1). 
For each composite endpoint, a subject is considered as having an event if the investigator 
reports the occurrence of any of the individual components in the eCRF.  
Subjects who did not experience an event will be censored at the date of last contact also 
reported in the eCRF.  


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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 first dose plus 1 divided by 7,  
• for censored subjects: the EOS date minus date of first dose plus 1 divided by 7. 
Time to death (all-cause mortality) up to EOS 
Subjects who are known to be alive, lost to follow up or prematurely withdrawn from the 
study will be censored at the date of last contact (e.g., date of last 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.  
10.2.2 Safety variables 
The safety variables are the following: 
• Treatment-emergent AEs and SAEs up to 30 days after OL treatment discontinuation 
• AEs leading to premature discontinuation of study treatment 
• AEs leading to death 
• Change in vital signs (systolic and diastolic arterial BP and pulse rate) including 
peripheral oxygen saturation (SpO2) and body weight up to all assessed time points 
during the study 
• Treatment-emergent marked laboratory abnormalities at all assessed time points 
during the study  
• Change in laboratory parameters from baseline to all assessed time points during the 
study  
• AEs of special interest (anemia/hemoglobin decrease, hepatic adverse events of 
special interest, hypotension, edema/fluid retention). 
10.2.2.1 Adverse events 
An AE is defined as any event that is recorded on the AE CRF module regardless of the 
onset date. As all subjects have received study medication in the AC-055H301 RUBATO 
DB study, all AEs are treatment emergent up to 30 days after EOT. When using the OLE, 
treatment-emergent events are those with onset date/time ≥ start date/time of AC-055H302 
RUBATO OL 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 at least 
‘reasonably possible’ by the investigator. 


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AEs leading to premature discontinuation of study treatment are those with action taken 
with study drug reported as ‘permanently discontinued’ by the investigator. 
AE of special interest (anemia/hemoglobin decrease, hepatic adverse events of special 
interest, hypotension, edema/fluid retention).  
All AEs will be coded using the latest available version of MedDRA dictionary. 
10.2.2.2 Laboratory data 
Measured values and changes in laboratory data (as defined in the Section 7.2.4.2) from 
baseline are described by visit and treatment group by means of summary tables in SI units. 
In addition, treatment-emergent marked laboratory abnormalities will be summarized for 
each laboratory parameter by treatment group providing their incidence and frequency.  
10.2.2.3 Vital signs 
Systolic BP, diastolic BP, pulse rate, SpO2, height and body weight are measured at all 
scheduled visits and reported in the eCRF.  
10.2.2.4 Echocardiography 
Single ventricle ejection fraction, Fontan circulation stenosis, and valvular defects (severe 
AV valve regurgitation, outflow obstruction) are measured at the enrolment and yearly 
visits and reported in the eCRF.  
10.2.3 Other variables 
10.2.3.1 Exposure to study drug 
The duration of treatment exposure is defined as the time elapsing between study drug 
initiation and discontinuation, inclusive. Premature Discontinuation of treatment and study. 
Number and percentage of subjects who prematurely discontinued treatment and study will 
be presented and adjustment for treatment exposure.  
10.2.3.2 Pharmacoeconomic variables related to hospitalization 
The number and percentage of subjects who are hospitalized per year and overall: 
• All-cause hospitalizations 
Fontan-related hospitalizations will be reported in the eCRF with an admission date. 
10.3 Description of statistical analyses 
Missing data for efficacy variables will be handled similarly to AC-055H301 RUBATO 
DB. Further details will be provided in the SAP. 
The variables in Section 10.2 will be summarized as follows:  


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• The long-term safety of macitentan will be assessed on the TMAS. Results will be 
presented overall, and baseline for this will be the last non-missing assessment obtained 
prior to the start of macitentan. 
• The long-term efficacy of macitentan will be assessed on the LTMAS. Results will be 
presented overall and over time until the end of AC-055H301 RUBATO DB or 
AC-055H302 RUBATO OL, whichever is the latest. Baseline for this will be the last 
non-missing assessment obtained prior to the start of macitentan in AC-055H301 
RUBATO DB. 
• Both efficacy and safety will also be assessed on the OLES. Results will be presented 
overall and by ex-placebo or ex-macitentan:  
− Ex-placebo subjects are defined as subjects who received placebo in AC-055H301 
RUBATO DB and enrolled into AC-055H302 RUBATO OL, and  
− Ex-macitentan subjects are defined as subjects who received macitentan in 
AC-055H301 RUBATO DB and enrolled into AC-055H302 RUBATO OL.  
Baseline for this will be the last non-missing assessment obtained prior to the start of 
study drug intake in the AC-055H302 RUBATO OL extension. 
Table 3 
Usage of Analysis sets 
LTMAS 
OLES 
TMAS 
 
 
(N = 67) 
Previously on 
DB macitentan 
(N = up to 
67*) 
Previously on 
DB placebo 
(N = up to 67*) 
All subjects 
 
(N = up to 
134*) 
All subjects 
N = up to 134* 
DB = double-blind; LTMAS = Long-term Macitentan Analysis Set; OLES = Open-label extension Set; TMAS = Total 
Macitentan Analysis Set. 
*See Section 10.5 Sample Size (Baseline is as defined in Section 10.1) 
 
Variables are summarized using appropriate descriptive statistics: 
• For continuous variables (e.g., the change in peak VO2 over time, the change in mean 
count per minute of daily PA-Ac from baseline to post-baseline assessment, change in 
ventilatory efficiency from baseline to post-baseline assessment, percent of baseline in 
NT-proBNP and absolute change from baseline to post-baseline assessments in 
NT-proBNP, change in laboratory parameters from baseline to post-baseline 
assessment): number of non-missing observations, mean, standard deviation, 
minimum, Q1, median, Q3 and maximum. 
• For dichotomous or categorical variables (e.g., treatment-emergent AEs, SAEs, AEs 
leading to premature discontinuation of study treatment, AEs leading to death, AE of 
special interest, change in vital signs, treatment-emergent marked laboratory 
abnormalities: number of non-missing observations, and frequency with percentage per 
category. Denominators for percentages are the number of subjects in corresponding 
analysis data sets, unless otherwise specified. 


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• For time-to-event variables (time to death, time to first occurrence of composite 
endpoint of event related to Fontan-palliated clinical worsening, time to first 
occurrence of events related to Fontan-palliated morbidity): number of events, number 
at risk, number of censored observations and KM estimates with 2 sided 95% 
confidence intervals at relevant time points.  
• Rules for KM curves going upwards or downwards (curves will go upwards if there is 
a low number of events, i.e., the KM less than 50%) and the graphical presentation for 
KM follows the recommendations from Pocock [Pocock 2002].  
Truncation of the x-axis when only 10% of the subjects are still in follow-up. 
Graphical presentations for continuous variables, e.g., categorical and time-to-event 
variables will be included when appropriate. More details will be specified in the SAP:  
Demographics, medical history, previous/current use of medications 
Demographics and medical history, previous/current use of medications at baseline will be 
summarized for all analysis sets and per type of variables as explained above. 
Exposure to study drug 
The duration of treatment exposure, study drug interruption and duration of treatment 
duration of treatment exposure including interruption will be summarized as continuous 
variables for each analysis set. 
Premature Discontinuation of treatment and study 
Number and percentage of subjects who prematurely discontinued treatment and study will 
be summarized as a categorical variable for each analysis set.  
AEs 
The number and percentage of subjects with at least one treatment-emergent AE / with at 
least one SAE / with at least one AE leading to premature discontinuation of study 
treatment/ with at least on AE with fatal outcome will be tabulated for each analysis set 
and by: 
• System Organ Class and Preferred Term within System Organ Class, in descending 
order of incidence. 
• Preferred Term, in descending order of incidence 
The same analysis will be performed considering the maximum intensity of reported AEs 
and relationship to study treatment. 


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Listings will be provided for all reported AEs, including SAEs. In addition, separate 
listings will be provided for all SAE, for all AEs leading to premature discontinuation of 
study treatment, and for all AEs with fatal outcome.  
Adjustment for treatment exposure 
In order to account for differences in the duration of treatment exposure among subjects, 
incidence rates of AEs, SAEs, AEs leading to discontinuation, AEs of special interest, 
number of hospitalizations and deaths will be presented as adjusted for subject-years 
exposure (SYE).  
Subject-time will be calculated as follows: 
i) For subjects without events: by summing the days of treatment duration (study treatment 
end date – study treatment start date + 1);  
ii) For subjects with an event: by summing the days of treatment duration up to the start 
date of first event (min [date of first event, study treatment end date] – study treatment start 
date + 1)  
Subject-years exposure (SYE) will be calculated by dividing the total subject time by 
365.25 days. 
The incidence rate for an AE (or SAE) per 100 Subject-years will be calculated by dividing 
the number of subjects with AEs (or SAEs) by the SYE and multiplying by 100. 
Adjusted Incidence Rate = 100 × (Number of subjects with at least one AE/SYE) 
Laboratory variables 
Using “evaluation of drug-induced serious hepatotoxicity” (eDISH) plots, graphical 
representations of total bilirubin versus ALT will be produced, to identify possible Hy’s 
Law cases. Also, box plots over time will be produced to describe laboratory variables over 
time. This variable will be summarized for each analysis set.  
Vital signs 
Number and percentage of subjects with systolic BP drops to < 90 mmHg (< 85 mmHg for 
subjects < 18 years old and < 150 cm of height) will be tabulated over time. In addition, 
absolute changes from baseline in vital sign parameters will be presented graphically via 
box plots for each analysis set. 
Pharmacoeconomic variables related to hospitalization 
The number and percentage of subjects who are hospitalized per year and overall will be 
summarized for each analysis set and adjusted by treatment exposure. 


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Efficacy variables 
Analyses of efficacy variables will be descriptive and as specified under 
continuous/categorical variables above. Graphical presentation of variables over time will 
be shown. More details will be in the SAP. 
10.3.1 Overall testing strategy 
No formal hypothesis testing will be performed, as all efficacy analyses are considered 
exploratory. No inferential analysis is planned for the efficacy variables. Any p-values are 
presented for information only. No multiplicity adjustment will be made.  
10.3.2 Sub-group analyses 
Following sub-group analyses for AEs leading discontinuation, AE of special interest, and 
SAEs will be performed: 
• Age (< 18, ≥ 18 years) 
• Sex (Male, Female) 
• Geographical region (America, Europe, Asia, Oceania), 
• Region (US, non-US). 
• Ventricular dominance (left ventricle, right ventricle/mixed). 
Other subgroups will be defined in the CSR SAP. 
10.4 Interim analyses 
No interim analyses are planned for the OL study.  
Periodic review of the efficacy data in parallel to the safety data will be performed, 
allowing an assessment of risk/benefit [see Section 3.3]. An independent statistical analysis 
center, involved in the main study but not otherwise involved in the design, conduct and 
analysis of the study, will prepare reports for review by the IDMC (for IDMC review 
meetings during the course of the trial) in accordance with the charter. There is no limit to 
the number of reviews meetings or reports, which have the aim of guaranteeing the safety 
of the subjects. 
10.5 Sample size 
This is an extension study of AC-055H301 RUBATO DB, hence the sample size will be 
up to the number of randomized subjects in AC-055H301 RUBATO DB study (planned to 
be approximately 134 subjects or may be increased to a maximum of 268 subjects based 
on the interim analysis for sample size re-estimation during the double blind AC-055H301 
RUBATO DB study).  


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11 DATA HANDLING 
11.1 Data collection 
The investigator/delegate is responsible for ensuring the accuracy, completeness and 
timelines of the data reported. All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of the data. Data reported in the eCRF derived 
from source documents must be consistent with the source documents. 
eCRF data will be captured via electronic data capture (using the Rave system provided by 
Medidata Solutions, Inc., a web-based tool). The investigator and site personnel will be 
trained to enter and edit the data via a secure network, with secure access features 
(username, password, and identification – an electronic password system). A complete 
electronic audit trail will be maintained. The investigator/delegate will approve the data 
(i.e., confirm the accuracy of the data recorded) using an electronic signature (ref. to 
US 21 CFR Part 11). 
Subject 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 enrollment. 
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. 


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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) 
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. 
CPET and PA-Ac data are processed by a central reading facility and the results will be 
sent electronically to Actelion. 
AEs are coded according to the latest Medical Dictionary for Regulatory Activities 
(MedDRA) used by Actelion. 
After the database has been declared complete and accurate, the database will be closed. 
Any changes to the database after that time may only be made as described in the 
appropriate Actelion Quality System documents. After database closure, the investigator 
will receive the case report forms of the subjects of his/her site (including all data changes 
made) on electronic media or as a paper copy. 
12 PROCEDURES AND GOOD CLINICAL PRACTICE 
12.1 Ethics and Good Clinical Practice 
Actelion personnel and the investigators will ensure that the study is conducted in full 
compliance with ICH-GCP Guidelines, the principles of the “Declaration of Helsinki”, and 
with the laws and regulations of the country in which the study is conducted. 
12.2 Independent Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document(s) provided to the 
subject 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, the documents reviewed, and the date of approval. 


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Modifications made to the protocol or the ICF after receipt of the approval must also be 
submitted as amendments by the investigator to the IEC/IRB in accordance with local 
procedures and regulations [see Section 12.6]. 
A list of members participating in the IEC/IRB meetings must be provided, including the 
names, qualifications, and functions of these members. If that is not possible, the attempts 
made to obtain this information along with an explanation as to why it cannot be obtained 
or disclosed must be documented in the study documentation.  
If a member of the study personnel was present during an IEC/IRB meeting, it must be 
clear that this person did not vote. 
12.3 Informed consent 
Pediatric subjects are legally unable to provide informed consent. Therefore, full informed 
consent must be obtained from parent(s) or a legally designated representative. 
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). 
Assent must be obtained from study participants who are developmentally capable. The 
criteria for developmental capability to give assent follow 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. 
The ICF will be provided in the country local language(s). 
Site personnel (according to local regulation) authorized to participate in the consent 
process and/or to obtain consent from the subject and/or legally designated representative 
will be listed on the Delegation of Authority form supplied by Actelion. A study physician 
must always be involved in the consent process. 
The subject and/or legally designated representative and authorized site personnel listed on 
the Delegation of Authority form supplied by Actelion must sign, personally date, and time 


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(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.  
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. 
For studies that offer reimbursement and/or compensation, use the following wording: 
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. 
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. 


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12.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. An 
amended protocol must be submitted to the IEC/IRB and regulatory authorities, according 
to their requirements. 
12.7 Essential documents and retention of documents 
The investigator/delegate must maintain adequate records necessary for the reconstruction 
and evaluation of the study. A number of attributes are considered of universal importance 
to source data and the records that hold those data. These include that the data and records 
are accurate, legible, contemporaneous, original (or certified copy), attributable, complete, 
consistent, enduring, and available when needed. 
These records are to be classified into two different categories of documents: ISF and 
subjects’ source documents. 
These records must be kept by the investigator for as long as is necessary to comply with 
Actelion’s requirements (i.e., as specified in the clinical study agreement), and national 
and/or international regulations, whichever would be the longest period. If the investigator 
cannot guarantee this archiving requirement at the site for any or all of the documents, 
special arrangements, respecting the data confidentiality, must be made between the 
investigator and Actelion to store these documents outside the site, so that they can be 
retrieved in case of a regulatory inspection. No study document should be destroyed 
without prior written approval from Actelion. Should the investigator wish to assign the 
study records to another party, or move them to another location, Actelion must be notified 
in advance. 
If the site is using an electronic/computerized system to store subject medical records, it 
can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 or 
equivalent standard) and if the CRA has been provided personal and restricted access to 
study subjects only, to verify consistency between electronic source data and the CRF 
during monitoring visits. 
If the site is using an electronic/computerized system to store subject medical records but 
it could not be confirmed that the system is validated or if the CRA could not be provided 
access to the system, the site is requested to print the complete set of source data needed 
for verification by the CRA. The print-outs must be numbered, stapled together with a 
coversheet, signed and dated by the investigator/delegate to confirm that these certified 
copies are exact copies having the same information as the original source data. The 
printouts will be considered as the official clinical study records and must be filed either 
with the subject’s medical records or with the subject’s CRF. 


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In order to verify that the process the site uses to prepare certified copies is reliable, the 
CRA must be able to observe this process and confirm that the comparison of the source 
documents and the certified copy did not reveal inconsistencies. The CRA does not need 
to verify this process for all data of all subjects but at least for some of them (e.g., first 
subject; regular check during the study of critical data like inclusion/exclusion criteria, 
endpoints for some subjects) as per Actelion’s instructions. If it were not possible for the 
CRA to observe this process, it would not be possible to rely on the site’s certified copies 
and therefore the site cannot be selected for the clinical study. 
12.8 Monitoring 
Prior to study start, a Site Initiation Visit (SIV) will be performed after the required 
essential study documents are approved by Actelion. The study treatment will be shipped 
to the site upon approval of the required essential documents. 
The PI must ensure that all site personnel involved in the study are present during the SIV 
and will dedicate enough time to it. Site Information Technology support should also be 
available during the SIV. 
The SIV must be completed before the site can start the screening of study subjects. 
Following the SIV, a copy of the completed initiation visit report and follow-up letter will 
be provided to the PI and filed in the ISF. 
During the study, the CRA will contact and visit the site regularly and must be permitted, 
on request, to have access to study facilities and all source documents needed to verify 
adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered in the CRFs and other protocol-related documents. Actelion monitoring standards 
require full verification that informed consent has been provided, verification of adherence 
to the inclusion/exclusion criteria, documentation of SAEs, and the recording of the main 
efficacy, safety, and tolerability endpoints. Additional checks of the consistency of the 
source data with the CRFs will be performed according to the study-specific monitoring 
guidelines. The frequency of the monitoring visits will be based on subject recruitment rate 
and critical data-collection times. 
The PI must ensure that the CRF is completed after a subject’s visit (site visit or telephone 
call), and that all requested subject files (e.g., ICFs, medical notes/charts, other 
documentation verifying the activities conducted for the study) are available for review by 
the CRA. The required site personnel must be available during monitoring visits and allow 
adequate time to meet with the CRA to discuss study-related issues. 
The investigator agrees to cooperate with the CRA(s) to ensure that any issues detected in 
the course of these monitoring visits are resolved. If the subject is hospitalized or dies in a 


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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 
The Sponsor's Global Quality Management representatives may audit the investigator site 
(during the study or after its completion). The purpose of this visit will be to determine the 
investigator’s adherence to ICH-GCP, the protocol, and applicable regulations; adherence 
to Actelion’s requirements (e.g., standard operating procedures [SOPs]) will also be 
verified. Prior to initiating this audit, the investigator will be contacted by Actelion to 
arrange a time for the audit. 
The investigator and site personnel must cooperate with the auditor(s) and allow access to 
all study documentation (e.g., subject records) and facilities. 
12.11 Inspections 
Health authorities and/or IEC/IRB may also conduct an inspection of this study (during the 
study or after its completion) at the site. 


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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 publically accessible 
databases (e.g., clinicaltrials.gov, EU database), as required by law and regulation. 
Study results will be documented in a CSR that will be signed by Actelion representatives 
and the Coordinating Investigator (or PI for single-center studies). 
In accordance with the Good Publication Practices and ethical practice, the results of the 
study will be submitted for publication in a peer-reviewed journal. Study results can be 
submitted for presentation at a congress before submission to a peer-reviewed journal. 
The Coordinating Investigator and the Steering Committee, if any, will have the 
opportunity to review the analysis of the data and to discuss the interpretation of the study 
results with Actelion personnel prior to submission to a peer-reviewed journal or 
presentation at a congress. 
Authorship will be determined in accordance with the International Committee of Journal 
Editors criteria, and be based on: 
• substantial contributions to the conception or design of the study, or the acquisition, 
analysis, or interpretation of data; and 
• 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 
[AHA/ACC Guideline 2014] Nishimura RA, Otto CM, et al. 2014 AHA/ACC Guideline 
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[Agnoletti 2017] Agnoletti G, Gala S, Ferroni F, Bordese R, Appendini L, Pace 
Napoleone C, et al. Endothelin inhibitors lower pulmonary vascular resistance and 
improve functional capacity in patients with Fontan circulation. J Thorac Cardiovasc 
Surg. 2017 Jun;153(6):1468-1475. 
[Benza 2010] Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, 
Coffey CS, et al. Predicting Survival in Pulmonary Arterial Hypertension: Insights 
From the Registry to Evaluate Early and Long-Term Pulmonary Arterial 
Hypertension Disease Management (REVEAL). Circulation. 2010;122:164–172. 
[Child-Pugh(2012)] Child-Pugh. In: Vincent JL, Hall JB. (eds) Encyclopedia of Intensive 
Care Medicine. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-
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[CTCAE 2010] Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
Published: May 28, 2009 (v4.03: June 14, 2010) U.S. Department of Health And 
Human Services. National Institutes of Health National Cancer Institute. 
[Dabal 2014] Dabal RJ, Kirklin JK, Kukreja M, et al. The modern Fontan operation shows 
no increase in mortality out to 20 years: a new paradigm. J Thorac Cardiovasc Surg 
2014;148:2517–2523;e2511.  
[Derk 2015] Derk G, An R, Aboulhosn J. Endothelin receptor antagonism in single 
ventricle physiology with fontan palliation: A systematic review and meta-
analysis.Clinical Trials and Regulatory Science in Cardiology 2015;4:1-5. 
[Diller 2005] Diller GP, Dimopoulos K, Okonko D, et al. Exercise intolerance in adult 
congenital heart disease: comparative severity, correlates, and prognostic 
implication. Circulation 2005;112:828–35. 
[Diller 2010] Diller GP, Giardini A, Dimopoulos K, et al. Predictors of morbidity and 
mortality in contemporary Fontan patients: results from a multicenter study 
including cardiopulmonary exercise testing in 321 patients. Eur Heart J. 
2010;31:3073–3083.  


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[Diller 2015] Diller GP, Kempny A, Alonso-Gonzalez R, Swan L, Uebing A, Li W, et al. 
Survival Prospects and Circumstances of Death in Contemporary Adult Congenital 
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Kidney Disease Epidemiology Collaboration). A new equation to estimate 
glomerular filtration rate. Ann Intern Med. 2009 May 5;150(9):604-12. 


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[Macitentan IB] Investigator’s Brochure for macitentan, version 15. Actelion 
Pharmaceuticals Ltd, October2017. 
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et al. ATS/ERS Task Force. General considerations for lung function testing. Eur 
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outcomes in clinical trials: good practice and pitfalls. Lancet 2002;359:1686–89. 
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mortality in pulmonary arterial hypertension. New Engl J Med 2013; 369:809–18. 
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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. 
2015 Oct 13;66(15):1700-10. 
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CP, Tinggaard, J, Mouritsen A, et al. Validity of Self-Assesment of Pubertal 
Maturation. Pediatrics. 2015;135(1):86-93. 
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hypertension and portal hypertension: analysis of its pathophysiology and clinical, 
laboratory and hemodynamic manifestations. J Am Coll Cardiol. 1991;17:492-8. 
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children and adolescents. Clin J Am Soc Nephrol. 2009;4(11):1832-43. 
[Silversides 2010] Silversides CK, Kiess M, Beauchesne L, et al. Canadian 
Cardiovascular Society 2009 Consensus Conference on the management of adults 
with congenital heart disease: Outflow tract obstruction, coarction of the aorta, 
tetralogy of Fallot, Ebstein anomaly and Marfan’s syndrome. Can J Cardiol. 
2010;26(3):e80-e97. 


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Martin N, Savale L, Kim N. Efficacy and safety of macitentan in portopulmonary 
hypertension: The PORTICO trial. ePoster presented at the European Respiratory 
Society International Congress 2018, 15–19 September, Paris, France. OA267. 
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Phyisical activity in the United States measured by accelerometer. Med Sci Sports 
Exerc. 2008;40(1):181-8. 
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cardiopulmonary exercise testing in Fontan patients: a systematic review. Open 
Heart. 2018;5(1):e000812.. 
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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 4 may be defined in the central laboratory manual.  


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Table 4 
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 
Potassium (mmol/L) 
< 3.2 
< 3.0 
> 5.5 
> 6.0 
Sodium (mmol/L) 
ND 
< 130 
> 150  
> 155  


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Parameter (SI unit) 
LL 
LLL 
HH 
HHH 
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 5.1.10]; 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.” 
 
 
 


Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H302, RUBATO OL 
Version 4 
19 November 2020, page 106/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 


Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H302, RUBATO OL 
Version 4 
19 November 2020, page 107/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
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. 
 
 
 
                                                                                              
 
 


Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H302, RUBATO OL 
Version 4 
19 November 2020, page 108/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
Appendix 4 
Specific Activity Scale 
 
 
 
Modified from [Goldman 1981]. 


Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H302, RUBATO OL 
Version 4 
19 November 2020, page 109/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
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]  


Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H302, RUBATO OL 
Version 4 
19 November 2020, page 110/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
Appendix 6 
Comparison of RUBATO OL procedures versus standard of care: comparison of burden and risks 
SoC procedures 
RUBATO OL procedures 
Burden  
Risk 
Conclusion 
Patients’ status 
  
  
  
  
Anamnesis, clinical  
& physical 
examinations 
(yearly or bi-yearly) 
3 Visits at a specialized 
cardiologist during a 
12-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 and contributes 
to significant risk reduction 
(3 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) 
With each CPET (once over 
12 months). 
Performed during the 
CPET: See CPET. 
= 
Same burden and same risk as SoC. 
Worsening/morbidity 
event assessment 
(yearly or bi-yearly) 
3 times (clinically) over 12 
months. 
Monthly (clinically) for 12 
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 (3 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.  


Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H302, RUBATO OL 
Version 4 
19 November 2020, page 111/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO OL procedures 
Burden  
Risk 
Conclusion 
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. 
 
 
 


Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H302, RUBATO OL 
Version 4 
19 November 2020, page 112/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO OL 
procedures 
Burden  
Risk 
Conclusion 
Imaging 
  
  
  
  
Echocardiogram 
(yearly) 
2 times over 12 months. 
= 
Same monitoring in RUBATO 
OL. 
= 
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. 
CPET (between twice 
a year to not 
necessarily every year) 
1 times over 12 months. 
= 
Same monitoring in RUBATO 
OL. 
= 
Same burden and same risk 
as SoC. 
 


Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H302, RUBATO OL 
Version 4 
19 November 2020, page 113/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO OL procedures 
Burden  
Risk 
Conclusion 
Blood tests  
  
  
  
  
Many blood 
parameters are 
surveyed 
(yearly or  
bi-yearly) 
Comprehensive set of 
parameters are monitored in 
RUBATO. 
3 times over 12 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.  
Liver function 
related common 
blood parameters 
Will be controlled monthly 
for the first 6 months and 
then every 12 weeks until 
EOT. 
 
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) 
1 times over 12 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-055H302, RUBATO OL 
Version 4 
19 November 2020, page 114/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO OL 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. 
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. 


Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H302, RUBATO OL 
Version 4 
19 November 2020, page 115/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
SoC procedures 
RUBATO OL procedures 
Burden  
Risk 
Conclusion 
Not part of SoC 
Medications triggering a drug-
drug-interaction with 
macitentan 
Not allowed in RUBATO OL. 
= 
Exclusion at baseline 
or forbidden 
concomitant 
medications. 
Concomitant 
medications (with 
doses) are recorded at 
each visit. 
 
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. 
Non-medicinal treatment 
 
  
  
  
  
Pacemaker 
Allowed in RUBATO OL. 
No burden 
No risk 
 
Implanted defibrillators 
Allowed 
No burden 
No risk 
  


Macitentan / ACT-064992 
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Protocol AC-055H302, RUBATO OL 
Version 4 
19 November 2020, page 116/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
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. 
AE = adverse event; CPET = cardiopulmonary exercise testing; DDI = drug-drug interaction; ERA = endothelin receptor antagonist; FC = functional class; OL = open-
label; 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-055H302, RUBATO OL 
Version 4 
19 November 2020, page 117/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
Appendix 7 
Child-Pugh Score 
The Child-Pugh classification will be used to assess the severity of the liver disease 
according to the following table. 
 
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.  
 
 


Macitentan / ACT-064992 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H302, RUBATO OL 
Version 4 
19 November 2020, page 118/118 
Confidential 
EudraCT 2018-002821-45 
Doc No D-20.426 
 
Confidential – FOIA Exemptions Apply in U.S. 
 
Appendix 8 
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 amendment is 
provided below. 
 
Amendment 
Date 
Main reason(s) 
1 
20 Feb 
2019 
Introducing the “flying nurse service” for laboratory 
collection; reducing mandatory safety monitoring after the 
first half year; clarifying contraception measures for new 
countries 
2 
16 Jul 
2020 
Updates to exclusion criteria, forbidden medication and 
concomitant therapy sections based on newly identified 
drug-drug interactions. 
3 
21 July 
2020 
To update the exclusion criteria, initiation of forbidden 
medication and concomitant therapy sections pertaining to 
newly identified drug-drug interactions (DDI) between 
macitentan and fluconazole (a dual moderate inhibitor of 
CYP3A4 & CYP2C9) from a pre-clinical study on 
implications of role of CYP2C9 in the metabolism of 
macitentan. 
 


CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
1 
Status: Approved, Date: 17 June 2020 
Actelion Pharmaceuticals Ltd 
Janssen Research & Development * 
Clinical Protocol 
COVID-19 Appendix 
Protocol Title 
Prospective, multi-center, single-arm, open-label long-term study assessing the safety, 
tolerability, and effectiveness of macitentan in Fontan palliated adult and adolescent 
subjects 
 RUBATO OL 
Macitentan in Fontan-palliated subjects 
Protocol AC-055H302; 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-20.159 
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. 
NCT03775421


COVID-19 Appendix  
 
JNJ-67896062/ACT-064992 Macitentan  
Clinical Protocol AC-055H302  
 
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 
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 investigational 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-055H302  
 
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 
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 efficacy assessments 
If subjects cannot conduct their cardiopulmonary exercise testing (CPET) assessments as 
expected, these should be done at the earliest possibility during a scheduled or unscheduled 
visit. 
For Week 104, the CPET assessment could be conducted up to 8 weeks later. 
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).  
The accelerometer will be assigned by sites and shipped to the subject 4 weeks prior to the 
expected visit. The subject will be instructed to wear it for 9 consecutive days after (or for 


COVID-19 Appendix  
 
JNJ-67896062/ACT-064992 Macitentan  
Clinical Protocol AC-055H302  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
4 
Status: Approved, Date: 17 June 2020 
Week 104 before) the expected visit date, and subsequently ship the activity monitor back to 
the site at the end of the wear period.  
Missed CPET or PA-Ac assessments will be identified as issues in the CTMS as “COVID-
19-related issues” 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 measurements at the next planned IDMC meeting, as long as the 
AC-055H301 RUBATO study continues. 
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 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.