Clinical trial NCT03904693
Conditions: Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH)
Keywords: Pulmonary Arterial Hypertension PAH macitentan tadalafil fixed dose combination therapy
Sponsor: Actelion
Start date: 2019-07-29; Completion date: 2024-09-27
Enrollment: 187 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Combination therapy in pulmonary arterial hypertension (PAH) has been the subject of active investigation for more than a decade, with the benefit of targeting different pathways known to be involved in the pathogenesis of the disease. Adherence to prescribed therapy has an impact on clinical outcomes. Reducing the pill/tablet count and frequency has a major impact on patients' adherence to therapies and therefore the observed clinical outcomes. One way to simplify treatment is to use fixed-dose combination (FDC) products that combine multiple treatments targeting different pathways into a single tablet.

This study aims to demonstrate that the FDC of macitentan and tadalafil is more effective than therapy with 10 mg of macitentan alone or 40 mg of tadalafil alone. This phase 3 study will evaluate the efficacy and safety at 16 weeks of an FDC (macitentan 10 mg and tadalafil 40 mg) against these two PAH-approved therapies given as monotherapy to further confirm the added value of the FDC.

Detailed description:
PAH is characterized by a progressive increase in pulmonary arterial pressure (PAP) and in pulmonary vascular resistance (PVR) potentially leading to right heart failure and death. Current PAH-specific therapeutic options include treatments that target the three pathways (endothelin, nitric oxide, and prostacyclin pathways). While combination treatment is common, FDC pills or tablets that combine two or more PAH-specific therapies are not available, thereby requiring participants to take multiple pills/tablets daily. An FDC is an attractive option for PAH participants because it simplifies the treatment regimen by combining two therapies (which would otherwise involve a total of three tablets: one macitentan 10 mg tablet and two tadalafil 20 mg tablets) into a single tablet. Macitentan is an orally active, non-peptide, potent dual endothelin receptor A and B antagonist. Tadalafil is a selective inhibitor of phosphodiesterase type-5 (PDE-5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). This study comprises the following consecutive periods: Screening period (lasts up to 30 days), Double-blind treatment period (consists of the titration phase \[the first 2 weeks\] and the maintenance phase \[Week 3 through Week 16\]), Open-label treatment period, End-of-Treatment (EOT), Safety follow-up (S-FU) period, and End of Study (EOS). The total study duration for a participant will be up to 30 months. Study assessments like physical examinations, vital signs, right heart catheterization, 6-minute walk test will be performed. Safety will be assessed throughout the study.

Arms: arm 1: Subjects to receive FDC macitentan/tadalafil (macitentan 10 mg and tadalafil 40 mg) plus matching placebos for the two other study treatments. arm 2: Subjects to receive macitentan 10 mg plus matching placebos for the two other study treatments. arm 3: Subjects to receive tadalafil 40 mg (2 x 20 mg) plus matching placebos for the two other study treatments.
Interventions: intervention 1: FDC macitentan/tadalafil intervention 2: Macitentan 10 mg intervention 3: Tadalafil 40 mg intervention 4: Placebo FDC intervention 5: Placebo macitentan intervention 6: Placebo tadalafil
Intervention descriptions: intervention 1: Film-coated tablet with 10 mg macitentan and 40 mg tadalafil, to be administered orally once daily. intervention 2: Film-coated tablet with 10 mg macitentan, to be administered orally once daily. intervention 3: Film-coated tablet with 40 mg tadalafil (2 x 20 mg tablets), to be administered orally once daily. intervention 4: Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily. intervention 5: Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily. intervention 6: Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.

Protocol documents:
Prot_000.pdf: 
Actelion Pharmaceuticals Ltd.*
(a Janssen Pharmaceutical Company of Johnson & Johnson)
Confidential FOIA Exemptions Apply in U.S.
Macitentan / Tadalafil
Pulmonary Arterial Hypertension
Protocol AC-077A301
A DUE
Prospective, multi-center, double-blind, randomized, active-controlled, triple-dummy,
parallel-group, group-sequential, adaptive Phase 3 clinical study to compare the efficacy and
safety of macitentan and tadalafil monotherapies with the corresponding fixed dose
combination in subjects with pulmonary arterial hypertension (PAH), followed by an open-
label treatment period with macitentan and tadalafil fixed dose combination therapy
*Actelion Pharmaceuticals Ltd (“Actelion”) is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Actelion studies may vary, such as, but not
limited to Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; or Janssen Research &
Development, LLC. The term “sponsor” is used throughout the protocol to represent these various legal entities; the
sponsor is identified on the Contact Information page that accompanies the protocol.
Study Phase: 
3
EudraCT Number: 
2014-004786-25
Status and version: 
Final Version 7
Date: 
21 November 2022
Document type: 
Global Protocol
EDMS Number: 
EDMS-RIM-263896, 5.0
Confidentiality statement
The information provided herein contains Company trade secrets, commercial or financial information that the
Company customarily holds close and treats as confidential. The information is being provided under the assurance
that the recipient will maintain the confidentiality of the information under applicable statutes, regulations, rules,
protective orders or otherwise.
NCT03904693


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SPONSOR CONTACT DETAILS
Sponsor 
Actelion Pharmaceuticals Ltd*
Gewerbestrasse 16
CH-4123 Allschwil
Switzerland
 
+41 61 565 65 65
Clinical Trial Physician 
Contact details of the Clinical Trial Physician can be
found in the Investigator Site File
Medical Emergency Hotline 
Toll phone number: 
Site-specific toll telephone numbers and toll-free
numbers for the Medical Emergency Hotline can be
found in the Investigator Site File
* Actelion Pharmaceuticals Ltd. (“Actelion”) is a Janssen pharmaceutical company of Johnson & Johnson and is
hereafter referred to as the sponsor of the study.


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CONTRACT RESEARCH ORGANIZATION INFORMATION
CENTRAL LABORATORY 
Covance, Inc. / 8211 SciCor Drive,
Indianapolis, IN 46214, USA
Contact person: 
Please refer to the Central Laboratory Manual.
CENTRAL 
RANDOMIZATION/IxRS  
Almac Clinical Technologies / 25 Fretz Road,
Souderton, PA 18964, USA
Contact person 
Please refer to Vendor Manual
CENTRAL IMAGE PROCESSING 
CENTER  
WorldCare Clinical
7 Bulfinch Place
Boston, MA 02114
USA
Contact person 
Please refer to Vendor Manual
INDEPENDENT 
STATISTICAL 
SUPPORT GROUP 
Frontier Science Foundation
440 Science Drive, Suite 401
Madison WI 53711, USA
CLINICAL 
OUTCOMES 
SOLUTIONS LLC  
1820 E River Rd. #220
Tucson, AZ 85718 US
A list of site-specific contact details for Contract Research Organizations (CROs) can be found
in the Investigator Site File.


Macitentan / tadalafil (M/T FDC)
Pulmonary arterial hypertension
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 6, Version 7 
21 November 2022
Amendment 5, Version 6 
27 April 2021
Amendment 4, Version 5 
20 October 2020
Amendment 3, Version 4 
17 July 2020
Amendment 2, Version 3 
28 February 2020
Amendment 1, Version 2 
12 August 2019
Original Protocol, Version 1 
22 February 2019
Amendment 6 Version 7 (21November 2022)
Overall Rationale for the Amendment: To capture participant experience while on M/T FDC, a
semi- structured qualitative interview substudy will assess the participant's experience with study treatment,
with regard to satisfaction with treatment regimen and adherence to treatment.
The Changes made to the clinical protocol AC-077A301 as part of Protocol Amendment 6 are listed below,
including the rationale of each change and a list of all applicable sections. Changes made in previous
protocol amendments are listed in Section 14.11 Appendix 11: Protocol Amendment History.
Section Number 
and Name
Description of Change 
Brief Rationale
Protocol Synopsis 
Updated as per changes made to the protocol body text 
To obtain information on patient’s
experience with FDC
7.1.2 
Unscheduled
visits
Table 5 Open label treatment period visit and assessment
schedule is updated to add the qualitative interview and
footnote 13 is added
To obtain information on patient’s
experience with FDC
7.2.2.12 Qualitative 
Interview  
A new subsection on Semi structured qualitative
interview, including its description and design is added
To capture participant experience while
on M/T FDC, a semi structured
qualitative interview substudy will
assess the patient's experience with
study treatment, satisfaction with
treatment regimen, and adherence to
treatment.
9.1.2 Intensity of
adverse events
Updated AE reporting process if there is a change in
intensity as per Janssen SAE/AE reporting process
To fulfill the HA requirement
3.1 
Study
Design,
10.4 Interim Analysis
for Efficacy, Futility,
and Adaptive Sample
Size Re estimation
Text is rephrased to clarify that the IA will only include
data from countries in which the global amendment 5
has been approved
This clarification was made via a
Protocol Clarification Communication
issued on 10 Sep 2021 (prior to IA
conducted in March 2022)
Throughout the
protocol
Minor grammatical, formatting, or spelling changes are
made.
Minor errors were noted


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Pulmonary arterial hypertension
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TABLE OF CONTENTS
SPONSOR CONTACT DETAILS...................................................................................... 2
CONTRACT RESEARCH ORGANIZATION INFORMATION......................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE................................4
TABLE OF CONTENTS..................................................................................................... 5
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................13
PROTOCOL SYNOPSIS AC-077A301............................................................................17
PROTOCOL ...................................................................................................................... 32
1 BACKGROUND......................................................................................................... 32
1.1 
Indication...................................................................................................... 32
1.1.1 
Pulmonary Arterial Hypertension.....................................................32
1.1.2 
Current treatment practice ................................................................32
1.2 
Study Treatment(s) .......................................................................................33
1.2.1 
Macitentan/Tadalafil FDC................................................................33
1.2.1.1 
Nonclinical results of combination macitentan and tadalafil..33
1.2.1.2 
Clinical pharmacology of combination macitentan and tadalafil
................................................................................................. 33
1.2.1.3 
Clinical efficacy of combination macitentan and tadalafil......34
1.2.1.4 
Summary of safety profile of combination macitentan and
tadalafil....................................................................................34
1.2.2 
Macitentan ........................................................................................34
1.2.2.1 
Non-clinical results of macitentan...........................................34
1.2.2.2 
Clinical pharmacology of macitentan......................................35
1.2.2.3 
Clinical efficacy of macitentan................................................35
1.2.2.4  
Summary of safety profile of macitentan................................35
1.2.3 
Tadalafil............................................................................................ 35
1.2.3.1 
Non-clinical results of tadalafil...............................................35
1.2.3.2 
Clinical pharmacology of tadalafil..........................................36
1.2.3.3 
Clinical efficacy of tadalafil....................................................36
1.2.3.4  
Summary of safety profile of tadalafil ....................................36
1.3 
Purpose and Rationale of the Study..............................................................36
1.4 
Summary of Known and Potential Risks and Benefits.................................37
1.4.1 
Benefits............................................................................................. 37
1.4.2 
Possible risks..................................................................................... 37
1.4.3 
Benefit/risk analysis..........................................................................38
2 STUDY OBJECTIVES............................................................................................... 39
2.1 
Primary Objective.........................................................................................39


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2.2 
Secondary Objectives ...................................................................................39
2.3 
Other Objectives........................................................................................... 39
3 
OVERALL STUDY DESIGN AND PLAN...............................................................39
3.1 
Study Design................................................................................................. 39
3.1.1 
Study periods ....................................................................................40
3.1.1.1 
Stratified randomization summary..........................................45
3.1.1.2 
Premature study treatment discontinuation.............................45
3.1.2 
Study duration...................................................................................45
3.2 
Study Design Rationale ................................................................................46
3.3 
Site Personnel and Roles ..............................................................................47
3.3.1 
Right heart catheterization................................................................47
3.3.2 
6-minute walk test.............................................................................47
3.4  
Study Committees......................................................................................... 47
4 SUBJECT POPULATION..........................................................................................47
4.1 
Subject Population Description....................................................................47
4.2 
Rationale for the Selection of the Study Population.....................................48
4.3 
Inclusion Criteria..........................................................................................48
4.4  
Exclusion Criteria.........................................................................................49
4.5 
Criteria for Women of Childbearing Potential .............................................51
4.5.1 
Definition of childbearing potential..................................................51
4.5.2 
Acceptable methods of contraception...............................................52
5 TREATMENTS .......................................................................................................... 53
5.1 
Study Treatment ...........................................................................................53
5.1.1 
Investigational treatment: description and rationale.........................53
5.1.1.1 
M/T FDC.................................................................................53
5.1.2 
Comparator treatments: description and rationale............................53
5.1.2.1 
Macitentan 10 mg....................................................................53
5.1.2.2 
Tadalafil 20 mg .......................................................................53
5.1.3 
Study treatment administration.........................................................53
5.1.3.1 
Double-blind treatment period ................................................53
5.1.3.2 
Open-label treatment period....................................................56
5.1.4 
Treatment assignment.......................................................................58
5.1.5 
Blinding ............................................................................................ 58
5.1.6 
Unblinding........................................................................................59
5.1.6.1 
Timing of study analyses.........................................................59
5.1.6.2 
Unblinding for IDMC..............................................................60
5.1.6.3 
Unblinding for the final double-blind treatment period analysis
................................................................................................. 60
5.1.6.4  
Unblinding for suspected unexpected serious adverse reactions
................................................................................................. 60
5.1.6.5 
Emergency procedure for unblinding......................................60


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5.1.7 
Study treatment supply.....................................................................61
5.1.7.1 
Study treatment packaging and labeling .................................61
5.1.7.2 
Study treatment distribution and storage.................................61
5.1.7.3 
Study treatment dispensing .....................................................62
5.1.7.4 
Study treatment return and destruction ...................................62
5.1.8 
Study treatment accountability and compliance with study treatment62
5.1.8.1 
Study treatment accountability................................................62
5.1.8.2 
Study treatment compliance....................................................62
5.1.9 
Study treatment dose adjustments and interruptions ........................63
5.1.10 
Premature discontinuation of study treatment..................................64
5.1.11 
Study-specific criteria for interruption / premature discontinuation of
study treatment..................................................................................65
5.1.11.1 
Pregnancy................................................................................65
5.1.11.2 
Liver aminotransferases abnormalities....................................65
5.1.11.3 
Hemoglobin abnormalities ......................................................66
5.1.11.4 
Severe renal impairment..........................................................67
5.1.11.5 
Vision disorder........................................................................67
5.1.11.6 
Start of doxazosin and/or organic nitrates...............................67
5.1.12 
Study treatment overdose and treatment...........................................67
5.2 
Previous and Concomitant Medications.......................................................67
5.2.1 
Definitions ........................................................................................67
5.2.2 
Reporting of previous/concomitant medications in the eCRF..........67
5.2.3 
Allowed concomitant therapy...........................................................67
5.2.4  
Forbidden concomitant therapy........................................................68
6 STUDY ENDPOINTS ................................................................................................69
6.1 
Efficacy Endpoints .......................................................................................69
6.1.1 
Primary efficacy endpoint.................................................................69
6.1.2 
Secondary efficacy endpoints...........................................................70
6.1.3 
Other efficacy endpoints...................................................................70
6.1.3.1 
Other efficacy endpoints for double-blind treatment period...70
6.1.3.2 
Other efficacy endpoints for open-label treatment period.......71
6.2 
Safety endpoints ...........................................................................................72
7 VISIT SCHEDULE AND STUDY ASSESSMENTS................................................72
7.1 
General Information .....................................................................................72
7.1.1 
Screening/re-screening......................................................................73
7.1.2 
Unscheduled visits............................................................................73
7.2 
Study Assessments .......................................................................................79
7.2.1 
Demographics / baseline characteristics...........................................79
7.2.2 
Efficacy assessments.........................................................................80
7.2.2.1 
Right heart catheterization.......................................................80
7.2.2.2 
6-minute walk test and Borg CR10 Scale® .............................81
7.2.2.3 
PAH-SYMPACT questionnaire ..............................................82
7.2.2.4  
WHO FC..................................................................................83


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7.2.2.5 
Morbidity/Mortality event assessment....................................83
7.2.2.6 
NT-proBNP .............................................................................84
7.2.2.7 
Optional biomarker assessment...............................................84
7.2.2.8 
EQ-5D-5L................................................................................84
7.2.2.9 
Work Productivity and Activity Impairment Questionnaire©:
General Health (WPAI©: GH) V2.0........................................85
7.2.2.10 
Patient Global Assessment of Disease Severity (PGA-S).......85
7.2.2.11 
Patient Global Impression of Change (PGI-C)........................86
7.2.2.12 
Semi-structured Qualitative Interview ....................................86
7.2.2.13 
Survival Follow-up..................................................................86
7.2.3 
Safety assessments............................................................................87
7.2.3.1 
Concomitant Medications........................................................87
7.2.3.2 
Physical examination...............................................................87
7.2.3.3 
Vital signs, weight, and height................................................87
7.2.4 
Laboratory assessments ....................................................................87
7.2.4.1 
Type of laboratory...................................................................87
7.2.4.2 
Laboratory tests.......................................................................88
8 STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL CARE90
8.1 
Study Completion per Protocol ....................................................................90
8.2 
Premature Withdrawal From Study..............................................................90
8.3 
Premature Termination or Suspension of the Study.....................................91
8.4 
Medical Care of Subjects After Study Completion / Withdrawal From Study
...................................................................................................................... 91
9 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS...........................92
9.1 
Adverse Events............................................................................................. 92
9.1.1 
Definition of adverse events .............................................................92
9.1.2 
Intensity of adverse events................................................................92
9.1.3 
Relationship to study treatment ........................................................93
9.1.4 
Reporting of adverse events..............................................................93
9.1.5 
Follow-up of adverse events and serious adverse events .................93
9.2 
Serious Adverse Events................................................................................93
9.2.1 
Definitions of serious adverse events ...............................................93
9.2.2 
Reporting of serious adverse events .................................................94
9.2.3 
Follow-up of serious adverse events.................................................94
9.2.4 
After the 30-day follow-up period....................................................94
9.2.5 
Reporting procedures........................................................................95
9.3 
Pregnancy ..................................................................................................... 95
9.3.1 
Reporting of pregnancy ....................................................................95
9.3.2 
Follow-up of pregnancy....................................................................96
9.4 
Product Quality Complaints .........................................................................96
9.4.1 
Definition..........................................................................................96
9.4.2 
Reporting Procedures........................................................................96
9.5 
Special Reporting Situations ........................................................................96


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9.6 
Study Safety Monitoring ..............................................................................97
10 STATISTICAL METHODS ....................................................................................... 97
10.1 
Analysis Sets................................................................................................. 97
10.1.1 
Screened Analysis Set.......................................................................97
10.1.2 
All Randomized Analysis Set...........................................................98
10.1.3 
Full Analysis Set...............................................................................98
10.1.4 
Safety Set..........................................................................................98
10.1.5 
Open-label Set...................................................................................98
10.1.6 
Combination Safety Set....................................................................98
10.1.7 
Long-term M/T FDC Set ..................................................................98
10.1.8 
QoL analysis sets ..............................................................................98
10.1.9 
Usage of the analysis sets .................................................................99
10.2 
Variables....................................................................................................... 99
10.2.1 
Primary efficacy variable..................................................................99
10.2.2 
Secondary efficacy variables ............................................................99
10.2.2.1 
6-minute walk distance............................................................99
10.2.2.2 
PAH-SYMPACTTM Symptom domains scores.......................99
10.2.2.3 
WHO FC................................................................................100
10.2.3 
Other efficacy variables..................................................................100
10.2.4  
Safety variables...............................................................................100
10.2.4.1 
Double-blind treatment-emergent period..............................100
10.2.4.2 
Combination treatment-emergent period...............................100
10.3 
Description of Statistical Analyses.............................................................100
10.3.1 
Overall testing strategy...................................................................100
10.3.2 
Analysis of the primary efficacy variable.......................................101
10.3.2.1 
Estimand................................................................................101
10.3.2.2 
Hypotheses and statistical model ..........................................102
10.3.2.3 
Treatment groups...................................................................103
10.3.2.4  
Handling of missing data.......................................................103
10.3.2.5 
Main analysis.........................................................................104
10.3.2.6 
Supportive/sensitivity analyses .............................................104
10.3.3 
Analysis of secondary efficacy variables........................................106
10.3.3.1 
Change from baseline to EDBT in 6MWD...........................106
10.3.3.2 
Change from baseline to EDBT in PAH-SYMPACTTM symptom
domain scores........................................................................107
10.3.3.3 
Proportion of subjects with no worsening in WHO FC between
baseline and EDBT................................................................108
10.3.4  
Sub-group analyses.........................................................................108
10.3.5 
Analysis of the safety variable(s)....................................................109
10.3.5.1 
Adverse events ......................................................................109
10.3.5.2 
Laboratory variables..............................................................110
10.3.5.3 
Vital signs and body weight..................................................110
10.4 
Interim Analysis for Efficacy, Futility, and Adaptive Sample Size
Re-estimation.............................................................................................. 110


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10.5 
Sample Size ................................................................................................ 111
10.5.1 
Sample size assumptions ................................................................113
10.5.2 
Sample size sensitivity....................................................................114
11 DATA HANDLING.................................................................................................. 114
11.1 
Data Collection........................................................................................... 114
11.2 
Maintenance of Data Confidentiality .........................................................115
11.3 
Database Management and Quality Control...............................................115
12 PROCEDURES AND GOOD CLINICAL PRACTICE...........................................116
12.1 
Ethics and Good Clinical Practice..............................................................116
12.2 
Independent Ethics Committee / Institutional Review Board....................116
12.3 
Informed Consent....................................................................................... 116
12.4 
Indemnification, Compensation and Refund of Expenses to Subjects and
Investigators................................................................................................ 117
12.5 
Protocol Adherence/Compliance................................................................118
12.6 
Protocol Amendments ................................................................................118
12.7 
Essential Documents and Retention of Documents....................................118
12.8 
Monitoring.................................................................................................. 119
12.9 
Investigator Site File................................................................................... 120
12.10 Audit........................................................................................................... 120
12.11 Inspections.................................................................................................. 120
12.12 
Reporting of Study Results and Publication...............................................121
13 REFERENCES.......................................................................................................... 122
14 APPENDICES........................................................................................................... 126
14.1 
Appendix 1 Sponsor Guidelines for the Right Heart Catheterization Procedure
.................................................................................................................... 126
14.1.1 
MATERIAL AND METHODS......................................................126
14.1.1.1 
HEART CATHETERIZATION PROCEDURES.................126
14.1.1.2 
HEART CATHETERIZATION MEASUREMENTS..........127
14.1.1.3 
Other measurements..............................................................129
14.1.2 
DOCUMENTATION .....................................................................129
14.1.2.1 
Tracings.................................................................................129
14.1.2.2 
Heart catheterization worksheet............................................129
14.1.3 
ASSESSMENTS.............................................................................130
14.1.3.1 
Hemodynamic variables measured during RHC:..................130
14.1.3.2 
Calculated hemodynamic variables:......................................130
14.1.4 
IDENTIFYING ABNORMALLY ELEVATED OR LOW PAWP131
14.1.4.1 
The problem:.........................................................................131
14.1.4.2 
How to identify an incorrect wedge:.....................................131
14.1.4.3 
Tips in case of suspected partial occlusion:..........................132
14.2 
Appendix 2 Sponsor Guidelines for the 6MWT.........................................133


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14.2.1 
INSTRUCTIONS............................................................................133
14.2.1.1 
General ..................................................................................133
14.2.1.2 
Training tests.........................................................................134
14.2.1.3 
Timing...................................................................................134
14.2.2 
TEST REQUIREMENTS...............................................................134
14.2.2.1 
Participant..............................................................................134
14.2.2.2 
Equipment to perform the test...............................................134
14.2.3 
PERFORMING THE 6MWT.........................................................135
14.2.3.1 
Instructions to the participant before the 6MWT..................135
14.2.3.2 
Instructions to the participant during the 6MWT..................135
14.2.3.3 
Instructions to the participant after the 6MWT.....................137
14.2.4  
6MWT WORKSHEET...................................................................138
14.2.5 
THE BORG SCALE [to be used for patients randomized under
protocol versions 1 and 2]...............................................................138
14.2.6 
THE BORG CR10 SCALE® [to be used for patients randomized
under protocol versions 3 and later] ...............................................139
14.3 
Appendix 3 WHO Functional Classification of Pulmonary Hypertension 143
14.4  
Appendix 4 Marked Laboratory Abnormalities .........................................144
14.5 
Appendix 5 PAH-SYMPACT™Questionnaire..........................................146
14.5.1 
Administration and Scoring............................................................146
14.5.1.1 
Administration.......................................................................146
14.5.1.2 
Scoring...................................................................................146
14.5.1.3 
Symptoms..............................................................................150
14.5.1.4 
Impacts ..................................................................................151
14.5.2 
Sample Questionnaire.....................................................................152
14.6 
Appendix 6 EQ-5D-5L............................................................................... 162
14.7 
Appendix 7 PGA-S and PGI-C Scales .......................................................164
14.7.1 
Patient Global Assessment of Disease Severity (PGA-S) ..............164
14.7.2 
Patient Global Impression of Change (PGI-C)...............................165
14.8 
Appendix 8 Model for End-stage Liver Disease (MELD) Score...............166
14.9 
Appendix 9 Work Productivity and Activity Impairment Questionnaire:
General Health (WPAI©: GH) V2.0 ...........................................................167
14.10 Appendix 10 Study Conduct During a Natural Disaster ............................169
14.11 Appendix 11 Protocol Amendment History...............................................170
INVESTIGATOR AGREEMENT................................................................................... 171


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LIST OF TABLES
Table 1 
Acceptable methods of contraception........................................................52
Table 2 
Treatment administration in the double-blind treatment period.................55
Table 3 
Treatment administration in the open-label treatment period....................57
Table 4  
Double-blind treatment period visit and assessment schedule...................74
Table 5 
Open-label treatment period visit and assessment schedule ......................77
Table 6 
Alpha spending in scenario with recruitment rates proportional to strata size
.................................................................................................................. 111
Table 7 
Sample size sensitivity for the main analysis...........................................114
Table 8 
Symptoms (n  11)................................................................................... 146
Table 9 
Impacts (n  11) ....................................................................................... 149
LIST OF FIGURES
Figure 1 
Study design............................................................................................... 44
Figure 2 
Study analyses............................................................................................ 59
Figure 3 
Randomization Scheme............................................................................112
Figure 4  
Contribution of Randomization Treatment Allocation to the Comparison of
Interest...................................................................................................... 113


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LIST OF ABBREVIATIONS AND ACRONYMS
6MWT  
6-minute walk test
6MWD  
6-minute walk distance
AE 
Adverse event
ALT  
Alanine aminotransferase
ANCOVA  
Analysis of covariance
AST 
Aspartate aminotransferase
ATS  
American Thoracic Society
BMI 
Body mass index
BSA  
Body surface area
CEC  
Clinical Event Committee
cGMP  
Cyclic guanosine monophosphate
CI 
Confidence interval
CL 
Confidence limit
CO  
Cardiac output
CRO  
Contract Research Organization
CSR  
Clinical Study Report
CSS  
Combination safety set
CTT  
Clinical Trial Team
CYP  
Cytochrome P450
DBP  
Diastolic blood pressure
dPAP  
Diastolic pulmonary artery pressure
ECG  
Electrocardiogram
eCRF  
Electronic case report form
EDBT  
End of Double-blind Treatment
eGFR  
Estimated glomerular filtration rate
EOLT  
End of Open-Label Treatment
EOS  
End-of-Study
EOT  
End-of-Treatment
EQ-5D-5L 
Euro Quality of Life-5D-5L
ERA  
Endothelin receptor antagonist
FAS  
Full Analysis Set
FC  
Functional class
FDC  
Fixed dose combination
FEV1 
Forced expiratory volume in 1 second


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FVC  
Forced vital capacity
GCP  
Good Clinical Practice
GM  
Geometric mean
GMP  
Good Manufacturing Practice
GMR  
Geometric means ratio
HIV  
Human immunodeficiency virus
HR  
Heart rate
IA  
Interim analysis
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
IRB  
Institutional Review Board
IRT  
Interactive Response Technology
ISF  
Investigator Site File
LHC  
Left heart catheterization
LFT  
Liver function tests
LS  
Least squares
LTFDCS  
Long-term M/T FDC Set
LVEDP  
Left ventricular end-diastolic pressure
M/M  
Morbidity/Mortality
M/T  
Macitentan/tadalafil
mCTMS  
Medidata clinical trial management system
MedDRA  
Medical Dictionary for Regulatory Activities
MELD  
Model for end-stage liver disease
mPAP  
Mean pulmonary arterial pressure
mRAP  
Mean right atrial pressure
NT-proBNP  
N-terminal pro B-type natriuretic peptide
OLS  
Open-label Set
OR  
Odds ratio
PA  
Pulmonary artery
PAC  
Pulmonary artery compliance
PAH  
Pulmonary arterial hypertension


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PAP  
Pulmonary arterial pressure
PAPi 
Pulmonary artery pulsatility index
PAWP  
Pulmonary artery wedge pressure
PDE-5 
Phosphodiesterase type-5
PDE-5i 
Phosphodiesterase type-5 inhibitor
PGA-S  
Patient Global Assessment of Severity
PGI-C  
Patient Global Impression of Change
PI 
Principal Investigator
PQC  
Product quality complaint
PVR  
Pulmonary vascular resistance
QoL 
Quality of Life
QS  
Quality System
RHC  
Right heart catheterization
RSI 
Reference safety information
RVSWI 
Right ventricular stroke work index
SAE 
Serious adverse event
SAP  
Statistical Analysis Plan
SBP 
Systolic blood pressure
S-FU  
Safety follow-up
SI 
International System of Units
SIV  
Site initiation visit
SOC  
System organ class
sPAP  
Systolic pulmonary artery pressure
SS 
Safety analysis Set
SSG 
Statistical support group
sSAP  
Systolic systemic artery pressure
SM 
Site Manager
SUSAR  
Suspected unexpected serious adverse reaction
SV 
Stroke volume
SVI 
Stroke volume index
TPR  
Total pulmonary resistance
ULN  
Upper limit of normal
VAS  
Visual analog scale
WHO  
World Health Organization
WPAI©: GH  
Work Productivity and Activity Impairment©: General Health


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WU  
Wood units


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PROTOCOL SYNOPSIS AC-077A301
TITLE
Prospective, 
multi-center, 
double-blind, 
randomized,
active-controlled, triple-dummy, parallel-group, group-sequential,
adaptive Phase 3 clinical study to compare the efficacy and safety of
macitentan and tadalafil monotherapies with the corresponding fixed
dose combination in subjects with pulmonary arterial hypertension
(PAH), followed by an open-label treatment period with macitentan
and tadalafil fixed dose combination therapy
ACRONYM
A DUE
OBJECTIVES
Primary objective
The study has 2 co-primary objectives:
1. To evaluate the effect of the fixed dose combination (FDC) of
macitentan 10 mg and tadalafil 40 mg vs macitentan 10 mg alone
on pulmonary vascular resistance (PVR) at End of Double-blind
Treatment (EDBT) in participants with symptomatic World
Health Organization (WHO) Group 1 PAH who are
PAH-specific treatment-naïve or are currently being treated with
an endothelin receptor antagonist (ERA) as monotherapy.
2. To evaluate the effect of the FDC of macitentan 10 mg and
tadalafil 40 mg vs tadalafil 40 mg alone on PVR at EDBT in
participants with symptomatic WHO Group 1 PAH who are
PAH-specific treatment-naïve or currently being treated with a
phosphodiesterase type-5 inhibitor (PDE-5i) as monotherapy.
Secondary objectives
 To evaluate the effect of the macitentan/tadalafil (M/T) FDC
compared to the respective monotherapies on:
- Exercise capacity.
- PAH symptoms in participants’ cardiopulmonary and
cardiovascular function
- WHO functional class (FC).
 To evaluate the safety and tolerability of the M/T FDC in the
participant population.
Other objectives
Other objectives are described in Section 2.3.
DESIGN
A 
prospective, 
multi-center, 
double-blind, 
randomized,
active-controlled, triple-dummy, parallel-group, group-sequential,
adaptive Phase 3 clinical study with an open-label treatment period.


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PERIODS
Screening period: Lasts up to 30 days; starts with the signature of
the informed consent form (Visit 1) and ends the day prior to
Randomization (Visit 2).
Double-blind treatment period:Starts on the day of randomization
(Visit 2) and ends on the day of the EDBT visit (Visit 8).
The double-blind treatment period consists of the titration phase (the
first 2 weeks) and the maintenance phase (Week 3 through Week
16).
 Titration phase: Starts on the day of randomization (Visit 2)
and lasts 2 weeks, ending the day before Visit 4 (end of Week
2).
- Week 1: Loose combination 10/20: Participants are
treated with a loose combination of macitentan 10 mg
and/or tadalafil 20 mg and relevant placebos, depending
on treatment arm, for 7 days from Randomization
(Visit 2, Day 1) to the end ofWeek 1 (Day 7).
- Week 2: Loose 
combination 
10/40 
up-titration:
Participants are treated with a loose combination of
macitentan 10 mg and/or tadalafil 40 mg and relevant
placebos depending on treatment arm from Day 8 to the
end of Week 2 (Day 14).
- Note: If a participant is already receiving a stable dose of
PDE-5i within prespecified dose range at baseline (ie,
40 mg tadalafil, 60 120 mg sildenafil, or 10 mg
vardenafil daily), no up-titration is needed and they will
receive 40 mg tadalafil from Day 1.
 Maintenance phase: Participants are treated with macitentan
10 mg, tadalafil 40 mg, M/T FDC, or their respective placebos,
depending on treatment arm. This period starts on Day 15 and
lasts until the EDBT visit (Visit 8).
- Note: If a participant cannot tolerate 40 mg tadalafil
during the up-titration period, the participant will remain
on 20 mg tadalafil. The participant is allowed to be
up-titrated once again to 40 mg tadalafil during the first
2 weeks of the maintenance phase of the double-blind
treatment period (ie, between Visits 4 and 5) [Section
5.1.9].
- Note: if a participant prematurely discontinues
double-blind study treatment, they will be asked to return
for an EDBT visit (within ±2 days of the time of
treatment discontinuation and before initiation of new
PAH-specific therapy), a safety follow-up visit 30 days
after last treatment administration, and all remaining


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1 
The open label titration phase treatment assignment will be done through interactive response technology to maintain
blinding of the double blind treatment period treatment.
visits up until the Week 120 visit (excluding Visits 9 and
10). If the participant did not withdraw consent for study
participation and regular visits to the site are not possible,
phone contacts can be performed, at the scheduled visits,
until the Week 120 visit. During these phone calls,
morbidity and mortality events, AE, and concomitant
medication 
information 
will 
be 
collected.
[Section 5.1.10].
Open-label treatment period1: For those participants who
complete 16 weeks of double-blind treatment, the open-label
treatment period starts with the first dose of the open-label FDC
study treatment. All participants will have a titration phase of 2
weeks, during which the 2 drugs will be given as a loose
combination. The open-label treatment period ends 24 months later
with the End-of-Open-Label-Treatment (EOLT) visit.
 Titration phase:
- First week open-label titration: Begins the first day of
open-label treatment and lasts for 7 days. Participants
who were randomized to the macitentan arm, or who
could not tolerate 40 mg tadalafil (or corresponding
placebo), in the double-blind treatment period will
receive a loose combination of macitentan 10 mg and
tadalafil 20 mg. Participants who were randomized to the
M/T FDC or to the tadalafil monotherapy arms and who
tolerated 40 mg tadalafil in the double-blind treatment
period, will receive a loose combination of macitentan 10
mg and tadalafil 40 mg during this week.
- Second week open-label titration: Begins the 8th  day of
open-label treatment and lasts until the 14th  day of
open-label treatment. All participants are treated with a
loose combination of macitentan 10 mg and tadalafil 40
mg. Participants who cannot tolerate 40 mg tadalafil are
not eligible to proceed to the open-label treatment period
maintenance phase and should complete an End of Study
(EOS) visit [see Section 8.1].
 Maintenance phase: Begins the 15th  day of open-label
treatment and ends with the EOLT visit. All participants are
treated with M/T FDC.
- Note: if a participant prematurely discontinues study
treatment, they will be asked to return for an EOLT visit
within ±7 days of the time of treatment discontinuation,


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a safety follow-up visit 30 days after last treatment
administration, and all remaining visits up until the Week
120 visit (excluding Visits 9 and 10). If the participant
did not withdraw consent for study participation and
regular visits to the site are not possible, phone contacts
can be performed, at the scheduled visits, until the Week
120 visit. During these phone calls, M/M, AE, and
concomitant medication information will be collected.
[Section 5.1.10].
End  of Treatment (EOT): The end of all study treatment for an
individual participant.
Safety follow-up (S-FU) period:Starts on the day after the last dose
of study treatment and ends at the Safety Follow-up visit 30 35 days
thereafter.
For participants who completed the 24-months of open-label
treatment and who are eligible for a continued access program (post-
trial access program or other open-label extension study) the S-FU
period will be waived. In such case enrollment into the continued
access program should occur on the same day as the last visit in this
study, ie, EOS visit.
End  of Study (EOS): EOS is reached when all participants have
completed their EOS visit, died, or are lost to follow-up.
For an individual participant, EOS visit is defined as follows:
 For participants that complete treatment, EOS visit is defined as
the safety follow-up visit 30 35 days after last study treatment
intake.
 For participants that prematurely discontinue study treatment,
EOS visit is defined as either the safety follow-up visit
30 35 days after last study treatment intake or the Week 120
visit, whichever comes last.
 For participants who complete treatment and who are eligible for
a continued access program (post-trial access or other open-label
extension study) the EOS visit is defined as the EOLT visit.
SUB-STUDIES
A substudy with semi-structured qualitative interviews will be
conducted in  selected countries among participants that have
reached the open-label treatment period of the study and provided
specific consent to participate in this substudy. Description of the
participant experience with M/T FDC through a content analysis of
the qualitative interview transcripts will be conducted separately to
this study.


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PLANNED DURATION
In total, including the open-label phase, approximately 54 months
from first participant, first visit to last participant, last visit.
In the blinded part of the study, approximately 30 months from first
participant, first visit to last participant, last visit.
SITE(S)
/ COUNTRY(IES)
Approximately 150 sites in approximately 25countries
PARTICIPANTS / GROUPS
170 participants are planned to be randomized into the study.
Treatment allocation will be stratified by treatment status at
baseline, ie, treatment-naïve or treated by an ERA or a PDE-5i as a
monotherapy:
 treatment-naïve participants will be randomized in a 2:1:1 ratio
to M/T FDC, macitentan, or tadalafil.
 participants on ERA monotherapy will be randomized in a 2:1
ratio to M/T FDC or macitentan.
 participants on PDE-5i monotherapy will be randomized in a 2:1
ratio to M/T FDC or tadalafil.
The sample size will be re-estimated at the interim analysis (IA)
based on unblinded effect estimates, following rules as described in
the IDMC charter. If the study is not terminated early for efficacy or
futility, the total size of the sample shall not exceed N  250
participants and shall not be below N
150 participants, accounting
for the overrun of participants recruited during the 16 weeks of
follow-up.
INCLUSION CRITERIA
1. Signed and dated Informed Consent Form.
2. Male and female participants ≥18 years old.
3. Confirmed diagnosis of symptomatic PAH in WHO FC II or III.
4. Symptomatic PAH belonging to one of the following subgroups
of WHO group 1 pulmonary hypertension [Simonneau 2013]:
- Idiopathic.
- Heritable.
- Drug- or toxin-induced.
- Associated with one of the following:
o Connective tissue disease.
o HIV infection.
o Portal hypertension.
o Congenital 
heart 
disease 
with 
simple
systemic-to-pulmonary shunt (atrial septal defect,
ventricular septal defect, patent ductus arteriosus) with
persistent pulmonary hypertension documented by a
right heart catheterization (RHC) ≥1 year after surgical
repair.


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2 
PAH specific treatment is defined as prostanoids, prostacyclin receptor agonists, guanylate cyclase stimulators, ERAs, or
PDE 5is prescribed to treat PAH.
5. PAH diagnosis confirmed by hemodynamic evaluation (based
on central reading) at rest, evaluated within 5 weeks prior to
randomization.
- Mean pulmonary artery pressure  25mmHg; AND
- Pulmonary artery wedge pressure or left ventricular end
diastolic pressure ≤15mmHg; AND
- PVR  3 Wood Units (ie, ≥240 dyn∙sec∙cm 5)
6. Negative vasoreactivity test in idiopathic, heritable, and
drug/toxin-induced PAH. (Patients for whom no vasoreactivity
test was performed at diagnosis can be eligible if currently
treated with PAH therapy for more than 3 months and PAH
diagnosis confirmed by hemodynamic evaluation at least 3
months after introduction of their PAH therapy).
7. Criterion modified per Amendment 5
7.1 Currently receiving a stable dose of ERA or PDE-5i
monotherapy for at least 3 months prior to baseline RHC, within
the prespecified doses below or no history of PAH-specific
treatment2:
- Bosentan: 250 mg total daily dose.
- Macitentan: 10 mg total daily dose.
- Ambrisentan: 10 mg total daily dose.
- Sildenafil: 60 120 mg total daily dose.
- Tadalafil: 40 mg total daily dose.
- Vardenafil: 10 mg total daily dose.
8. Participant able to perform the 6-minute walk test with a
minimum distance of 100 m and maximum distance of 450 m at
Screening.
9. A woman of childbearing potential is eligible only if the
following applies:
- Negative serum pregnancy test at Screening and a
negative urine pregnancy test at Randomization.
- Agreement to undertake monthly urine pregnancy tests
during the study and up to at least 30 days after study
treatment discontinuation.
- Agreement to follow the contraception scheme from
Screening up to at least 30 days after study treatment
discontinuation.
EXCLUSION CRITERIA
PAH treatments:
1. Treatment with a soluble guanylate cyclase stimulator,
L-arginine, any form of prostanoid, or prostacyclin-receptor


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agonist (including oral, inhaled, or infused routes) in the 3-
month period prior to start of treatment.
2. Treatment with combination therapy of ERA and PDE-5i in the
3-month period prior to start of treatment, or history of
intolerance to ERA and PDE-5i combination therapy.
3. Hypersensitivity to any of the study treatments or any excipient
of their formulations.
Other therapies:
4. Treatment with a strong cytochrome P450 (CYP) 3A4 inducer
(eg, rifabutin, rifampin, rifampicin, rifapentin, carbamazepine,
phenobarbital, phenytoin, or St. John’s Wort) in the 1-month
period prior to start of treatment.
5. Criterion modified per Amendment 3
Treatment with a strong CYP3A4 inhibitor (eg, ketoconazole,
itraconazole, voriconazole, clarithromycin, telithromycin,
nefazodone, ritonavir, or saquinavir) or a moderate dual
CYP3A4/CYP2C9 inhibitor (eg fluconazole, amiodarone) or co-
administration of a combination of moderate CYP3A4 and
moderate CYP2C9 inhibitors in the 1-month period prior to start
of treatment.
6. Treatment with doxazosin.
7. Treatment with any form of organic nitrate, either regular or
intermittent.
8. Diuretic treatment initiated or dose changed within 1 week prior
to the RHC or start of treatment.
9. Treatment with another investigational drug in the 3month
period prior to start of treatment.
Medical history/current medical conditions:
10. Body mass index (BMI) >40 kg/m2 at Screening.
11. Known presence of 3 or more of the following risk factors for
heart failure with preserved ejection fraction at Screening:
 BMI >30 kg/m2.
 Diabetes mellitus of any type.
 Essential hypertension (even if well controlled).
 Coronary artery disease, ie, any of the following:
o History of stable angina; or
o Known more than 50% stenosis in a coronary artery; or
o History of myocardial infarction; or
o History of or planned coronary artery bypass grafting
and/or coronary artery stenting.
12. Known presence of moderate or severe obstructive lung disease
(forced expiratory volume in 1 second [FEV1] / forced vital
capacity [FVC] <70% and FEV1 <65% of predicted after
bronchodilator administration) any time prior to Screening.


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3
See Section 14.8 for MELD scoring criteria.
4
Calculated creatinine clearance is measured as eGFR in this study (Section 7.2.4.2).
13. Known presence of moderate or severe restrictive lung disease
(total lung capacity or FVC <60% of normal predicted value)
any time prior to Screening.
14. Clinically significant aortic or mitral valve disease; pericardial
constriction; restrictive or congestive leftsided cardiomyopathy;
life-threatening cardiac arrhythmias; significant left ventricular
dysfunction; or left ventricular outflow obstruction, in the
opinion of the investigator
15. Known permanent atrial fibrillation, in the opinion of the
investigator.
16. Known or suspected uncontrolled thyroid disease (hypo or
hyperthyroidism).
17. Documented pulmonary veno-occlusive disease.
Criteria linked to macitentan/tadalafil use:
18. Hemoglobin <100 g/L (<10 g/dL) at Screening.
19. Known severe hepatic impairment defined as a Model for
End-Stage Liver Disease score ≥19.3
20. Serum 
aspartate 
aminotransferase 
and/or 
alanine
aminotransferase >1.5 upper limit of normal (ULN) at
Screening.
21. Criterion modified per Amendment 5
21.1 
Severe renal impairment (Chronic Kidney Disease
Epidemiology Collaboration 2009 equation [Levey 2009]
calculated creatinine clearance <30 mL/min) at Screening.4
22. Systemic hypotension (systolic blood pressure [SBP]
<90 mmHg or diastolic blood pressure [DBP] <50 mmHg) at
Screening or Randomization.
23. Systemic hypertension (SBP >160 mmHg or DBP >100 mmHg)
at Screening.
24. Acute myocardial infarction or cerebrovascular event (eg,
stroke) within the last 26 weeks prior to Screening.
25. Known bleeding disorder, in the opinion of the investigator.
26. Loss of vision in one or both eyes because of nonarteritic anterior
ischemic optic neuropathy, regardless of whether or not this
episode was in connection with previous PDE5i treatment.
27. Hereditary degenerative retinal disorders, including retinitis
pigmentosa.
28. History of priapism, conditions that predispose to priapism (eg,
sickle cell anemia, multiple myeloma, or leukemia), or


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anatomical deformation of the penis (eg, angulation, cavernosal
fibrosis, or Peyronie’s disease).
General restrictions:
29. Difficulty swallowing large pills/tablets that would interfere
with the ability to comply with study treatment regimen.
30. Any planned surgical intervention (including organ transplant)
during the double-blind treatment period, except minor
interventions.
31. Exercise training program for cardiopulmonary rehabilitation in
the 12-week period prior to start of treatment, or planned to be
started during the double-blind period of the study.
32. Pregnant, planning to become pregnant, or lactating.
33. Any known factor or disease that might interfere with treatment
adherence, study assessments, study conduct, or interpretation of
the results as judged by the investigator (eg, drug or alcohol
dependence, psychiatric disease, use of walking aids, etc.).
34. Known concomitant life-threatening disease with a life
expectancy <12 months.
Other therapies:
35. Criterion added per Amendment 5
Calcium channel blocker treatment initiated, or dose changed
within 3 months prior to RHC at screening.
STUDY TREATMENTS
Investigational treatment
M/T FDC will be provided as film-coated tablets.
The doses of macitentan (10 mg) and tadalafil (40 mg) selected for
the M/T FDC are those recommended for each compound and
correspond to the doses used for monotherapy.
Comparator
Monotherapy arms of macitentan 10 mg and tadalafil 40 mg
(2 × 20 mg tablets).
Matching placebo tablets will not contain any active substance but
are otherwise identical in appearance to the respective active drug
tablet.
ENDPOINTS
Primary efficacy endpoint
 Change in PVR expressed as the ratio of the geometric means of
EDBT to baseline.
Secondary efficacy endpoints
The secondary efficacy endpoints are:


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 Change from baseline to EDBT in 6-minute walk distance.
 Change from baseline to Week 16 in PAH-Symptoms and
ImpactTM  (PAH-SYMPACTTM) in Cardiopulmonary symptom
domain score
 Change from baseline to Week 16 in PAH-SYMPACTTM in
Cardiovascular symptom domain score
 Proportion of participants with absence of worsening in WHO
FC from baseline to EDBT.
Other efficacy endpoints
Other efficacy endpoints are described in Section 6.1.3.
Safety endpoints
Safety endpoints for the double-blind and open-label treatment
periods are:
 Treatment-emergent adverse events (AEs).
 Serious adverse events (SAEs).
 Deaths.
 AEs leading to premature discontinuation of study treatment.
 Change in vital signs (SBP and DBP and pulse rate) and body
weight from baseline to all assessed time points during the study.
 Treatment-emergent marked laboratory abnormalities.
 Proportion of participants with a treatment-emergent ALT
and/or AST abnormality (≥3, ≥5, and ≥8 × ULN).
 Proportion of participants with a treatment-emergent ALT
and/or AST abnormality (≥3 × ULN) associated with total
bilirubin ≥2 × ULN (and increased as compared to baseline).
 Proportion 
of 
participants 
with  a treatment-emergent
hemoglobin abnormality (<100 g/L, and <80 g/L).
 Treatment-emergent AEs of special interest (hypotension,
anemia, edema, liver events).
ASSESSMENTS
Refer to the schedule of assessments in Section 7.
STATISTICAL
METHODOLOGY
This study implements an adaptive group-sequential design with
early futility and efficacy stopping rules and sample size re-
estimation. It includes an IA (according to group-sequential design
methodology) when approximately 100 participants have completed
their Week 16 assessment or have discontinued the study prior to
their Week 16 assessment and after the global amendment 5 has
been approved in all the countries.
Analysis sets


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The All Randomized Analysis Set includes all participants who were
randomized in the study.
The Full Analysis Set (FAS) includes all participants assigned to a
study treatment who received at least one dose (for participants in
FDC at least one dose of either macitentan or tadalafil) of study
treatment.
The Safety Set includes all participants who received at least one
dose of study treatment in the double-blind treatment period.
The Combination Safety Set includes all participants randomized to
M/T FDC in the double-blind period who received at least one dose
of M/T FDC double-blind study treatment and received at least one
dose of M/T FDC study treatment in the open-label period.
The PAH-SYMPACT™ Symptoms Analysis Set includes all
participants included in the FAS for whom at least one baseline
value of symptoms domain is provided.
The PAH-SYMPACT™ Impacts Analysis Set includes all
participants included in the FAS for whom at least one baseline
value of impacts domain is provided.
Primary endpoint analysis
The primary endpoint will be tested on the FAS (including imputed
EDBT PVR values when applicable) using 2 analysis of covariance
(ANCOVA) models separately comparing the combination group to
each monotherapy.
The primary estimand targets an “on-treatment” estimate of the
treatment differences between M/T FDC and each monotherapy
arm. Specifically, assessments obtained after introduction of
prohibited 
PAH 
therapy 
or 
study 
treatment
discontinuation/interruption for more than 2 days immediately prior
to the EDBT visit are not included in the primary analysis (will be
imputed).
Each null hypothesis will be tested at the alpha level as determined
by the Hwang, Shih and DeCani alpha spending function with
gamma (γ) 
2 dependent on the information fraction at the time of
the IA. Only if both are rejected will the study be declared to show
conclusive evidence of efficacy. The overall alpha is controlled so
as not to exceed 5%.
The null hypotheses will be tested by means of 2 ANCOVA models
on the loge-transformed ratios of EDBT to baseline PVR values.
Model covariates will include randomized treatment, the


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loge-transformed baseline PVR value and the stratification factor
(treatment-naïve, prior-ERA, or prior-PDE-5i). The resulting least
squares means (LS-means) and 95% confidence limits (CLs)
obtained in each treatment group and the LS-means differences
(95% CLs) for M/T FDC vs macitentan 10 mg and M/T FDC vs
tadalafil 40 mg will be inversely transformed using the exponential
function and multiplied by 100 to provide:
1. the adjusted geometric mean of the ratios of EDBT to baseline
PVR values and corresponding 95% CLs, expressed as a
percentage, in each treatment group, and;
2. the adjusted geometric mean ratios (GMRs) and corresponding
95% CLs for M/T FDC vs macitentan 10 mg (GMR1) and for
M/T FDC vs tadalafil 40 mg (GMR2).
The global null hypothesis will be rejected if the p-values from each
test are less than the alpha allocated at the time of the IA or, if the
study is not stopped at the time of the IA, less than the remaining
alpha at the time of the final analysis. Median unbiased parameter
estimates and repeated CLs will be presented in the final analysis.
Secondary variables
The secondary efficacy variables will be analyzed at the same alpha
level as the primary endpoint using a hierarchical testing procedure
following the order specified in the secondary endpoints
[Section 10.3.3].
Safety variables
Treatment-emergent AEs, SAEs, deaths, AEs leading to permanent
discontinuation of study treatment, AEs of special interest, and
laboratory marked abnormalities will be summarized by frequency
tables. Change from baseline in vital signs and body weight will be
summarized for each scheduled visit. Safety variables will be
presented for the double-blind treatment period on the Safety Set and
separately for the entire FDC treatment period (ie, for participants
treated with M/T FDC either in the double-blind or open-label
period) on the Combination Safety Set (CSS).
Subgroup analyses
In order to assess the consistency of the treatment effect across
different participant subgroups, analyses will be performed on the
primary and secondary efficacy variables classifying participants
according to relevant demographic characteristics.
The subgroups to be considered are:
 Geographical region (eg, US, Europe, Asia).


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 Region (US, non-US).
 WHO FC (II vs III).
Treatment-by-subgroup interaction will be investigated by means of
tests of heterogeneity.
In addition, the treatment effects of:
 M/T FDC vs each monotherapy arm will be assessed in the
treatment-naïve stratum only;
 M/T FDC vs tadalafil 40 mg will be assessed in the prior-PDE-5i
stratum only; and
 M/T FDC vs macitentan 10 mg will be assessed in the prior-ERA
stratum only.
Interim analysis
One IA will be conducted when approximately 100 participants have
either completed their Week 16 assessment or have discontinued
from the study prior to their week 16 assessment. The IA will only
include data from countries in which the global amendment 5 has
been approved.
The IA will be conducted on the primary endpoint to allow for early
study termination due to overwhelming efficacy or futility, and for
adaptive sample size re-estimation (to between 150 and 250
participants) if the study is not terminated. The Independent Data
Monitoring Committee (IDMC) will review the interim results and
make corresponding recommendations in line with the IDMC
charter. The independent statistical support group (SSG) will
perform the IA and make unblinded results available to the IDMC.
Following the IA, recruitment will be stopped if futility or
superiority is demonstrated. In the event the study is stopped for
futility, all participants will be requested to return for an EOT visit
and be transitioned to system organ class (SOC). In the event the
study is stopped for efficacy, all participants in the double-blind
treatment period will be requested for a EDBT visit and transitioned
to the open-label treatment, participants already enrolled in the
open-label period of the study will be allowed to continue through
the end of the open-label treatment period. In the case the IA results
in early study stop, RHC at EDBT will not be required for this study
for participants after IA decision, however if RHC is done as SOC,
results should be recorded in the eCRF.
Sample size
The trial will enroll between 150 and 250 participants.


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Sample size is calculated based on the statistical requirements for
detection of a clinically relevant difference between the FDC group
and both monotherapy groups using a 2:1 randomization ratio for
each pairwise comparison and taking into account an IA with
unblinded sample size re-estimation. Each test comparing the FDC
to a monotherapy arm has a two-sided Type I error of 5% and a Type
II error of 13% (87% power).
The following assumptions are made:
 The effect, as measured by the ratio of geometric means of the
EDBT / baseline PVR values for FDC compared to the most
efficient of the 2 monotherapies is assumed to be 0.75, and to be
consistent across the treatment-naïve, prior-ERA, and prior-
PDE-5i strata.
 A coefficient of variation of the ratio of 0.45.
 One interim analysis is planned using an alpha spending function
from the Hwang, Shih and DeCani class with (γ) 
2.
 Normal distribution for the loge-transformed ratio of EDBT to
baseline PVR values.
Given those assumptions, 170 participants are targeted to be
randomized overall into the trial. Depending on the conditional
power at the IA, the sample size can be re-calculated to between 150
and 250 participants.
STUDY COMMITTEES
A Steering Committee has been appointed by the sponsor to oversee
conduct of the study.
An IDMC has overall responsibility for safeguarding the interests of
participants by monitoring unblinded 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 to the highest scientific and ethical standards. The IDMC
will interpret the results of the planned IA performed by the
independent SSG as outlined in Section 10.4. The IDMC and
independent SSG will be fully operational prior to enrollment of the
first participant into the study. The composition and operation of the
IDMC is described in the IDMC charter.
An independent Clinical Events Committee of PAH experts will
review and confirm all reported mortality and morbidity events,
including start date of the event, in a blinded fashion.
An Independent Liver Safety Data Review Board (an external expert
committee of hepatologists) has been appointed to monitor all
studies with macitentan, and to provide ongoing assessment and


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advice regarding serious hepatic AEs of special interest that require
further evaluation during the study.


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PROTOCOL
1 BACKGROUND
1.1 Indication
1.1.1 Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a serious chronic disorder of the pulmonary circulation
of diverse etiology and pathogenesis. PAH is characterized by a progressive increase in pulmonary
arterial pressure (PAP) and in pulmonary vascular resistance (PVR) potentially leading to right
heart failure and death [Benza 2010, Kylhammar 2014, Tonelli 2013]. The complex pathogenesis
of PAH involves dysfunction of 3 key pathways: the endothelin pathway, the nitric oxide pathway,
and the prostacyclin pathway [Humbert 2004].
PAH is currently hemodynamically characterized by a resting mean pulmonary arterial pressure
(mPAP) of at least 25 mmHg with normal pulmonary artery wedge pressure (PAWP; or left
ventricular end-diastolic pressure [LVEDP]) of 15 mmHg or less, and a PVR greater than 3 Wood
Units (WU) [Hoeper 2013].
The 2013 clinical classification of pulmonary hypertension [Simonneau 2013] classifies the
numerous conditions that are known to lead to or be associated with the development of PAH into
4 groups, based on their similar clinical presentation, pathology, pathophysiology, prognosis, and,
most of all, similar therapeutic approach. PAH may occur in the absence of a demonstrable cause
/ associated etiology (idiopathic), in a familial setting (heritable), or as the result of the use of
certain drugs or toxins, or it can be associated with a connective tissue disease, HIV infection,
portal hypertension, congenital heart disease, or schistosomiasis.
1.1.2 Current treatment practice
Current PAH-specific therapeutic options include treatments that target the 3 pathways mentioned
above (endothelin, nitric oxide, and prostacyclin pathways). Many patients, in accordance with
current treatment guidelines, are treated with combination therapies to target multiple pathways at
once [Sitbon 2016; Galiè2015a].
Recent studies have supported the efficacy of both initial and sequential combination therapy. Data
from the pivotal Phase 3 study that demonstrated the safety and efficacy of macitentan compared
to placebo (SERAPHIN) support the benefits of combination therapy. Approximately 64% of
participants in this study received a background PAH therapy, either phosphodiesterase type-5
inhibitors (PDE-5is; 96.4% of those on background therapy) or oral or inhaled prostanoids (8.5%
of those on background therapy). Based on a sub-analysis of SERAPHIN data, participants on
combination therapy (ie, macitentan and background PAH therapy) showed a 38% reduced risk of
morbidity/mortality (M/M) compared to participants on background PAH therapy alone (hazard
ratio: 0.62, 95% confidence interval [CI] 0.49 0.89, p
0.009, n
154) [Jansa 2018].
Benefits of the combination of an endothelin receptor antagonist (ERA) and a PDE-5i were further
demonstrated in a study with the ERA ambrisentan and the PDE-5i tadalafil (AMBITION trial)
comparing the up-front combination of both drugs vs monotherapy with ambrisentan or PDE-5i.
This study showed a benefit with a 50% relative reduction on a composite endpoint of clinical


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failure events (ie, death, hospitalization, PAH progression, and unsatisfactory clinical status) for
the combination therapy group vs the pooled monotherapy group (95% CI 0.35 0.72; p <0.001)
[Galiè2015b].
While combination treatment is common, fixed-dose combination (FDC) pills or tablets that
combine 2 or more PAH-specific therapies are not available, thereby requiring patients to take
multiple pills/tablets daily.
1.2 Study Treatment(s)
1.2.1 Macitentan/Tadalafil FDC
ACT-064992D is an FDC of macitentan (ACT-064992) 10 mg and tadalafil 40 mg in one film-
coated tablet, to be administered orally once daily (o.d.).
1.2.1.1 Nonclinical results of combination macitentan and tadalafil
To test the effect of the combination of macitentan and tadalafil vs macitentan alone and tadalafil
alone, the acute hemodynamic effects of combined treatment with macitentan and tadalafil were
investigated in conscious Dahl-S and spontaneously hypertensive rats, 2 animal models of
systemic hypertension associated with endothelial dysfunction. The results demonstrated a
synergistic hemodynamic effect of macitentan and tadalafil in combination.
To confirm that the synergism observed in hypertensive rats could also apply to pulmonary
hypertension, the effect of the combination of macitentan and tadalafil vs macitentan alone and
tadalafil alone was investigated in conscious hypoxia / Sugen 5416 rats. Single-dose oral
administration ofthe individual monotherapies vs combination therapy showed a decreased mPAP
with combination therapy equal to the sum of the effect of each monotherapy and an area between
the treatment vs time-control curves greater than the sum of each monotherapy. These results
indicate an additive/synergistic effect on pulmonary hemodynamics.
Based on these data, it was concluded that compared to monotherapy, the combination of
macitentan and tadalafil provides a benefit to pulmonary hemodynamics in a well-established rat
model of pulmonary hypertension without increasing the risk of exaggerated systemic
vasodilation, ie, without increasing the risk of systemic hypotension. Taken together with the
previous studies performed in rats with systemic hypertension, the data demonstrate that the
combination of macitentan and tadalafil provides selective benefits in vascular territories
associated with endothelial dysfunction.
For non-clinical results specific to the 2 constituent monotherapies, please refer to Section 1.2.2.1,
Section 1.2.3.1, and the Investigator’s Brochure (IB) [Macitentan/tadalafil FDC IB].
1.2.1.2  Clinical pharmacologyof combination macitentan and tadalafil
In total, over 160 healthy participants were treated with macitentan/tadalafil (M/T) FDC in 2 Phase
1 trials to show bioequivalence between the loose combination of monotherapies and FDC. The
M/T FDC was well tolerated in both studies. The most frequently reported adverse event (AE) was
headache [Macitentan/tadalafil FDC IB].
For clinical pharmacology specific to the 2 constituent monotherapies, please refer to Section
1.2.2.2, Section 1.2.3.2, and the Investigator’s Brochure [Macitentan/tadalafil FDC IB].


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1.2.1.3 Clinical efficacyof combination macitentan and tadalafil
To date, there is no clinical experience with the M/T FDC (ie, the combination given as a single
tablet) in PAH patients. Clinical efficacy has been established for both of the constituent
monotherapies alone [Section 1.2.2.3, Section 1.2.3.4, Macitentan/tadalafil FDC IB].
In the OPTIMA study, an ongoing open-label Phase 4 study in which newly diagnosed PAH
patients in World Health Organization (WHO) functional class (FC) II III receive macitentan 10
mg and tadalafil 40 mg o.d. (administered as a loose combination), efficacy data from the first
30 participants who completed 16 weeks of treatment indicate a substantial decrease of PVR
(reduced by 51% from baseline [95% CI 44, 57]) and N-terminal pro B-type natriuretic peptide
(NT-proBNP; reduced by 78% from baseline [95% CI 64, 88]), and a numerical increase in 6-
minute walk distance (6MWD; mean increase of 31 m from baseline [95% CI 1, 64]). None of
the participants had a worsening of WHO functional class [Macitentan/tadalafil FDC IB].
1.2.1.4 Summary of safety profile of combination macitentan and tadalafil
The safety of the M/T FDC (ie, the combination given as a single tablet) in patients with PAH has
not been established. Summaries of the safety profiles of the constituent monotherapies are
provided in Sections 1.2.2.4 and 1.2.3.4
In Phase 1 studies with healthy volunteers, M/T FDC was well tolerated.
In OPTIMA, at the interim analysis (IA) of the first 30 participants, 80% of participants had at
least 1 AE and 13.3% (4 participants) had at least 1 serious adverse event (SAE). The most
frequently reported AEs were headache (in 27%) and peripheral edema (in 17%). The information
from this IA suggest that the co-administration of macitentan 10 mg and tadalafil 40 mg was well
tolerated. The data did not indicate any specific tolerability or safety concerns
[Macitentan/tadalafil FDC IB].
1.2.2 Macitentan
Macitentan is approved in the US, the EU, and an increasing number of other countries for the
treatment of PAH [Opsumit® SmPC, Opsumit® USPI].
1.2.2.1 Non-clinical results of macitentan
Macitentan is an orally active, non-peptide, potent dual endothelin receptor A and B antagonist.
Macitentan showed dose-dependent efficacy in nonclinical models of systemic hypertension and
pulmonary hypertension. In nonclinical safety studies, no effects on normal physiological
functions or electrocardiogram (ECG) variables including cardiac repolarization were observed,
with the exception of a decrease in systemic arterial blood pressure observed in a cardiovascular
study in dogs. Macitentan has no genotoxic and no carcinogenic potential. In the pivotal 26-week
and 39-week toxicity studies, the exposures in animals at the no-observed-adverse-effect levels
were above the anticipated clinical exposures and provided a margin of safety for studies in
humans. Reproductive toxicity studies showed that macitentan is teratogenic. Teratogenicity is
considered to be an ERA class effect. Like other ERAs, macitentan  may have an  adverse effect
on  spermatogenesis [Opsumit® USPI].


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1.2.2.2  Clinical pharmacologyof macitentan
During the Phase 1 program, more than 200 healthy participants, 24 participants with hepatic
impairment, and 8 participants with renal impairment were treated with macitentan. Macitentan
was well tolerated in all studies. The most frequently reported AE was headache [Opsumit® USPI;
Macitentan/tadalafil FDC IB].
1.2.2.3 Clinical efficacyof macitentan
Efficacy was established in the SERAPHIN study, a long-term study in 742 PAH patients with
predominantly WHO FC II III symptoms treated for an average of 2 years [Pulido 2013]. Patients
had idiopathic or heritable PAH (57%), PAH associated with connective tissue disorders (31%),
and PAH associated with congenital heart disease with repaired shunts (8%), and were treated with
macitentan monotherapy or in combination with PDE-5is or inhaled prostanoids.
The trial demonstrated that macitentan 10 mg reduces the risk of M/M  in patients with
symptomatic PAH, with a hazard ratio vs placebo of 0.55, 97.5% confidence limits (CLs): 0.39,
0.76, p <0.001. This represents a risk reduction of 45% [Pulido 2013]. The effect of macitentan
was observed regardless of whether the patient was receiving another therapy, including a PDE-
5i, for PAH.
The placebo-corrected mean change in 6MWD from baseline to Month 6 (24 26 weeks) showed
an increase of 22.0 m (97.5% CLs: 3.2, 40.8, p 0.008) with macitentan 10 mg. The WHO FC
improved from baseline to Month 6 in 13% of the patients in the placebo group, compared to 22%
of those in the group that received 10 mg of macitentan (p
0.006) [Pulido 2013].
A hemodynamic substudy in 187 participants showed a placebo-corrected mean reduction of PVR
from baseline (mean PVR at baseline for the overall SERAPHIN population was
1026 dyn∙sec∙cm 5) to Month 6 of 38.5% (97.5% CLs: 25.7%, 49.0%) with macitentan 10 mg
[Pulido 2013].
1.2.2.4 Summary of safety profile of macitentan
The safety of macitentan has been evaluated in a long-term placebo-controlled trial of 742 patients
with symptomatic PAH, the SERAPHIN study [Pulido 2013, Macitentan/tadalafil FDC IB]. The
mean treatment duration was 103.9 weeks in the macitentan 10 mg group and 85.3 weeks in the
placebo group. The most commonly reported adverse drug reactions were nasopharyngitis
(14.0%), headache (13.6%), and anemia (13.2%). The majority of adverse reactions were mild to
moderate in intensity. The overall incidence of treatment discontinuations because of adverse
events was similar across macitentan 10 mg and placebo treatment groups (approximately 11%).
1.2.3 Tadalafil
Tadalafil is approved in the US [Adcirca® USPI], the European Union [Adcirca® SmPC], and
many other countries (see local prescribing information) for the treatment of PAH.
1.2.3.1 Non-clinical results of tadalafil
Tadalafil is a selective inhibitor of phosphodiesterase type-5 (PDE-5), the enzyme responsible for
the degradation of cyclic guanosine monophosphate (cGMP). PAH is associated with impaired
release of nitric oxide by the vascular endothelium and consequent reduction of cGMP
concentrations in the pulmonary vascular smooth muscle. PDE-5 is the predominant


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phosphodiesterase in the pulmonary vasculature. Inhibition of PDE-5 by tadalafil increases the
concentrations of cGMP, resulting in relaxation of pulmonary vascular smooth muscle cells and
vasodilation of the pulmonary vascular bed [Adcirca® USPI].
1.2.3.2  Clinical pharmacology of tadalafil
In clinical pharmacology studies, tadalafil (5 20 mg) was shown to potentiate the hypotensive
effect of nitrates. Tadalafil must not be used in patients taking any form of organic nitrates
[Adcirca® SmPC].
For other pharmacodynamics effects, interactions, and the pharmacokinetics of tadalafil, see the
Summary of Product Characteristics and US Prescribing Information  [Adcirca® SmPC,
Adcirca® USPI].
1.2.3.3 Clinical efficacyof tadalafil
Tadalafil was evaluated in a Phase 3, randomized, double-blind, 16-week placebo-controlled study
conducted in 405 patients with PAH [Galiè2009]. Allowed background therapy included bosentan
(maintenance dosing up to 125 mg twice daily), which, like macitentan, is a dual endothelin
receptor A and B antagonist. Participants were randomly assigned to 1 of 5 treatment groups
(tadalafil 2.5, 10, 20, or40 mg, or placebo) in a 1:1:1:1:1 ratio. PAH etiologies were predominantly
idiopathic PAH (61%) and related to collagen vascular disease / connective tissue disorders (24%).
More than half (53%) of the participants in the study were receiving concomitant bosentan therapy.
The majority of participants had a WHO FC III (65%) or II (32%). The mean baseline 6MWD was
343 m. The primary efficacy endpoint was the change from baseline at Week 16 in 6MWD. In the
tadalafil 40 mg treatment group, the placebo-adjusted mean increase in 6MWD was 33 m (95%
CI: 15 50 m; p <0.001). There was increased time to and decreasedincidence of clinical worsening
(p  0.04) (defined as death, lung transplantation, atrial septostomy, hospitalization because of
worsening PAH, initiation of new PAH therapy, or worsening WHO FC) in the tadalafil 40 mg
group compared to the placebo group and the groups that used lower doses of tadalafil.
1.2.3.4 Summary of safety profile of tadalafil
In the pivotal placebo-controlled study of tadalafil for the treatment of PAH, a total of 323 patients
were treated with tadalafil at doses ranging from 2.5 mg to 40 mg o.d. and 82 patients were treated
with placebo. The duration of treatment was 16 weeks. The overall frequency of discontinuation
due to AEs was low (tadalafil 16%, placebo 16%). The most commonly reported adverse reactions,
occurring in ≥10% of patients in the tadalafil 40 mg treatment arm, were headache, nausea, back
pain, dyspepsia, flushing, myalgia, nasopharyngitis, and pain in extremity. The adverse reactions
reported were transient and generally mild or moderate. [Adcirca® USPI, Macitentan/tadalafil
FDC IB].
1.3 Purpose and Rationale of the Study
Study purpose
This study is a Phase 3 clinical study to demonstrate that M/T FDC is superior to 10 mg of
macitentan alone, and to 40 mg of tadalafil alone, as measured by the change from baseline in PVR
at End of Double-Blind Treatment (EDBT).


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Study rationale
PAH continues to be a progressive and fatal disease, with a life expectancy of only about 7 10
years, despite the availability of PAH-specific therapies [Benza 2012a; Fares 2016]. ERAs and
PDE-5is are the most widely used therapies for PAH. The safety and efficacy of oral combination
therapy with ERAs and PDE-5is have been the participant of active investigation for more than a
decade, with the benefit oftargeting different pathways known to be involved in the pathogenesis
of the disease [Sitbon 2016]. The 2015European Treatment Guidelines provide recommendations
for the use of initial or sequential combination therapy, according to WHO FC [Galiè2015a].
Adherence to prescribed therapy has an impact on clinical outcomes and there is strong evidence
that reducing the pill/tablet count and frequency has a major impact on patients’ adherence to
therapies in general and to PAH therapies in particular [Thom 2013]. One way to simplify
treatment is to use FDC products that combine multiple treatments into a single tablet.
This study will evaluate the efficacy and safety at 16 weeks of an FDC, macitentan 10 mg and
tadalafil 40 mg, against either of these 2 PAH-approved therapies given as monotherapy to further
confirm the added value of the FDC.
Study description
This is a prospective, multi-center, double-blind, randomized, active-controlled, triple-dummy,
parallel-group, group-sequential, adaptive Phase 3 clinical study with a double-blind treatment
period duration of16 weeks followed by a 24-month single-arm open-label extension period.
1.4 Summary of Known and Potential Risks and Benefits
1.4.1 Benefits
An FDC is an attractive option for PAH patients because it simplifies the treatment regimen by
combining 2 therapies (which would otherwise involve a total of 3 tablets: one macitentan 10 mg
tablet and 2 tadalafil 20 mg tablets) into a single tablet. This therapeutic approach is consistent
with the European Society of Cardiology and the European Respiratory Society treatment
guidelines and with clinical practice, which favor combination therapy in order to target separate
signaling pathways known to be involved in the pathogenesis of the disease. The efficacy of the 2
component medications administered individually, macitentan and tadalafil, in adult patients with
symptomatic PAH has been demonstrated in randomized clinical trials.
The efficacy of the loose combination ofmacitentan 10 mg / tadalafil 40 mg is being evaluated in
the ongoing open-label OPTIMA trial. An analysis of the first 30 participants to complete 16 weeks
of treatment with macitentan and tadalafil showed a substantial decrease of PVR and NT-proBNP,
and a numerical increase in 6MWD. FC improved in the majority of these first 30 participants
[Macitentan/tadalafil FDC IB].
1.4.2 Possible risks
The safety profiles of ERAs and PDE5i administered either as mono- or combination therapy in
PAH patients have been well characterized through relatively large event-driven clinical trials such
as SERAPHIN and PHIRST. Based on the known characteristics of macitentan and tadalafil, no
pharmacokinetic interaction is expected when administered concomitantly.


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Known safety concerns associated with ERA treatment include hepatic events, hemoglobin
decrease, and embryo-fetal toxicity. Known safety concerns associated with PDE-5i treatment
include hypotension, visual loss, hearing loss, and priapism [Macitentan/tadalafil FDC IB]. With
regard to the specific combination of macitentan and tadalafil, the Phase 1 studies assessing the
pharmacokinetics of the M/T FDC yielded a high reporting rate of headache in healthy volunteers,
similar to the loose combination and the FDC formulations, but no concerns arose regarding blood
pressure or other safety measures.
In the AMBITION study, which compared initial combination therapy with the ERA ambrisentan
and tadalafil versus monotherapy (ie, ambrisentan or tadalafil), AEs of peripheral edema,
headache, nasal congestion, and anemia were more common in the combination therapy group
than in either monotherapy group [Galiè2015b]. Preliminary data from an ongoing study
(OPTIMA), where the up-front loose combination of macitentan 10 mg and tadalafil 40 mg is
administered to PAH patients, did not indicate any tolerability or safety concerns specific to
combination treatment [Macitentan/tadalafil FDC IB].
The following measures are being taken to minimize the risks for the participants participating in
the study:
 Exclusion of potential participants with increased liver function test (LFT) values or decreased
hemoglobin values [Section 4.4].
 Regular monitoring of LFTs [Section 7.2].
 Exclusion of women of childbearing potential who are unable or unwilling to comply with
study-mandated contraception methods [Section 4.3].
 Close monitoring of the study by an external Independent Data Monitoring Committee (IDMC)
throughout the study [Section 3.4].
 Regular physical examination during the study [Section 7.2].
 Regular vital sign checks during the study [Section 7.2].
1.4.3 Benefit/risk analysis
It is the investigator’s responsibility to monitor the benefit/risk ratio of study treatment
administration, as well as the degree of distress caused by study procedures at an individual
participant level, and to discontinue study treatment or the study if, on balance, they believe that
continuation would be detrimental to the participants’ well-being.
Given the extensive and long-term controlled efficacy and safety data available for macitentan and
tadalafil individually, in addition to the extensive available post-marketing surveillance data, and
the careful follow-up of participants mandated by this protocol, the benefit/risk analysis supports
the current study.


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2 
STUDY OBJECTIVES
2.1 Primary Objective
This study has 2 co-primary objectives:
1. To evaluate the effect of the M/T FDC vs macitentan 10 mg alone on PVR at EDBT  in
participants with symptomatic WHO Group 1 PAH who are PAH-specific treatment-naïve or
are currently being treated with an ERA as monotherapy.
2. To evaluate the effect of the M/T FDC vs tadalafil 40 mg alone on PVR at EDBTin participants
with symptomatic WHO Group 1 PAH who are PAH-specific treatment-naïve or are currently
being treated with a PDE-5i as monotherapy.
2.2 Secondary Objectives
The secondary objectives are:
 To evaluate the effect of the M/T FDC compared to the respective monotherapies on:
- Exercise capacity.
- PAH symptoms in participants’ cardiopulmonary and cardiovascular function
- WHO FC.
 To evaluate the safety and tolerability of the M/T FDC in the participant population.
2.3 Other Objectives
Other objectives for the 16-week double-blind treatment period are:
 To evaluate the effect of the M/T FDC compared to the respective monotherapies on:
- PAH impacts on participants’ physical and cognitive/emotional functions.
- Time to first M/M event.
- Time to death due to PAH or PAH-related hospitalization.
- Other hemodynamic measures.
- Participant’s quality of life (QoL).
- Participant’s work and productivity.
- Pharmacoeconomic measures.
- Time to death (all causes)
Other objectives for the 24-month open-label treatment period are:
 To evaluate the long-term safety of the M/T FDC.
 To evaluate the long-term effect of the M/T FDC on: Exercise capacity.
- WHO FC.
- Time to first M/M event.
- Time to death due to PAH or PAH-related hospitalization.
- Pharmacoeconomic measures.
 Time to death (all causes)
3 
OVERALL STUDY DESIGN AND PLAN
3.1 Study Design
This is a prospective, multi-center, double-blind, randomized, active-controlled, triple-dummy,
parallel-group, group-sequential, adaptive Phase 3 clinical study with a treatment period duration
of 16 weeks followed by a 24-month single-arm open-label treatment period. In the double-blind


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treatment period, the FDC of macitentan 10 mg and tadalafil 40 mg is compared to each
monotherapy of macitentan 10 mg or tadalafil 40 mg given o.d.
In total, 170 participants are planned to be randomized into the study (range 150 250) to receive
either M/T FDC, macitentan 10 mg, or tadalafil 40 mg given o.d. Participants will also receive
matching placebos for the 2 other study treatments to maintain the blind. Treatment allocation will
be stratified by treatment status at baseline, ie, treatment-naïve or treated by an ERA or a PDE-5i
as a monotherapy:
 treatment-naïve participants will be randomized in a 2:1:1 ratio to M/T FDC, macitentan, or
tadalafil.
 participants on allowed ERA monotherapy will be randomized in a 2:1 ratio to M/T FDC or
macitentan.
 participants on allowed PDE-5i monotherapy will be randomized in a 2:1 ratio to M/T FDC or
tadalafil.
After completion of the double-blind treatment period, participants will continue the study in an
open-label treatment period for 24 months, during which all participants will receive M/T FDC.
All EDBT assessments must be completed before the participant enters the open-label treatment
period.
The study will be conducted in approximately 150 sites in approximately 25 countries.
An IA will be conducted when approximately 100 participants have either completed their Week
16 assessment or have discontinuedfrom the study prior to their Week 16. The IA will only include
data from countries in which the global amendment 5 has been approved.
The recruitment rate will be closely monitored in a blinded manner to ensure there are at least 50%
participants in treatment-naïve stratum at the time of the final analysis.
This analysis can allow for early termination for efficacy or futility, or unblinded reassessment of
sample size required for the primary endpoint. Following the IA, recruitment will be stopped if
futility or superiority is demonstrated. In the event the study is stopped for futility, all participants
will be requested to return for an EOT visit and be transitioned to system organ class (SOC). In
the event the study is stopped for efficacy, all participants in the double-blind treatment period will
be requested for a EDBT visit and transitioned to the open-label treatment, participants already
enrolled in the open-label period of the study will be allowed to continue through the end of the
open-label treatment period. In the case the IA results in early study stop, right heart catheterization
(RHC) at EDBT will not be required for this study for participants after IA decision, however if
RHC is done as standard of care, results should be recorded in the eCRF.
3.1.1 Study periods
The study comprises the following consecutive periods:
Screening period: Lasts up to 30 days; starts with the signature of the Informed Consent Form
(ICF; Visit 1) and ends the day prior to randomization (Visit 2).


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Double-blind treatment period:Starts on the day of randomization (Visit 2) and ends on the day
of the EDBT visit (Visit 8).
The double-blind treatment period consists of the titration phase (the first 2 weeks) and the
maintenance phase (Week 3 through Week 16).
 Titration phase: Starts on the day of randomization (Visit 2, Day 1) and lasts 2 weeks, ending
on Day 14 (end of Week 2).
- Week 1: Loose combination 10/20: Participants are treated with a loose combination
of macitentan 10 mg and/or tadalafil 20 mg and relevant placebos, depending on
treatment arm, for 7 days from randomization (Visit 2, Day 1) to the end of Week 1
(Day 7).
- Week 2: Loose combination 10/40 Uptitration: Participants are treated with a loose
combination of macitentan 10 mg and/or tadalafil 40 mg and relevant placebos
depending on treatment arm from Day 8 to the end of Week 2 (Day 14).
- Note: If a participant is already receiving a stable dose of PDE-5i within prespecified
dose ranges at baseline (ie, 40 mg tadalafil, 60 120 mg sildenafil, or 10 mg vardenafil
daily), no up-titration is needed and they will receive 40 mg tadalafil from Day 1.
 Maintenance phase: Participants are treated with macitentan 10 mg, tadalafil 40 mg, M/T
FDC, or their respective placebos, depending on treatment arm. The period starts on Day 15
and lasts until EDBT (Visit 8).
- Note: If a participant cannot tolerate 40 mg tadalafil during the titration period, the
participant will remain on 20 mg tadalafil. The participant is allowed to be up-titrated
once again to 40 mg tadalafil during the first 2 weeks of the maintenance phase of the
double-blind treatment period (ie, between Visits 4 and 5) [Section 5.1.9].
- Note: if a participant prematurely discontinues double-blind study treatment, they will
be asked to return for a EDBT visit (within ±2 days of the time of treatment
discontinuation and before initiation of new PAH-specific therapy), a safety follow-up
visit 30 days after last treatment administration, and all remaining visits up until the
Week 120 visit (excluding Visits 9 and 10). If the participant did not withdraw consent
for study participation and regular visits to the site are not possible, phone contacts can
be performed, at the scheduled visits, until the Week 120 visit. During these phone
calls, morbidity and mortality events (M/M) AE, and concomitant medication
information will be collected [Section 5.1.10].
Open-label treatment period: For those participants who complete 16 weeks of double-blind
treatment, the open-label treatment period starts with the first dose of the open-label FDC study
treatment. All participants will have a titration phase of 2 weeks, during which the 2 drugs will be
given as a loose combination. The open-label treatment period lasts at least 24 months and ends
with the End-of-Open-Label-Treatment (EOLT) visit. Participation in the open-label treatment
period may be prolonged beyond 24 months until macitentan and tadalafil are accessible at the
required doses, through other options according to local regulations. Refer to Section 8.1 for
definition of study completion and Section 8.4 for details of continued access to study intervention.


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 Titration phase5: Starts on the first day of open-label treatment and lasts for 2 weeks.
- First week open-label titration: Begins the first day of open-label treatment and ends
the 7th day of open-label treatment. Participants who receivedmacitentan monotherapy,
or could not tolerate 40 mg tadalafil, in the double-blind treatment period will receive
a loose combination of macitentan 10 mg and tadalafil 20 mg. Participants who had
received the M/T FDC or tadalafil monotherapy treatment and could tolerate 40 mg
tadalafil in the double-blind treatment period, will receive a loose combination of
macitentan 10 mg and tadalafil 40 mg during this week.
- Second week open-label titration: Begins the 8th  day of open-label treatment and ends
on the 14th  day of open-label treatment. All participants are treated with a loose
combination of macitentan 10 mg and tadalafil 40 mg. Participants who cannot tolerate
40 mg tadalafil are not eligible to proceed to the open-label treatment period
maintenance phase and should complete an End ofStudy (EOS) visit [see Section 8.1].
 Maintenance phase: Begins the 15th day of open-label treatment and ends with the EOLT. All
participants are treated with M/T FDC.
- Note: if a participant prematurely discontinues study treatment, they will be asked to
return for an EOLT visit within ±7 days of the time of treatment discontinuation and a
safety follow-up visit 30 days after last treatment administration. If the participant did
not withdraw consent for study participation, regular contacts will be conducted
thereafter, at the scheduled visits until the Week 120 visit. If regular visits to the site
are not possible, phone contacts can be performed, at the scheduled visits, until the
Week 120 visit. During these phone calls, morbidity and mortality events (M/M) AE,
and concomitant medication information will be collected [Section 5.1.10].
End-of-Treatment (EOT): For an individual participant is the end of all study treatment.
Safety follow-up (S-FU) period: Starts on the day after the last dose of study treatment and ends
at the Safety Follow-up Visit 30 35 days thereafter.
For participants who completed the 24-months of open-label treatment and who are eligible for a
continued access program (post-trial access program or other open-label extension study) the S-
FU period will be waived. In such case enrollment into the continued access program should occur
on the same day as the last visit in this study, ie, EOS visit.
End of Study (EOS): EOS is reached when all participants have completed their EOS visit, died,
or are lost to follow-up.
For an individual participant, EOS visit is defined as follows:
For participants who complete treatment, EOS  visit is defined as the safety follow-up visit
30 35 days after last study treatment intake.
For participants who complete treatment and who are eligible for a continued access program
(post-trial access or other open-label extension study) the EOS visit is defined as the EOLT visit.
5 
The open label titration phase treatment assignment will be done through Interactive Response Technology (IRT) to maintain
blinding of the double blind treatment period treatment.


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For participants who prematurely discontinue study treatment, EOS visit is defined as either the
safety follow-up visit 30 35 days after last study treatment intake or the Week 120 visit, whichever
comes last.
The visit schedule and protocol-mandated procedures are performed according to the tables of
assessments [Table 4 and Table 5] and are described in Section 7.
The overall study design is depicted in Figure 1.


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Figure 1 
Study design
BL  baseline; EDBT  End of Double blind Treatment; EOLT  End of Open Label Treatment; EOS  End of Study; ERA 
endothelin receptor antagonist; FDC   fixed dose combination; IRT  Interactive Response Technology; LC
 loose
combination; M/T FDC
macitentan/tadalafil FDC; PDE 5i
Phosphodiesterase type 5 inhibitor; V
visit.
* Participants who were on an allowed dose of PDE 5i at baseline (40 mg tadalafil, 60 120 mg sildenafil, or 10 mg vardenafil
daily) will not up titrate and will receive 40 mg tadalafil starting on study Day 1. If a participant cannot tolerate the higher
tadalafil dose (or placebo) during the double blind titration phase, the dose will be decreased back to 20 mg daily. Within the
first 2 3 weeks after decreasing the dose (up to and including Week 4 / Visit 5) and with the investigator’s approval, the
participant is allowed to be re uptitrated to the tadalafil 40 mg daily dose (or its matching placebo equivalent). If the participant
cannot tolerate the 40 mg dose again on the 2nd attempt to up titrate the tadalafil dose (or its matching placebo equivalent), then
they are to stay on the 20 mg tadalafil daily dose (or its placebo equivalent) for the remainder of the double blind treatment
period. These participants will receive the same treatment they received during their double blind titration phase Week 1
throughout the entire double blind treatment period.
** At the beginning of the open label treatment period, participants who were randomized to macitentan 10 mg only, or who could
not tolerate 40 mg tadalafil, will receive an LC of 10 mg macitentan and 20 mg tadalafil for one week. Participants who were
randomized to FDC or tadalafil 40 mg only and completed 16 weeks ofdouble blind treatment with 40 mg tadalafil will receive
an LC of 10 mg macitentan and 40 mg tadalafil during the first week of open label treatment. During the second week of
open label treatment, all participants will receive an LC of 10 mg macitentan and 40 mg tadalafil. Treatment during the open
label titration phase will be assigned by the IRT. Following the titration phase, all participants receive M/T FDC. Participants
who cannot tolerate 40 mg tadalafil will be required to prematurely discontinue study treatment.
*** Participants who have discontinued double blind study treatment prematurely, will continue participation until Week 120 but
will not receive open label treatment. Participants who have completed the 24 months of the open label period and are
benefiting from the study intervention, as determined by their investigator, will be able to continue participation in the open
label period beyond 24 months until alternative continued access is available in the patients country and as per local regulations
via an open label extension study or via post study independent requests from their investigators if tadalafil 40 mg and
macitentan 10 mg are not accessible for PAH in the patient's country.
**** For participants who completed the 24 months of open label treatment and who are eligible for a continued access program
(post trial access program or other open label extension study) the S FU period will be waived. For these participants the EOS
visit is defined as the EOLT and which should occur only if immediate transition, ie, on the same day as EOS into the continues
access program is ensured.


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3.1.1.1 Stratified randomization summary
Participants on ERA therapy at baseline are randomized 2:1 to M/T FDC or macitentan 10 mg,
respectively.
Participants on PDE-5i therapy at baseline are randomized 2:1 to M/T FDC or tadalafil 40 mg,
respectively.
Treatment-naïve participants at baseline are randomized 2:1:1 to M/T FDC, macitentan 10 mg, or
tadalafil 40 mg, respectively.
3.1.1.2  Premature studytreatment discontinuation
If a participant prematurely discontinues study treatment:
 Prior to prematurely discontinuing study treatment, participants should contact the site and
schedule an EOT visit.
 If study treatment is prematurely discontinued during the double-blind treatment period, an
EDBT visit is to be conducted within ±2 days of last study treatment intake, before initiation
of any new PAH-specific therapy, and, if not possible, within 7 days after last study treatment
intake. The participant will be asked to return for a safety follow-up visit 30 35 days after last
study treatment intake and all other visits up until the Week 120 visit (excluding Visits 9 and
10). If the participant did not withdraw consent for study participation and regular visits to the
site are not possible, phone contacts can be performed, at the scheduled visits, until the Week
120 visit. During these phone calls, M/M, AE, and concomitant medication information will
be collected.
 If study treatment is prematurely discontinued during the open-label treatment period, an
EOLT visit is to be conducted within 7 days of last study treatment intake. The participant will
be asked to return for a safety follow-up visit 30 35 days after last study treatment intake, and
all other visits up until the Week 120 visit (excluding Visits 9 and 10). If the participant did
not withdraw consent for study participation and regular visits to the site are not possible,
phone contacts can be performed, at the scheduled visits, until the Week 120 visit. During these
phone calls, M/M, AE, and concomitant medication information will be collected.
 Survival status follow-up will be collected for all participants starting at the time of double-
blind database lock and yearly thereafter until death or study closure [Section 8.2]. Refer to
Section 7.2.2.13 for more details.
3.1.2 Study duration
The study starts with the first act of recruitment (ie, signature of the first ICF) and ends with the
last visit of the last participant. It is estimated to last approximately 54 months.
The total study duration for a participant will be up to 30 months.
The study will continue at each site until all participants have completed the study or the sponsor
decides to end the study.


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3.2 Study Design Rationale
This is a prospective, multi-center, double-blind, randomized, active-controlled, triple-dummy,
parallel-group, group-sequential, adaptive Phase 3 clinical study with a double-blind treatment
period duration of 16 weeks, followed by an open-label treatment period of up to 24 months.
A double-blind, randomized trial provides the most definitive and rigorous method of evaluating
the efficacy of a medical treatment. The use of active comparators is essential to the trial’s
objective of evaluating the effect of the FDC vs the individual monotherapies.
The double-blind treatment period is planned for 16 weeks, as a study duration of 16 weeks has
been demonstrated to be sufficient to observe improvement in hemodynamics as measured by RHC
in studies of ERAs and PDE-5is individually [Ghofrani 2017, Galiè2009]. Previous studies of
PAH therapies have shown an average improvement in PVR of ~25%, which is considered to be
clinically relevant [Krause 2018, Ghofrani 2017, Galiè2009]. A decrease of PVR on PAH
therapies has been associated with improvement in clinical outcomes [Gerges 2016, Tiede 2013,
Nickel 2012]. The primary endpoint will be assessed at end of double-blind treatment, either at
completion of 16 weeks or at time of premature discontinuation, to ensure an on-treatment
measurement.
The tadalafil dose will be up-titrated over the first 2 weeks after randomization to align with current
clinical practice.
One IA is planned when approximately 100 participants have completed their Week 16 assessment
or have discontinued from the study  prior to their Week 16 assessment and after the global
amendment 5 has been approved in all the countries. The purpose of this IA is to stop early for
efficacy, to avoid exposing too many participants to monotherapy, if the FDC is shown to be the
best treatment option, and to allow earlier access to a formulation that may help to improve
compliance; to reassess the sample size based on conditional power and adapt if the initial
assumptions are different than those observed; or to stop for futility in the case of low probability
of success.
Participants who complete 16 weeks of double-blind treatment are eligible to continue into an
open-label treatment period, during which all participants will be treated with M/T FDC. An open-
label treatment period allows for the collection oflong-term safety and tolerability information on
the M/T FDC for participants who have already participated in the double-blind treatment period.
Such  designs are widely used in clinical programs to collect long-term safety data beyond
completion of the original study.
 Regardless of length of study treatment, all participants will be followed until Week 120 and
M/M data collected. Survival status follow-up will be collected for all participants starting at
the time of double-blind database lock and yearly thereafter until death or study closure
[Section 8.2]. Refer to Section 7.2.2.13 for more details.


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3.3 Site Personnel and Roles
3.3.1 Right heart catheterization
Detailed guidance on the conduct of RHCs is provided in  Section 14.1. Site team members
conducting the RHCs must be instructed on these RHC guidelines. A training log must be collected
upon completion of the training.
The RHC laboratory  should be equipped to do thermodilution and/or indirect (assumed) Fick
cardiac outputs, and should have the ability to record and print out all pressure tracings with clear
scales and concurrent ECG tracings, as well as thermodilution curves and a standard log (printed
electronic or hand-written paper log) of the procedure that includes the times and the measured
vital signs during the procedure as is standard practice for any RHC laboratory. Use of the provided
RHC worksheet is mandatory.
3.3.2 6-minute walk test
Site team members conducting the 6-minute walk test (6MWT) must be instructedon the sponsor’s
6MWT guidelines [Section 14.2], and a training log must be collected upon completion of the
training. Use of the provided 6MWT worksheet is mandatory.
3.4 Study Committees
A Steering Committee has been appointed by the sponsor to oversee the conduct of the study. The
committee is governed by a dedicated Steering Committee charter.
An Independent Data Monitoring Committee (IDMC) has overall responsibility for safeguarding
the interests of participants by monitoring unblinded 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 to the highest scientific and ethical standards. The IDMC will interpret the
results of the planned IA performed by the independent statistical support group (SSG), as outlined
in Section 10.4. The IDMC and independent SSG will be fully operational prior to enrollment of
the first participant into the study. The composition and operation of the IDMC is described in the
IDMC charter.
An independent Clinical Events Committee (CEC) of PAH experts will review and confirm all
reported mortality and morbidity events, including start date of the event, in a blinded fashion.
An Independent Liver Safety Data Review Board (ILSDRB, an external expert committee of
hepatologists) has been appointed to monitor all studies with macitentan, and to provide ongoing
assessment and advice regarding serious hepatic adverse events (AEs) of special interest that
require further evaluation during the study.
4 SUBJECT POPULATION
4.1 Subject Population Description
This study will enroll male and female participants ≥18 years of age with RHC confirmed
diagnosis of PAH (WHO Group 1). The study will include approximately 50% participants who
are PAH-specific treatment-naïve.


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Participants must be in WHO FC II or III and be eligible for dual therapy with an ERA and a PDE-
5i. Participants with concomitant significant pulmonary or cardiac conditions other than PAH are
not eligible to enter the study.
Eligible participants must be able and willing to give informed consent to participate in the clinical
study.
4.2 Rationale for the Selection of the Study Population
Inclusion/exclusion criteria are selected to define a participant population with WHO Group 1
pulmonary hypertension (ie, PAH), the labeled indication for macitentan and tadalafil.
Furthermore, inclusion/exclusion criteria were written in accordance with the labeled
contraindications, precautions, and warnings for macitentan and tadalafil.
The minimum 6MWD is 100 m in order to avoid the imputation of missing values in participants
who can hardly walk or cannot walk at all.
Exclusion of the remaining concomitant diseases and therapies listed below is based on the
prescribing information or other background information for one or more of the study treatments
[Macitentan/tadalafil FDC IB].
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 participant.
1. Signed and dated ICF.
2. Male and female participants ≥18 years old.
3. Confirmed diagnosis of symptomatic PAH in WHO FC II or III.
4. Symptomatic PAH belonging to one of the following subgroups of WHO Group 1 pulmonary
hypertension [Simonneau 2013]:
- Idiopathic.
- Heritable.
- Drug- or toxin-induced.
- Associated with one of the following:
o Connective tissue disease.
o HIV infection.
o Portal hypertension.
o Congenital heart disease with simple systemic-to-pulmonary shunt (atrial septal defect,
ventricular septal defect, patent ductus arteriosus) with persistent pulmonary
hypertension documented by an RHC ≥1 year after surgical repair.
5. PAH diagnosis confirmed by hemodynamic evaluation  at rest (through central reading),
evaluated within 5weeks prior to randomization.
- Mean pulmonary artery pressure (mPAP)  25mmHg, AND
- Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure
(LVEDP) ≤15mmHg, AND
- Pulmonary vascular resistance (PVR)  3 WU (ie, ≥240 dyn∙sec∙cm 5).
6. Negative vasoreactivity test in idiopathic, heritable, and drug/toxin-induced PAH. (Patients for
whom no vasoreactivity test was performed at diagnosis can be eligible if currently treated


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with PAH therapy for more than 3 months and PAH diagnosis confirmed by hemodynamic
evaluation at least 3 months after introduction of their PAH therapy).
7. Criterion modified per Amendment 5
7.1 
Currently receiving a stable dose of ERA or PDE-5i monotherapy for at least 3 months
prior to baseline RHC, within the prespecified doses below or no history of PAH-specific
treatment6:
- Bosentan: 250 mg total daily dose
- Macitentan: 10 mg total daily dose
- Ambrisentan: 10 mg total daily dose
- Sildenafil: 60 120 mg total daily dose
- Tadalafil: 40 mg total daily dose
- Vardenafil: 10 mg total daily dose
8. Participant able to perform the 6MWT with a minimum distance of 100 m and maximum
distance of 450 m at Screening.
9. A woman of childbearing potential is eligible only if the following applies:
- Negative serum pregnancy test at Screening and a negative urine pregnancy test at
Randomization.
- Agreement to undertake monthly urine pregnancy tests during the study and up to at
least 30 days after study treatment discontinuation.
- Agreement to follow the contraception scheme from Screening up to at least 30 days
after study treatment discontinuation.
4.4 Exclusion Criteria
Participants must not fulfill any of the following exclusion criteria. It is not permitted to waive any
of the criteria for any participant.
PAH treatments:
1. Treatment with a soluble guanylate cyclase stimulator, L-arginine, any form of prostanoids or
prostacyclin-receptor agonists (including oral, inhaled, or infused routes) in the 3-month period
prior to start of treatment.
2. Treatment with combination therapy of ERA and PDE-5i in the 3-month period prior to start
of treatment or history of intolerance to ERA and PDE-5i combination therapy.
3. Hypersensitivity to any of the study treatments or any excipient of their formulations.
Other therapies:
4. Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer (eg, rifabutin, rifampin,
rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John’s Wort) in the
1month period prior to start of treatment.
5. Criterion modified per Amendment 3
Treatment with a strong CYP3A4 inhibitor (eg, ketoconazole, itraconazole, voriconazole,
clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) or a moderate dual
CYP3A4/CYP2C9 inhibitor (eg, fluconazole, amiodarone) or co-administration of a
6 
PAH specific treatment is defined as prostanoids, prostacyclin receptor agonists, guanylate cyclase stimulators, ERAs, or
PDE 5is prescribed to treat PAH.


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combination of moderate CYP3A4 and moderate CYP2C9 inhibitors in the 1-month period
prior to start of treatment.
6. Treatment with doxazosin.
7. Treatment with any form of organic nitrate, either regularly or intermittently
8. Diuretic treatment initiated or dose changed within 1 week prior to the RHC or start of
treatment.
9. Treatment with another investigational drug in the 3-month period prior to start of treatment.
Medical history/current medical conditions:
10. Body mass index (BMI) >40 kg/m2 at Screening.
11. Known presence of 3 or more of the following risk factors for heart failure with preserved
ejection fraction at Screening:
- BMI >30 kg/m2.
- Diabetes mellitus of any type.
- Essential hypertension (even if well controlled).
- Coronary artery disease, ie, any of the following:
o History of stable angina, or
o Known more than 50% stenosis in a coronary artery, or
o History of myocardial infarction, or
o History of or planned coronary artery bypass grafting and/or coronary artery stenting.
12. Known presence of moderate or severe obstructive lung disease (forced expiratory volume in
1 second [FEV1] / forced vital capacity [FVC] <70%; and FEV1 <65% of predicted after
bronchodilator administration) any time prior to Screening.
13. Known presence of moderate or severe restrictive lung disease (total lung capacity or FVC
<60% of normal predicted value) any time prior to Screening.
14. Clinically significant aortic or mitral valve disease; pericardial constriction; restrictive or
congestive leftsided cardiomyopathy; life-threatening cardiac arrhythmias; significant left
ventricular dysfunction; or left ventricular outflow obstruction, in the opinion of the
investigator
15. Known permanent atrial fibrillation, in the opinion of the investigator.
16. Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism).
17. Documented pulmonary veno-occlusive disease.
Criteria linked to macitentan/tadalafil use:
18. Hemoglobin <100 g/L (<10 g/dL) at Screening.
19. Known severe hepatic impairment defined as a Model for End-Stage Liver Disease (MELD)
score ≥19.7
20. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >1.5  upper
limit of normal (ULN) at Screening.
21. Criterion modified per Amendment 5
7 
See Section 14.8 for MELD scoring criteria.


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21.1 
Severe renal impairment (Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) 2009 equation [Levey 2009] calculated creatinine clearance <30 mL/min) at
Screening.8
22. Systemic hypotension (systolic blood pressure [SBP] <90 or diastolic blood pressure [DBP]
<50 mmHg) at Screening or Randomization.
23. Systemic hypertension (SBP >160 or DBP >100 mmHg) at Screening.
24. Acute myocardial infarction or cerebrovascular event (eg, stroke) within the last 26 weeks
prior to Screening.
25. Known bleeding disorder in the opinion of the investigator.
26. Loss of vision in one or both eyes because of non-arteritic anterior ischemic optic neuropathy,
regardless of whether or not this episode was in connection with previous PDE-5i treatment.
27. Hereditary degenerative retinal disorders, including retinitis pigmentosa.
28. History of priapism, conditions that predispose to priapism (eg, sickle cell anemia, multiple
myeloma, or leukemia) or anatomical deformation of the penis (eg, angulation, cavernosal
fibrosis, or Peyronie’s disease).
General restrictions:
29. Difficulty swallowing large pills/tablets that would interfere with the ability to comply with
study treatment regimen.
30. Any planned surgical intervention (including organ transplant) during the double-blind
treatment period, except minor interventions.
31. Exercise training program for cardiopulmonary rehabilitation in the 12-week period prior to
Start of treatment, or planned to be started during the double-blind period of the study.
32. Pregnant, planning to become pregnant or lactating.
33. Any known factor or disease that might interfere with treatment adherence, study assessments,
study conduct, or interpretation of the results as judged by the investigator (eg, drug or alcohol
dependence, psychiatric disease, use of walking aids, etc.).
34. Known concomitant life-threatening disease with a life expectancy <12 months.
Other therapies:
35. Criterion added per Amendment 5
Calcium channel blocker treatment initiated, or dose changed within 3 months prior to RHC at
screening.
4.5 Criteria for Women of Childbearing Potential
4.5.1 Definition of childbearing potential
A woman is considered to be of childbearing potential unless she meets at least one of the
following criteria:
 Previous bilateral salpingectomy, bilateral salpingo-oophorectomy, or hysterectomy,
8 
Calculated creatinine clearance is measured as eGFR in this study (Section 7.2.4.2)


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 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, or
uterine agenesis.
The reason for not being of childbearing potential will be recorded in the electronic Case Report
Form (eCRF).
4.5.2 Acceptable methods of contraception
Women of childbearing potential must use one of the following methods of contraception from
Screening up to at least 30 days after study treatment discontinuation [Table 1].
Table 1 
Acceptable methods of contraception
Option 1 
OR  
Option 2
One method from
this list
OR  
Option 3 
OR  
Option 4
 Tubal
sterilization
(occlusion or
ligation of tubes
at least 6 weeks
prior to
Screening)
 Intrauterine
devices
 Implantable*
hormonal
contraceptives
 Oral*,
 Transdermal*, or
 Injectable*
hormonal
contraceptives
 Sterilization of the
male partner with
documented post-
vasectomy
confirmation of the
absence of sperm in
the ejaculate
 True abstinence
from intercourse
with a male partner
only when this is in
line with the
preferred lifestyle
of the participant.
PLUS one
method from this
list
PLUS one method
from this list
 Diaphragm,
 female condom
 cervical cap,
 partner’s use of a
condom
 Oral*,
 Implantable*,
 Transdermal*, or
 Injectable*
hormonal
contraceptives
 Intrauterine devices
 Diaphragm,
 female condom
 cervical cap,
 partner’s use of a
condom
* If a hormonal contraceptive is chosen from this group, it must be taken for at least 28 days prior to Randomization.
Rhythm methods or the partner’s use of a condom alone are not considered acceptable methods of
contraception for this study.


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The methods of contraception used (including non-pharmacological methods) must be recorded in
the eCRF.
To ensure compliance, the study personnel must remind women of childbearing potential at each
visit to use the methods of contraception defined for this study. The reminders must be documented
in the source documents.
5 TREATMENTS
5.1 Study Treatment
5.1.1 Investigational treatment: description and rationale
Study treatments are M/T FDC, macitentan, tadalafil, and their respective matching placebos.
Details and references are provided in Section 1.2.
5.1.1.1 M/T FDC
M/T FDC will be provided as film-coated tablets.
The doses of macitentan (10 mg) and tadalafil (40 mg) selected for the M/T FDC are those
recommended for each compound and correspond to the doses used for monotherapy.
The matching placebo tablets will not contain any active substance but are otherwise identical in
appearance to the active drug tablets.
5.1.2 Comparator treatments: description and rationale
5.1.2.1 Macitentan 10 mg
Macitentan 10 mg will be provided as film-coated tablets debossed with ‘10’ on both sides.
The macitentan dose (10 mg) is the recommended dose and corresponds to the dose used, both
separately and concomitantly, in the clinical setting.
The matching placebo tablets do not contain any active substance but are otherwise identical in
appearance to the trial product.
5.1.2.2  Tadalafil 20 mg
Tadalafil 20 mg will be provided as over-encapsulated film-coated tablets.
The dose of tadalafil (40 mg) is the recommended dose and corresponds to the dose used, both
separately and concomitantly, in the clinical setting.
The matching placebo tablets do not contain any active substance but are otherwise identical in
appearance to the trial product.
5.1.3 Study treatment administration
5.1.3.1 Double-blind treatment period
Study treatment is to be taken from the day of the Randomization visit (Day 1). Tablets are to be
taken at the same time each day, preferably in the morning, including on days of study visits.


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Table 2 summarizes the different treatment administrations during the double-blind treatment
period for each study treatment group.


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Table 2 
Treatment administration in the double-blind treatment period
Randomization 
M/T FDC1 
Macitentan 
monotherapy1 
Tadalafil
monotherapy1
Titration phase Week 12 
Macitentan 10 mg tablet × 1 
Tadalafil 20 mg tablet × 1 
Tadalafil placebo tablet × 1 
Macitentan 10 mg tablet × 1 
Tadalafil placebo tablet × 2 
Macitentan placebo tablet × 1
Tadalafil 20 mg tablet × 1
Tadalafil placebo tablet × 1
Titration phase Week 23 
Macitentan 10 mg tablet × 1 
Tadalafil 20 mg tablet × 2 
Macitentan 10 mg tablet × 1 
Tadalafil placebo tablet × 2 
Macitentan placebo tablet × 1
Tadalafil 20 mg tablet × 2
Maintenance phase2 
Macitentan placebo tablet × 1 
Tadalafil placebo tablet × 2 
M/T FDC tablet × 1 
Macitentan 10 mg tablet × 1 
Tadalafil placebo tablet × 2 
M/T FDC placebo tablet × 1 
Macitentan placebo tablet × 1
Tadalafil 20 mg tablet × 2
M/T FDC placebo tablet × 1
M/T FDC  macitentan/tadalafil fixed dose combination; PDE 5i  phosphodiesterase type 5 inhibitor.
1 
Table lists tablets to be taken per day. All tablets are to be taken together daily. Tablets are to be taken at the same time of day each day, preferably in the morning, including days of
study visits.
2 
Participants who were on an allowable dose of PDE 5i at baseline (40 mg tadalafil, 60 120 mg sildenafil, or 10 mg vardenafil daily) will not up titrate and will receive 40 mg tadalafil
starting on study Day 1.
3. If a participant cannot tolerate the higher tadalafil dose (or placebo) during the titration period, the dose will be decreased back to 20 mg daily. Within the first
2 3 weeks after decreasing the dose (up to and including Week 4 / Visit 5) and with the investigator’s approval, the participant is allowed to be re uptitrated to the tadalafil 40 mg daily
dose (or its matching placebo equivalent). If the participant cannot tolerate the 40 mg dose again on the 2nd attempt to up titrate the tadalafil dose (or its matching placebo equivalent),
then they are to stay on the 20 mg tadalafil daily dose (or its placebo equivalent) for the remainder of the double blind treatment period. These participants will receive the same treatment
they received during their titration phase Week 1 throughout the entire double blind treatment period.


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5.1.3.2  Open-label treatment period
All participants will receive M/T FDC.
In order to maintain the blind as participants enter the open-label treatment period, all
participants will complete a 2-week titration phase, during which macitentan and tadalafil
will be administered as a loose combination. Treatment during this titration period will be
assigned by the Interactive Response Technology (IRT) system. Participants who
completed 16 weeks of treatment with 40 mg tadalafil during the double-blind treatment
period will not be up-titrated but will receive macitentan 10 mg and tadalafil 40 mg directly
from Week 1.
The first dose of open-label treatment will be taken  after all Week 16 assessments are
complete, including RHC, either in the evening after the visit or the following day,
depending on the participant’s normal dosing schedule. On the following days, tablets are
to be taken at the same time of day each day, preferably in the morning, including on days
of study visits.
Table 3 summarizes the different treatment administrations during the open-label treatment
period for each study treatment group.


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Table 3 
Treatment administration in the open-label treatment period
Randomization 
M/T FDC1 
Macitentan 
monotherapy1 
Tadalafil
monotherapy1
Titration phase Week 12 
Macitentan 10 mg tablet × 1 
Tadalafil 20 mg tablet × 2 
Macitentan 10 mg tablet × 1 
Tadalafil 20 mg tablet × 1 
Tadalafil placebo tablet × 1
Macitentan 10 mg tablet × 1
Tadalafil 20 mg tablet × 2
Titration phase Week 23 
Macitentan 10 mg tablet × 1 
Tadalafil 20 mg tablet × 2 
Macitentan 10 mg tablet × 1 
Tadalafil 20 mg tablet × 2 
Macitentan 10 mg tablet × 1
Tadalafil 20 mg tablet × 2
Maintenance phase 
M/T FDC tablet × 1 
M/T FDC tablet × 1 
M/T FDC tablet × 1
M/T FDC  macitentan/tadalafil fixed dose combination.
1 
Table lists tablets to be taken per day. Tablets are to be taken at the same time of day each day, preferably in the morning each day, including days of study visits.
2 
Participants who received M/T FDC or tadalafil monotherapy and who completed 16 weeks of treatment with 40 mg tadalafil during the double blind treatment period will receive
tadalafil 40 mg (tadalafil 20 mg tablet × 2) during Week 1. Participants allocated to these arms who could not tolerate 40 mg tadalafil during the double blind treatment period will up
titrate from 20 mg to 40 mg during the first 2 weeks of open label treatment. If they can tolerate 40 mg tadalafil, they will be able to proceed to the open label treatment period maintenance
phase with the fixed dose combination. Treatment will be provided to all participants as a loose combination to preserve the blind from the double blind treatment period.
3 
Participants unable to tolerate 40 mg tadalafil during the titration period are ineligible to continue onto the maintenance period.


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5.1.4 Treatment assignment
At Screening, participants will be assigned a study-specific participant number by the IRT system.
This number is kept throughout the study and is the main participant identifier. Note: In case of
re-screening, a new participant number will be assigned.
After having verified that the participant meets all inclusion criteria and none of the exclusion
criteria, the investigator/delegate contacts the IRT system at Visit 2 to randomize the participant.
The IRT assigns a randomization number to the participant and assigns the treatment kit number,
which matches the treatment arm assigned by the randomization list to the randomization number.
The randomization list is generated by an independent Contract Research Organization (CRO).
Participants will be stratified based on their prior PAH therapy:Treatment-naïve, on ERA therapy,
or on PDE-5i therapy.
The treatment-naïve participants will be randomized in a 2:1:1 ratio into M/T FDC, macitentan 10
mg, or tadalafil 40 mg daily, respectively. Participants on ERA therapy will be randomized in a
2:1 ratio to M/T FDC or macitentan 10 mg daily, respectively. Participants on PDE-5i will be
randomized in a 2:1 ratio to M/T FDC or tadalafil 40 mg daily, respectively.
Participants will be assigned treatment for the open-label treatment period titration phase by the
IRT system in order to maintain the blind from the double-blind study period.
Further details are provided in the IRT specification document and study-specific IRT usermanual.
5.1.5 Blinding
The first 16 weeks of this study will be performed in a double-blind fashion. The investigator and
study personnel, the participants, the Site Managers (SMs), sponsor personnel, and CRO personnel
involved in the conduct of the study will remain blinded to the study treatment until the final
double-blind analysis, ie, until the last randomized participant has completed 16 weeks of double-
blind treatment or prematurely discontinues from the study and the database is finalized, or until
the study is stopped prematurely.
Treatment arm assignment in the double-blind treatment period will remain blinded when
participants enter the open-label treatment period.
Study treatments and their matching placebos are indistinguishable. All treatment kits will be
packaged in the same way.
Sponsor personnel responsible for clinical study supply distribution will need to be unblinded to
ensure adequate supply of study treatment. These persons will be clearly identified, their
unblinding will be documented in the trial master file, and measures taken per sponsor’s standard
operating procedure to maintain blinding of the study team.
Until the time of sponsor unblinding, the randomization list is kept strictly confidential and
accessible only to authorized persons who are not involved in the conduct of the study.


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5.1.6 Unblinding
5.1.6.1 Timing of study analyses
The database will be cleaned and the data extracted and analyzed at 3 time points during the study
[see Figure 2]:
1. The IA will take place when approximately 100 participants have either completed their Week
16 assessment or have discontinued from the study prior to their Week 16 assessment and after
the global amendment 5 has been approved in all the countries.
2. Unless the study is stopped prematurely during the IA, the final analysis of the double-blind
period will occur when all participants have reached Week 16 or prematurely discontinued
from the study.
3. The final analysis of the study will occur when all participants have performed their EOS visit
(once the last participant has completed the open-label treatment period).
Figure 2 
Study analyses
CRO  Contract Research Organization; EOS  End of Study; DB  double blind; IDMC  Independent Data Monitoring
Committee; SM  Site Manager; SSG  statistical support group; FSFV
First Subject First Visit; LSLV
 Last Subject Last
Visit; M/T FDC  macitentan / tadalafil FDC; OL open label; W  week.


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A Conducted by the independent SSG and interpreted by the IDMC when approximately 100 participants have either completed
their Week 16 assessment or have discontinued from the study prior to their Week 16 assessment and after the global
amendment 5 has been approved in all the countries.
Analysis for efficacy or futility and sample size re estimation
B When all participants have reached Week 16 or prematurely discontinued from the study
Analysis of primary endpoint, secondary endpoints, and “other” endpoints for the double blind treatment period
C When all participants have performed their EOS visit
Final analysis of the study
5.1.6.2  Unblinding for IDMC
An independent SSG not otherwise involved in the design, conduct, or analysis of the study, will
have access to the randomization code in order to prepare unblinded reports for review by the
IDMC, as described in the IDMC charter. The independent SSG will be represented by an
independent statistician. The randomization code will be made available to the independent SSG
in accordance with the sponsor’s Quality System (QS) documents.
5.1.6.2.1 Unblinding for the interim analysis
The independent SSG will have access to full randomization information for all participants
randomized [see Section 5.1.6.2]. In accordance with the IDMC charter, the IDMC will review the
study results [see Section 10.4] and will provide a recommendation on early study termination for
efficacy or futility or on sample size adjustments.
If the study is terminated for efficacy, unblinding will occur after all enrolled participants have
completed Week 16 assessments or prematurely discontinued the study.
5.1.6.3 Unblinding for the final double-blind treatment period analysis
Full randomization information will be made available to the sponsor for data analysis [see Figure
2] only after the last randomized participant has completed 16 weeks of double-blind treatment or
has prematurely  discontinued from the study, the database is cleaned, the data extraction  is
performed, in accordance with sponsor QS documents [see Figure 2].
Following each participant’s completion of the double-blind treatment period, they will enter the
open-label treatment period. In order to preserve the blind of each individual participant until the
final double-blind analysis, all participants will enter a 2-week blinded titration period prior to
initiating their M/T FDC treatment [see Section 5.1.3].
5.1.6.4 Unblinding for suspected unexpected serious adverse reactions
If a suspected unexpected serious adverse reaction (SUSAR) occurs for a participant participating
in the study, the sponsor will request the unblinding of the treatment assignment. The treatment
assignment will not be communicated to site personnel or to the sponsor’s CTT. Unblinded
SUSAR information will be provided to respective health authorities and Independent Ethics
Committees (IECs) or Institutional Review Boards (IRBs) only. SUSARs will be reported to
investigators in a blinded fashion.
5.1.6.5 Emergency procedure for unblinding
The investigator, study personnel, and sponsor personnel must remain blinded to the participant’s
treatment assignment. The identity of the study treatment may be revealed only if the participant


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experiences a medical event, the management of which would require knowledge of the blinded
treatment assignment. In this case, the investigator can receive the unblinded treatment assignment
through the IRT  system. In these situations, the decision to unblind resides solely with the
investigator. Whenever it is possible, and if it does not interfere with (or does not delay) any
decision in the best interest of the participant, the investigator is invited to discuss the intended
unblinding with sponsor personnel.
The occurrence of any unblinding during the study must be clearly justified and explained by the
investigator. In all cases, sponsor personnel must be informed as soon as possible before or after
the unblinding.
Unblinding must lead to study treatment discontinuation. Instructions for premature study
treatment discontinuation are found in Section 5.1.10.
The circumstances leading to unblinding must be documented in the Investigator Site File (ISF)
and eCRF.
5.1.7 Study treatment supply
The manufacture, labeling, packaging, and supply of study treatment will be conducted according
to Good Manufacturing Practice (GMP), Good Clinical Practice (GCP), and any local or national
regulatory requirements.
All study treatment supplies are to be used only in accordance with this protocol, and not for any
other purpose.
5.1.7.1 Study treatment packaging and labeling
Study treatment is provided as tablets and supplied in childproof blister packs during the double-
blind treatment period and the titration phase of the open-label treatment period. Thereafter, during
the open-label treatment period maintenance phase, study treatment is provided as tablets supplied
in childproof bottles.
Study treatment is labeled to comply with the applicable laws and regulations of the countries in
which the study sites are located.
5.1.7.2  Studytreatment distribution and storage
The investigator is responsible for the safe and proper handling and storage of the study treatments
at the investigational site, and for ensuring that the study treatments are administered only to
participants enrolled in the study and in accordance with the protocol. Study treatments must be
kept in a locked cabinet or room, that can be accessed only by the pharmacist, the investigator, or
another duly designated person.
Study treatment supplies must be kept in an appropriate, secure area and stored according to the
conditions specified on the label.
At the site, a temperature log must be maintained, and temperature control should occur at least on
a weekly basis.


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5.1.7.3 Study treatment dispensing
The participants will receive sufficient study treatment to cover the period up to the next visit at
which treatment dispensing is scheduled. Participants are asked to return all used, partially used,
and unused study treatment blister packs/bottles at each visit. The protocol-mandated study
treatment dispensing procedures may not be altered without prior written approval from the
sponsor. The IRT system will allow dispensation of study treatment outside the scheduled visit.
An accurate record of the date and amount of study treatment dispensed to each participant must
be available for inspection at any time.
5.1.7.4 Study treatment return and destruction
Used and unused study treatment containers will be destroyed at the site once study treatment
accountability is finalized and has been checked by sponsor personnel or the deputy, and written
permission for destruction has been obtained from the sponsor, except in specific circumstances
to be determined by the sponsor.
5.1.8 Study treatment accountability and compliance with study treatment
5.1.8.1 Study treatment accountability
The inventory of study treatment dispensed to and returned by the participant (ie, 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 studytreatment dispensing and
accountability log and in the eCRF and checked by the SM during site visits and at the end of the
study. The study treatment accountability log in the eCRF  will include at least the following
information for each study treatment unit (ie, blister or bottle) dispensed to the participant:
 Allocated blister or bottle number (pre-populated in the eCRF).
 Dispensed blister or bottle number.
 Date dispensed / number of tablets dispensed.
 Date returned / number of tablets returned.
All study treatment supplies, including partially used or empty blisters or bottles must be retained
at the site for review by the SM.
If the participant forgets to bring the remaining study treatment to a study visit, they  must be
instructed to not take any tablets from the remaining study treatment blisters or bottles and to return
them at the next visit.
5.1.8.2  Study treatment compliance
Study treatment compliance must be evaluated by the SM. It is based on study treatment
accountability. Compliance will be calculated separately for the 3 study treatments between 2
dispensing visits.
Compliance  [(number of tablets dispensed  number of tablets returned) / Total number of tablets
that should have been taken during the period] × 100
The total number of tablets that should have been taken is calculated as follows:


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Titration phase 
Maintenance phase
Week 1 
Week 2
M/T FDC or placebo 
Not applicable 
Current visit date 
 previous
visit date
Tadalafil 20 mg* or placebo
2 × (Current visit date  previous visit date)
Macitentan 10 mg* or placebo 
Current visit date previous visit date
* Calculation of compliance for these tablets is not applicable during the open label treatment period maintenance phase.
Compliance is expected to be between 80% and 120%. Compliance values outside of this range
will be considered as protocol deviations, which will be reported in the mCTMS by the SM. The
investigator must discuss the non-compliance with the participant to clarify the reasons and to take
appropriate actions to avoid reoccurrence. This discussion and its outcome must be documented
in the source documents.
5.1.9 Study treatment dose adjustments and interruptions
Ifa participant cannot tolerate 40 mg of tadalafil, the investigator may down-titrate the participant
to 20 mg tadalafil.
If down-titration is determined to be necessary, an unscheduled visit is required, at which the
investigator/delegate will contact the IRT  system and new blister packs will be assigned in a
blinded manner.
If down-titration occurs during the double-blind titration period, re-uptitration to 40 mg tadalafil
may be attempted once during the first 2 weeks of the double-blind maintenance period. Re-
uptitration may be performed at an unscheduled visit during the first 2 weeks of the double-blind
maintenance period or at Visit 5. Re-uptitration can be done using originally assigned blister packs
from the most recent study treatment dispensing visit.
Dose adjustments are not allowed for macitentan.
No dose adjustment is allowed during the open-label treatment period.
Study treatment may be temporarily interrupted in response to an AE, a diagnostic or therapeutic
procedure, a laboratory abnormality, or for administrative reasons. Study-specific criteria for
interruption of study treatment are described in Section 5.1.11.
If study treatment is interrupted by the participant for any reason, they must immediately inform
the investigator.
It is not allowed to interrupt only one of the study treatments (ie, tadalafil / macitentan / M/T FDC
and/or matching placebos). All study treatments must be interrupted at the same time.


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Interruptions of study treatment must be kept as short as possible. If treatment is stopped for more
than 14 consecutive days, re-introduction is not permitted, and treatment must be permanently
discontinued [see Section 5.1.10].
Study treatment dose adjustments / interruptions must be recorded in the eCRF.
5.1.10 Premature discontinuation of study treatment
The decision to prematurely discontinue study treatment may be made by the participant, the
investigator, or sponsor personnel. The main reason for and originator of the decision to
prematurely discontinue study treatment must be documented in the eCRF.
It is not allowed to discontinue only one of the study treatments (ie, tadalafil / macitentan / M/T
FDC and/or matching placebos). All study treatments must be discontinued at the same time.
A participant 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 (ie, premature withdrawal from the study [see Section 8.2]). Although a
participant is not obliged to give their 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 participant’s rights.
The investigator must discontinue study treatment for a given participant if, on balance, they
believe that continued administration would be contrary to the best interests of the participant.
Study-specific criteria for discontinuation of study treatment are described in Section 5.1.11.
A participant who prematurely discontinues study treatment is NOT considered withdrawn from
the study.
If premature study treatment discontinuation occurs during the double-blind treatment period, the
participantwill be asked to return for a premature EDBT visitwithin ±2 days of last study treatment
intake and before initiation of new PAH therapy (or, if not possible, within 7 days of the last intake
of double-blind study treatment), a safety follow-up visit 30 35 days after the last intake of study
treatment, and all remaining visits up until the Week 120 visit (excluding Visits 9 and 10). If the
participant did not withdraw consent for study participation and regular visits to the site are not
possible, phone contacts can be performed, at the scheduled visits, until the Week 120 visit. During
these phone calls, M/M, AE, and concomitant medication information will be collected.
Participants unable or unwilling to participate in these visits and/or phone calls should withdraw
consent for the study. Participants that prematurely discontinue study treatment during the double-
blind treatment period are not eligible to be treated with the M/T FDC  during the open-label
treatment period.
 Note: It is allowed to combine any of the above listed visits if their allowed visit windows
overlap.
If premature study treatment discontinuation occurs during open-label treatment period, the
participant will be asked to return for a premature EOLT visit within ±7 days of last intake of study
treatment, safety follow-up visit 30 35 days after last intake of study treatment, and all remaining
visits up until the Week 120 visit (excluding Visits 9 and 10). If the participant did not withdraw


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consent for study participation and regular visits to the site are not possible, phone contacts can be
performed, at the scheduled visits, until the Week 120 visit. During these phone calls, only M/M,
AE, and concomitant medication information will be collected. Participants unable or unwilling to
participate in these visits and/or phone calls should withdraw consent for the study.
 Note: it is allowed to combine any of the above listed visits if their allowed visit windows
overlap.
A participant who prematurely discontinues study treatment and withdraws consent to participate
in any further study assessments is considered withdrawn from the study. Participants who die or
are lost to follow-up are also considered withdrawn from the study. Withdrawal from the study
and follow-up medical care of participants withdrawn from the study, if applicable, are described
in Sections 8.2 and 8.4, respectively. Survival status follow-up will be collected for all participants
starting at the time of double-blind database lock and yearly thereafter until death or study closure
[Section 8.2]. Refer to Section 7.2.2.13 for more details.
5.1.11 Study-specific criteria for interruption / premature discontinuation of study
treatment
Study treatment interruptions exceeding 14 consecutive days must lead to permanent
discontinuation of study treatments. If treatment interruption exceeds 14 consecutive days and
thereby requires permanent discontinuation of study treatment, premature EOT visit should occur
within 7 days of the discontinuation criteria being met. RHC is not required if it cannot be done
within 7 days of last double-blind treatment administration.
5.1.11.1 Pregnancy
If a female participant becomes pregnant after study start (ie, signing of ICF) and up to 1 month
following discontinuation of study treatment, a pregnancy form must be completed [see Section
9.3.1]. Therapy with all study treatments must be discontinued and the investigator should arrange
for an appropriate standard-of-care approved PAH-specific therapy as needed.
5.1.11.2 Liver aminotransferases abnormalities
Interruption of study treatment
Study treatment must be interrupted in the following case:
 Aminotransferases (ie, ALT and/or AST) ≥3 and <8 × ULN
Perform a re-test of aminotransferases (ALT and AST), total and direct bilirubin, and alkaline
phosphatase within 1 week. If AST and/or ALT elevation is confirmed, continue to monitor
aminotransferases, total and direct bilirubin, and alkaline phosphatase levels 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, reintroduction ofstudy treatment can be considered.
Reintroduction of study treatment after treatment interruption should only be considered if the
potential benefits 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.


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Liver aminotransferase levels must be checked within 3 days after re-introduction, then again after
a further 10 14 days and thereafter, if results remain within normal levels, per the normal
assessment schedule described in Section 7.
Permanent discontinuation of study treatment
Study treatment must be stopped and its reintroduction is not to be considered in any of the
following cases:
 Aminotransferase ≥8 × ULN.
 Aminotransferase ≥3 × ULN and associated clinical symptoms of liver injury, eg, nausea,
vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue, or flu-like syndrome
(arthralgia, myalgia, fever).
 Aminotransferase ≥3 × ULN and associated increase in total bilirubin ≥2 × ULN.
Aminotransferases, total and direct bilirubin, and alkaline phosphatase levels must be monitored
weekly after study treatment discontinuation until values return to pre-treatment levels or within
normal ranges.
Other diagnoses (eg, viral hepatitis, mononucleosis, toxoplasmosis, cytomegalovirus) and/or
etiologies (eg, acetaminophen-related liver toxicity) should be considered and ruled out by
performing the appropriate tests.
All liver aminotransferase abnormalities leading to study treatment interruption or discontinuation
must be recorded as AEs [see Section 9.1].The ILSDRB provides ongoing assessment and advice
regarding serious hepatic events that require further evaluation during the study.
5.1.11.3 Hemoglobin abnormalities
In the case of a hemoglobin decrease from baseline of >20 g/L during the study, a re-test must be
performed within 10 days; additional (local) laboratory evaluations 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; and
 indirect bilirubin.
If hemoglobin values continue to remain >20 g/L below the baseline value at subsequent visits,
further re-tests will be performed as per investigator’s judgment.
Study treatment must be temporarily interrupted if clinically mandated based on the investigator’s
judgment, or in any of the following situations (unless clearly unrelated to study treatment, eg,
hemoglobin decrease due to a bleeding event):
 A decrease in hemoglobin to <80 g/L (<4.9 mmol/L).
 A decrease in hemoglobin from baseline of >50 g/L.


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 The need for transfusion.
Reintroduction of study treatment may be considered if hemoglobin recovers, ie, if the hemoglobin
value returns to above the lower limit of the normal range or to a value close to that at baseline,
and if the potential benefits of reintroducing study treatment outweigh the potential risks.
5.1.11.4Severe renal impairment
Study treatment must be discontinued in the event of severe renal impairment (estimated creatinine
clearance <30 mL/min, CKD-EPI 2009 equation [Levey 2009]).
5.1.11.5 Vision disorder
Study treatment must be discontinued in case of loss of vision in one or both eyes.
5.1.11.6 Start of doxazosin and/or organic nitrates
Study treatment must be discontinued if doxazosin or any organic nitrate is started during
treatment.
5.1.12 Study treatment overdose and treatment
For this study, any dose of study medication higher than the planned total daily dose in a single
day will be considered an overdose.
In the event of an overdose, standard supportive measures must be taken, as required.
5.2 Previous and Concomitant Medications
5.2.1 Definitions
A previous medication is any treatment for which the end date is prior to the signing of the ICF.
A medication that is study-concomitant is any treatment that is ongoing or initiated after the
signing of the ICF or initiated up to EOS.
A medication that is study treatment-concomitant is any treatment that is either ongoing at the start
of study treatment or initiated during the treatment period.
5.2.2 Reporting of previous/concomitant medications in the eCRF
The use of all study-concomitant medications (including contraceptives and traditional and
alternative medicines, eg, plant-, animal-, or mineral-based medicines) will be recorded in the
eCRF. Previous medications must be recorded in the eCRF if discontinued less than 30 days prior
to the signing of the ICF. 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
 Treatment with diuretics. Optimization of the dose of diuretics is allowed during the treatment
period. Dose must be stable for at least 1 week prior to RHCs.
 Treatment with calcium channel blockers, if present at a stable dose for at least 3 months before
RHC.


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 During the 24 month open-label treatment period, addition of other PAH-specific therapy such
as prostanoids or prostacyclin-receptor agonists (including oral, inhaled, or infused routes),
soluble guanylate cyclase stimulators, or L-arginine is allowed after the first PAH worsening
event as evaluated by the investigator.
 During the 24 month open-label treatment period, the patient may participate in pulmonary
rehabilitation.
5.2.4 Forbidden concomitant therapy
During the 16-week double-blind treatment period:
 Treatment with any PAH therapy other than the study treatments, eg, other ERAs, other PDE-
5is, prostanoids or prostacyclin-receptor agonists (including oral, inhaled, or infused routes),
soluble guanylate cyclase stimulators, or L-arginine.
- For participants on ERA or PDE-5i at baseline, the previous ERA or PDE-5i will be
stopped on the day before the first administration of study treatment.
During open-label treatment period:
 Treatment with any ERA or PDE-5i other than the study drug.
 Treatment with prostanoids or prostacyclin-receptor agonists (including oral, inhaled, or
infused routes), soluble guanylate cyclase stimulators, or L-arginine until the first suspected
worsening event.
At any time during the study:
 Strong CYP3A4 inducers (eg, carbamazepine, rifampin, rifampicin, rifabutin, rifapentin,
phenobarbital, phenytoin, and St. John’s Wort).
 Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, voriconazole, clarithromycin,
telithromycin, nefazodone, ritonavir, and saquinavir).
 Moderate dual CYP3A4/CYP2C9 inhibitors (eg, fluconazole, amiodarone) or co-
administration of a combination of moderate CYP3A4 (eg, ciprofloxacin, cyclosporine,
diltiazem, erythromycin, verapamil) and moderate CYP2C9 inhibitors (eg, miconazole,
piperine) until study intervention discontinuation, refer to Food and Drug Administration
website [FDA 2020].
 Treatment with doxazosin.
 Any form of organic nitrate, either regularly or intermittently.
- If treatment with organic nitrates (eg, nitroglycerin) is required for angina chest pain,
at least 48 hours should elapse between the last dose of study medication and
administration of nitrates. If nitrates are administered <48 hours after the last dose of
study medication, close medical supervision with hemodynamic monitoring is strongly
recommended.
 Any other investigational drug.
Study treatment must be interrupted if the participant requires treatment with a forbidden
medication (see above). Study treatment maybe restarted if the forbidden treatment is discontinued
and study drug interruption does not exceed 14 days (see Section 5.1.11). Initiation of doxazosin
or organic nitrates require (see Section 5.1.11.6) permanent study treatment discontinuation and
the participant must complete an EOT visit.


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Every effort should be made to complete EDBT efficacy assessments, most importantly RHC,
within ±2 days of last study treatment intake and before initiation of any new PAH-specific
therapy.
If patients enrolled in a prior version (protocol versions 1 through 3) of this protocol are currently
stable on a moderate dual CYP3A4/CYP2C9 inhibitor (eg, fluconazole, amiodarone) or co-
administration of a combination of moderate CYP3A4 (eg, ciprofloxacin, cyclosporine, diltiazem,
erythromycin, verapamil) and moderate CYP2C9 inhibitors (eg, miconazole, piperine), the patient
may remain on current treatment per the investigator’s discretion based on his/her clinical
judgement and risk-benefit assessment. However, the patient will not be eligible to enter the open-
label treatment period unless the forbidden medication is discontinued 1-month prior to open-label
treatment period.
6 STUDY ENDPOINTS
6.1 Efficacy Endpoints
All endpoints will be derived using values that have been collected while on double-blind
treatment. The choice of an on-treatment is to reflect the treatment effect as any discontinuation of
study treatment and/or introduction of another PAH medication is expected to have an immediate
impact on hemodynamic characteristics. The definition of “on-treatment” values will be detailed
in the estimand section of each endpoint.
The baseline value is the last valid assessment obtained prior to first dose of study treatment.
6.1.1 Primary efficacy endpoint
 Change in PVR expressed as the ratio of geometric means of EDBT to baseline.
Hemodynamic measures as outcomes in studies of PAH provide a robust and objective
assessments of the status of the pulmonary circulation and are predictive of a participant’s clinical
outcome. RHC is the standard approach for the initial confirmation of the presence of pulmonary
hypertension, for establishing the specific diagnosis (eg, PAH), determining the severity and
prognosis of pulmonary hypertension, and for guiding therapy [Hoeper 2013, Galiè2015a]. PVR
(as measured by RHC) was chosen as the primary endpoint due to its association with disease
severity and correlation with mortality [Benza 2012b, Fares 2016, Section 1.3]. In addition to its
diagnostic [Hoeper 2013] and prognostic value, PVR as determined by RHC is needed to obtain
an objective judgment on the hemodynamic response to treatment and to guide disease
management [Tiede 2013, Galiè2015a]. An increase in PVR worsens right ventricular afterload
and thus leads to right ventricular overload, hypertrophy, dilatation, and eventually to right
ventricular failure and death [Kholdani 2015, Vonk-Noordegraaf2013, Ryan 2015, Galiè2010].
Data from the SERAPHIN study support a correlation between changes in baseline PVR and
clinical benefit. A statistically significant correlation  (coefficient of correlation of 0.36 in 48
macitentan 10 mg patients and 50 placebo patients) was observed between percentage changes in
PVR and percentage changes in 6MWD at Month 6. The effect change was consistent with the
change in PVR defined as the log of the ratio of Month 6 to baseline PVR. Additional analyses
were carried out to further characterize the log of the ratio of PVR as a potential “surrogate” for 2
clinical outcomes: absolute change from baseline to Month 6 in 6MWD and time to first M/M
event up to EOT. The proportion of the treatment effect explained by the log (Month 6 PVR /


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baseline PVR) was 66% for change in 6MWD and 40% for time to first M/M event in a Cox
regression analysis (data on file).
6.1.2 Secondary efficacy endpoints
The secondary efficacy endpoints are listed here according to the hierarchical order that will be
statistically tested:
 Change from baseline to EDBT in 6MWD.
This endpoint reflects the participants’ exercise capacity  and has been associated with
participants’ prognosis / clinical outcomes including mortality [Benza 2012b, Benza 2015] and
hemodynamics. It has also been the basis for registration of several of the currently approved
PAH therapies.
 Change from baseline to Week 16 in PAH-Symptoms and ImpactTM  (PAH-SYMPACT in
Cardiopulmonary symptom domain score
 Change from baseline to Week 16 in PAH-SYMPACTÔin Cardiovascular symptom domain
score
 Proportion of participants with absence of worsening in WHO FC from baseline to EDBT.
PAH-SYMPACT™is a PAH-specific patient-reported outcomes instrument that quantifies PAH
symptoms and impacts [McCollister 2016, Chin 2018].
WHO FC reflects the severity of a PAH patient’s symptoms and the impact of these symptoms on
their activities of daily life. WHO FC is directly associated with prognosis including mortality
[Benza 2012b], and improvement in WHO FC correlates with survival in participants with PAH
[Ghofrani 2016].
6.1.3 Other efficacy endpoints
6.1.3.1 Other efficacy endpoints for double-blind treatment period
Other efficacy endpoints for the double-blind treatment period are:
 Change from baseline to EDBT in PAH-SYMPACT™Physical impact domain score.
 Change from baseline to EDBT in PAH-SYMPACT™ Cognitive/emotional impact domain
score.
 Time to first morbidity or mortality event occurring between baseline and EDBT, defined as
any of the following:
- Death (all causes).
- Non-planned PAH-related hospitalization.
- Initiation of IV or subcutaneous prostacyclin or prostacyclin analog for worsening
PAH.
- Clinical worsening defined as:
o Deterioration in exercise testing, confirmed by two 6MWTs performed on different
days within 2 weeks, showing at least 15% decrease in 6MWD from baseline.
AND
o Worsening of PAH symptoms, defined as at least one of the following
o Increase in WHO FC.


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o Appearance or worsening of signs/symptoms of right heart failure that do not
respond to optimized oral diuretic therapy.
 Time to death due to PAH or hospitalization for PAH occurring between baseline and EDBT:
- Death due to PAH, or onset of a treatment-emergent AE that led to permanent
discontinuation of double-blind study treatment with a fatal outcome due to PAH
occurring within 4 weeks of double-blind study treatment discontinuation.
OR
- Non-planned PAH-related hospitalization.
 Time to death (all causes) occurring between randomization and double-blind database lock.
 Change from baseline to EDBT in NT-proBNP.
 Change from baseline to EDBT in QoL, assessed by the Euro Quality of Life-5D-5L (EQ-5D-
5L).
 Change from baseline to EDBT in work productivity and activity impairment, assessed by the
Work Productivity and Activity Impairment Questionnaire©: General Health (WPAI©: GH).
 Changes from baseline to EDBT in the following hemodynamic variables:
- Right atrial pressure.
- Right ventricular stroke work index (RVSWI).
- Right atrial pressure / PAWP ratio.
- Stroke volume index (SVI).
- Pulmonary artery pulsatility index.
- Pulmonary artery compliance.
 Proportion of participants who achieve a right atrial pressure of <8 mmHg at EDBT.
 Number per year of all-cause and PAH-related hospitalizations, from baseline up to EDBT.
 Number per year of in-patient hospital days for all causes and PAH-related causes, from
baseline up to EDBT.
 Number per year ofemergency room visits for all causes and PAH-related causes that do not
result in hospital admittance from baseline up to EDBT.
6.1.3.2  Other efficacy endpoints for open-label treatment period
Other efficacy endpoints for the open-label treatment period are:
 Change from baseline up to EOLT, by visit, in exercise capacity, as measured by the 6MWD.
 Change from baseline up to EOLT, by visit, in WHO FC.
 Time to first morbidity or mortality event occurring between baseline and EOLT, defined as
any of the following:
- Death (all causes).
- Non-planned PAH-related hospitalization.
- Initiation of IV or subcutaneous prostacyclin or prostacyclin analog for worsening
PAH.
- Clinical worsening defined as:
o Deterioration in exercise testing, confirmed by two 6MWTs performed on different
days within 2 weeks, showing at least 15% decrease of 6MWD from baseline.
AND
o Worsening of PAH symptoms, defined as at least one of the following
 Increase in WHO FC.


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 Appearance or worsening of signs/symptoms of right heart failure that do not
respond to optimized oral diuretic therapy.
 Time to death due to PAH or hospitalization for PAH occurring between baseline and EOLT:
- Death due to PAH, or onset of a treatment-emergent AE that led to permanent
discontinuation of study treatment with a fatal outcome due to PAH occurring within 4
weeks of study treatment discontinuation
OR
- Non-planned PAH-related hospitalization.
 Time to death (all causes) occurring between randomization and open-label database lock.
 Change from baseline up to EOLT, by visit, in NT-proBNP.
 Number per year of all-cause and PAH-related hospitalizations, from baseline up to EOLT.
 Number per year of in-patient hospital days for all causes and PAH-related causes, from
baseline up to EOLT.
 Number per year of emergency room visits for all causes and PAH-related causes that do not
result in hospital admittance from baseline up to EOLT.
6.2 Safety endpoints
For the safety endpoints, analysis will be done for each of the safety sets defined in [Section 10.1]
The safety endpoints are:
 Treatment-emergent AEs.
 SAEs.
 Deaths.
 AEs leading to premature discontinuation of study treatment.
 Change in vital signs (SBP, DBP, and pulse rate) and body weight from baseline to all assessed
time points during the study.
 Treatment-emergent marked laboratory abnormalities as detailed in Section 14.4.
 Proportion of participants with a treatment-emergent ALT and/or AST abnormality (≥3, ≥5,
and ≥8 × ULN).
 Proportion of participants with a treatment-emergent ALT and/or AST abnormality
(≥3 × ULN) associated with total bilirubin ≥2 × ULN (and increased as compared to baseline).
 Proportion of participants with a treatment-emergent hemoglobin abnormality (<100 g/L, and
<80 g/L).
 Treatment-emergent AEs of special interest (hypotension, anemia, edema, liver events).
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS
7.1 General Information
The study visits are listed in Table 4 and Table 5. For all visits, the participants must be seen on
the designated day with an allowed visit window of 7 days, however all efforts must be made to
have EDBT efficacy assessments completed within ±2 days of last study treatment intake and
before initiation of any new PAH-specific therapy. A follow-up safety visit must be performed
30 35 days after intake of the last dose of study treatment. All assessments pertaining to a visit
should be performed on the same day. If it is not possible to complete all assessments on the same
day, a visit may extend over more than 1 day within the allowed time window.


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Participants who prematurely discontinue study treatment for any reason will not be replaced.
7.1.1 Screening/re-screening
Screening starts with the signature of the ICF. The date on which the first screening assessment is
performed corresponds to the date of the Screening visit.
It is the responsibility of the investigator/delegate to obtain written informed consent from each
participant participating in this study after adequate face-to-face explanation of the objectives,
methods, and potential hazards of the study. The participants who agree to participate in the study
and the investigator/delegate must sign the ICF prior to any study-related assessment or procedure.
Participants who have signed the ICF and are in screening when the enrollment target has been
met may still be randomized.
It is permitted to re-screen participants once, if the reason for non-eligibility was transient (eg,
abnormal laboratory test, insufficient washout period of a forbidden medication). All screening
assessments (except RHC if already done for initial screening and still within 5weeks of
randomization) should be repeated at the time of 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 (eg, 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
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** The PAH SYMPACT questionnaire is filled out on an electronic device by the participant at home for 7 consecutive days prior to the applicable visit. Participants will
be trained on how to use the PAH SYMPACT questionnaire during the Screening period. For the baseline questionnaire during the Screening period, the participant is
given the questionnaire at the Screening visit and is to fill it out during 7 consecutive days in the Screening period. The baseline RHC is not to be done during the
7 consecutive days of the PAH SYMPACT.
†RHC conducted per guidelines in Section 14.1 done before Screening period is allowed provided it is done no more than 5 weeks prior to the date of randomization.
Vasoreactivity test required for incidence patients. For prevalent patients without prior vasoreactivity test, they can be eligible if currently treated with PAH therapy
for more than 3 months and PAH diagnosis confirmed by hemodynamic evaluation at least 3 months after introduction of their PAH therapy.
Visit may be conducted by phone.
X mandatory assessment; (X) Optional assessment.
1 
Unscheduled visits may be performed at any time during the study and may include all or some of the indicated assessments, including dispensing of down titration
kits, based on the judgment of the investigator.
2 
Height is only measured at Visit 1.
3 
Includes hematology and blood chemistry.
4 
Serum pregnancy test at Screening only, urine pregnancy test for the following visits. Women of childbearing potential only.
5 
Scheduled study medication dispensing/return procedures may be adapted according to the site practice. Not applicable after premature study treatment discontinuation
after last dispensed drug has been returned.
6 
All AEs and SAEs that occur after signing the ICF and up to EOS must be reported.
7 
The physical examination at Visit 1 and 2 must be performed in entirety for all participants but afterwards it must be tailored to organs that are prompted ad hoc by
anamnesis.
8 
Biomarker samples collected for participants who agreed to biomarker sample collection in the ICF.
9 
EDBT efficacy assessments are to be conducted within 2 days after last study treatment intake and before introduction of any prohibited medications as listed in
Section 5.2.4.
10. If participant does not enter open label treatment period, Safety Follow up visit is to be performed 30 35 days after last double blind study treatment intake [see
Table 5]. Participants that prematurely discontinue study treatment during the double blind treatment period are not eligible to be treated during the open label treatment
period.
11. RHC is to be performed at time of study treatment discontinuation. If RHC is performed at premature EDBT, then it is not to be performed at Week 16.
12 If the study treatment is prematurely discontinued within 6 weeks after randomization, a post baseline RHC is not required.
13 If study treatment is prematurely discontinued, these assessments are not required after the Safety Follow up visit.
14. Survival information will be collected for all participants (within 2 months prior to last participant’s Week 16 visit [announced]). Thereafter survival status is collected
approximately yearly until death or within 2 months prior to the last participants last visit (announced), including those who prematurely discontinued from the study
at any time (Section 7.2.2.13 and Section 8.2).
6MWT  6 minute walk test; AE  adverse event; EDBT  End ofDouble Blind Treatment; EQ 5D 5L  Euro Quality of Life 5D 5L; F U  follow up; ICF
Informed
Consent Form; NT proBNP  N terminal pro B type natriuretic peptide; RHC  right heart catheterization; SAE  serious adverse event; WHO FC
World Health
Organization functional class; WPAI©
 Work Productivity and Activity Impairment Questionnaire©.


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Table 5 
Open-label treatment period visit and assessment schedule
PERIODS  
Name 
Open-label treatment period  
SAFETY 
FOLLOW-UP6
Survival F-U
PHASES  
Name 
Titration 
Maintenance
VISITS 
Number 
8 
9 
10 
11 
12 
13 
14 
U1, U2, …  
15
Name 
EDBT  
 
 
EOLT11 
Premature 
EOLT  
Unschedule 
d visit1 
Safety Follow-
up
Time 
Week 16/ 
Day 113 
( 7 days) 
Week 17/ 
Day 120 
( 3 days) 
Week 18/ 
Day 127 
( 3 
days) 
Week 42/ 
Day 295 
( 7 
days) 
Week 68/ 
Day 477 
( 7 days) 
Week 94/ 
Day 659 
( 7 
days) 
Week 120/ 
Day 841 
( 7 days) 
or 
premature
discontinu
ation
At time of 
premature 
discontinuation
( 7 days)
Any time 
30 35 days
after last dose6
For all participants: Within
2 months prior to last
participant’s Week 16 visit
(announced) and yearly
thereafter until death or
within 2 months prior to the
last participants last visit
(announced)12
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X
Physical examination5 
X 
X 
X 
X 
X 
X 
(X)
Vital signs, body weight 
X 
X 
X 
X 
X 
X 
(X)
6MWT, Borg, WHO FC  
X 
X 
X 
X 
X 
X 
(X)
NT-proBNP*,8 
X 
X 
X 
X 
X 
X
Biomarker sample7,8 
X 
X 
X 
X 
X 
X
Laboratory tests*,8, 10 
X10 
X 
X 
X 
X 
X 
(X) 
X
Liver function tests*,8,9 
X 
Monthly  
( 7days)
Every 3 months ( 7days)
X
X
Pregnancy tests2,8 
Monthly ( 7days) 
X 
X
Morbidity/mortality event assessment 
X 
X 
X 
X 
X 
X
(X) 
X
Study treatment dispensing/return3 
X 
X 
X 
X 
X 
X 
(X)
Semi-structured qualitative interview13 
(X)
Adverse events4 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X
Serious adverse events4 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X
Survival F-U12
X


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* Transferred electronically by an external service provider.
Visit may be conducted by phone, not required if the participant has discontinued study treatment.
X mandatory assessment; (X) Optional assessment.
1 
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.
2 
Urine pregnancy tests may be performed by women of childbearing potential at home and the results relayed to the site via phone call.
3 
Scheduled study medication dispensing/return procedures may be adapted according to the site practice. Not applicable after premature study treatment discontinuation
after last dispensed drug has been returned.
4 
All AEs and SAEs that occur after signing the ICF and up to EOS must be reported.
5. 
The physical examination may be tailored to organs that are prompted ad hoc by anamnesis.
6 
Safety Follow up visit happens after last dose of study treatment, this may be after the double blind treatment period or the open label treatment period. The S FU
period will be waived for participants who completed the 24 months of open label treatment and who are eligible for continued access program (post trial access
program or other open label extension study). For these participants the EOS visit is defined as the EOLT and which should occur only if immediate transition into the
continues access program is ensured, ie, on the same day as EOS.
7. 
Biomarker samples collected for participants who agreed to biomarker sample collection in ICF.
8 
If study treatment is prematurely discontinued, these assessments are not required after the Safety Follow up visit
9 
During the open label treatment period, liver function tests are to be done monthly up until Week 42, and at least every 3 months thereafter up until the EOLT. Monthly
liver tests are recommended during the entirety of the open label treatment period
10 Includes hematology laboratory test at Weeks 20, 24, and 36.
11. Participants who have completed 24 months of the open label period and are benefiting from the study intervention, as determined by their investigator, will be able to
continue participation in the open label period until alternative continued access is available in the patient’s country and as per local regulations via an open label
extension study or via post study independent requests from their investigators if tadalafil 40 mg and macitentan 10 mg are not accessible for PAH in the patient's
country.
12 Survival information will be collected for all participants (within 2 months prior to last participant’s Week 16 visit [announced]). Thereafter survival status is collected
approximately yearly until death or within 2 months prior to the last participants last visit (announced), including those who prematurely discontinued from the study
at any time (Section 7.2.2.13 and Section 8.2).
13 Qualitative interviews will be conducted by an external vendor during the maintenance phase of the OL treatment period in participants that provided consent, as well
as a subset of investigators as soon as amendment version 6 has been approved at the respective study site.
6MWT  6 minute walk test; AE  adverse event; eCRF  electronic Case Report Form; EDBT  End of Double blind Treatment; EOLT  End ofOpen Label Treatment;
EOS  End ofStudy; F U
follow up; ICF  Informed Consent Form; NT proBNP
N terminal pro B type natriuretic peptide; SAE  serious adverse event; WHO
FC  World Health Organization functional class.


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7.2 Study Assessments
The study assessments are listed in  Table 4 and Table 5. The assessments that are mandatory
during a visit are marked with an ‘X’. Optional assessments are marked with an ‘(X)’.
All study assessments are performed by qualified study personnel (medical, nursing, or specialist
technical personnel, as required) and are recorded in the eCRF, unless otherwise specified. Study
assessments performed during unscheduled visits will also be recorded in the eCRF.
At Screening, the RHC (which is the most invasive study-specific procedure) should be performed
after all other assessments are done and the participant has met all inclusion criteria and none of
the exclusion criteria up to that point.
At all visits, the following order of assessments is recommended:
 PAH-SYMPACT™ completed at participant’s home, 7 consecutive days prior to visit
(when applicable).
 PGA-S, PGI-C, EQ-5D-5L and WPAI©: GH questionnaires (when applicable).
 Vital signs and physical exam.
 WHO FC evaluation (when applicable).
 6MWT (when applicable).
 Blood samples for complete laboratory tests including hematology, blood chemistry, serum
pregnancy test (for females of childbearing potential only), and biomarkers.
 RHC at rest (when applicable).
If the Principal Investigator (PI) delegates any study procedure/assessment for a participant to an
external facility, they should inform the sponsor to whom these tasks are delegated. The set-up and
oversight will be agreed upon with the sponsor. The supervision of any external facilities remains
the responsibility of the PI.
Calibration certificates / evidence of equipment maintenance for the below-listed equipment used
to perform study assessments must be available prior to the screening of the first participant:
 Temperature measurement devices for study treatment storage area.
 Temperature measurement devices for freezer storage of biomarker samples.
 Evidence of maintenance of the RHC equipment.
Calibration certificates of other equipment must be available per local requirements.
7.2.1 Demographics / baseline characteristics
Demographic and baseline characteristics data to be collected on all randomized participants
include: age, sex, race, ethnicity, and the reason why a female is considered not to be of
childbearing potential. They are recorded in the eCRF at Visit 1 / Screening. Relevant medical
history/ current medical conditions based on the investigator’s judgment (eg, chronic and ongoing
acute conditions, serious past conditions) present before and/or at the time of signature of the ICF
will be recorded on the medical history page. Where possible, diagnoses and not symptoms will
be recorded.
The Screening RHC should be done only after all other inclusion/exclusion criteria have been met.


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For participants who failed screening, the following data will be recorded in the eCRF if available:
 Date of screening.
 Reason for screening failure.
 All baseline data collected until confirmation of the screening failure.
7.2.2 Efficacy assessments
For the primary and secondary efficacy endpoints, the baseline value is the last valid assessment
obtained prior to Randomization.
7.2.2.1 Right heart catheterization
For the RHC  methodology to be used, see the sponsor guidelines for the RHC  procedure
[Section 14.1].
Results and other corresponding RHC documents must be kept as source data in the participant’s
file at the site.
The RHC laboratory  should be equipped to do thermodilution and/or indirect (assumed) Fick
cardiac outputs and should have the ability to record and print out all pressure tracings with clear
scales and concurrent ECG tracings, as well as thermodilution curves.
Inclusion will be based on central reader evaluation of RHC data collected within 5 weeks prior to
Randomization.
Completion of baseline and follow-up RHC will be confirmed by the site staff in the eCRF and
the raw data (traces) will be made available to the central reading facility. The site will enter the
following variables into the eCRF at baseline and EDBT:
 Date and time ofthe RHC.
 Date and time of last dose of study treatment intake prior to RHC.
 Heart rate during RHC.
 Systolic systemic artery pressure (Noninvasively measured).
 Diastolic systemic artery pressure (Noninvasively measured).
 Mean right atrial pressure (mRAP).
 Systolic pulmonary artery pressure.
 Diastolic pulmonary artery pressure.
 Pulmonary artery wedge pressure (PAWP).
 Left ventricular end diastolic pressure (LVEDP) (if available/measured).
 Pulmonary Vascular Resistance (PVR).
 Arterial oxygen saturation (non-invasively measured via an oximeter).
 Mixed venous oxygen saturation (blood sample taken from the distal port of the pulmonary
artery catheter when the catheter is successfully placed in the pulmonary artery).
 Cardiac output (calculated by thermodilution and/or Fick).
 Hemoglobin value used to calculate Indirect Fick cardiac output.
The central reader evaluates the raw data in a blinded fashion and provides the following variables
via central data transfer:


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 Pulmonary Vascular Resistance (PVR)
 Mean right atrial pressure (mRAP).
 Systolic pulmonary artery pressure.
 Diastolic pulmonary artery pressure.
 Mean pulmonary artery pressure (mPAP).
 Pulmonary artery wedge pressure (PAWP).
 Left ventricular end diastolic pressure (LVEDP) (if available/measured).
 Cardiac output (calculated by thermodilution and/or Indirect Fick).
For all invasively measured pressures, the value should be entered as measured at end expiration,
not as software-generated electronic average.
Other hemodynamic variables (including, cardiac index, RVSWI, etc.) will be calculated by the
sponsor from the above measured hemodynamic variables [see Section 14.1].
If the primary investigational site does not have the possibility to perform an RHC, the sponsor
could support the assessment at another investigational specialized site participating in this study
(preferentially in the same country). The investigator at the primary site remains accountable for
the review and submission of RHC data to the central reader.
Results of RHC are to be recorded on the provided sponsor Heart Catheterization Worksheet.
7.2.2.1.1 Baseline RHC
All participants must have an RHC performed per guidelines detailed in Section 14.1.
A historical RHC performed before ICF signature but within 5 weeks prior to Randomization
(Visit 2) is allowed, provided conditions will be reproduced for the post-baseline RHC and meet
the criteria detailed in the sponsor guidelines for RHC [Section 14.1].
7.2.2.1.2 EDBTRHC
EDBT RHC is an on-treatment assessment and is to be done no more than 2 days after last double-
blind study treatment intake and before initiation of any new PAH-specific therapy. In the
extraordinary case this is not possible, RHC can be performed up to 7 days after last double-blind
study treatment intake. If RHC is performed more than ±2 days after the last day of double-blind
study treatment intake or after initiation of new PAH-specific therapy, the results will not be used
for the primary analysis on the primary endpoint; rather they will be used for a supportive analysis
on the primary endpoint. If RHC cannot be performed within 7 days post last double-blind
treatment administration, RHC procedure is not mandated for this study.
The EDBT RHC must be performed at the same location, under the same conditions (eg, same
method, same flow of oxygen if applicable), and preferably by the same operator as the baseline
RHC, and according to the guidelines detailed in Section 14.1.
7.2.2.2  6-minute walk test and Borg CR10 Scale®
See Table 4 and Table 5for time points of assessment.
The 6-minute walk test (6MWT) is a non-encouraged test that measures, the distance walked in
6 minutes [Holland 2014]. The Borg CR10 Scale® measures a participant’s dyspnea [Borg 1998].


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Detailed guidelines on correct execution of these tests, the “Sponsor guidelines for the 6MWT”,
are provided in Section 14.2. The site team member conducting the 6MWT must be trained on
these 6MWT guidelines. A training log must be collected upon completion ofthe training. Use of
the provided 6MWT worksheet is mandatory.
Before study start, it must be verified (via the sponsor “6MWT Corridor Card”) that the site can
comply with these guidelines. The exact length of the corridor used at site should be documented
on the site 6MWT Corridor Card. The same corridor should be used for all assessments.
It is important that, for each individual participant, the 6MWT is conducted under the same
conditions throughout the study (eg, same corridor). In addition, if possible, for each individual
participant, the 6MWT should be conducted by the same tester and preferably at the same time at
each visit.
Note 1: If oxygen supplementation is needed during the 6MWT at Randomization then oxygen
should be delivered using the same method, carrying the bottle in the same way, and using the
same flow during all study 6MWTs by that participant. If the flow must be increased during
subsequent visits (eg, due to worsening / increased oxygen requirements), this should be indicated
in the source notes as well as in the concomitant medication forms of the eCRF.
Note 2: The oxygen flow rate (if applicable) must remain constant from 1 hour prior to each 6MWT
until the completion of heart rate (HR) measurement 2 minutes after the end of the 6MWT.
Note 3: For consistency reasons, participants who were enrolled before the approval of Protocol
AC-077A301 Amendment 2 Version3 in their country must use the originally provided Borg Scale
through the study.
Note 4: If the participant must wear a face mask during 6MWD assessment (eg, due to COVID-
related safety measures), this must be documented in the source documents and in the eCRF.
The data related to 6MWT will be recorded in the eCRF  and the provided sponsor 6MWT
Worksheet.
7.2.2.3 PAH-SYMPACT questionnaire
The PAH SYMPACT™questionnaire is a patient-reported outcome instrument that was developed
by Actelion Pharmaceuticals Ltd for use in PAH patients [McCollister 2016; Chin 2018].
Participants will be trained on how to use the PAH SYMPACT™ questionnaire during the
Screening period.
The PAH-SYMPACT™will be administered during the Screening period and for the 7 consecutive
days prior to the Week 16 visit (and premature EDBT  visit for participants who prematurely
discontinue during double-blind treatment).
The baseline PAH-SYMPACT™is to be completed for 7 consecutive days during the Screening
period. The baseline RHC should not be done during the 7 consecutive days of PAH-SYMPACT™.
The EDBT PAH-SYMPACT™is to be completed for the 7 consecutive days prior to the EDBT
visit.


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The PAH SYMPACT™questionnaire is to be completed by the participant.
The PAH-SYMPACT™will not be administered to illiterate participants, defined as participants
who were unable to sign the ICF for themselves. It will also not be administered if the questionnaire
is not available in a language that can be easily understood and read by the participant.
The PAH-SYMPACT™should be completed in the evening, before bedtime.
The PAH-SYMPACT™consists of 2 parts: Symptoms and Impacts.
The Symptom part is a daily diary that contains 11 items. The respondent is asked to rate each of
the items for the past 24 hours. The response options for each item range from 0 “no [symptom]
at all” to 4 “very severe”. The symptom part is completed daily, as symptoms are experienced on
a daily basis and severity may vary from one day to the next.
The Symptom part is completed for the 7 consecutive days (ie, starting 7 days prior to the visit
day).
The Impact part has a 7-day recall period, as impacts of symptoms may not be experienced every
day. It contains 11 items pertaining to the impact of the disease on the participant’s life. The
response options for each item range from 0 “yes, with no difficulty at all” to 4 “no, not able at
all” / “yes, with extreme difficulty” / “extremely” / “very much”. The Impact part is completed
once on the 7th day of the symptoms diary data collection period, together with the Symptom part
(ie, in the evening).
A sample of the PAH-SYMPACT™questionnaire (US English) is provided as Section 14.5.
The PAH-SYMPACT™will be administered on an electronic device. Participants will be trained
on the completion of this questionnaire by the site staff during Visit 1 (Screening), prior to them
completing the PAH-SYMPACT™for the first time.
7.2.2.4 WHO FC
See Table 4 and Table 5for time points of assessment.
When applicable, the WHO FC assessment should be performed before the 6MWT. The WHO FC
will be collected in the eCRF.
WHO functional classification of pulmonary hypertension is found in Section 14.3.
7.2.2.5 Morbidity/Mortality event assessment
See Table 4 and Table 5for time points of assessment.
Occurrence and date of M/M events will be collected in a separate eCRF page.
Morbidity/mortality events are also AEs/SAEs and must be assessed up to EOS.
Morbidity/mortality events, including start date of the event, will be adjudicated by an independent
CEC in a blinded fashion to confirm they meet the definition of a M/M endpoint event as defined
in Section 6.1.3. The CEC may request additional data from sites if it is needed for adjudication.


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7.2.2.6  NT-proBNP
See Table 4 and Table 5for time points of assessment.
A blood sample for analysis of NT-proBNP will be drawn at each applicable visit.
NT pro-BNP samples will be stored frozen (between 20 °C [ 4 °F] and 80 °C [ 112 °F], ±2 °C
[±3.6 °F]).
A temperature log must be maintained and temperature control should occur at least on a weekly
basis.
Further details regarding blood sampling procedures and the collection and shipment of
biomarkers samples are described in the central laboratory manual.
7.2.2.7  Optional biomarker assessment
See Table 4 and Table 5for time points of assessment.
When signing the ICF, participants are able to opt-in to optional blood collection for analysis of
additional exploratory biomarkers related to pulmonary and cardiac function. Samples will be
drawn using the central laboratory kit. Biomarkers tested will include, but are not limited to:
 sEndoglin.
 sFLT-1.
 VEGF-A.
Additional biomarkers may be included in the analysis if scientific rationale becomes available
through research.
The biomarker analysis will be performed after study closure and will not be included in the study
report.
Blood sampling procedures and the storage and shipment of the biomarker samples are described
in the central laboratory manual. The biomarker samples will be transferred to a
sponsor-designated biobank when the study is closed and may be stored there for a maximum of
15years. Participants may request that these samples be destroyed at any time during or after the
study.
7.2.2.8 EQ-5D-5L
The EQ-5D-5L will be administered at Randomization (Visit 2) and the Week 16 visit (Visit 8;
and premature EDBT for participants who prematurely discontinue during double-blind
treatment).
The EQ-5D-5L is to be completed by the participant and will be administered on an electronic
device. It is recommended that the EQ-5D-5L be completed prior to any clinical assessments.
Preferably, participants will complete the EQ-5D-5L while waiting for their appointment before
any interaction with health care providers to avoid any potential bias in their responses.


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The EQ-5D-5L will not be administered to illiterate participants, defined as participants who were
unable to sign the ICF for themselves. It will also not be administered if the questionnaire is not
available in a language that can be easily understood and read by the participant.
The EQ-5D-5L consists of a descriptive system (the questionnaire), and the EQ visual analog scale
(VAS):
 The questionnaire assesses health status according to 5dimensions (Mobility, Self-care, Usual
activities, Pain/discomfort, Anxiety/depression). Each dimension is divided into 5 levels (I
have no problem, I have slight problem, I have moderate problem, I have severe problem, I am
unable to perform the described activity).
 The EQ VAS is a vertical scale, with endpoints of 100 (best imaginable state) at the top and 0
(worst imaginable state) at the bottom, which offers a simple method for obtaining a self-rating
of current health-related QoL.
Only the version of the questionnaire and scale provided by the sponsor can be used. A sample of
the EQ-5D-5L questionnaire (English version for the UK) and VAS is provided as Section 14.6.
Janssen has been granted a license agreement for the use of the EQ-5D-5L.
7.2.2.9 Work Productivity and Activity Impairment Questionnaire©: General Health
(WPAI©: GH) V2.0
The WPAI©: GH will be administered at Randomization (Visit 2) and the Week 16 visit (Visit 8;
and premature EDBT visit for participants who prematurely discontinue).
The WPAI©: GH [Section 14.9] is a patient-reported quantitative assessment of the amount of
absenteeism, presenteeism, and daily activity impairment attributable to general health
[Reilly 1993]. It has a recall period of 1 week.
Each individual participant will enter their scores on an electronic device. Written permission is
neither required nor provided to researchers using the WPAI©: GH.
The WPAI©: GH will not be administered to illiterate participants, defined as participants who
were unable to sign the ICF for themselves. It will also not be administered if the questionnaire is
not available in a language that can be easily understood and read by the participant.
7.2.2.10 Patient Global Assessment of Disease Severity (PGA-S)
The PGA-S is a single item that asks participants to describe the severity of their PAH over the
same 7 days as the PAH-SYMPACT was administered, with responses of “none,” “mild,”
“moderate,” “severe,” and “very severe” [see Section 14.7].
The PGA-S is administered at Day 1/Visit 2 and Week 16 / EDBT (Visit 8) [or premature EDBT].
It is administered on an electronic device.
PGA-S will be administered to all participants screened after the implementation of PGA-S scale
on the electronic device


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7.2.2.11 Patient Global Impression of Change (PGI-C)
The PGI-C is a single item that asks the participant to rate the change of the patient’s PAH since
beginning of study treatment administration (Visit 2). The response options are “much better,” “a
little better,” “no change,” “a little worse,” and “much worse” [see Section 14.7].
PGI-C will be administered to all participants with Week 16 visit occurring after implementation
of PGI-C scale on the electronic device.
7.2.2.12 Semi-structured Qualitative Interview
An optional substudy with a semi-structured qualitative interview will be conducted in selected
countries among participants that have reached the open-label treatment period of the study and
provided specific consent to participate in this substudy. The objectives of this semi-structured
qualitative interview substudy are to assess the participant's experience with M/T FDC treatment
with regard to satisfaction with treatment, adherence to treatment, and convenience of treatment.
Interviews will be scheduled and conducted by an external vendor, who will ask clinical sites to
share an enrollment log via a secure online file sharing platform which will include the names and
contact information of the participants who have provided consent to participate in the qualitative
interview. All interviews will be conducted in the participants’ preferred language and last
approximately 45 minutes.
An optional semi-structured qualitative interview will also be conducted with a subset of site
Investigators to assess their experience of treating participants with M/T FDC . All interviews will
be conducted in PI’s preferred language and last approximately 20 minutes.
In the event that a participant reports possible adverse events during the qualitative interview, the
trained interviewer, will report any potential AE as per Janssen’s pharmaco-vigilance process and
report them to the site/study physician within one business day of completing the interview. Sites
will then evaluate the reported event(s) for AEs/SAEs based on procedures described in protocol
Section 9.1and 9.2. The interviewer will also instruct the participant to contact their study
physician (ie, Investigator) to report their concerns.
These interviews are semi-structured and designed to allow participants to provide their own
impressions of the M/T FDC, thus the data will not be used within the study CSR. The content
analysis will present qualitative themes that emerge from the narrative data. Data will be shared
via secure file transfer protocols, or Health Insurance Portability and Accountability Act
(HIPAA)/General Data Protection Regulation (GDPR) compliant platforms. Details of participant
and Investigator semi-qualitative interview, including study design, interview guides, qualitative
analysis plan, data retention and protection are providedin a separate standalone substudy manual.
7.2.2.13 Survival Follow-up
For all participants including those who prematurely discontinue the study at any time, survival
information will be collected starting at the time of double-blind database lock (announced) and
thereafter approximately yearly until death or study closure (ie, within 2 months prior to the last
participants last visit [announced]) [Section 8.2]. The following information will be collected in
the eCRF: vital status (including date and cause of death).


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7.2.3 Safety assessments
The definitions, reporting and follow-up of AEs, SAEs, and pregnancies are described in Section 9.
Note: All safety and tolerability assessments detailed below are to be performed up to 30 days after
last intake of study treatment. For participants who enter a continued access program all safety and
tolerability assessments are to be performed up to their EOS (see Section 3.1.1).
7.2.3.1 Concomitant Medications
Concomitant medications for a participant will be assessed at every visit. Changes in therapy or
dose will be recorded in the eCRF.
7.2.3.2  Physical examination
See Table 4 and Table 5for time points of assessment.
Physical examination (ie, inspection, percussion, palpation, and auscultation) includes the
examination of general appearance (heart, lungs, abdomen, skin, extremities, eyes, ears, nose,
throat, lymph nodes, nervous system, etc.).
Other exams will be performed if indicated, based on medical history and/or symptoms, as deemed
necessary / indicated by the PI. Information for all physical examinations will be included in the
source documentation at the study site. Clinically relevant findings that are present prior to signing
of informed consent must be recorded on the Medical History eCRF page. 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.
7.2.3.3 Vital signs, weight, and height
See Table 4 and Table 5for time points of assessment.
Non-invasive SBP and DBP and pulse measurements will be measured in a supine or sitting
position. It is recommended to allow the participant to rest for at least 5minutes, to perform the
measurements, and to use the same device, same position (supine or sitting), same arm, same
operator, and appropriate cuff size throughout the study for an individual participant.
7.2.4 Laboratory assessments
7.2.4.1 Type of laboratory
A central laboratory (see central laboratory manual for contact details) will be used for all protocol-
mandated laboratory tests, including re-tests due to laboratory abnormalities and laboratory tests
performed at unscheduled visits. Central laboratory information can be found in the ISF.
If the results from the central laboratory are not available in time for randomization of the
participant, an additional blood sample may be drawn to verify eligibility (eg, hemoglobin, kidney
function, and LFTs) based on a local laboratory test. The local laboratory results (with the
corresponding normal ranges) must be recorded in the eCRF.
Other exceptional circumstances that will require recording of local laboratory results of the
variables described in Section 7.2.4.2 (with corresponding normal ranges) include hospitalization


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of the participant due to a medical emergency and missing central laboratory results from a
scheduled or unscheduled visit.
If a central laboratory sample(s) is lost or cannot be analyzed for whatever reason, the investigator
will collect an additional sample(s) as soon as possible for repeat analysis, unless a local laboratory
sample was collected within the same time window and these test results are available.
Central laboratory reports will be sent to the investigator. In case of specific (pre-defined)
laboratory abnormalities, the central laboratory will alert sponsor personnel and the relevant site
personnel. Alert flags that will trigger such notifications can be found in the laboratory manual.
All laboratory reports must be reviewed, signed, and dated by the investigator or delegate within
10 working days of receipt and filed as source documents. The investigator/delegate must indicate
on the laboratory report whether abnormal values are considered clinically relevant or not.
Clinically relevant laboratory findings that are known at the time of signing of the ICF must be
recorded on the Medical History page of the eCRF. Any clinically relevant laboratory
abnormalities detected after the signing of the ICF  must be reported as an AE or SAE as
appropriate [see Section 9], and must be followed until the value returns to within the normal range
or is stable, or until the change is no longer clinically relevant.
Details about the collection, sampling, storage, shipment procedures, and reporting of results and
abnormal findings can be found in the laboratory manual.
7.2.4.2  Laboratory tests
See Table 4 and Table 5for time points of assessment.
During the double-blind treatment period, LFTs levels are monitored monthly. During the
open-label treatment period, LFTs level monitoring is required monthly up to Visit 11 and every
3 months thereafter until EOLT. It is at the investigator’s discretion to decide (taking into account
the participant’s medical history and AEs) if monthly tests after Visit 11 during the open-label
treatment period are required/justified. Local laboratories may be used.
When LFT  monitoring is performed between visits, a visiting nurse service may be used, if
possible, to collect laboratory samples from the participant at home if available and allowed by
local regulations. The visiting nurse service is to be provided by the sponsor and any laboratory
samples collected in this fashion will be analyzed by the central laboratory. In exceptional
circumstances a local laboratory affiliated with the site may be usedand data recorded in the eCRF.
If the local laboratory results show an increase in AST/ALT ≥3 × ULN, the results must be
reported in the eCRF, the participant must return to the site, and the AST/ALT re-test must be
performed centrally.
Hematology
Rules for additional investigations and study treatment interruptions in case of hemoglobin
abnormalities are provided in Section 5.1.11.
 Hemoglobin (SI Unit: g/L; conventional unit: g/dL).
 Hematocrit (SI Unit: L/L; conventional unit: %).
 Erythrocyte count (reticulocyte count) (SI Unit: 1012/L; conventional unit: 106/μL).


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 Leukocyte count with differential counts (SI Unit: 109/L; conventional unit: 103/μL).
 Platelet count (SI Unit: 109/L; conventional unit: 103/μL).
Clinical chemistry
Rules for additional investigations and study treatment interruptions in case of liver enzyme
abnormalities or severe renal impairment are provided in Section 5.1.11.
 ALT (U/L).
 AST (U/L).
 Alkaline phosphatase (U/L).
 Total and direct bilirubin (SI unit: μmol/L; conventional unit: mg/dL).
 Creatinine (SI unit: μmol/L; conventional unit: mg/dL).
 Blood urea nitrogen (SI unit: mmol/L; conventional unit: mg/dL).
 Uric acid (SI unit: μmol/L; conventional unit: mg/dL).
 Glucose (SI unit: mmol/L; conventional unit: mg/dL).
 Sodium, potassium, chloride, calcium, magnesium (mmol/L).
 Total protein, albumin (SI unit: g/L; conventional unit: g/L).
 Albumin/globulin ratio.
The CKD-EPI 2009 equation [Levey 2009] is used for estimation of the creatinine clearance:
eGFR  141×min (SCr/K, 1) a×max (SCr/K, 1) 1.209×0.993Age×1.018 [if female]×1.159 [if black]. 
Where:
eGFR (estimated glomerular filtration rate)  mL/min/1.73m2
SCr (standardized serum creatinine)  mg/dL
K  0.7 (females) or 0.9 (males)
a  0.329 (females) or 0.411 (males)
min  indicates the minimum of SCr/K or 1
max  indicates the maximum of SCr/K or 1
age  years
Coagulation tests
 Prothrombin time and/or International normalized ratio.
 Activated partial thromboplastin time.
Pregnancy test
A serum pregnancy test will be performed for women of childbearing potential at Screening and
urine pregnancy tests will be performed monthly thereafter. The participants will be provided with
validated urine pregnancy test kits by the site. The investigator/delegate will follow-up on the
results of the urine pregnancy test with a telephone call and record the result of the test in the
eCRF. If pregnancy is suspected during the study, a serum pregnancy test must be performed
immediately, and the study treatment should be discontinued until pregnancy is ruled out.


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8 STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL
CARE
8.1 Study Completion per Protocol
A participantwho completes Week16 of the double-blind treatment period, and the Safety Follow-
up visit if he/she is not entering the open-label treatment period, is considered to have completed
the study double-blind treatment period.
A participant who completes the full 120 weeks of the treatment and a Safety Follow-up visit is
considered to have completed the study per protocol.
Study completion is reached once all participants have completed the EOS and is communicated
to the sites via a study closure letter.
8.2 Premature Withdrawal From Study
Participants may voluntarily withdraw from the study without justification for any reason at any
time. Participants are considered withdrawn if they state an intention to withdraw further
participation in all components of the study (eg, withdrawal of consent), die, or are lost to follow-
up. If a participant withdraws consent, no further data will be collected in the eCRF from the date
of withdrawal onward. The investigator may withdraw a participant from the study (without regard
to the participant’s consent) if, on balance, they believe that continued participation in the study
would be contrary to the best interests of the participant. Withdrawal from the study may also
result from a decision by the sponsor for any reason, including premature termination or
suspension of the study.
Participants 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
participant being lost to follow-up (eg, document different ways of contact such as telephone
number, home address, email address, person to be contacted in case the participant cannot be
reached). If the participant cannot be reached, the site must make a reasonable effort to contact the
participant, document all attempts, and enter the loss of follow-up information into the eCRF. The
following methods must be used: at least 3 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 (eg, a visit
by site personnel to the participant’s home), respecting the participant’s right to privacy. If the
participant is still unreachable after all contact attempts listed above, they will be considered to be
lost to follow-up.
If premature withdrawal occurs for any reason, the reason (if known) for premature withdrawal
from the study, along with who made the decision (participant, investigator, or sponsor personnel)
must be recorded in the eCRF, if known.
If, for whatever reason (except death or loss-to-follow-up), a participant 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 participant, collect unused study treatment, and discuss follow-up
medical care. Data obtained during this last appointment / telephone call will be recorded in the
participants’ medical records but will not be collected in the eCRF. The investigator must provide


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follow-up medical care for all participants who are prematurely withdrawn from the study, or must
refer them for appropriate ongoing care, as described in Section 8.4. Survival status follow-up will
be collected after the study discontinuation except for reason "withdrawal of consent" until death
or study closure (Section 7.2.2.13).
8.3 Premature Termination or Suspension of the Study
The sponsor 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, the sponsor will promptly inform the
investigators, the IECs/IRBs, and health authorities, as appropriate, and provide the reasons for
the suspension or termination.
If the study is suspended or prematurely terminated for any reason, the investigator
in agreement
with the sponsor
must promptly inform all enrolled participants and ensure their appropriate
treatment and follow-up, as described in Section 8.4. The sponsor may inform the investigator of
additional procedures to be followed in order to ensure that adequate consideration is given to the
protection of the participants’ interests.
In addition, if the investigator suspends or terminates the participation of their site in the study
without prior agreement from the sponsor, the investigator must promptly inform sponsor
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 sponsor personnel and provide a detailed written explanation of the
termination or suspension.
Any suspension or premature termination of the study must be discussed with the IDMC.
8.4 Medical Care of Subjects After Study Completion / Withdrawal From Study
After the participants’ study completion or premature withdrawal from the study, whichever
applies, the investigator/delegate will explain to the participants what treatment(s) / medical care
is necessary and available according to local regulations.
Local regulations on continued access will always take precedence. Plans for continued access
stated in this protocol may change if new information on the benefit-risk profile of insert M/T FDC
becomes available during the study or program.
Participants who have completed the 24 months of the open-label period and are benefiting from
the study intervention, as determined by their investigator, will be able to continue participation in
the open-label period until alternative continued access is available in the patients country and as
per local regulations via an open-label extension study or via post-study independent requests from
their investigators if tadalafil 40 mg and macitentan 10 mg are not accessible for PAH in the
patient's country.
Survival status follow-up will be collected after the study discontinuation until death or study
closure (Section 7.2.2.13 and Section 8.2). Investigators may re-contact the participant to obtain


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long-term follow-up information regarding the participant’s safety or survival status as noted in
the ICF (refer to Informed Consent in Section 12.3).
9 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS
9.1 Adverse Events
9.1.1 Definition of adverse events
An AE is any untoward medical occurrence, ie, any unfavorable and unintended sign, including
an abnormal laboratory finding, symptom, or disease that occurs in a participant 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
start of treatment until 30 days after study treatment discontinuation) whether or not considered by
the investigator as related to study treatment.
AEs include:
 Exacerbation of a pre-existing disease.
 Increase in frequency or intensity of a pre-existing episodic disease or medical condition.
 Disease or medical condition detected or diagnosed during the course of the study even though
it may have been present prior to the start of the study.
 Continuous persistent disease or symptoms present at study start that worsen following the
signing of informed consent form.
 Abnormal assessments, eg, change on physical examination, if they represent a clinically
significant finding that was not present at study start or worsened during the course of the
study.
 Laboratory test abnormalities if they represent a clinically significant finding, symptomatic or
not, that was not present at study start, worsened during the course of the study, or led to dose
reduction, interruption, or permanent discontinuation of study treatment.
Overdose of the study treatment and study treatment errors will be reported as an AE when
associated with signs or symptoms.
9.1.2 Intensity of adverse events
The intensity of clinical AEs is graded on a three-point scale 
mild, moderate, severe 
and is
reported on specific AE pages of the eCRF.
As per Janssen SAE/AE reporting process, sites should record each AE separately if there is a
change in intensity. Sites are to enter a stop date for the previous intensity and enter a new AE
with start date to document when the change in intensity occurred. For AEs ongoing at the start of
study treatment, if the intensity worsens after the start of study treatment, the change in intensity
and the date on which it occurred must be reported in the eCRF.
The 3 categories of intensity are defined as follows:


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 Mild
The event may be noticeable to the participant. It does not usually influence daily activities, and
normally does not require intervention.
 Moderate
The event may make the participant 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
participant 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 each ofthe study treatments 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 the signing of the ICF and up to 30 days after study treatment
discontinuation (up to EOS for participants who enter a continued access program on the same day
as the EOS visit, see Section 3.1.1) must be recorded on specific AE pages of the eCRF.
9.1.5 Follow-up of adverse events and serious adverse events
AE/SAEs still ongoing more than 30 days after study treatment discontinuation must be followed
up until they are no longer considered clinically relevant or until stabilization. The follow-up
information obtained after the participant’s EOS visit will not be collected by the sponsor.
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or
product quality complaint (PQC) as fully as possible. This may include additional laboratory tests
or investigations, histopathological examinations, or consultation with other health care
professionals.
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:


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 Fatal.
 Life-threatening: Refers to an event in which the participant was at risk of death at the time of
the event. It does not refer to an event that hypothetically might have caused death had it been
more severe.
 Requiring in-patient hospitalization or prolongation of existing hospitalization.
 Resulting in persistent or significant disability or incapacity.
 Congenital anomaly or birth defect.
 Medically significant: Refers to important medical events that may not immediately result in
death, be life-threatening, or require hospitalization but may be considered to be SAEs when,
based upon appropriate medical judgment, they may jeopardize the participant, and may
require medical or surgical intervention to prevent one of the outcomes listed in the definitions
above.
 Is a suspected transmission of any infectious agent via a medicinal product.
The following reasons for hospitalization are not considered as SAEs:
 Hospitalization for cosmetic elective surgery, or social and/or convenience reasons.
 Hospitalization for standard monitoring of a pre-existing disease or medical condition that did
not worsen, eg, hospitalization for coronary angiography in a participant with stable angina
pectoris.
However, complications that occur during hospitalization are AEs or SAEs (eg, if a complication
prolongs hospitalization).
9.2.2 Reporting of serious adverse events
All SAEs occurring after signature of the ICF up to 30 days after study treatment discontinuation
(up to EOS for participants who enter a continued access program on the same day as the EOS
visit see Section 3.1.1) must be reported on AE pages in the eCRF and on an SAE form, regardless
of the investigator-attributed causal relationship with study treatment or study-mandated
procedures.
An SAE is defined as related to protocol-mandated procedures if it appears to have a reasonable
possibility of a causal relationship to either the study design or to protocol-mandated procedures
(eg, discontinuation of a participant’s previous treatment during a washout period, leading to
exacerbation of underlying disease).
9.2.3 Follow-up of serious adverse events
SAEs still ongoing more than 30 days after study treatment discontinuation must be followed up
until resolution or stabilization, or until the event outcome is provided. The follow-up information
obtained after the participant’s EOS visit / telephone call must be reported to the sponsor, but 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.


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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
participant, 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, eg, 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. The sponsor personnel may contact the investigator to obtain further information.
If the participant 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 IB. [Tadalafil SmPC] Any SAE thatis assessed as related
and unexpected against the RSI is known as a SUSAR and must be reported by the sponsor to
concerned health authorities, IECs/IRBs, and investigators.
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 SUSARs. The investigator (or sponsor where required) must report SUSARs to the
appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved
the protocol unless otherwise required and documented by the IEC/IRB. A SUSAR will be
reported to regulatory authorities unblinded. Participating investigators and IEC/IRB will receive
a blinded SUSAR summary, unless otherwise specified.
9.3 Pregnancy
If a woman becomes pregnant while on study treatment, study treatment must be discontinued.
The investigator must counsel the participant and discuss the risks of continuing with the
pregnancy and the possible effects on the fetus.
9.3.1 Reporting of pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the event
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and
must be reported using an SAE reporting form. Any participant who becomes pregnant during the
study must discontinue further study intervention.


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9.3.2 Follow-up of pregnancy
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required.
Any AE associated with the pregnancy occurring during the follow-up period after studytreatment
discontinuation must be reported on separate AE pages in the eCRF. Abnormal pregnancy
outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic
pregnancy) are considered SAEs and must be reported on an SAE form as described in
Section 9.2.5.
9.4 Product Quality Complaints
9.4.1 Definition
A PQC is defined as any suspicion of a product defect related to manufacturing, labeling, or
packaging, ie, any dissatisfaction relative to the identity, quality, durability, reliability, or
performance of a distributed product, including its labeling, drug delivery system, or package
integrity. A PQC may have an impact on the safety and efficacy of the product. In addition, it
includes any technical complaints, defined as any complaint that indicates a potential quality issue
during manufacturing, packaging, release testing, stability monitoring, dose preparation, storage
or distribution of the product or the drug delivery system.
9.4.2 Reporting Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after
being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.
9.5 Special Reporting Situations
Safety events of interest on the study treatment that require expedited reporting or safety evaluation
include, but are not limited to:
 
Suspected abuse/misuse of a sponsor study intervention
 
Overdose of a sponsor study intervention
 
Accidental or occupational exposure to a sponsor study intervention
 
Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study
intervention
 
Unexpected therapeutic or clinical benefit from use of 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, eg, product name confusion, product label confusion, intercepted
prescribing or dispensing errors)
 
Exposure to a sponsor study intervention from breastfeeding


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Special reporting situations should be recorded in the eCRF. Any special reporting situation that
meets the criteria of an SAE should be recorded on the SAE page of the eCRF.
9.6 Study Safety Monitoring
Study safety information (AEs, SAEs, laboratory values, vital signs, and study-specific
examinations as required) is monitored and reviewed on a continuous basis by the sponsor Clinical
Team (in charge of ensuring participants’ safety as well as data quality). In addition, an IDMC
monitors safety data [see Section 3.4]. The sponsor may request additional data pertaining to the
diagnostic work-up of an AE or SAE (eg, medical imaging, local laboratory values) for the purpose
of safety monitoring. Such additional anonymized data may be shared with external experts.
10 STATISTICAL METHODS
This study implements an adaptive group-sequential design with early futility and efficacy
stopping rules and sample size re-estimation. It includes an IA (according to group-sequential
design methodology) when approximately 100 participants have completed their EDBT
assessment or have prematurely discontinued from the study.
If the study is not stopped early for futility or efficacy, a final analysis will be carried out when
approximately 150 250 participants (based on conditional power considerations on PVR) have
completed their EDBT assessment or prematurely discontinued from the study. The double-blind
part of the study will then be reported. Study closure is defined as when the last participant
performs their EOS visit. The double-blind and open-label parts will then be reported.
Conditional to positive outcome of the interim PVR results, all secondary endpoints will be
formally evaluated according to the testing hierarchy. In case of negative outcome of the interim
PVR results, secondary endpoints will only be evaluated at the final analysis according to the
testing hierarchy.
A Statistical Analysis Plan (SAP) will be written and finalized before database cut-off and
unblinding of the randomization codes by the IDMC for the IA. The SAP and IDMC charter will
provide full details of the analyses, data displays, algorithms to be used for data derivations, and
the IA decision-making process.
The SAP will include the definition of protocol deviations and the link between protocol deviations
and the analysis sets. The protocol deviations will be identified by medically trained staff before
study closure.
Individual participant listings will be provided for efficacy and safety endpoints, as well as for
baseline and other participant characteristics. Each listing will be broken down by treatment group,
stratum, site, participant number, and assessment date, where appropriate.
10.1 Analysis Sets
10.1.1 Screened Analysis Set
The Screened Analysis Set includes all participants who are screened and have a participant
identification number.


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10.1.2 All Randomized Analysis Set
The All Randomized Analysis Set includes all participants who were randomized in the study.
10.1.3 Full Analysis Set
The Full Analysis Set (FAS) includes all randomized participants who received at least one dose
(for participants in FDC at least one dose of either macitentan or tadalafil) of study treatment.
Participants are evaluated according to the study treatment they have been assigned to, which may
be different from the study treatment they have received.
10.1.4 Safety Set
The Safety Set (SS) includes all participants who received at least one dose ofstudy treatment in
the double-blind treatment period. Participants are evaluated according to the study treatment
received. The treatment received will be different from the treatment assigned at randomization
(randomized treatment) only in the case of a dispensing error that was sustained throughout the
entire double-blind study period. Short-term dispensing errors will not qualify for a change from
the randomized treatment group.
10.1.5 Open-label Set
The Open-label Set (OLS) includes all participants who receive at least one dose of open-label
study treatment in the open-label period.
10.1.6 Combination Safety Set
The CombinationSafety Set (CSS) includes all participants randomized to M/T FDC in the double-
blind period and who received at least one dose of M/T FDC double-blind study treatment (ie,
macitentan [10 mg] and tadalafil [20 mg or 40 mg]) and all participants who received at least one
dose of M/T FDC study treatment (ie, macitentan [10 mg] and tadalafil [20 mg or 40 mg]) in the
open-label period.
10.1.7 Long-term M/T FDC Set
The Long-term M/T FDC Set (LTFDCS) includes all participants randomized to M/T FDC in the
double-blind study.
10.1.8 QoL analysis sets
The PAH-SYMPACT™Symptoms Analysis Set includes all participants included in the FAS for
whom at least one baseline value of symptoms domain is provided.
The PAH-SYMPACT™ Impacts Analysis Set includes all participants included in the FAS for
whom at least one baseline value of impacts domain is provided.
The EQ-5D-5L Analysis Set includes all participants included in the FAS for whom at least one
baseline value is provided.
The WPAI© Analysis set includes all participants included in the FAS for whom at least one
baseline value is provided.


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10.1.9 Usage of the analysis sets
The main analyses of the primary, secondary (except QoL variables), and other efficacy variables
in the double-blind period will be performed on the FAS based on the treatment as randomized.
The QoL variables will be analyzed based on PAH-SYMPACT™Symptoms, PAH-SYMPACT™
Impacts, EQ-5D-5L, and WPAI© analysis sets, as applicable. The other efficacy variables that are
assessed during the open-label period will be analyzed based on the OLS and LTFDCS.
The analyses of safety variables will be performed on the SS for the double-blind treatment period
based on study treatment received as detailed in Section 10.1.4. The CSS  will be used for the
analyses of the safety variables in the entire study treatment period, including open-label treatment
period.
Listings will be prepared on the FAS, unless otherwise specified. Participant disposition will be
summarized for the randomized analysis set and the FAS.
10.2 Variables
10.2.1 Primary efficacy variable
The primary efficacy variable is the ratio of EDBT to baseline PVR and is assumed to follow a
log-normal distribution. Consequently, the statistical analysis will be performed on the log of this
ratio. The results will however be presented on the original scale (geometric means) after
exponentiation of the means obtained on the log scale.
The PVR values (in dyn∙sec∙cm 5) calculated by the sponsor [Section 14.1] will be used for the
analysis.
If PVR value is missing at EDBT, it will be imputed according to the rules described in
Section 10.3.2.4.
10.2.2 Secondary efficacy variables
10.2.2.1 6-minute walk distance
The variable for the analysis of the secondary endpoint, change from baseline to EDBT in exercise
capacity, is the absolute change in 6MWD (m) from baseline to EDBT defined as:
 6MWD (m) at EDBT
6MWD (m) at baseline
10.2.2.2 PAH-SYMPACTTM Symptom domains scores
The Symptoms part has 2 domains: Cardiopulmonary Symptoms Domain and Cardiovascular
Symptoms Domain which contain 6 and 5items, respectively.
Scores for the individual items and domains ranged from 0 4, with higher scores indicating greater
symptom severity or worse impact. Mean weekly symptom item scores are calculated as an
average of the daily item scores and a mean symptom domain score is then calculated as the
average of the mean weekly scores for its included items.
Domain scores are set to missing if more than half of the respective item scores are missing. For
more details on scoring algorithm including handling of missing item responses, see Section 14.5.


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The main variables for the analysis of the secondary endpoint, change from baseline to EDBT in
PAH-SYMPACT™ Symptoms domains scores, are the absolute changes from baseline to EDBT,
defined as:
 Domain score at EDBT  Domain score at baseline
10.2.2.3 WHO FC
Absence of worsening in WHO FC level at EDBT as compared to baseline is characterized based
on the following dichotomous variable:
 Worsening: X  0 if (difference between EDBT and baseline in WHO FC) >0
 No worsening: X  1 if (difference between EDBT and baseline in WHO FC) ≤0
The secondary endpoint is the proportion of participants who remained stable or improved (no
worsening) (X  1) between baseline and EDBT.
10.2.3 Other efficacy variables
See Section 6.1.3 for endpoint definitions. Additional details will be provided in the SAP.
10.2.4 Safety variables
The safety endpoints as defined in Section 6.2 will be presented according to the following 2
different treatment-emergent periods.
10.2.4.1 Double-blind treatment-emergent period
For the double-blind treatment period, treatment-emergent is defined from first intake of study
treatment in double-blind period up to end of double-blind treatment + 30 days or start of open-
label treatment, whichever occurs first.
10.2.4.2 Combination treatment-emergent period
The combination treatment-emergent period is defined from first intake of macitentan 10 mg and
tadalafil (20 mg or 40 mg) in double-blind or open-label treatment period up to EOT (EDBT or
EOLT) + 30 days. The baseline value for the combination treatment period is defined as the last
valid assessment obtained prior to the first intake of macitentan and tadalafil (double-blind or
open-label).
10.3 Description of Statistical Analyses
10.3.1 Overall testing strategy
The primary endpoint will be tested on the FAS using 2 analysis of covariance (ANCOVA) models
separately comparing the combination group to each monotherapy. Only if both tests are
statistically significant and M/T FDC is shown to be superior to both monotherapies will the study
be declared to show conclusive evidence of efficacy.
Each null hypothesis will be tested (and family wise error rate preserved) during the IA using a
Hwang, Shih and DeCani alpha spending function with gamma (γ)
2:
α1()  α (1-exp(-γt))/(1-exp(-γ)),
where  is the information fraction for a given pairwise comparison.


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The alpha to be spent at the IA depends on the fraction of available information at the timing of
the IA for each pairwise comparison, which depends on the recruitment process within each
stratum. For each hypothesis, the information fraction is calculated individually based on the
number of participants entering the test of the respective null hypothesis at the IA and on the
number of participants originally planned for the final analysis. The earliest the IA can be
performed when the global amendment 5 is approved in all countries. This is expected to occur
when the information fraction (100/170) is 59% for each pairwise comparison. In this case, the
alpha to be used will be 0.018 for both pairwise comparisons.
If the study is not terminated early, the inverse normal combination method will be utilized to
combine first- and second-stage p-values for the control of the type-1 error rate [Lehmacher 1999].
The guideline for calculating the combination weights will be included in the IDMC charter (and
SAP), and will be based on the available individual information fractions at the time of the IA.
Combination weights will not be adjusted based on the IA decision. Median unbiased parameter
estimates and repeated CIs will be presented in the final analysis using ADDPLAN™6.1
(ADDPLAN, Inc., an Aptiv Solutions company).
Secondary efficacy endpoints will be analyzed at the 1() level using a hierarchical testing
procedure following the order of the endpoints as listed in Section 6.1.2.
Long-term efficacy data from the open-label phase will be analyzed descriptively.
10.3.2 Analysis of the primary efficacy variable
10.3.2.1 Estimand
The primary PVR estimand is described according to the following 4 attributes:
A. Population: FAS (all randomized participants who received at least one dose (for participants
in FDC at least one dose of either macitentan or tadalafil) of study treatment), as randomized.
B. Variable: Absolute change from baseline to EDBT visit of the log-transformed PVR values.
The results will be presented on the original scale (geometric means) after exponentiation of the
absolute mean changes obtained on the log scale.
C. Intercurrent events (events that preclude observation of the variable or affect its
interpretation):
 Death occurring prior to the EDBT visit,
 Prohibited PAH-specific medication [see Section 5.2.4] received for any reason prior to EDBT
visit,
 Study treatment discontinuation/interruption for more than 2 days immediately prior to the
EDBT visit,
 Study treatment(s) dose adjustments at any time prior to the EDBT visit.
D. Population-level summary: Ratios of the geometric means between the M/T FDC group and
each monotherapy group (macitentan 10 mg and tadalafil 40 mg) separately.
This estimand targets the effect of treatment initiation on the variable measurement prior to the
occurrence of death or introduction of prohibited PAH-specific medication and follows a “while


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on treatment” strategy. For purposes of the primary endpoint, on-treatment is defined as up to 2
days after last double-blind treatment intake.
Intercurrent events will be handled as follows:
 “Death occurring prior to the EDBT visit” will be addressed by imputing the EDBT PVR value
using the rules defined in Section 10.3.2.4.
 “Prohibited PAH-specific medication received for any reason prior to EDBT visit” will be
addressed by disregarding the PVR assessments obtained at the EDBT visit and imputing them
with the rules defined in Section 10.3.2.4.
 “Study treatment discontinuation/interruption for more than 2 days immediately prior to the
EDBT visit” will be addressed by disregarding the PVR assessments obtained more than 2
days after study treatment discontinuation and imputing them with the rules defined in Section
10.3.2.4.
 “Study treatment(s) dose adjustments at any time prior to the EDBT visit” will not lead to
exclusion of on-treatment PVR assessments obtained at EDBT, and those values, if available,
will be used in the primary analysis, otherwise they will be imputed with the rules defined in
Section 10.3.2.4.
10.3.2.2 Hypotheses and statistical model
GMFDC denotes the geometric mean of the ratios of EDBT to baseline PVR values for participants
randomized to the M/T FDC group.
GMmacitentan 10 mg denotes the geometric mean of the ratios of EDBT to baseline PVR values for
participants randomized to the macitentan 10 mg group.
GMtadalafil 40 mg denotes the geometric mean of the ratios of EDBT to baseline PVR values for
participants randomized to the tadalafil 40 mg group.


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The global null hypothesis (HO) is the union of 2 null hypotheses:
HO: HO1 ∪HO2,
where:
HO1 is “GMFDC /GMmacitentan 10 mg  1” in the combined treatment-naïve and prior-ERA stratum,
HO2 is “GMFDC /GMtadalafil 40 mg  1” in the combined treatment-naïve and prior-PDE-5i stratum.
The global alternative hypothesis (H1) is the intersection of 2 alternative hypotheses:
H1: H11 ∩ H12,
Where:
H11 is “GMFDC /GMmacitentan 10 mg ≠ 1” in the combined treatment-naïve and prior-ERA stratum,
H12 is “GMFDC /GMtadalafil 40 mg≠ 1” in the combined treatment-naïve and prior-PDE-5i stratum.
Additional details about the strata are given in Section 10.5.
10.3.2.3 Treatment groups
For the comparison between M/T FDC and macitentan 10 mg, only participants randomized to
M/T FDC or macitentan 10 mg in the treatment-naïve or prior-ERA strata will be included.
For the comparison between M/T FDC and tadalafil 40 mg, only participants randomized to M/T
FDC or tadalafil 40 mg in the treatment-naïve or prior-PDE-5i strata will be included.
Data collected on participants who did not tolerate up-titration to tadalafil 40 mg and remained on
tadalafil 20 mg or tadalafil 20 mg + macitentan 10 mg as separate tablets will be kept in the
statistical analysis under the tadalafil 40 mg and M/T FDC arms respectively.
10.3.2.4Handling of missing data
By design, only one post-baseline PVR measurement must be taken at the time of the scheduled
EDBT visit. In some instances, the EDBT assessment may be missing with no other post-baseline
assessment available.
If PVR cannot be calculated due to missing PAWP, the following conventions will be applied for
the calculation at a visit at which both mPAP and CO are assessed and not missing:
1. If PAWP is missing, LVeDP will be used.
2. If PAWP and LVEDP are missing at post-baseline, the available baseline PAWP (or LVeDP)
for the participant is used as a substitute for the missing post-baseline PAWP.
In the case of a missing PVR assessment at EDBT, the following missing data imputation rules
will be used:
 If the participant dies prior to Week 16, the highest observed individual ratio of the last
on-treatment PVR to the baseline PVR in the FAS, amongst all participants in the same stratum


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is imputed, (or a value of 1 [ie, no change from baseline] is imputed if this worst observed
value is an improvement [ie, decrease] from baseline).
 If the participant has a disease progression/worsening as confirmed by the CEC, the
75th  percentile of the ratio of the last on-treatment PVR to the baseline PVR from all
participants in the same stratum will be used to impute the on-treatment PVR value.
 If the participant does not die and does not experience a disease progression/worsening as
confirmed by the CEC, the 50th  percentile of the ratio of the last on-treatment PVR to the
baseline PVR from all participants in the same stratum and treatment group will be used to
impute the on-treatment PVR value.
10.3.2.5 Main analysis
The null hypotheses will be tested by means of 2 ANCOVA models on the loge-transformed ratios
of EDBT  to baseline PVR values. Model covariates will include randomized treatment, the
loge-transformed baseline PVR value and the stratification factor (treatment-naïve, prior-ERA, or
prior-PDE-5i). The resulting least squares (LS) means and 95% CLs obtained in each treatment
group, and the LS-means differences (95% CLs) for M/T FDC vs macitentan 10 mg and M/T FDC
vs tadalafil 40 mg will be inversely transformed using the exponential function and multiplied
by 100 to provide:
1. the adjusted geometric mean of the ratios of EDBT to baseline PVR values and corresponding
95% CLs, expressed in percent, in each treatment group, and
2. the adjusted geometric mean ratios (GMRs) and corresponding 95% CLs for M/T FDC vs
macitentan 10 mg (GMR1) and for M/T FDC vs tadalafil 40 mg (GMR2).
The 2 p-values obtained from the tests of GMR1 and GMR2 (ie, the p-values for the LS-means
differences) will be used to determine the superiority of M/T FDC vs macitentan 10 mg and
tadalafil 40 mg. The global null hypothesis will be rejected if both tests are significant at the
appropriate alpha level according to the testing strategy detailed in Section 10.3.1. Median
unbiased parameter estimates and repeated CLs will be presented in the final analysis using
ADDPLAN™6.1 (ADDPLAN, Inc., an Aptiv Solutions company).
10.3.2.6 Supportive/sensitivity analyses
i. 
Sensitivity analyses to assess the impact of missing values and their imputation
To assess the robustness of the model towards possible stratum or treatment-arm-related drop-out
patterns, the following 3 sensitivity analyses for the primary endpoint will be conducted:
Sensitivity analysis 1: Repeat the primary imputation rule with the exceptions that the values to
be imputed in case of death or disease progression have to be determined regardless of stratum
instead of within the same stratum as defined for the primary analysis.
Sensitivity analysis 2: Use of multiple imputation where each missing value is replaced with a set
of plausible values that represent the uncertainty about the right value to impute. Each one of the
imputed data sets is analyzed using the same model as for the primary analysis and eventually
aggregated using Rubin’s rule [Rubin 1987].


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Sensitivity analysis 3: A tipping-point analysis will be performed where missing data are replaced
with a range of values to see how extreme the imputed value of the missing data must be for the
results of the study to tip from significant to not significant.
To assess the impact of missing values and their imputation, the following sensitivity analyses will
be run on the FAS:
Sensitivity analysis 4: An observed case analysis applying the main ANCOVA model without
any imputation [see Section 10.3.2.5].
ii. 
Sensitivity analyses for potential deviations from the normality assumptions
Sensitivity analysis 5: To address the impact of potential deviations from the assumption of
normality of the residuals from the primary ANCOVA models, a rank-based linear model using
Wilcoxon rank pseudo norm will be performed as follows:
 Missing EDBT values will be imputed as specified for the primary analysis in Section 10.3.2.4.
 A rank-based linear model will be performed on the primary variable (loge-transformed ratios
of EDBT to baseline PVR values) using the Wilcoxon rank pseudo norm [Hettmansperger
2011] rather than the least squares pseudo norm. Model covariates will include randomized
treatment, the loge
transformed baseline PVR value and the stratification factor (treatment-
naïve, prior-ERA, or prior-PDE-5i).
iii. 
Other sensitivity analyses
Sensitivity analysis 6: The primary endpoint analysis (ANCOVA) will be repeated without
adjustment for the stratification factors.
iv. 
Other estimands
Five additional estimands will also be assessed:
 same as the primary estimand except that “prohibited PAH-specific medication received prior
to EDBT visit” will not be considered as an intercurrent event and PVR assessments obtained
after such an event will not be excluded from the analysis for that reason,
 same as the primary estimand except that on-treatment is defined as up to 7 days after last
double-blind treatment intake instead of 2 days for the primary estimand,
 same as the primary estimand except that:
- “prohibited PAH-specific medication received prior to EDBT visit” will not be
considered as an intercurrent event and PVR assessments obtained after such an event
will not be excluded from the analysis for that reason,
- on-treatment is defined as up to 7 days after last double-blind treatment intake instead
of 2 days for the primary estimand,
 same as the primary estimand except for the variable of interest which is the absolute change
from baseline to EDBT in PVR instead of the ratio of EDBT to baseline PVR,
 same as the primary estimand except that in the populationdefinition, participants are analyzed
according to treatment received as opposed to treatment assigned.


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10.3.3 Analysis of secondary efficacy variables
The primary estimands for each of the secondary endpoint variables defined in Section 10.2.2
follow the same approach as the primary endpoint estimand with the following exceptions:
 participants with missing baseline value are excluded,
 on-treatment is defined as up to 7 days after last double-blind treatment intake,
 assessments obtained in participants receiving prohibited PAH-specific medication for any
reason prior to EDBT visit are not excluded from the analysis.
The rationale for handling intercurrent events differently for the secondary endpoint estimands
compared to the primary endpoint is to minimize missing data. We allow a slightly wider window
before exclusion of assessments as an immediate impact of prohibited PAH medication / study
treatment discontinuation on the values being measured is not expected.
The primary endpoint estimand strategy will also be applied to the secondary endpoints as a
sensitivity analysis.
10.3.3.1 Change from baseline to EDBTin 6MWD
The change from baseline to EDBT in 6MWD will be analyzed for each comparison of interest by
means of an ANCOVA model and will include treatment group, baseline 6MWD value and the
stratification factor (treatment-naïve, prior-ERA, or prior-PDE-5i) as covariates. The null
hypothesis will be rejected upon achieving a statistically significant difference at a two-sided
significance level of 1() in favor of the FDC vs each monotherapy arm (macitentan 10 mg and
tadalafil 40 mg). The 2 p-values obtained from each test (ie, the p-values for the LS-means
differences) will be used to determine the superiority of M/T FDC vs macitentan 10 mg and
tadalafil 40 mg. The global null hypothesis will be rejected if both tests are significant at the
appropriate alpha level according to the testing strategy. Median unbiased parameter estimates and
repeated CLs will be presented in the final analysis using ADDPLAN™6.1 (ADDPLAN, Inc., an
Aptiv Solutions company). LS  estimates for each treatment group and for the treatment effects
(M/T FDC vs macitentan 10 mg and M/T FDC vs tadalafil 40 mg) will be displayed with means,
95% CLs, and p-value.
The assumptions of the ANCOVA model (normality of the residuals and homogeneity of variance)
will be investigated graphically (eg, Q-Q plot and residual plots). If there are major deviations
from the assumptions, non-parametric tests will be conducted.
In the main analysis, if an  EDBT assessment is missing for participants with a post-baseline
6MWD measurement obtained before EDBT, the (last) post-baseline 6MWD measurement will
be carried forward unless this imputation would lead to an improvement, in which case a change
of 0 m (no change) will be imputed. For participants without a post-baseline 6MWD measurement,
a change of 0 m (no change) will be imputed. If the participant dies before Week 16, the lowest
(worst deterioration) change from baseline recorded amongst all participants in the same treatment
group will be imputed.
To assess the impact of missing values and their imputation, the following sensitivity analyses will
be run on the FAS:


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 An observed case analysis, applying the main ANCOVA without any imputation of missing
EDBT assessments.
 An analysis applying the main ANCOVA without adjustment for the stratification factors.
 A mixed model repeated measure analysis of variance model performed on the FAS using the
observed data up to EDBT, ie, at baseline, Week 8, and Week 16.
10.3.3.2 Change from baseline to EDBT in PAH-SYMPACTTM symptom domain scores
Change from baseline to EDBT in PAH-SYMPACT™ Symptom domain scores will be analyzed by
means of ANCOVA, as described in Section 10.3.3.1.
In the main analysis, in case of a missing Symptom domain score at EDBT, the following missing
data imputation rules will be used:
 If the participant dies prior to Week 16, the highest observed individual change of the last
on-treatment Symptom domain score from the baseline score in the PAH-SYMPACT™
symptoms analysis set, amongst all participants in the same stratum is imputed, (or a value of
0 [ie, no change from baseline] is imputed if this worst observed value is an improvement [ie,
decrease] from baseline).
 If the participant has a disease progression/worsening as confirmed by the CEC, the
75th  percentile of the change of the last on-treatment Symptom domain score from the baseline
score from all participants in the same stratum will be used to impute the on-treatment value.
 If the participant does not die and does not experience a disease progression/worsening as
confirmed by the CEC, the 50th  percentile of the change of the last on-treatment Symptom
domain score from the baseline score from all participants in the same stratum and treatment
group will be used to impute the on-treatment value.
To assess the impact of missing values and their imputation, the following sensitivity analyses will
be run on the PAH-SYMPACT™symptoms analysis set:
 Within the proposed imputation rules (see above), if the participant does not die and does not
experience a disease progression/worsening, then multiple imputation method will be used to
impute the missing scores. Each one of the imputed data sets will be analyzed using the same
model as for the primary analysis and eventually aggregated using Rubin’s rule [Rubin 1987].
 A tipping point analysis will be performed where missing data are replaced with a range of
values to see how extreme the imputed value of the missing data must be for the results of the
study to tip from significant to not significant.
 An observed case analysis, applying the main ANCOVA without any imputation of missing
EDBT assessments.
 An analysis applying the main ANCOVA without adjustment for the stratification factors.
 An analysis applying the main ANCOVA and imputing the last observation carried forward
(including the baseline score) in case of missing EDBT scores.


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10.3.3.3 Proportion of subjects with no worsening in WHO FC between baseline and EDBT
The proportion of participants who improved or remained stable (absence of worsening) from
baseline to EDBT in WHO FC (ie, a change ≤0) will be analyzed for each comparison of interest
as a binary variable (no worsening vs worsening) by means of a logistic regression model. The
model for the decrease from baseline to EDBT ‘Yes/No’ in WHO FC, representing a shift to a
lower FC, will include treatment group, baseline WHO FC, and the stratification factor
(treatment-naïve, prior-ERA, or prior-PDE-5i) as covariates. The null hypothesis will be rejected
upon achieving a statistically significant difference at a two-sided significance level of 1() in
favor of the FDC vs each of monotherapy arm (macitentan 10 mg and tadalafil 40 mg). The 2 p-
values obtained from each  test (ie, the p-values for the LS-means differences) will be used to
determine the superiority of M/T FDC vs macitentan 10 mg and tadalafil 40 mg. The global null
hypothesis will be rejected if both tests are significant at the appropriate alpha level according to
the testing strategy. Median unbiased parameter estimates and repeated CLs will be presented in
the final analysis using ADDPLAN™6.1 (ADDPLAN, Inc., an Aptiv Solutions company). The
adjusted odds ratio (OR) for the treatment effects (M/T FDC vs macitentan 10 mg and M/T FDC
vs tadalafil 40 mg) will be displayed with 95% CLs and p-value. An OR above 1 can be interpreted
as a larger improvement in WHO FC (or stable) occurring in the M/T FDC group compared to the
reference group.
In the main analysis, if an  EDBT  assessment is missing, participants will be assumed to have
worsened at EDBT.
To assess the impact of missing values and their imputation, the following sensitivity analyses will
be run on the FAS:
 An observed case analysis without any imputation of missing EDBT assessments.
 In participants with a post-baseline WHO FC measurement obtained before Week 16, the post-
baseline WHO FC measurement will be carried forward. This imputation will be performed
unless the following occurs:
- If a participant dies without a prior EDBT WHO FC assessment, then the EDBT WHO
FC is imputed by class IV.
10.3.4 Sub-group analyses
In order to assess the consistency of the treatment effect across different participant subgroups,
analyses will be performed on the primary endpoint and on the change from baseline to EDBT in
6MWD, PAH-SYMPACTTM symptom domains, and WHO FC, classifying participants according
to relevant demographic characteristics.
The subgroups to be considered are:
 Geographical region (eg, US, Europe, Asia).
 Region (US, non-US).
 WHO FC (II vs III).
Analyses in subgroups on the FAS population are carried out the same way as on the entire
population as described in Sections 10.3.2 and 10.3.3.1 for the primary endpoint and on the
secondary endpoints, respectively. The treatment effects within subgroups will primarily be


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displayed with their corresponding 95% CLs and presented in a forest plot. Treatment-by-subgroup
interaction will be investigated by means of tests of heterogeneity.
In addition, the treatment effects of:
 M/T FDC vs each monotherapy arm will be assessed in the treatment-naïve stratum only;
 M/T FDC vs tadalafil 40 mg will be assessed in the prior-PDE-5i stratum only; and
 M/T FDC vs macitentan 10 mg will be assessed in the prior-ERA stratum only.
Further details will be provided in the SAP.
10.3.5 Analysis of the safety variable(s)
The safety analyses presented below will be performed using descriptive statistics on:
 The Safety Set for the double-blind treatment period. For these analyses, treatment-emergent
period is defined in Section 10.2.4.1. Analyses will be presented by treatment groups as
described in Section 10.3.2.3 and in addition for the pooled M/T FDC (ie, all participants
treated with M/T FDC in the double-blind period across all 3 strata).
 The CSS for the combination treatment period. For these analyses, treatment-emergent period
is defined in Section 10.2.4.2. Analyses will be presented by treatment received in the double-
blind period:
- Double-blind macitentan participants, ie, participants treated with macitentan
monotherapy in the double-blind period.
- Double-blind tadalafil participants, ie, participants treated with tadalafil monotherapy
in the double-blind period.
- Double-blind M/T FDC participants, ie, participants treated with combination of
macitentan and tadalafil in the double-blind period.
Safety analyses may also be further presented by stratum (ie, treatment-naïve, prior-ERA, prior-
PDE-5i).
All safety data will be listed, with flags for quantitative abnormalities. AEs in participants who
were screened but not treated will be listed.
10.3.5.1 Adverse events
For the definition of AEs, see Section 9.1.1.
The number and percentage of participants experiencing treatment emergent AEs and SAEs at
least once will be tabulated by:
 MedDRA SOC and individual preferred term within each SOC, in descending order of
incidence.
 Frequency of participants with events coded with the same preferred term, in descending order
of incidence.
Furthermore, treatment-emergent AEs, and SAEs will be tabulated as described above by intensity
and relationship to study treatment.


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The number and percentage of participants experiencing at least one treatment-emergent AE of
special interest will be presented by descending Preferred Term frequency for each category of AE
of special interest.
AEs leading to premature discontinuation of study treatment will be summarized as described
above.
Listings will be provided for all reported AEs, including SAEs. In addition, separate listings will
be provided for SAEs and for AEs leading to premature discontinuation of study treatment.
10.3.5.2 Laboratory variables
For laboratory variables measured see Section 7.2.4.2.
Sponsor internal guidelines will be used forthe definitions of marked abnormalities [Section 14.4].
All laboratory data will be transformed to standard units. All laboratory data transferred (provided
by central or local laboratory) will be taken into account for identification of abnormalities
regardless of whether they correspond to scheduled (per protocol) or unscheduled visits.
Treatment-emergent marked laboratory abnormalities will be summarized for each laboratory
variable providing their incidence and frequency.
10.3.5.3 Vital signs and body weight
Blood pressure (SBP and DBP), pulse rate, and body weight will be summarized at each study
visit using the usual location and scale summary statistics for both absolute values and changes
from baseline. Participants for whom no post-baseline value is available are excluded from the
analysis of the changes from baseline.
10.4 Interim Analysis for Efficacy, Futility, and Adaptive Sample Size
Re-estimation
One IA will be conducted when approximately 100 participants have completed their Week 16
assessment or have discontinued from the study prior to their Week 16 assessment. The IA will
only include data from countries in which the global amendment 5 has been approved.
Differences in recruitment rates in each stratum will lead to different information fractions for the
2 pairwise comparisons at the time of the IA. The alpha spending for each pairwise comparison
will hence not be the same. The recruitment rate in each stratum will be closely monitored in a
blinded manner on an ongoing basis to appropriately quantify the actual IF for each comparison.
The IA will be conducted by the independent SSG on the primary endpoint to allow for early study
termination due to overwhelming efficacy  or futility, as well as for adaptive sample size
re-estimation if the study is not terminated. The IDMC will review the interim results and make
corresponding recommendations in line with the IDMC charter. The independent SSG will make
unblinded results available to the IDMC.
Hwang, Shih and DeCani alpha spending function with gamma (γ)
2 will be used to determine
the required alpha levels for statistical testing which guarantee overall Type I error control in


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presence of the multiplicity induced by the multiple looks at the primary endpoint. The calculations
have been done in EAST 6.4 based on the formula:
α1()  α (1-exp(-γt))/(1-exp(-γ)),
where  is the information fraction for a given pairwise comparison.
Table 6 summarizes the alpha spent at the IA (with 100 participants) and final analysis for the
scenario with recruitment rates proportional to the strata size and with 100 participants
corresponding to 59% information fraction.
Table 6 
Alpha spending in scenario with recruitment rates proportional to strata
size
Look  
Information 
fraction 
Cumulative 
alpha spent
P-value
Interim analysis 
59.0%  
0.018 
0.018
Final analysis 
100%  
0.05 
0.042
If the study is not stopped for success, it may be stopped for futility (non-binding) if the conditional
probability of reaching final study success is considered to be too low with the pre-planned sample
size.
The sample size will be re-estimated at the IA based on unblinded effect estimates, following rules
described in the IDMC charter. If the study is not terminated early for efficacy, the total size of the
study shall not exceed N  250 participants and shall not be below N  150 participants, accounting
for the overrun of participants recruited during the 16 weeks offollow-up.
The IDMC may recommend, based on the unblinded interim data, that the sponsor:
1. Stop the study for futility if the conditional success probability is <2.5% in either pairwise
comparison, given the observed interim data.
2. Stop the study for efficacy if the interim test for PVR is positive for both pairwise comparisons
at the two-sided α1(t).
3. Continue the study with reassessed sample size, based on the conditional power, to a total
between 150< N ≤250 participants.
Detailed guidelines for interim decision-making are further described in the IDMC charter. The
boundaries to be used for the IA will depend on the actual information fraction and will be re-
calculated by the independent SSG [Lehmacher 1999]. Any departure from the assumptions may
lead to different stopping boundaries and decision-making rules.
10.5 Sample Size
The sample size calculations presented in this section were carried out using East software version
6.4.
Randomization will be stratified by prior background PAH treatment at study entry (treatment-
naïve, ERA, or PDE-5i). Treatment-naïve participants will be randomized 2:1:1 to M/T FDC,


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macitentan, or tadalafil. ERA participants will be randomized 2:1 to M/T FDC or macitentan and
PDE-5i participants will be randomized 2:1 to M/T FDC  or tadalafil. Figure 3 shows the
randomization scheme followed in this study.
Figure 3 
Randomization Scheme
ERA  endothelin receptor antagonist; FDC  fixed dose combination; PDE 5i  phosphodiesterase type 5 inhibitor; Tx 
treatment.
The contribution of the randomization allocation of treatment to the strata to the 2 pairwise
comparison of interest is illustrated in Figure 4.


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Figure 4 
Contribution of Randomization Treatment Allocation to the Comparison of
Interest
According to the contribution of the randomization treatment allocation to the comparisons of
interest and, as per current accrual projections (assuming 50 % naïve, 20% on ERA monotherapy
and 30% on PDE5i therapy homogeneously over time) we expect approximately 98 participants
to contribute to FDC vs. Macitentan  10 mg and approximately 115 participants for FDC vs.
tadalafil 40 mg.
10.5.1 Sample size assumptions
Sample size is calculated based on the statistical requirements to detect a clinically relevant
difference between the FDC group and both monotherapy groups using a 2:1 randomization ratio
for each pairwise comparison. Each test comparing FDC to a monotherapy arm has a two-sided
Type I error of5% and a Type II error of 13% (87% power).
The following assumptions were made:
 the effect of FDC is assumed to be of similar extent vs each monotherapy and consistent across
the treatment-naïve, prior-ERA, and prior-PDE-5i strata, ie, a ratio of geometric means of the
EDBT  / baseline PVR values equal to 0.75 for FDC vs the most efficient of the 2
monotherapies;
 a coefficient of variation of the ratio of 0.45;
 one IA is planned using an alpha spending function from the Hwang, Shih and DeCani class
with gamma (γ)
2 [see Section 10.4]; and
 normal distribution for the loge-transformed ratio of EDBT to baseline PVR values.
If the 2 comparisons between the FDC and each monotherapy were completely statistically
independent, the overall power of the test for the global null hypothesis would be 79.5%. It is,
however, expected that those 2 tests are not independent and therefore that the overall power will
be in excess of 79.5% up to a maximum of 86.8%.


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These results are based on a difference in means test for independent samples with one interim
analysis.
10.5.2 Sample size sensitivity
With a sample size of 98 for FDC vs macitentan 10 mg pairwise comparison  (65 FDC vs 33
monotherapy), and sample size of 115 for FDC vs tadalafil 40 mg pairwise comparison (77 FDC
vs 38 monotherapy), the power for showing superiority of FDC over macitentan 10 mg and of
FDC over tadalafil 40 mg depends on the ratio of geometric means and the coefficient of variation
of the percent of baseline PVR at EDBT. Table 7 displays power calculations for different
assumptions for these 2 parameters and a two-sided α
0.05.
Table 7 
Sample size sensitivity for the main analysis
Scenario 
Ratio of
GMs
CV 
Power* 
FDC vs 
Maci 
Power*
FDC vs 
Tada
Overall power
Sensitivity 1 
0.70 
0.40 
98.9%  
99.6%  
98.6% to 98.9%
Sensitivity 2 
0.70 
0.45 
96.9%  
98.5%  
95.5% to 96.9%
Sensitivity 3 
0.75 
0.40 
93.0%  
96.1%  
89.3% to 93.0%
Sample size
assumptions
0.75 
0.45 
86.8%  
91.5%  
79.5% to 86.8%
Sensitivity 4  
0.80 
0.40 
75.7%  
82.1%  
62.1% to 75.7%
Sensitivity 5 
0.80 
0.45 
66.3%  
73.3%  
48.6% to 66.3%
* For each pairwise comparison between FDC and monotherapy, assuming that the monotherapies achieve the same therapeutic
effect.
CV  coefficient of variation; FDC  fixed dose combination; GM
 geometric mean.
11 DATA HANDLING
11.1 Data Collection
The investigator/delegate is responsible for ensuring the accuracy, completeness, and timeliness
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 (ie, confirm the accuracy of the data
recorded) using an electronic signature (refer to US 21 CFR Part 11).
Entries recorded by the participant in the patient-reported outcome questionnaires, either in written
or electronic format, (PAH-SYMPACT™, EQ-5D-5L, WPAI©: GH, PGA-S, PGI-C) are
considered source data.


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Participant screening and enrollment data will be completed for all participants (ie, eligible and
non-eligible) through the IRT system and the eCRF.
For each participant enrolled, regardless of study treatment initiation, an eCRF must be completed
and signed by the investigator/delegate. This also applies to those participants who fail to complete
the study. If a participant withdraws from the study, the reason must be noted on the eCRF.
11.2 Maintenance of Data Confidentiality
The investigator/delegate must ensure that data confidentiality is maintained. On CRFs or other
documents (eg, documents attached to SAE forms / pregnancy forms) submitted to the sponsor
and any CROs, participants must be identified only by number and never by their name or initials,
date of birth, hospital numbers, or any other identifier. The investigator/delegate must keep a
participant identification code list at the site, showing the screening/randomization number, the
participant’s name, date of birth, and address or any other locally accepted identifiers. Documents
identifying the participants (eg, signed ICFs) must not be sent to the sponsor, and must be kept in
strict confidence by the investigator/delegate.
11.3 Database Management and Quality Control
eCRFs will be used for all participants. The investigators will have access to the site eCRF data
until the database is closed. Thereafter, they will have read-only access for 6 months after database
lock, after which data from the eCRF will be provided to the site using relevant storage media.
The eCRF must be kept current to reflect participant status at any time point during the course of
the study.
While entering the data, the investigator/delegate will be instantly alerted to data queries by
validated programmed checks. Additional data review will be performed by sponsor 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 the sponsor 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 participant confidentiality is protected.
This process will continue until database lock.
The central reading facility for RHC data will send results electronically to the study sponsor.
Laboratory samples will be processed through a central laboratory and the results will be
electronically sent to the sponsor.
NT-proBNP samples will be processed through the central laboratory and the results will be sent
electronically to the sponsor.
Testing of other biomarkers may happen after database lock and results will not be included in the
clinical database.


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AEs are coded according to the latest Medical Dictionary for Regulatory Activities (MedDRA)
used by the sponsor.
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 sponsor
QS docs. After database lock, the investigator will receive the CRFs of the participants 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
Sponsor 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 participant
(such as the ICF) to an IEC/IRB. Approval from the committee/board must be obtained before
starting the study and must be documented in a dated letter to the investigator, clearly identifying
the study, the documents reviewed, and the date of approval.
Modifications made to the protocol or the ICF after receipt of the approval must also be submitted
as amendments by the investigator to the IEC/IRB in accordance with local procedures and
regulations [see Section 12.6].
A list of members participating in the IEC/IRB meetings must be provided, including the names,
qualifications, and functions of these members. If that is not possible, the attempts made to obtain
this information along with an explanation as to why it cannot be obtained or disclosed must be
documented in the study documentation.
If a member of the study personnel was present during an IEC/IRB meeting, it must be clear that
this person did not vote.
12.3 Informed Consent
It is the responsibility of the investigator/delegate to obtain informed consent according to ICH-
GCP and Declaration of Helsinki guidelines and local regulations from each individual
participating in this study and/or legally designated representative. The investigator/delegate must
explain to participants 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 participant populations and of
individual participants, as well as to the methods used to give the information. Finally, participants
will be informed that the investigator will maintain a participant identification register for the
purposes of long-term follow-up, if needed and that their records may be accessed by health
authorities and authorized sponsor personnel without violating the confidentiality of the
participant, to the extent permitted by the applicable law(s) or regulations. By signing the ICF the
participant is authorizing such access, which includes permission to obtain information about his
or her survival status. It also denotes that the participant agrees to allow his or her study physician


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to re-contact the participant for the purpose of obtaining consent for additional safety evaluations,
and subsequent disease-related treatments, if needed. Adequate time shall be given for the
participant and/or legally designated representative to consider his or her decision to participate in
the study and it shall be verified that the participant has understood the information (eg, by asking
the participant to explain what is going to happen).
The ICF will be provided and administered in the respective country’s local language(s).
Site personnel (according to local regulation) authorized to participate in  the consent process
and/or to obtain consent from the participant and/or legally designated representative will be listed
on the Delegation of Authority form supplied by the sponsor. A study physician must always be
involved in the consent process.
The participant and/or legally designated representative and authorized site personnel listed on the
Delegation of Authority form supplied by the sponsor must sign, personally date, and time (if the
first study-mandated procedure is to be performed on the same day as the informed consent is
obtained) the ICF before any study-related procedures (ie, any procedures required by the protocol)
begin.
A copy of the signed and dated ICF is given to the participant and/or legally designated
representative; the original is filed in the site documentation. The informed consent process must
be fully documented in the participant’s medical records. This must include at a minimum the
study reference, the participant number, the date and, if applicable, time when the participant was
first introduced to the study, the date and, if applicable, time of consent, who participated in the
consent discussion, who consented the participant, and any additional person present during the
consent process (eg, participant’s family member[s]), and the information that a copy of the signed
ICF was given to the participant/legally designated representative.
If the site intends to recruit participants who are considered as vulnerable (eg, participant cannot
read or write, does not speak or understand the ICF language), additional measures must be
implemented in order to ensure participant’s rights are respected and the consent obtained is legally
valid. The sponsor, the regulatory authorities (if applicable), and the IEC/IRB must be informed
prior to such recruitment. The consent process (eg, involvement of an impartial witness) must be
fully described, submitted to, and approved by the IEC/IRB, according to procedures and before
participants are recruited.
12.4 Indemnification, Compensation and Refund of Expenses to Subjects and
Investigators
The sponsor 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 participant in the event of study-related injuries will comply with
applicable regulations.
Study participants will be reimbursed for the study-related expenses (eg, travel costs, meals, hotel)
to the extent permitted by applicable local regulations.


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12.5 Protocol Adherence/Compliance
The investigator must conduct the study in compliance with the IEC/IRB and/or the regulatory
authority-approved version of the protocol and must not implement any deviation/change from the
protocol, except when deviation is necessary to eliminate an immediate hazard to the participant.
If a protocol deviation occurs, the investigator/delegate will inform  the sponsor 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 the sponsor or (overruling) local
requirements.
All major protocol deviations will be reported in the Clinical Study Report (CSR). IECs/IRBs will
be provided with listings of protocol deviations per local requirements.
12.6 Protocol Amendments
Any change to the protocol can only be made through a written protocol amendment. An amended
protocol must be submitted to the IEC/IRB and regulatory authorities, according to their
requirements.
12.7 Essential Documents and Retention of Documents
The investigator/delegate must maintain adequate records necessary for the reconstruction and
evaluation of the study. A number of attributes are considered of universal importance to source
data and the records that hold those data. These include that the data and records are accurate,
legible, contemporaneous, original (or certified copy), attributable, complete, consistent, enduring,
and available when needed.
These records are to be classified into 2 different categories of documents: ISF and participants’
source documents.
These records must be kept by the investigator for as long as is necessary to comply with ’the
sponsor’s requirements (ie, 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 the
sponsor 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
the sponsor. Should the investigator wish to assign the study records to another party, or move
them to another location, the sponsor must be notified in advance.
If the site is using an electronic/computerized system to store participant medical records, it can
be used for the purpose of the clinical study if it is validated (per 21 CFR Part 11 or equivalent
standard) and if the SM has been provided personal and restricted access to study participants only,
to verify consistency between electronic source data and the eCRF during monitoring visits.
If the site is using an electronic/computerized system to store participant medical records but it
could not be confirmed that the system is validated or if the SM could not be provided access to
the system, the site is requested to print the complete set of source data needed for verification by


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the SM. 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 print-outs will be considered as the official clinical
study records and must be filed either with the participant’s medical records or with the
participant’s eCRF.
In order to verify that the process the site uses to prepare certified copies is reliable, the SM 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 SM does not need to verify this process for all
data of all participants but at least for some of them (eg, first participant; regular check during the
study of critical data like inclusion/exclusion criteria, endpoints for some participants) per ’the
sponsor’s instructions. If it were not possible for the SM 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 the sponsor. 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 participants. 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 SM 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. Sponsor 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 participant recruitment rate and critical data collection times.
The PI must ensure that the eCRF is completed after a participant’s visit (site visit or telephone
call), and that all requested participant files (eg, ICFs, medical notes/charts, other documentation
verifying the activities conducted for the study) are available for review by the SM. The required
site personnel must be available during monitoring visits and allow adequate time to meet with the
SM to discuss study-related issues.
The investigator agrees to cooperate with the SM(s) to ensure that any issues detected in the course
of these monitoring visits are resolved. If the participant is hospitalized or dies in a hospital other


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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 participants
and all follow-up issues have been resolved. In case a site does not enroll any participants, the
close-out visit may be performed prior to study database lock at the discretion of the sponsor.
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 contents listing the essential documents. All study-related
documentation must be maintained in the ISF.
In some cases, exceptions can be discussed with the SM 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 the sponsor. If the site needs to transfer the ISF to another
location and/or if the site facility can no longer store the ISF, the PI must immediately inform the
sponsor.
If the PI will change, or if the site will relocate, the SM must be notified as soon as possible.
12.10 Audit
The sponsor’s 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 ’the sponsor’s requirements (eg,
standard operating procedures) will also be verified. Prior to initiating this audit, the investigator
will be contacted by the sponsor 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 (eg, participant records) and facilities.
12.11 Inspections
Health authorities and/or IEC/IRB may also conduct an inspection of this study (during the study
or after its completion) at the site.
Should an inspection be announced by a health authority and/or IEC/IRB, the investigator must
immediately inform the sponsor (usually via the SM) that such a request has been made.
The investigator and site personnel must cooperate with the inspector(s) and allow access to all
study documentation (eg, participant records) and study facilities.


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12.12 Reporting of Study Results and Publication
The sponsor will post the key elements of this protocol and the summary of results on ’the
sponsor’s Clinical Trial Register and within the required timelines on publiclyaccessible databases
(eg, clinicaltrials.gov, EU database), as required by law and regulation.
Study results will be documented in a CSR that will be signed by sponsor 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 will have the opportunity to review the analysis of the data and to
discuss the interpretation of the study results with sponsor 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 ofany publication of study results may include representatives of the sponsor
and will be determined by mutual agreement.
Any study-related publication written independently by investigators must be submitted to the
sponsor for review at least 30 days priorto submission for publication or presentation at a congress.
Upon review, the sponsor 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
[Adcirca® SmPC] 
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europa.edu/docs/en_GB/document_library/EPAR_-_Product_Information/human/
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[ATS Guidelines 2002] American Thoracic Society. ATS statement: guidelines for the six-minute
walk test. Am J Respir Crit Care Med. 2002;166:111-117.
[Benza 2010] Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, et al.,
Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate
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Circulation. 2010;122(2):154-72.
[Benza 2012a] Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An
evaluationoflong-termsurvival fromtime ofdiagnosis inpulmonary arterial hypertension from
the REVEAL Registry. Chest. 2012 Aug;142(2):448-456.
[Benza 2012b] Benza RL, Gomberg-Maitland M, Miller DP, Frost A, et al. The REVEAL Registry
risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest.
2012;141(2):354-362.
[Benza 2015] Benza RL, Miller DP, Foreman AJ, Frost AE, et al. Prognostic implication of serial
risk score assessments in patients with pulmonary arterial hypertension: A Registry to Evaluate
Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL)
analysis. J Heart Lung Transplant. 2015;34(3):356-61.
[Borg 1998] Borg’s perceived exertion and pain scales. Champaign, IL: Human Kinetics, 1998.
[Chin 2018] Chin KM, Gomberg-Maitland M, Channick RN, Cuttica MG, Fischer A, et al.
Psychometric validation of the pulmonary arterial hypertension-symptoms and impact (PAH-
SYMPACT) questionnaire: Results of the SYMPHONY trial. Chest. 2018;S0012-
3692(18):30649-4.
[Fares 2016] Fares WH, Bellumkonda L, Tonelli AR, Carson SS, et al. Right arterial
pressure/pulmonary artery wedge pressure ratio: A more specific predictor of survival in
pulmonary arterial hypertension. J Heart Lung Transplant. 2016;(6):760-7.
[FDA 2020] Food and Drug Administration. Drug Development and Drug Interactions: Table of
Substrates, Inhibitors and Inducers (Table 2-2). https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers.
Accessed 09 July 2020.
[Galiè2009] Galiè N, Brundage BH, Ghofrani HA, Oudiz RJ, et al. Tadalafil therapy for
pulmonary arterial hypertension. Circulation. 2009;119(22):2894-903.


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[Galiè2010] Galiè N, Palazzinin M, Manes A. Pulmonary arterial hypertension: from the kingdom
of the near-dead to multiple clinical trial meta-analyses. Eur Heart J. 2010;(17):2080-6.
[Galiè2015a] Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the
diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and
Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the
European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and
Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation
(ISHLT). Eur Respir J. 2015;46(4):903-75.
[Galiè2015b] Galiè N, Barberà JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV,
Peacock AJ, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial
Hypertension. N Engl J Med. 2015 Aug 27;373(9):834-44.
[Gerges 2016] Gerges C, Gerges M, Skoro-Sajer N, Zhou Y, et al. Hemodynamic Thresholds for
Precapillary Pulmonary Hypertension. Chest. 2016;149(4):1061-73.
[Ghofrani 2016] Ghofrani HA, Grimminger F, Grunig E, Huang Y, et al. Predictors of long-term
outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the
PATENT-2 open-label, randomized, long-term extension trial. Lancet Respir Med.
2016;(5):361-71.
[Ghofrani 2017] Ghofrani HA, Simonneau G, D’Armini AM, Fedullo P, et al. Macitentan for the
treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results
from the multicentre, phase 2, randomised, double-blind, placebo-controlled study. Lancet
Respir Med. 2017;5(10):785-794.
[Hettmansperger 2011] Hettmansperger TP, McKean JW. Robust Nonparametric Statistical
Methods. Second Edition, 2011.
[Hoeper 2013] Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, et al. Definitions and diagnosis
of pulmonary hypertension. J Am Coll Cardiol. 2013;(25 Suppl):D42-50.
[Holland 2014] Holland AE, Spruit MA, Troosters T, et al. An official European Respiratory
Society/ American Thoracic Society technical standard field walking tests in chronic respiratory
disease. Eur Respir J. 2014;44:1428-1446.
[Humbert 2004] Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan With
epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004;24(3):353-
9.
[Jansa 2018] Jansa P, Pulido T. Macitentan in Pulmonary Arterial Hypertension: A Focus on
Combination Therapy in the SERAPHIN Trial. Am J Cardiovasc Drugs. 2018;18(1):1-11.
[Kholdani 2015] Kholdani CA, Oudiz RJ, Fares WH. The assessment of the right heart failure
syndrome. Semin Respir Crit Care Med. 2015;36:934 942.
[Krause 2018] Krause A, Zisowsky J, Dingemanse J. Modeling of pharmacokinetics, efficacy, and
hemodynamic effects of macitentan in patients with pulmonary arterial hypertension. Pulm
Pharmacol Ther. 2018;49:140-146.


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[Kylhammar 2014] Kylhammar D, Persson L, Hesselstrand D, Radegran G. Prognosis and
response to first-line single and combination therapy in pulmonary arterial hypertension. Scand
Cardiovas J. 2014;48(4):223-33.
[Lehmacher 1999] Lehmacher W, Wassmer G. Adaptive sample size calculations in group
sequential trials. Biometrics. 1999 Dec;55(4):1286-90.
[Levey 2009] Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular
filtration rate. Ann Intern Med. 2009;150(9):604-612.
[Macitentan/tadalafil FDC IB] Investigator’s Brochure for the fixed dose combination of the ERA
macitentan and the PDE-5 inhibitor tadalafil, version 2. Actelion Pharmaceuticals Ltd; April
2018.
[McCollister 2016] McCollister D, Shaffer S, Badesch DB, Filusch A, Hunsche E, et al.
Development 
of the 
Pulmonary 
Arterial 
Hypertension-Symptoms 
and 
Impact
(PAH-SYMPACTTM) questionnaire: a new patient-reported outcome instrument for PAH.
Respir Res. 2016;17(10):72.
[Nickel 2012] Nickel N, Golpon H, Greer M, Knudsen L, et al. The prognostic impact of follow-
up assessments in patients with idiopathic pulmonary arterial hypertension. Eur Respir J.
2012;39(3):589-96.
[Opsumit® SmPC] 
Opsumit 
Summary 
of 
Product 
Characteristics.
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_
Information/human/002697/WC500160899.pdf.
[Opsumit® USPI] 
Opsumit 
Prescribing 
Information. 
https://www.accessdata.fda.gov/
drugsatfda_docs/label/2013/204410s000lbl.pdf.
[Pulido 2013] Pulido T, Adzerikho I, Channick RN et al; SERAPHIN Investigators.
Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med.
2013 Aug 29;369(9):809-18.
[Reilly 1993] Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a Work
Productivity and Activity Impairment Instrument. PharmacoEconomics 1993, 4(5):353-65.
	Rubin 1987
 Rubin DB. Multiple imputation for nonresponse in surveys. New York: Wiley; 1987.
[Ryan 2015] Ryan JJ, Huston J, Kutty S, Hatton ND, et al. Right ventricular adaptation and failure
in pulmonary arterial hypertension. Can J Cardiol. 2015;(4):391-406.
[Simonneau 2013] Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, et al. Updated clinical
classification of pulmonary hypertension. Cardiol. 2014;63(7):746.
[Sitbon 2016] Sitbon O, Gaine S. Beyond a single pathway: combination therapy in pulmonary
arterial hypertension. Eur Respir Rev. 2016;25:408-17.


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[Thom 2013] Thom S, Poulter N, Field J, Patel A, Prabhakaran D, Stanton A, et al;
UMPIRE Collaborative Group. Effects of a fixed-dose combination strategy on adherence and
risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial.
JAMA. 2013 Sep 4;310(9):918-29.
[Tiede 2013] Tiede H, Sommer N, Milger K, Voswinckel R, et al. Short-term improvement in
pulmonary hemodynamics is strongly predictive of long-term survival in patients with
pulmonary arterial hypertension. Pulm Circ. 2013;(3):523-32.
[Tonelli 2013] Tonelli AR, Arelli V, Minai OA, Newman J, Bair N, Heresi GA, et al. Causes and
circumstances of death in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013
Aug 1;188(3):365-9.
[Vonk-Noordegraaf2013] Vonk-Noordegraaf A, Haddad F, Chin KM, Forfia PR, et al. Right heart
adaption to pulmonary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol.
2013;(25 Suppl):D22-33.


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14 APPENDICES
14.1 Appendix 1 Sponsor Guidelines for the Right Heart Catheterization
Procedure
CCI


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CCI


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CCI


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CCI


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CCI


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CCI


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CCI


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14.2 Appendix 2 Sponsor Guidelines for the 6MWT
14.2.1 INSTRUCTIONS
14.2.1.1 General
The 6-Minute Walk Test (6MWT) must be performed indoors, along a long, flat, straight,
enclosed corridor (or similar location) with a hard surface that can be blocked for traffic
during the conduct of the test. The track length for the 6MWT must be free of obstacles.
The use of treadmill and a continuous course, eg a circuit, is not allowed.
The ideal track length used for the 6MWT is 30 meters (If the track is shorter, it must be
no shorter than 15 meters in length). The track must be marked at regular intervals to
facilitate measurement of the distance walked (markings every 3 meters are
recommended). The turnaround points must be marked with a cone. A starting line, which
marks the beginning and the end of each lap (one lap is twice the length of the track used
at the site), needs to be marked on the floor. Ensure that the participant walks the same
track on each 6MWT.
Local safety guidance regarding medical emergencies and contraindications for 6MWT
must be followed at each participating site.
The person administering the 6MWT (tester) needs to stand near the starting line during
the 6MWT and must not walk with the participant, and not get distracted during the conduct
of this 6MWT (eg, by talking to someone).
Rest periods are allowed if the participant can no longer continue. If the participant needs
to rest, he/she may pause, lean against the wall and continue walking whenever he/she feels
able. The timer must continue to run even if the participant stops to rest. The 6MWT can
be stopped at any moment as due to medical emergencies or safety issues such as chest
pain, intolerable dyspnea, leg cramps, staggering, diaphoresis, and pale or ashen
appearance.
The 6MWT is a non-encouraged test. An even tone of voice must be used when using the
standard phrases. No other instructions or words of encouragement are given during the
test, other than the pre-scripted phrases (see Section 14.2.3.1). Eye contact and body
language signaling the participant to speed up must be avoided during the test.
Whenever possible, for an individual participant, repeat 6MWTs must be conducted in the
same corridor and by the same tester, and preferably at about the same time of the day (ie,
within a 4-hour window of the baseline test) to minimize variability.


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If a participant is oxygen dependent, the flow rate must remain constant from 1 hour prior
to each 6MWT, until the completion of all protocol-mandated assessments after the
6MWT. Additionally, the way oxygen is delivered (delivery device, application route, way
of carrying delivery device) must be the same for all 6MWTs, unless a change is required
for documented medical reasons.
14.2.1.2 Training tests
For participants who have not previously performed a 6MWT, a training 6MWT must be
performed before the first protocol-mandated 6MWT is performed.
Data from the training 6MWT are not collected in the CRF but must be documented in the
source data.
14.2.1.3 Timing
The interval between two 6MWTs must be at least 2 hours. Only two 6MWTs can  be
performed on the same day.
14.2.2 TEST REQUIREMENTS
14.2.2.1 Participant
 The participant must wear comfortable clothing and appropriate walking shoes.
 The participant must not have exercised vigorously within 2 hours of beginning the
test.
 It is recommended that the participant rests for at least 10 minutes before the test starts.
 If the participant is used to take bronchodilators before a walk, he/she must take them
5 30 min before the test.
 Participants can use their usual walking aids during the test (eg, cane). The same
walking aid should be used for all 6MWTs. Walkers are not allowed.
14.2.2.2 Equipment to perform the test
 Countdown timer
 Mechanical lap counter
 Two cones to mark the turnaround points
 A chair that can be easily moved along the track
 6MWT Worksheet
 Borg CR10 Scale®


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 Pulse oximeter
14.2.3 PERFORMING THE 6MWT
14.2.3.1 Instructions to the participant before the 6MWT
Before the 6MWT, the tester shows the Borg CR10 Scale®* to the participant and asks him/
her using the following dialogs:
 "Please grade your dyspnea using this scale".
If using a pulse oximeter, measure SpO2 and pulse rate from the oximeter and enter the
values on the 6MWT worksheet.
* For consistency reasons, participants who were enrolled before the approval of Protocol
AC-077A301 Amendment 2 Version 3 in their country must use the originally provided
Borg Scale through the study and the tester uses the following dialogs:
“I would like to use the following scale to indicate the maximal shortness of breath you
have now (indicate the Borg Scale).
Please grade your level of shortness of breath using this scale.
• 
If there is no shortness of breath at all you would point to 0;
• 
if your shortness of breath is slight you would choose from 0.5 to 2;
• 
if your shortness of breath is moderate you would select 3;
• 
if the breathing is getting very difficult, you would choose 4 to 9, depending on just
how hard or severe it is; 10 represents the most severe shortness of breath you have ever
experienced in your life”.
14.2.3.2 Instructions to the participant during the 6MWT
The tester uses the following exact dialogue with the participant:
“The object of this test is to walk as far as possible in 6 minutes. You will walk back and
forth in this hallway. Six minutes is a long time to walk, so you will be exerting yourself.
You will probably get out of breath or become exhausted. You are permitted to slow down,
to stop, and to rest as necessary. You may lean against the wall while resting, but resume
walking as soon as you are able.
You will be walking back and forth around the cones. You should pivot briskly around the
cones and continue back the other way without hesitation. Now I’m going to show you.
Please watch the way I turn without hesitation”.


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(The tester demonstrates the walking and pivots around a cone briskly).
“Are you ready to do that? I am going to use this counter to keep track of the number of
laps you complete. I will click it each time you turn around at this starting line. Remember
the object is to walk AS FAR AS POSSIBLE in 6 minutes, but don’t run or jog. I will tell
you when 2 minutes, 4 minutes have elapsed. Keep walking when I talk.”
After these instructions are given to the participant, the tester then asks:
“Do you have any questions about the test?”
“Please explain what you are going to do.”
“Are you ready?”
“Start now, or whenever you are ready”
As soon as the participant starts to walk, the tester starts the timer and writes down start
time. The tester tells the participant the time elapsed by saying:
“You have 4 minutes to go.”
“You have 2 minutes to go.”
If the participant stops walking during the test and needs a rest, the tester says:
“You can lean against the wall if you would like; then continue walking whenever you feel
able.”
The tester will not stop the timer. If the participant stops before the 6 minutes are up and
refuses to continue (or the tester decides that they should not continue), the tester wheels
the chair over for the patient to sit on, discontinue the walk, and note on the worksheet the
distance, the time stopped, and the reason for stopping prematurely.
When the timer is 15 seconds from completion, the tester says:
“In a moment I’m going to tell you to stop. When I do, just stop right where you are and I
will come to you”.
When the timer alarm rings the tester says:


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“Stop!”
14.2.3.3 Instructions to the participant after the 6MWT
The tester walks over to the participant, marks the spot where the participant stopped,
records the total distance walked in the 6MWT worksheet and congratulates the participant
on good effort.
The tester reminds the participant of their dyspnea that they chose before the 6MWT and
asks them to rate his/her dyspnea using the Borg CR10 Scale®*. The tester uses the
following dialogs:
 "Please grade your dyspnea using this scale".
The tester will record the post-6MWT dyspnea on the 6MWT worksheet.
* For consistency reasons, participants who were enrolled before the approval of Protocol
AC-077A301 Amendment 2 Version 3 in their country must use the originally provided
Borg Scale through the study and the tester uses the following dialogs:
“You have rated your shortness of breath as “xx” on this scale before the 6MWT. I would
like to use the following scale to indicate the maximal shortness of breath you had during
the walk test (indicate the Borg Scale).
Please grade your level of shortness of breath using this scale.
 If there is no shortness of breath at all you would point to 0;
 if your shortness of breath is slight you would choose from 0.5 to 2;
 if your shortness of breath is moderate you would select 3;
 if the breathing is getting very difficult, you would choose 4 to 9, depending on just
how hard or severe it is; 10 represents the most severe shortness of breath you have
ever experienced in your life”.
If using a pulse oximeter, measure SpO2 and pulse rate from the oximeter and enter the
values on the 6MWT worksheet.


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14.2.4 6MWT WORKSHEET
It is mandatory to use the 6MWT worksheet to capture documentation of each 6MWT
newly performed for the purpose of the study and report relevant data in the eCRF, as
indicated.
It is not mandatory to use the study 6MWT worksheet for historical 6MWTs.
14.2.5 THE BORG SCALE [to be used for patients randomized under protocol
versions 1 and 2]
Original Borg scale
For consistency reasons, participants who were enrolled before the approval of Protocol
AC-077A301 Amendment 2 Version 3 in their country must use the originally provided
Borg Scale through the study  .
As soon as possible following the walk test, the participant is asked to rate his/her dyspnea
using the Borg scale, tester will use the following dialog:
“You have rated your shortness of breath as “xx” on this scale before the 6MWT. I would
like to use the following scale to indicate the maximal shortness of breath you had during
the walk test (indicate the Borg scale).
If there was no shortness of breath at all you would point to 0;
if the shortness of breath was not very great you would choose from 0.5 to 2;
if you were somewhat more short of breath you would select 3;
and if the breathing was getting very difficult, you would choose 4 to 9, depending on
just how hard it was; 10 represents the greatest shortness of breath you have ever
experienced in your life.”


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14.2.6 THE BORG CR10 SCALE® [to be used for patients randomized under
protocol versions 3 and later]
The Borg CR10 Scale® must be printed on heavy paper (either DIN A4 or ANSI letter size
and perhaps laminated) in 20 point type size.
The Borg CR 10 Scale® will be explained in detail to the participants at Screening before
starting the first 6MWT (questionnaires and instructions will be provided in local
language).
The tester will provide the following instruction to the participant:
"Use this rating scale to report how strong your perception of dyspnea and level of exertion
is. First look at the verbal expressions. Start with them and then the numbers. Of these ten
(10) or ”Extremely strong”, “Maximal” is a very important intensity level. This is the most
intense perception or feeling you have ever had.
If your experience or feeling is “Very weak”, you should say “1”, if it is “Moderate”, say
“3”. Note that “Moderate” is “3” and thus weaker than “Medium”, “Mean” or “Middle”. If
the experience is “Strong” or “Heavy” (it feels “Difficult”) say “5”. Note that “Strong” is
about half of “Maximal”. If your feeling is “Very strong”, choose a number from 6 to 8. If
your perception or feeling is stronger than ”10”, - “Extremely strong”, “Maximal” you
can use a larger number, eg 12 or still higher (that’s why “Absolute maximum” is marked
with a dot “•”).


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It's very important that you report what you actually experience or feel, not what you think
you should report. Be as spontaneous and honest as possible and try to avoid under- or
overestimating. Look at the verbal descriptors and then choose a number.
When rating exertion give a number that corresponds to how hard and strenuous you
perceive the work to be. The perception of exertion is mainly felt as strain and fatigue in
your muscles and as breathlessness or any aches.
0 - ”Nothing at all”, means that you don’t feel any exertion whatsoever, no muscle
fatigue, no breathlessness or difficulties breathing.
1 - “Very weak” means a very light exertion. As taking a shorter walk at your own
pace.
3 - “Moderate” is somewhat but not especially hard. It feels good and not difficult
to go on.
5 - “Strong”. The work is hard and tiring, but continuing isn't terribly difficult. The
effort and exertion is about half as intense as “Maximal”.
7 - “Very strong” is quite strenuous. You can still go on, but you really have to push
yourself and you are very tired.
10 - “Extremely strong  Maximal” is an extremely strenuous level. For most
people this is the most strenuous exertion they have ever experienced previously in
their lives.
"•" - Is ”Absolute maximum” for example ”12” or even more.
Any questions?"
When rating dyspnea give a number that corresponds to how hard and strenuous you
perceive your breathing to be9. The perception of dyspnea is mainly the feeling that one
cannot breathe well enough.
0 - ”Nothing at all”, means that you don’t feel any shortness of breath.
1 - “Very weak” means a very light shortness of breath.
3 - “Moderate” is somewhat but not especially hard. You are somewhat shorter of
breath.
9 
The instructions for rating dyspnea have been customized by the Sponsor based on the instructions for rating
exertion. These modifications have not been validated by Borg Perception AB.


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5 - “Strong”. Breathing is getting difficult. The effort to breathe is about half as
intense as “Maximal”.
7 - “Very strong” is quite strenuous. You can still breathe, but breathing is getting
very difficult.
10 - “Extremely strong Maximal” is the greatest shortness of breath you have ever
experienced in your life.
"•" - Is ”Absolute maximum” for example ”12” or even more.


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14.3 Appendix 3 WHO Functional Classification of Pulmonary
Hypertension
Class I 
Patients with pulmonary hypertension but without resulting limitation
of physical activity. Ordinary physical activity does not cause undue
dyspnea or fatigue, chest pain, or near syncope.
Class II 
Patients with pulmonary hypertension resulting in slight limitation of
physical activity. They are comfortable at rest. Ordinary physical
activity causes undue dyspnea or fatigue, chest pain, or near syncope.
Class III 
Patients with pulmonary hypertension resulting in marked limitation
of physical activity. They are comfortable at rest. Less than ordinary
activity causes undue dyspnea or fatigue, chest pain, or near syncope.
Class IV  
Patients with pulmonary hypertension with inability to carry out any
physical activity without symptoms. These patients manifest signs of
right heart failure. Dyspnea and/or fatigue may even be present at rest.
Discomfort is increased by any physical activity.


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14.4 Appendix 4 Marked Laboratory Abnormalities
Hematology (SI Units)
Laboratory 
test name
(CDISC
Synonym[s])
LL 
LLL  
HH  
HHH
Hemoglobin  
<100 g/L  
<80 g/L 
>20 g/L above 
baseline 
>40 g/L above
baseline
Hematocrit; 
EVF; PCV
(male)
<0.32 L/L 
<0.20 L/L 
>0.60 L/L 
>0.65 L/L
Hematocrit; 
EVF; PCV)
(female)
<0.28 L/L 
<0.20 L/L 
>0.55 L/L 
>0.65 L/L
Platelets 
(assuming no
platelet cluster)
<75×109/L 
<50×109/L 
>600×109/L 
>999×109/L
Leukocytes; 
white blood
cells
<3.0×109/L 
<2.0×109/L 
>20.0×109/L 
>100.0×109/L
Neutrophils 
(Abs)
<1.5×109/L 
<1.0×109/L 
NA  
NA
Eosinophils 
(Abs)
NA  
NA  
>5.0×109/L 
NA
Lymphocytes 
(Abs)
<0.8×109/L 
<0.5×109/L 
>4.0×109/L 
>20×109/L
EVF  erythrocyte volume fraction; NA  not applicable; PCV  packed cell volume.


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Blood chemistry (SI Units)
Laboratory test 
name (CDISC
Synonym[s])
LL  
LLL  
HH  
HHH
Alanine 
aminotransferase
NA  
NA  
>3 × ULN  
>5 × ULN
Aspartate 
aminotransferase
NA  
NA  
>3 × ULN  
>5 × ULN
Alkaline 
phosphatase
NA  
NA  
>2.5 × ULN  
>5 × ULN
Bilirubin; Total 
bilirubin
NA  
NA  
>2 × ULN  
>5 × ULN
Creatinine 
NA  
NA  
>1.5 × ULN  
>3 × ULN
Sodium  
NA  
<130 mmol/L 
>150 mmol/L 
>155 mmol/L
Potassium  
<3.2 mmol/L  
<3.0 mmol/L  
>5.5 mmol/L 
>6.0 mmol/L
Creatinine 
clearance
<60 ml/min  
<30 ml/min  
NA  
NA
NA  not applicable; ULN  upper limit of normal.


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14.5 Appendix 5 
PAH-SYMPACT™Questionnaire
14.5.1 
Administration and Scoring
14.5.1.1 
Administration
The PAH-SYMPACT™is composed of 2 parts: the Symptoms part, which is administered
daily for 7 days, and the Impacts part, which is administered once at the end of the
seven-day administration period. The PAH-SYMPACT™ has been used in both an
electronic patient-reported outcome and a paper-pencil format.
The Symptoms part contains 11 symptom items across 2 domains plus one question about
oxygen use. There is no total symptom score; the 2 domains are: Cardiopulmonary
Symptoms and Cardiovascular Symptoms. The question on oxygen use stands on its own
and is not used as part of the domain scores. Symptoms items have a recall period of
“today,” and it is recommended that the questions be completed in the evening. As
symptoms vary by day, the Symptoms part should be completed daily over 7 consecutive
days.
The Impact part contains 11 items across 2 domains: Physical Impacts and
Cognitive/Emotional Impacts. Impact items have a recall period of the last week; hence,
the questions should be completed on the seventh  day of the seven-day administration
period of the Symptoms part.
14.5.1.2 
Scoring
Items have a five-point Likert response scale; responses are transcribed to numerical values
[see Table 8 below] for further analyses.
Table 8 
Symptoms (n  11)
 
 
Cardiopulmonary symptoms Domain
1. How would you rate your shortness of
breath?
No shortness of breath at all = 0
Mild = 1
Moderate = 2
Severe = 3
Very Severe = 4
2. How would you rate your fatigue? 
No fatigue at all = 0
Mild = 1
Moderate = 2
Severe = 3
Very Severe = 4


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3. How would you rate your lack of energy?
No lack of energy at all = 0
Mild = 1
Moderate = 2
Severe = 3
Very Severe = 4
4. How would you rate the swelling in your
ankles or legs?
No swelling in ankles or legs at all = 0
Mild = 1
Moderate = 2
Severe = 3
Very Severe = 4
5. How would you rate the swelling in your
stomach area?
No swelling in stomach area at all = 0
Mild = 1
Moderate = 2
Severe = 3
Very Severe = 4
6. How would you rate your cough?
No cough at all = 0
Mild = 1
Moderate = 2
Severe = 3
Very Severe = 4
Cardiovascular Symptoms Domain
7. How would you rate your heart
palpitations (heart fluttering)?
No heart palpitations (heart fluttering) at all = 0
Mild = 1
Moderate = 2
Severe = 3
Very Severe = 4
8. How would you rate your rapid heartbeat?
No rapid heartbeat at all = 0
Mild = 1
Moderate = 2
Severe = 3
Very Severe = 4
9. How would you rate your chest pain?
No chest pain at all = 0
Mild = 1
Moderate = 2
Severe = 3
Very Severe = 4


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10. How would you rate your chest tightness?
No chest tightness at all = 0
Mild = 1
Moderate = 2
Severe = 3
Very Severe = 4
11. How would you rate your
lightheadedness?
No lightheadedness at all = 0
Mild = 1
Moderate = 2
Severe = 3
Very Severe = 4


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Table 9 
Impacts (n  11)
 
 
Physical Impacts Domain
1. Were you able to walk slowly on a flat
surface?
Yes, with no difficulty at all = 0
Yes, with a little difficulty = 1
Yes, with some difficulty = 2
Yes, with much difficulty = 3
No, not able at all = 4
2. Were you able to walk quickly on a flat
surface?
Yes, with no difficulty at all= 0
Yes, with a little difficulty = 1
Yes, with some difficulty = 2
Yes, with much difficulty = 3
No, not able at all = 4
3. Were you able to walk uphill? 
Yes, with no difficulty at all= 0
Yes, with a little difficulty = 1
Yes, with some difficulty = 2
Yes, with much difficulty = 3
No, not able at all = 4
4. Were you able to carry things, such as
bags or baskets?
Yes, with no difficulty at all = 0
Yes, with a little difficulty = 1
Yes, with some difficulty = 2
Yes, with much difficulty = 3
No, not able at all = 4
5. Were you able to do light indoor 
household chores such as preparing food, 
cleaning surfaces, or tidying up? 
Yes, with no difficulty at all = 0
Yes, with a little difficulty = 1
Yes, with some difficulty = 2
Yes, with much difficulty = 3
No, not able at all = 4
6. Were you able to wash or dress yourself? 
Yes, with no difficulty at all = 0
Yes, with a little difficulty = 1
Yes, with some difficulty = 2
Yes, with much difficulty = 3
No, not able at all = 4


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7. How much did you need help from
others?
Not at all = 0
A little bit = 1
Some = 2
Quite a bit = 3
Very much = 4
Cognitive/Emotional Impacts Domain
8. Were you able to think clearly?
Yes, with no difficulty at all = 0
Yes, with a little difficulty = 1
Yes, with some difficulty = 2
Yes, with much difficulty = 3
No, not able at all = 4
9. How sad did you feel?
Not at all = 0
A little bit = 1
Somewhat = 2
Very = 3
Extremely = 4
10. How worried did you feel?
Not at all = 0
A little bit = 1
Somewhat = 2
Very = 3
Extremely = 4
11. How frustrated did you feel?
Not at all = 0
A little bit = 1
Somewhat = 2
Very = 3
Extremely = 4
14.5.1.3 
Symptoms
Individual mean weekly symptom item scores are determined across the days in a given
week (ie, the mean score for symptom 1 is the sum of the 7 days divided by the number of
days with non-missing data).
Each mean weekly symptom item score by definition has to range from 0 4.
No more than 3 missing days are allowed per week (can be consecutive or
non-consecutive).
The mean individual weekly symptom item scores are aggregated by domain, with the sum
then being divided by the number of symptom items in the respective domain.


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This leads to the average weekly domain score ranging from 0 4 for each patient.
The group-level domain scores are calculated by summing the individual domain scores
and taking the mean.
14.5.1.3.1 Missing data
If 2 adjacent responses (eg, mild and moderate) are both marked, the item score defaults to
the worst (ie, moderate). Electronic versions of the questionnaire should be programmed
so that only one response may be selected. Therefore, this should not occur unless the
instrument is administered via paper-pencil.
If more than one response is selected and they are not adjacent, the item is missing.
Electronic versions of the questionnaire should be programmed so that only one response
may be selected. Therefore, this should not occur unless the instrument is administered via
paper-pencil.
Domains with an even number of items can be scored as long as half of the items are
completed; for domains with an odd number of items, half plus one item must be
completed.
14.5.1.4 
Impacts
Individual impact item scores are aggregated by domain, with the sum divided by the
number of impact items in the respective domain.
The weekly domain score ranges from 0 4 for each patient.
The group-level domain scores are calculated by summing the individual domain scores
for all of the patients and taking the mean.
14.5.1.4.1 Missing data
If 2 adjacent responses (eg, not at all and a little bit) are both marked, the item score defaults
to the worst (ie, a little bit). Electronic versions of the questionnaire should be programmed
so that only one response may be selected. Therefore, this should not occur unless the
instrument is administered via paper-pencil.
If more than one response is selected and they are not adjacent, the item is missing.
Electronic versions of the questionnaire should be programmed so that only one response
may be selected. Therefore, this should not occur unless the instrument is administered via
paper-pencil.
Domains with an even number of items can be scored as long as half of the items are
completed; for domains with an odd number of items, half plus one item must be
completed.


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14.5.2 Sample Questionnaire
Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT)
Questionnaire
INSTRUCTIONS
Each day you will answer questions about your Pulmonary Arterial Hypertension symptoms over the
PAST 24 HOURS. Please select the answer that best describes your experience with your symptoms.
On the 7th  day you will answer questions about your Pulmonary Arterial Hypertension symptoms over the
PAST 24 HOURS and additional questions about how your life was affected by Pulmonary Arterial
Hypertension in the PAST 7 DAYS.
Please do not skip any questions. There are no right or wrong answers to any of the questions.


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SYMPTOMS (Day 1)
Today you will answer questions about your Pulmonary Arterial Hypertension symptoms over the PAST
24 HOURS. Please select the answer that best describes your experience with your symptoms.
1. In the past 24 hours …
Did you use oxygen?
0  No
1  Yes 
If yes: How many hours? 
Answer the questions that follow based on your experiences regardless of whether you were using
oxygen or not. Rate each symptom "at its worst".
2. In the past 24 hours …
How would you rate your shortness of breath?
0  No shortness of breath at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
3. In the past 24 hours …
How would you rate your fatigue?
0  No fatigue at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
4. In the past 24 hours …
How would you rate your lack of energy?
0  No lack of energy at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
5. In the past 24 hours …
How would you rate the swelling in your ankles or legs?
0  No swelling in ankles or legs at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
Continue onto the next page


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6. In the past 24 hours …
How would you rate the swelling in your stomach area?
0  No swelling in stomach area at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
7. In the past 24 hours …
How would you rate your cough?
0  No cough at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
8. In the past 24 hours …
How would you rate your heart palpitations (heart fluttering)?
0  No heart palpitations (heart fluttering) at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
9. In the past 24 hours …
How would you rate your rapid heartbeat?
0  No rapid heartbeat at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
10. In the past 24 hours …
How would you rate your chest pain?
0  No chest pain at all
1  Mild
2  Moderate
3  Severe
4  Very Severe


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11. In the past 24 hours …
How would you rate your chest tightness?
0  No chest tightness at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
12. In the past 24 hours …
How would you rate your lightheadedness?
0  No lightheadedness at all
1  Mild
2  Moderate
3  Severe
4  Very Severe


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INSTRUCTIONS (Day 7)
Today you will answer questions about your Pulmonary Arterial Hypertension symptoms over the PAST
24 HOURS and additional questions about how your life was affected by Pulmonary Arterial Hypertension
in the PAST 7 DAYS. Please do not skip any questions. There are no right or wrong answers to any of the
questions.
SYMPTOMS
1. In the past 24 hours …
Did you use oxygen?
0  No
1  Yes 
If yes: How many hours? 
Answer the questions that follow based on your experiences regardless of whether you were using
oxygen or not.
2. In the past 24 hours …
How would you rate your shortness of breath?
0  No shortness of breath at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
3. In the past 24 hours …
How would you rate your fatigue?
0  No fatigue at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
4. In the past 24 hours …
How would you rate your lack of energy?
0  No lack of energy at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
5. In the past 24 hours …
How would you rate the swelling in your ankles or legs?
0  No swelling in ankles or legs at all
1  Mild
2  Moderate
3  Severe
4  Very Severe


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Continue onto the next page
6. In the past 24 hours …
How would you rate the swelling in your stomach area?
0  No swelling in stomach area at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
7. In the past 24 hours …
How would you rate your cough?
0  No cough at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
8. In the past 24 hours …
How would you rate your heart palpitations (heart fluttering)?
0  No heart palpitations (heart fluttering) at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
9. In the past 24 hours …
How would you rate your rapid heartbeat?
0  No rapid heartbeat at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
10. In the past 24 hours …
How would you rate your chest pain?
0  No chest pain at all
1  Mild
2  Moderate
3  Severe
4  Very Severe
11. In the past 24 hours …
How would you rate your chest tightness?
0  No chest tightness at all


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£1  Mild
2  Moderate
3  Severe
4  Very Severe
Continue onto the next page
12. In the past 24 hours …
How would you rate your lightheadedness?
0  No lightheadedness at all
1  Mild
2  Moderate
3  Severe
4  Very Severe


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IMPACTS
For the following questions, please select the answer that best describes how your life was affected by
Pulmonary Arterial Hypertension in the in the PAST 7 DAYS. Answer the questions based on your
experiences regardless of whether you were using oxygen or not.
1. In the past 7 days …
Were you able to walk slowly on a flat surface?
0  Yes, with no difficulty at all
1  Yes, with a little difficulty
2  Yes, with some difficulty
3  Yes, with much difficulty
4  No, not able at all
2. In the past 7 days …
Were you able to walk quickly on a flat surface?
0  Yes, with no difficulty at all
1  Yes, with a little difficulty
2  Yes, with some difficulty
3  Yes, with much difficulty
4  No, not able at all
3. In the past 7 days …
Were you able to walk uphill?
0  Yes, with no difficulty at all
1  Yes, with a little difficulty
2  Yes, with some difficulty
3  Yes, with much difficulty
4  No, not able at all
4. In the past 7 days …
Were you able to carry things, such as bags or baskets?
0  Yes, with no difficulty at all
1  Yes, with a little difficulty
2  Yes, with some difficulty
3  Yes, with much difficulty
4  No, not able at all
5. In the past 7 days …
Were you able to do light indoor household chores, such as preparing food, cleaning surfaces, or
tidying up?
0  Yes, with no difficulty at all
1  Yes, with a little difficulty
2  Yes, with some difficulty
3  Yes, with much difficulty
4  No, not able at all
Continue onto the next page


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6. In the past 7 days …
Were you able to wash or dress yourself?
0  Yes, with no difficulty at all
1  Yes, with a little difficulty
2  Yes, with some difficulty
3  Yes, with much difficulty
4  No, not able at all
7. In the past 7 days …
How much did you need help from others?
0  Not at all
1  A little bit
2  Some
3  Quite a bit
4  Very much
8. In the past 7 days …
Were you able to think clearly?
0 Yes, with no difficulty at all
1  Yes, with a little difficulty
2  Yes, with some difficulty
3  Yes, with much difficulty
4  No, not able at all
9. In the past 7 days …
How sad did you feel?
0  Not at all
1  A little bit
2  Somewhat
3  Very
4  Extremely
10. In the past 7 days …
How worried did you feel?
0  Not at all
1  A little bit
2  Somewhat
3  Very
4  Extremely


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11. In the past 7 days …
How frustrated did you feel?
0  Not at all
1  A little bit
2  Somewhat
3  Very
4  Extremely


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Pulmonary arterial hypertension
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14.6 Appendix 6 EQ-5D-5L
Under each heading, please tick the ONE box that best describes your health TODAY
MOBILITY
I have no problems in walking about 

I have slight problems in walking about 

I have moderate problems in walking about 

I have severe problems in walking about 

I am unable to walk about 

SELF-CARE
I have no problems washing or dressing myself 

I have slight problems washing or dressing myself 

I have moderate problems washing or dressing myself 

I have severe problems washing or dressing myself 

I am unable to wash or dress myself 

USUAL ACTIVITIES (eg work, study, housework, family or leisure activities)
I have no problems doing my usual activities 

I have slight problems doing my usual activities 

I have moderate problems doing my usual activities 

I have severe problems doing my usual activities 

I am unable to do my usual activities 

PAIN / DISCOMFORT
I have no pain or discomfort 

I have slight pain or discomfort 

I have moderate pain or discomfort 

I have severe pain or discomfort 

I have extreme pain or discomfort 

ANXIETY / DEPRESSION
I am not anxious or depressed 

I am slightly anxious or depressed 

I am moderately anxious or depressed 

I am severely anxious or depressed 

I am extremely anxious or depressed 



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Pulmonary arterial hypertension
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14.7 Appendix 7 PGA-S and PGI-C Scales
14.7.1 Patient Global Assessment of Disease Severity (PGA-S)
Please choose the response that best describes the severity of your PAH symptoms over the past
7 days. (Choose one response)
 None
 Mild
 Moderate
 Severe
 Very severe


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14.7.2 Patient Global Impression of Change (PGI-C)
Please choose the response below that best describes the overall change in your PAH symptoms since you
started taking the study medication.
(Choose one response)
 Much Better
 A Little Better
 No Change
 A Little Worse
 Much Worse


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Pulmonary arterial hypertension
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14.8 Appendix 8 Model for End-stage Liver Disease (MELD) Score
MELD  3.78 × loge serum bilirubin (mg/dL) +
11.20 × loge international normalized ratio +
9.57 × loge serum creatinine (mg/dL) +
6.43 (constant for liver disease etiology)
Notes:
If the patient has been dialyzed twice within the last 7 days, then the value for serum creatinine
used should be 4.0.
Any value less than 1 is given as a value of 1 (ie, if bilirubin is 0.8, a value of 1.0 is to be used) to
prevent the occurrence of scores below 0 (the natural logarithm of 1 is 0, and any value below 1
would yield a negative result).


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14.9 Appendix 9 Work Productivity and Activity Impairment Questionnaire:
General Health (WPAI©: GH) V2.0
The following questions ask about the effect of your health problems on your ability to work and
perform regular activities. By health problems we mean any physical or emotional problem or
symptom. Please fill in the blanks or circle a number, as indicated.
1. Are you currently employed (working for pay)?
____NO __YES
If NO, check “NO” and skip to question 6.
The next questions are about the past 7 days, not including today.
2. During the past 7 days, how many hours did you miss from work because of your health
problems? Include hours you missed on sick days, times you went in late, left early, etc., because
of your health problems. Do not include time you missed to participate in this study.
_____HOURS
3. During the past 7 days, how many hours did you miss from work because of any other reason,
such as vacation, holidays, time off to participate in this study?
_____HOURS
4. During the past 7 days, how many hours did you actually work?
_____HOURS (If “0”, skip to question 6.)
5. During the past 7 days, how much did your health problems affect your productivity while you
were working? Think about days you were limited in the amount or kind of work you could do,
days you accomplished less than you would like, or days you could not do your work as carefully
as usual. If health problems affected your work only a little, choose a low number. Choose a high
number if health problems affected your work a great deal.


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Pulmonary arterial hypertension
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6. During the past 7 days, how much did your health problems affect your ability to do your regular
daily activities, other than work at a job? By regular activities, we mean the usual activities you
do, such as work around the house, shopping, childcare, exercising, studying, etc. Think about
times you were limited in the amount or kind of activities you could do and times you
accomplished less than you would like. If health problems affected your activities only a little,
choose a low number. Choose a high number if health problems affected your activities a great
deal.


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Pulmonary arterial hypertension
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14.10 Appendix 10Study Conduct During a Natural Disaster
Information on managing the impact of the Coronavirus Disease 2019 (COVID-19) pandemic on
the study is described in the COVID-19 Appendix (EDMS-RIM-264821, version 3.0).


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Pulmonary arterial hypertension
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14.11 Appendix 11Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents. Summary of previous amendments is provided below.
Amendment 
Date 
Main Reasons
1 
12 Aug 2019 
1. Eligibility criteria for hemodynamics will be confirmed
by the central reading.
2. Change the objective of the evaluation of PAH symptoms
and their impact on participant’s life from secondary to
“other” objective.
3. Update frequency of liver function test monitoring.
4. Update plan for follow-up of participants who
prematurely discontinue study treatment.
2 
28 Feb 2020 
To implement updated guidelines for the right heart
catheterization and 6MWT procedures in order to facilitate
alignment in RHC and 6MWT procedures and data
collection across all Actelion trials
3 
17 July 2020 
To update an exclusion criteria and concomitant therapy
section pertaining to newly identified drug-drug
interactions (DDI) between macitentan and fluconazole (a
dual moderate inhibitor of CYP3A4 and CYP2C9) from a
pre-clinical study on implications of role of CYP2C9 in the
metabolism of macitentan.
4 
20 October 2020 To move the cardiopulmonary and cardiovascular domain
scores of the PAH-SYMPACT™ from exploratory
endpoints to secondary endpoints following discussion
with the Food and Drug Administration (FDA).
5 
27 April 2021 
To change the requirements on the minimum number of
participants in each stratum (iea, treatment-naïve, prior-
endothelin 
receptor 
antagonists 
[ERA]; 
prior-
Phosphodiesterase type-5 inhibitor [PDE5i]) at the interim
and final analyses.


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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer: (Please add
the name here)
Name (typed or printed): 
.
Institution: 
Janssen Research & Development
Signature: 
[electronic signature appended at the end of the protocol] 
Date:
(Day Month Year)
Note: 
If the address or telephone number of the investigator changes during the study, written notification will be provided by
the investigator to the sponsor, and a protocol amendment will not be required.
PPD


Signature
User 
Date 
Reason
 
21-Nov-2022
12:42:28
(GMT)
Document Approval
 
21-Nov-2022
12:53:56
(GMT)
Document Approval
 
 
21-Nov-2022
14:07:01
(GMT)
Document Approval
PPD
PPD
PPD

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 31 January 2023
Actelion Pharmaceuticals Ltd
(a Janssen Pharmaceutical Company of Johnson & Johnson)
Statistical Analysis Plan - Part 2
A DUE Prospective, multi-center, double-blind, randomized, active-controlled, triple 
dummy, parallel-group, group-sequential, adaptive Phase 3 clinical study to compare the 
efficacy and safety of macitentan and tadalafil monotherapies with the corresponding fixed 
dose combination in subjects with pulmonary arterial hypertension (PAH), followed by an 
open-label treatment period with macitentan and tadalafil fixed dose combination therapy
Protocol AC-077A301; Phase 3
JNJ-68150420/ACT-064992D (Macitentan/Tadalafil fixed dose combination)  
Status:
Approved
Date:
31 January 2023
Prepared by:
Actelion Pharmaceuticals Ltd and Janssen Research & Development, a division of 
Janssen Pharmaceutical  
Document No
EDMS-RIM-657334, 3.0
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.
NCT03904693


JNJ-68150420/ACT-064992D (Macitentan/Tadalafil fixed dose combination)
Statistical Analysis Plan Part 2 AC-077A301
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 31 January 2023
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 4
LIST OF IN-TEXT FIGURES ........................................................................................................................ 4
VERSION HISTORY..................................................................................................................................... 5
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Objectives and Endpoints ................................................................................................................ 6
1.1.1.
Trial Objectives ............................................................................................................................. 6
1.1.2.
Trial Endpoints.............................................................................................................................. 6
1.2.
Study Design.................................................................................................................................... 8
1.2.1.
Study periods................................................................................................................................ 8
1.2.2.
Timing of analyses...................................................................................................................... 12
2.
STATISTICAL HYPOTHESES.......................................................................................................... 12
3.
SAMPLE SIZE DETERMINATION....................................................................................................12
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS.....................................................................13
4.1.
Usage of the Analysis Sets ............................................................................................................ 14
4.2.
Presentation based on strata/treatment groups............................................................................. 14
5.
STATISTICAL ANALYSES............................................................................................................... 15
5.1.
General Considerations ................................................................................................................. 15
5.1.1.
Visit Windows ............................................................................................................................. 17
5.1.2.
Study Day ................................................................................................................................... 19
5.1.3.
Baseline ...................................................................................................................................... 20
5.1.4.
Imputation Rules for Missing and Partial Dates .........................................................................20
5.2.
Participant Disposition.................................................................................................................... 22
5.3.
Primary Endpoint Analysis ............................................................................................................. 23
5.4.
Secondary Endpoints Analysis ...................................................................................................... 23
5.5.
Other Efficacy Endpoints Analysis ................................................................................................. 23
5.5.1.
Change from Baseline in 6MWD ................................................................................................ 24
5.5.1.1.
Definition.................................................................................................................................. 24
5.5.1.2.
Analysis Methods .................................................................................................................... 24
5.5.2.
Change from Baseline in WHO FC............................................................................................. 25
5.5.2.1.
Definition.................................................................................................................................. 25
5.5.2.2.
Analysis Methods .................................................................................................................... 25
5.5.3.
Time to First M/M Event Occurring Between Baseline and EOT + 7 days and Between 
Baseline and Week 120 visit ...................................................................................................... 26
5.5.3.1.
Definition.................................................................................................................................. 26
5.5.3.2.
Analysis Methods .................................................................................................................... 26
5.5.4.
Time to Death Due to PAH or Hospitalization for PAH Occurring Between Baseline and 
EOT + 7 days or Between Baseline and Week 120 Visit ...........................................................27
5.5.4.1.
Definition.................................................................................................................................. 27
5.5.4.2.
Analysis Methods .................................................................................................................... 28
5.5.5.
Time to Death (All Causes) Occurring Between First Dose in double-blind period and 
last available survival follow-up .................................................................................................. 28
5.5.5.1.
Definition.................................................................................................................................. 28
5.5.5.2.
Analysis Methods .................................................................................................................... 28
5.5.6.
Change from Baseline in NT-proBNP......................................................................................... 29
5.5.6.1.
Definition.................................................................................................................................. 29
5.5.6.2.
Analysis Methods .................................................................................................................... 29


JNJ-68150420/ACT-064992D (Macitentan/Tadalafil fixed dose combination)
Statistical Analysis Plan Part 2 AC-077A301
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Status: Approved, Date: 31 January 2023
5.5.7.
Number Per Year of All-cause and PAH-related Hospitalizations and In-patient Hospital 
Days, From Baseline up to EOLT...............................................................................................29
5.5.7.1.
Definition.................................................................................................................................. 29
5.5.7.2.
Analysis Methods .................................................................................................................... 30
5.5.8.
Number per Year of Emergency Room Visits From Baseline up to EOLT................................. 30
5.5.8.1.
Definition.................................................................................................................................. 30
5.5.8.2.
Analysis Methods .................................................................................................................... 31
5.6.
Safety Analyses ............................................................................................................................. 31
5.6.1.
Extent of Exposure ..................................................................................................................... 31
5.6.2.
Adverse Events........................................................................................................................... 32
5.6.3.
Additional Safety Assessments .................................................................................................. 34
5.6.3.1.
Clinical Laboratory Tests......................................................................................................... 34
5.6.3.2.
Vital Signs and Physical Examination Findings....................................................................... 34
5.7.
Other Analyses............................................................................................................................... 35
5.7.1.
Biomarkers.................................................................................................................................. 35
5.7.2.
Health Economics....................................................................................................................... 35
5.7.3.
Definition of Subgroups .............................................................................................................. 35
6.
DOCUMENTATION ........................................................................................................................... 36
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 36
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 37
6.3.
Appendix 3 Demographics and Baseline Characteristics..............................................................38
6.4.
Appendix 4 Protocol Deviations ..................................................................................................... 40
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................41
6.6.
Appendix 6 Medical History ........................................................................................................... 42
6.7.
Appendix 7 Treatment Compliance................................................................................................ 43
6.8.
Appendix 8 Adverse Events of Special Interest.............................................................................44
6.9.
Appendix 9 Medications of Special Interest................................................................................... 45
6.10.
Appendix 10 Laboratory Toxicity Grading...................................................................................... 46
6.11.
Appendix 11 Estimands Examples ................................................................................................ 47
7.
REFERENCES................................................................................................................................... 48


JNJ-68150420/ACT-064992D (Macitentan/Tadalafil fixed dose combination)
Statistical Analysis Plan Part 2 AC-077A301
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved, Date: 31 January 2023
LIST OF IN-TEXT TABLES
Table 1 – SAP Version History Summary..................................................................................................... 5
Table 2 – Analysis Sets............................................................................................................................... 13
Table 3 – Usage of analysis Sets ............................................................................................................... 14
Table 4 – Visit Windows for OL period on OLS .......................................................................................... 17
Table 5 – Visit Windows for combined DB/OL period on LTFDCS and FAS.............................................. 17
Table 6 – Visit Windows for combined DB/OL period on CSS ................................................................... 18
Table 7 – Demographic Variables............................................................................................................... 38
LIST OF IN-TEXT FIGURES
Figure 1 – Study Design.............................................................................................................................. 11


JNJ-68150420/ACT-064992D (Macitentan/Tadalafil fixed dose combination)
Statistical Analysis Plan Part 2 AC-077A301
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 31 January 2023
VERSION HISTORY
Table 1 – SAP Version History Summary
SAP 
Version
Approval Date
Change
Rationale
1
17 February 2022
Not Applicable
Initial release
2
16 September
2022
Exposure adjusted AE analysis is added. 
To account for differences in the 
duration of treatment exposure 
among participants.
In addition to tables, plan for graphical 
displays for selected laboratory 
parameters
For easier visualization of results.
Details on summaries of AEs with onset 
during the tadalafil 20 mg titration phase
added.
To add clarity.
Remove planned sensitivity analysis of 
M/M per investigator assessment.
This endpoint is listed only 
summary tables are removed due to 
expected low number of events.
Minor corrections and clarifications. 
To add clarity.
3
26 January 2023
Minor clarifications and changes to 
improve layout and display of analyses.
Small updates to safety data displays 
(including addition of liver function test 
outlier categories, layout of AE subgroup 
tables and tables of AEs during week 
1/tadalfil up-titration). 
Editorial updates and corrections have 
been applied.
To improve clarity.


JNJ-68150420/ACT-064992D (Macitentan/Tadalafil fixed dose combination)
Statistical Analysis Plan Part 2 AC-077A301
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status: Approved, Date: 31 January 2023
1.
INTRODUCTION
This Statistical Analysis Plan (SAP) Part 2 describes the planned statistical data analyses for the 
Clinical Study Report (CSR) at the end of the open-label (OL) period of study AC-077A301. It 
also includes the planned analysis of combined double-blind (DB) and OL data available after the 
end of the DB period of study AC-077A301, which will be included in submission summary 
documents. These analyses will be referred to as ‘final DB analysis/submission’ in this SAP. The 
analyses of the DB data planned at the end of the DB period of the study are described in a separate 
document, the AC-077A301 CSR SAP Part 1 (EDMS-RIM-657335). Definition of variables and 
analyses in this SAP Part 2 will refer to the SAP Part 1 document, where applicable.
This SAP is based on the AC-077A301 protocol Version 7 dated 21 November 2022, the 
AC-077A301 COVID-19 Appendix to the Clinical Protocol dated 27 April 2021, the case report 
form (CRF) Version 16.01 dated 27 January 2022, and the Clinical Event Committee (CEC)
Charter Version 5.0 dated 7 April 2022.
Source data for the analyses are provided as Statistical Analysis Software (SAS®) data sets 
according to Clinical Data Interchange Standards Consortium Study Data Tabulation Model 
(SDTM). All descriptive or formal statistical analyses will be performed using SAS statistical 
software (Version 9.4), unless otherwise specified.  
1.1.
Objectives and Endpoints
1.1.1.
Trial Objectives
The primary and secondary objectives of the study are related to the DB part of the trial and are 
described in SAP Part 1. These objectives are not covered in SAP Part 2, which focuses on the 
other objectives for the 24-month OL treatment period that are defined in the protocol. 
Other objectives for the 24-month OL treatment period are:
!
To evaluate the long-term safety of the M/T FDC (macitentan 10 mg and tadalafil 40 mg 
fixed dose combination). 
!
To evaluate the long-term effect of the M/T FDC on: 
o
Exercise capacity. 
o
WHO FC. 
o
Time to first morbidity/mortality event. 
o
Time to death due to PAH or PAH-related hospitalization. 
o
Pharmacoeconomic measures. 
o
Time to death (all causes).
1.1.2.
Trial Endpoints
The primary and secondary endpoints of the study are related to the DB part of the trial and are 
described in the SAP Part 1. Other efficacy endpoints for the DB period are also described in SAP 
Part 1. 


JNJ-68150420/ACT-064992D (Macitentan/Tadalafil fixed dose combination)
Statistical Analysis Plan Part 2 AC-077A301
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Status: Approved, Date: 31 January 2023
Other efficacy endpoints for the OL treatment period (as listed in the protocol) are:
!
Change from baseline up to EOLT, by visit, in exercise capacity, as measured by the 6MWD.
!
Change from baseline up to EOLT, by visit, in WHO FC.
!
Time to first morbidity or mortality event occurring between baseline and EOLT, defined as
any of the following:
-
Death (all causes).
-
Non-planned PAH-related hospitalization.
-
Initiation of IV or subcutaneous prostacyclin or prostacyclin analog for worsening
PAH.
-
Clinical worsening defined as:
o
Deterioration in exercise testing, confirmed by two 6MWTs performed on
different days within 2 weeks, showing at least 15% decrease of 6MWD from
baseline.
AND
o
Worsening of PAH symptoms, defined as at least one of the following

Increase in WHO FC.

Appearance or worsening of signs/symptoms of right heart failure that
do not respond to optimized oral diuretic therapy.
!
Time to death due to PAH or hospitalization for PAH occurring between baseline and EOLT:
-
Death due to PAH, or onset of a treatment-emergent AE that led to permanent
discontinuation of study treatment with a fatal outcome due to PAH occurring within
4 weeks of study treatment discontinuation
OR 
-
Non-planned PAH-related hospitalization.
!
Time to death (all causes) occurring between randomization and open-label database
lock. (This endpoint is clarified in Section 5.5.5).
!
Change from baseline up to EOLT, by visit, in NT-proBNP (analyzed on log scale).
!
Number per year of all-cause and PAH-related hospitalizations, from baseline up to EOLT.
!
Number per year of in-patient hospital days for all causes and PAH-related causes, from
baseline up to EOLT.
!
Number per year of emergency room visits for all causes and PAH-related causes that do not
result in hospital admittance from baseline up to EOLT.
The safety endpoints are:
!
Treatment-emergent AEs.
!
SAEs.
!
Deaths.
!
AEs leading to premature discontinuation of study treatment.
!
Change in vital signs (SBP, DBP, and pulse rate) and body weight from baseline to all assessed
time points during the study.
!
Treatment-emergent marked laboratory abnormalities as detailed in section 14.4 of the
protocol.


JNJ-68150420/ACT-064992D (Macitentan/Tadalafil fixed dose combination)
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Status: Approved, Date: 31 January 2023
!
Proportion of participants with a treatment-emergent ALT and/or AST abnormality (≥3, ≥5, 
and ≥8 × ULN). 
!
Proportion of participants with a treatment-emergent ALT and/or AST abnormality 
(≥3 × ULN) associated with total bilirubin ≥2 × ULN (and increased as compared to baseline). 
!
Proportion of participants with a treatment-emergent hemoglobin abnormality (<100 g/L, and 
<80 g/L). 
!
Treatment-emergent AEs of special interest (hypotension, anemia, edema, liver events). 
1.2.
Study Design
This is a prospective, multi-center, double-blind, randomized, active-controlled, triple-dummy, 
parallel-group, group-sequential, adaptive Phase 3 clinical study with a treatment period duration 
of 16 weeks followed by a 24-month single-arm open-label treatment period. 
In total, 170 participants are planned to be randomized into the study (range 150–250) to receive 
either M/T FDC, macitentan 10 mg, or tadalafil 40 mg given once daily. Participants will also 
receive matching placebos for the two other study treatments to maintain the blind. Treatment 
allocation will be stratified by treatment status at baseline, ie, treatment-naïve or treated by an 
ERA or a PDE-5i as a monotherapy: 
!
treatment-naïve participants will be randomized in a 2:1:1 ratio to M/T FDC, macitentan, 
or tadalafil. 
!
participants on allowed ERA monotherapy will be randomized in a 2:1 ratio to M/T FDC 
or macitentan. 
!
participants on allowed PDE-5i monotherapy will be randomized in a 2:1 ratio to M/T FDC 
or tadalafil. 
In the double-blind treatment period, the FDC of macitentan 10 mg and tadalafil 40 mg is 
compared to each monotherapy of macitentan 10 mg or tadalafil 40 mg given once daily.
After completion of the DB treatment period, participants will continue the study in an open-label 
treatment period for 24 months, during which all participants will receive M/T FDC. All EDBT 
assessments must be completed before the participant enters the open-label treatment period.
Participants who have discontinued double-blind study treatment prematurely will continue 
participation until Week 120 but will not receive open-label treatment. 
Regardless of length of study treatment, all participants will be followed until Week 120. 
The study will be conducted at approximately 150 sites in approximately 25 countries.
1.2.1.
Study periods
The study comprises the following consecutive periods as depicted in Figure 1.
Screening period: Lasts up to 30 days; starts with the signature of the Informed Consent Form 
(ICF; Visit 1) and ends the day prior to randomization (Visit 2).


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Double-blind treatment period: Starts on the day of randomization (Visit 2) and ends on the day 
of the EDBT visit (Visit 8). The DB treatment period consists of the titration phase (the first 
2 weeks) and the maintenance phase (Week 3 through Week 16): 
!
Titration phase: Starts on the day of randomization (Visit 2, Day 1) and lasts 2 weeks, ending
on Day 14 (end of Week 2).
∀
Week 1: Loose combination (LC) 10/20: Participants are treated with an LC of
macitentan 10 mg and/or tadalafil 20 mg and relevant placebos, depending on treatment
arm, for 7 days from randomization (Visit 2, Day 1) to the end of Week 1 (Day 7).
∀
Week 2: LC 10/40 Up-titration: Participants are treated with an LC of macitentan 10 mg
and/or tadalafil 40 mg and relevant placebos depending on treatment arm from Day 8 to
the end of Week 2 (Day 14).
∀
Note: If a participant is already receiving a stable dose of PDE-5i within pre-specified
dose ranges at baseline (ie, 40 mg tadalafil, 60–120 mg sildenafil, or 10 mg vardenafil
daily), no up-titration is needed, and they will receive 40 mg tadalafil from Day 1.
!
Maintenance phase: Participants are treated with macitentan 10 mg, tadalafil 40 mg, M/T
FDC, or their respective placebos, depending on treatment arm. The period starts on Day 15
and lasts until EDBT (Visit 8).
∀
Note: If a participant cannot tolerate 40 mg tadalafil during the titration period, the
participant will remain on 20 mg tadalafil. The participant is allowed to be up-titrated
once again to 40 mg tadalafil during the first 2 weeks of the maintenance phase of the DB
treatment period (ie, between Visits 4 and 5).
∀
Note: if a participant prematurely discontinues DB study treatment, they will be asked to
return for an EDBT visit (within ±2 days of the time of treatment discontinuation and
before initiation of new PAH-specific therapy), a safety follow-up (S-FU) visit 30 days
after last treatment administration, and all remaining visits up until the Week 120 visit
(excluding Visits 9 and 10). If the participant did not withdraw consent for study
participation and regular visits to the site are not possible, telephone contacts can be
performed, at the scheduled visits, until the Week 120 visit. During these telephone calls,
M/M, adverse event (AE), vital status and concomitant medication information will be
collected.
Open-label treatment period: For those participants who complete 16 weeks of DB treatment, 
the OL treatment period starts with the first dose of the OL study treatment. In case interim analysis 
results in early stopping of the DB period due to efficacy, participants may start OL study treatment 
prior to completing 16 weeks of DB treatment. All participants will have a titration phase of 
2 weeks, during which the two drugs will be given as a loose combination. The OL treatment 
period lasts at least 24 months and ends with the End-of-Open-Label-Treatment (EOLT) visit.
Participation in the open-label treatment period may be prolonged beyond 24 months until 
macitentan and tadalafil are accessible at the required doses, through other options according to 
local regulations.


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The OL period of the study comprises the following consecutive phases:
!
Titration phase: Starts on the first day of OL treatment and lasts for 2 weeks. The OL
titration phase treatment assignment will be done through Interactive Response 
Technology (IRT) to maintain blinding of the DB treatment period treatment.
-
First week OL titration: Begins the first day of OL treatment and ends the 7th day of 
OL treatment. Participants who received macitentan monotherapy, or could not tolerate 
40 mg tadalafil, in the DB treatment period will receive the loose combination of 
macitentan 10 mg and tadalafil 20 mg. Participants who had received the M/T FDC or 
tadalafil monotherapy treatment and could tolerate 40 mg tadalafil in the DB treatment 
period, will receive the loose combination of macitentan 10 mg and tadalafil 40 mg 
during this week.
-
Second week OL titration: Begins the 8th day of OL treatment and ends on the 14th day 
of OL treatment. All participants are treated with the loose combination of macitentan 
10 mg and tadalafil 40 mg. Participants who cannot tolerate 40 mg tadalafil are not 
eligible to proceed to the OL treatment period maintenance phase and should complete 
a premature End of OL treatment (EOLT) visit.
!
Maintenance phase: Begins the 15th day of open-label treatment and ends with the EOLT. 
All participants are treated with M/T FDC.
-
Note: if a participant prematurely discontinues study treatment, they will be asked to 
return for an EOLT visit within ±7 days of the time of treatment discontinuation and a 
safety follow-up visit 30 days after last treatment administration. If the participant did 
not withdraw consent for study participation, regular contacts will be conducted 
thereafter, at the scheduled visits until the Week 120 visit. If regular visits to the site 
are not possible, phone contacts can be performed, at the scheduled visits, until the 
Week 120 visit. During these phone calls, morbidity and mortality events (M/M) AE, 
vital status and concomitant medication information will be collected.
End-of-Treatment (EOT): For an individual participant is the end of all study treatment.
Safety follow-up (S-FU) period: Starts on the day after the last dose of study treatment and ends 
at the Safety Follow-up Visit 30–35 days thereafter.
For participants who completed the 24-months of open-label treatment and who are eligible for a 
continued access program (post-trial access program or other open-label extension study) the S-
FU period will be waived. In such case enrollment into the continued access program should occur 
on the same day as the last visit in this study, ie, EOS visit.
End of Study (EOS): EOS is reached when all participants have completed their EOS visit, died, 
or are lost to follow-up.




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1.2.2.
Timing of analyses
The database of the study (including open-label part) will be cleaned, and the data extracted and 
analyzed at 3 time points during the study:
Timepoint A: The IA will be conducted when approximately 100 participants have either 
completed their Week 16 assessment or have discontinued from the study prior to their Week 16 
assessment and will only include data from countries in which the global amendment 5 (protocol 
version 6) has been approved. This analysis can allow for early termination for efficacy or futility, 
or unblinded reassessment of sample size required for the primary endpoint. Following the IA, 
recruitment will be stopped if futility or superiority is demonstrated. In the event the study is 
stopped for futility, all participants will be requested to return for an EOT visit and be transitioned 
to Standard of Care. In the event the study is stopped for efficacy, all participants in the double-
blind treatment period will be requested for a EDBT visit and transitioned to the OL treatment, 
participants already enrolled in the OL period of the study will be allowed to continue through the 
end of the open-label treatment period. [Full details are covered in SAP Part 1]
Timepoint B: Unless the study is stopped prematurely following the IA outcome, the final analysis 
of the DB period will occur after all participants have reached Week 16 or prematurely 
discontinued from the study. [Full details are covered in SAP Part 1]
Timepoint C: The final analysis of the study will occur when all participants have performed their 
EOS visit (once the last participant has completed the OL treatment period or discontinued
prematurely). 
At or after the time of the final analysis of the DB period (occurring either at timepoint A if study 
is stopped prematurely during IA or at timepoint B) the open-label data will be analyzed together 
with the double-blind data. All available open-label data will be cleaned and analyzed up to an 
overall cut-off date defined for the submission. The results of these analyses will be reported in 
submission summary documents.  
2.
STATISTICAL HYPOTHESES
Formal hypothesis testing is performed only for the DB part of the study and is described in the 
SAP Part 1. No formal hypothesis testing is performed for the OL part of the study; hence no p-
value is presented for the OL period. All analyses described in the SAP Part 2 are considered 
exploratory. 
3.
SAMPLE SIZE DETERMINATION
The sample size calculation for the study is described in detail in SAP Part 1. The sample size for 
the open-label period will be up to the number of randomized subjects in the DB period.  


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4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
The Screened analysis set, all randomized analysis set, full analysis set, safety set and QoL analysis 
sets are defined in SAP Part 1 since they are used for the reporting of the DB period results.
Analysis sets used to assess OL and combined DB and OL periods are described in the table below.
Table 2 – Analysis Sets
Analysis Sets
Description
Open-label Set (OLS)
The Open-label Set (OLS) includes all participants who receive at 
least one dose of OL study treatment in the OL period.
Only data from the OL period are considered with the exception of 
baseline data which may origin from DB period. 
Analyses will be presented overall and by randomized DB treatment 
group.
Combination Safety Set 
(CSS)
The Combination Safety Set (CSS) includes all participants 
randomized to M/T FDC in the DB period and who received at least 
one dose of M/T FDC DB study treatment (ie, at least one dose of 
macitentan and tadalafil) and all participants who received at least 
one dose of M/T FDC study treatment (ie, at least one dose of 
macitentan and tadalafil) in the OL period.
For participants treated with M/T FDC study treatment in DB period, 
data from DB and OL period are considered. For participants treated 
with monotherapy in DB period, only data from the OL period are 
considered with the exception of baseline data which may origin 
from DB period. 
Analyses will be presented overall and by actual DB treatment
group.
Long-term M/T FDC 
Set (LTFDCS)
The Long-term M/T FDC Set (LTFDCS) includes all participants 
randomized to M/T FDC in the DB period.
Data from DB and OL period are considered. 
Treatment arm is based on randomized treatment   
Full analysis Set (FAS) 
As defined in the SAP Part 1. It includes all randomized participants 
who received at least one dose of study treatment (for participants on 
FDC at least one dose of either macitentan or tadalafil). 
Data from DB and OL period are considered. 
Analyses will be presented by randomized DB treatment group.


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4.1.
Usage of the Analysis Sets
Table 3 summarizes the usage of the analysis sets. 
Table 3 – Usage of analysis Sets
4.2.
Presentation based on strata/treatment groups
Data collected on participants who did not tolerate up-titration to tadalafil 40 mg and remained on 
tadalafil 20 mg or tadalafil 20 mg + macitentan 10 mg as separate tablets will be kept in the 
statistical analysis under the tadalafil 40 mg and M/T FDC arms, respectively. 
Treatment groups for each section will be presented in the following way:
For the OLS, outputs will show 4 columns, one including all participants included in the OLS 
(Total column) and 3 columns by randomized DB treatment group. Treatment arms 
Analysis Sets
Endpoints
OLS *
LTFDCS
CSS
FAS
Change in 6MWD
√
√
√
Change in WHO FC
√
√
√
Time to first M/M event
√
√
√
Time to PAH death or PAH hospitalization
√
√
√
Time to death
√
Fold change in NT-proBNP
√
√
√
Health economics 
√
√
AE
√
AESI
√
Clinical laboratory tests
√
Vital signs
√
* only for OL final analysis
OLS = Open-label Set; LTFDCS = Long-term Macitentan/Tadalafil fixed dose combination Set; CSS = 
Combination Safety Set; FAS = Full analysis Set; 6MWD = 6-minute walk distance; WHO FC = World Health 
Organization Functional class; M/M Morbidity/Mortality; NT-proBNP = N-terminal pro B-type natriuretic 
peptide


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“DB-Macitentan”, “DB-M/T FDC”, “DB-Tadalafil” follow the randomized treatment in DB. An 
example of treatment header for such a display is as follows:
All Strata
DB-Macitentan 
DB-Tadalafil 
DB-M/T FDC
OL M/T FDC (Total)
For LTFDCS outputs, 4 columns will be presented as follows:
DB-M/T FDC
Prior-ERA 
Prior-PDE-5i 
Treatment-naïve
All strata
For analyses on the FAS, data are presented without the strata as follows:
All Strata
DB-Macitentan 
DB-Tadalafil 
DB-M/T FDC
For the CSS, actual DB treatment groups will be displayed. For participants who received 
monotherapy during DB, treatment arms will be labeled “DB-Macitentan”, “DB-Tadalafil” and 
follow the actual treatment received in DB as defined in SAP Part 1. For participants who received 
M/T FDC during DB, the treatment arm is the actual treatment received in DB, it is labeled 
“DB-M/T FDC”. In addition, a total column with all participants included in the CSS will be 
labeled “DB/OL M/T FDC (Total)”.
An example of treatment header for such a display is as follows:
OL Period (M/T FDC)
DB/OL Period M/T FDC
M/T FDC
DB-Macitentan 
DB-Tadalafil 
DB-M/T FDC 
DB/OL M/T FDC (Total)
This display will be used for disposition, safety, treatment exposure and compliance, and 
concomitant medications outputs.
5.
STATISTICAL ANALYSES
5.1.
General Considerations
At or after the time of the final analysis of the DB period, all available OL data will be cleaned 
and analyzed together with the DB data up to an overall cut-off date defined for submission.
Analyses to be performed at the time of the final analysis of the DB will be identified in the DPS 
Part 1 of this SAP (column “use for what effort”, keyword “NDA/MAA submission”). The results 
of these analyses will be reported in submission summary documents.
For the final analysis of the OL period, all OL data will be cleaned and analyzed together with the 
DB data and also separately. Except where specified, all analyses listed in the DPS Part 1 of this 


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SAP are to be performed at the time of the final analysis of the OL. The results of these analyses 
will be reported in the CSR.
End of treatment in the DB treatment period (EOT-DB) is defined as the date of last intake of 
study drug in the DB period.
“EDBT visit” is defined as the last visit in the DB treatment period; this is Visit 8/Week 16 for 
participants who complete the DB treatment period or the premature EDBT visit for participants 
that prematurely discontinue study treatment during the DB treatment period.
End of treatment in the OL treatment period (EOT-OL) is defined only for participants treated in 
OL as the date of last intake of study drug in the OL treatment period. At the time of the final DB 
analysis/submission, it is defined as minimum (the last intake of study drug in the OL treatment 
period, cut-off date). Participants for whom the EOT-OL is imputed by the cut-off date are 
considered as ongoing in the OL treatment period.
EOT is defined as the date of last study drug intake in the study, ie, max (EOT-DB and EOT-OL).
“EOLT visit” is only defined for participants treated in OL and is defined as the last visit in the 
OL treatment period. EOLT visit date is Visit 14/Week 120 date for participants who complete the 
OL treatment period or premature EOLT visit date for participants who discontinue study 
treatment prematurely in the OL treatment period. At the time of final DB analysis/submission, it 
is the minimum of (Visit 14/Week 120, cut-off date) for participants who complete the OL 
treatment period or the minimum of (premature EOLT visit, cut-off date) for participants who 
discontinue study treatment prematurely in the OL treatment period. For participants considered 
as ongoing in the OL period (with EOT-OL imputed by the cut-off date), EOLT visit is imputed 
as the cut-off date.
Participants who have completed the 24 months of the OL period and are benefiting from the study 
intervention, as determined by their investigator, will be able to continue participation in the OL
period beyond 24-months until alternative continued access is available in the participant’s country 
and as per local regulations. These participants are to be followed through regular 6-monthly visits. 
For these participants EOLT visit may happen later than Visit 14 / Week 120. As only a very low 
number of participants is expected to continue treatment in the OL period beyond 24-months, in 
general by-visit displays will stop at the week 120 visit. However, the data collected after the week 
120 visit are included in listings and in summary tables that present treatment-emergent safety 
events.   
EOS visit is defined as the EOS visit as reported in the eCRF. At the time of the DB final 
analysis/submission, it is the minimum of (date of EOS visit as reported in the eCRF, cut-off date).
Participants for whom the EOS is imputed by the cut-off date are considered as ongoing in the 
study. 


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5.1.1.
Visit Windows
As participants do not always adhere to the protocol visit schedule, the following rules are applied 
to assign actual visits to analysis visits. Listed below are the visit windows and the target days for 
each visit. The reference day is described in Section 5.1.2. If a participant has 2 or more actual 
visits in 1 visit window, the visit closest to the target day will be used as the protocol visit for that 
visit window. The other additional visit(s) will not be used in the summaries or analyses but they 
can be used for determination of clinically important endpoints. If 2 actual visits are equidistant 
from the target day within a visit window, the later visit is used.
If more than one assessment falls on the same date, the worst assessment will be considered for 
categorical variables. For continuous variables the mean value of such assessments will be used.
All assignments will be made in chronological order. Once a visit date is assigned to a visit 
window, it will no longer be used for a later time point. Listed below (Table 4, Table 5, Table 6) 
are the analysis visit windows and the target days for each visit defined in the protocol; there are 
different visit window assignment depending on the analysis population, as described in the table.
Table 4 – Visit Windows for OL period on OLS
Parameter
Analysis 
Period
Scheduled 
Visit 
Number
Time Interval
(label on output)
Time Interval
(OL Day)*
Target Time 
Point (OL Day)
6MWT, WHO 
FC, NT-
proBNP
DB/OL
8
OL Baseline
<=1
1
OL
11
OL Month 6
2 to 272
182
OL
12
OL Month 12
273 to 454
364
OL
13
OL Month 18
455 to 636
546
OL
14
OL Month 24
>=637 
728
* OL Study day is defined in Section 5.1.2. 
Note: Efficacy assessments are assigned to visit windows as specified in the table, however on-treatment summaries 
will be done only up to EOT+7 days.
Table 5 – Visit Windows for combined DB/OL period on LTFDCS and FAS
Parameter
Scheduled 
Visit 
Number
Time Interval
(label on 
output)
Time Interval
(Study Day)*
Target Time 
Point (Study 
Day)
6MWT, 
WHO FC
2
Baseline
<=1
1
6
Week 8
For LTFDCS:
2 to Min(84, OL Day 1)**
For FAS:
2 to 84
57
8
Week 16
For LTFDCS:
85 to Min(203, OL Day 1)**
For FAS:
85 to 203
113
11
Week 42/OL 
Month 6
For LTFDCS:
Min(204, OL Day 1 +1)** to 385
295


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Parameter
Scheduled 
Visit 
Number
Time Interval
(label on 
output)
Time Interval
(Study Day)*
Target Time 
Point (Study 
Day)
For FAS:
204 to 385
12
Week 68/OL 
Month 12
386 to 567
477
13
Week 94/OL
Month 18
568 to 749
659
14
Week 120/OL 
Month 24
>=750  
841
NT-
proBNP
2
Baseline
<=1
1
8
Week 16
For LTFDCS:
2 to Min(203, OL Day 1)**
For FAS:
2 to 203
113
11
Week 42/OL 
Month 6
For LTFDCS:
Min(204, OL Day 1 +1)** to 385
For FAS:
204 to 385
295
12
Week 68/OL 
Month 12
386 to 567
477
13
Week 94/OL 
Month 18
568 to 749
659
14
Week 120/OL 
Month 24
>=750 
841
*Study day is defined in Section 5.1.2. 
** For analysis based on LTFDCS, assessments will be assigned to DB visits Week 8 and 16 only up to day date of 
first dose in OL (as participants may start OL prior to week 16 in case interim analysis resulted in early stopping of 
the DB period for efficacy). Assessments from day 204 or date of first dose in OL+1 day up to day 385 will be 
assigned to Week 42 visit window. 
Min = minimum.
Note: Efficacy assessments are assigned to visit windows as specified in the table, however on-treatment summaries 
will be done only up to EOT+7 days.
Table 6 – Visit Windows for combined DB/OL period on CSS
Parameter
Analysis Visit
(label on output)
Time Interval
(M/T FDC Day)*
Target Time Point 
(M/T FDC Day)
Laboratory tests (central lab, 
including liver tests, 
excluding hematology tests), 
vital signs
FDC Baseline
<=1
1
FDC Week 21 (16/26)
2 to 238
148
FDC Week 47 (42/52)
239 to 420
330
FDC Week 73 (68/78)
421 to 602
512
FDC Week 99 (94/104)
603 to 766
694
FDC Week 120
>= 767 
841
Hematology laboratory tests
FDC Baseline
<=1
1
FDC Week 4
2 to 42
29
FDC Week 8
43 to 101
54
FDC Week 21 (16/26)
102 to 238
148
FDC Week 47 (42/52)
239 to 420
330
FDC Week 73 (68/78)
421 to 602
512
FDC Week 99 (94/104)
603 to 766
694


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Parameter
Analysis Visit
(label on output)
Time Interval
(M/T FDC Day)*
Target Time Point 
(M/T FDC Day)
FDC Week 120
>= 767 
841
Liver tests (AST and ALT, 
central lab)
FDC Baseline
<=1
1
FDC Month 1
2 to 46
30
FDC Month 2
47 to 76
61
FDC Month 3
77 to 107
91
FDC Month 4
108 to 137
122
FDC Month 5
138 to 168
152
FDC Month 6
169 to 198
183
FDC Month 7
199 to 229
213
FDC Month 8
230 to 259
244
FDC Month 9
260 to 319
274
FDC Month 12
320 to 411
365
FDC Month 15
412 to 503
457
FDC Month 18
504 to 594
548
FDC Month 21
595 to 685
639
FDC Month 24
686 – 786
731
FDC Month 28
(Week 120)
>= 787
841
FDC Baseline
<=1
1
* M/T FDC Study day is defined in Section 5.1.2. 
Note: Safety assessments for treatment visits will be assigned to the visit windows only up to and including EOT+30 
days.
5.1.2.
Study Day 
Study Day 1 or Day 1 refers to the start of the first DB study treatment administration.
OL Day 1 refers to the start of the first OL study treatment administration.
M/T FDC Day 1 refers to the start of the first M/T FDC study treatment administration (ie, loose 
combination of macitentan [10 mg] and tadalafil [20 mg or 40 mg] or as fixed dose combination) 
either in DB or OL period. For participants from the actual DB M/T FDC group, it is the DB 
treatment start date (Study Day 1 as defined above). For OL treatment participants from the actual 
DB monotherapy group (tadalafil 40 mg or macitentan 10 mg as received) it is the OL treatment 
start date (OL Day 1). 
All efficacy and safety assessments at all visit/events will be assigned a day relative to these dates.
Study day for a visit/event is defined as:
!
Visit/event date - (date of Day 1) +1, if visit/event date is ≥ date of Day 1
!
Visit/event date - Date of Day 1, if visit/event date < date of Day 1
OL day for a visit/event is defined as:
!
Visit/event date - (date of OL Day 1) +1, if visit/event date is ≥ date of OL Day 1
!
Visit/event date - Date of OL Day 1, if visit/event date < date of OL Day 1


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M/T FDC day for a visit/event is defined as:
!
Visit/event date - (date of M/T FDC Day 1) +1, if visit/event date is ≥ date of M/T FDC Day 1
!
Visit/event date - Date of M/T FDC Day 1, if visit date < date of M/T FDC Day 1
There is no ‘Day 0’.
Study Day is used for presentation of data from the combined DB/OL period on the LTFDCS and 
on the FAS.
OL Day is used for presentation of data from the OL period on the OLS.
M/T Day is used for presentation of data from the combined DB/OL period on the CSS.
5.1.3.
Baseline
For the LTFDCS and FAS analysis population, baseline is defined as the last observation prior to 
the first DB study treatment administration (same definition as in the SAP Part 1).
For the OLS analysis population, baseline is defined as the last assessment obtained prior to the 
first intake of OL study treatment.
For the CSS analysis population, baseline is defined as the last assessment prior to the first intake 
of M/T FDC study treatment either in DB or OL period. The first M/T FDC intake can be either 
loose combination of macitentan and tadalafil or M/T FDC tablet.
If the assessment is collected on the same day as the first study treatment, such assessment will be 
considered pre-dose and will be used for derivation of the baseline. The exceptions are AEs, 
concomitant medications and hospitalizations. If such events start on Study Day 1 (or OL Day 1
or M/T FDC Day 1) they will be considered treatment-emergent/concomitant.
If more than one assessment falls on the same date, the worse assessment will be considered as 
baseline for categorical variables. For continuous variables the mean value of such assessments 
will be chosen as a baseline.
5.1.4.
Imputation Rules for Missing and Partial Dates
General rules for an imputation of missing and partial dates for AEs, prior and concomitant 
medications, hospitalizations, death date and date of diagnosis are described SAP Part 1. Partial 
and missing dates of assessments not described in SAP Part 1 will not be imputed and will be used 
as collected.
In order not to miss any treatment-emergent or concomitant records in OL for participants 
switching from monotherapy in DB to M/T FDC in OL, the following rules will be followed for 
this subset of participants:


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Adverse Events
If the onset date of an AE is missing the day only, it will be set to:
!
The day of first dose of OL study treatment, if the month/year of the onset of AE is the 
same as month/year of the first dose of OL study treatment and month/year of the AE 
resolution date is different
!
The day of first dose of OL study treatment or day of AE resolution date, whichever is 
earliest, if month/year of the onset of AE and month/year of the first dose of OL study 
treatment and month/year of the AE resolution date are the same
If the onset date of an AE is missing both the day and month, it will be set to:
!
Month and day of the first dose of OL study treatment or the AE resolution date, whichever 
is earliest, if year of the onset of AE and year of the first dose of OL study treatment and 
year of the AE resolution date are the same.
All other imputation rules for AE onset and resolution dates will follow rules in SAP Part 1.
Prior and Concomitant Medications
If the onset date of a medication is missing the day only, it will be set to:
!
The day of first dose of OL study treatment, if the month/year of the start of medication is 
the same as month/year of the first dose of OL study treatment and month/year of the 
medication end date is different
!
The day of first dose of OL study treatment or day of medication end date, whichever is 
earliest, if month/year of the start of medication and month/year of the first dose of OL 
study treatment and month/year of the medication end date are the same
If the onset date of a medication is missing both the day and month, it will be set to:
!
Month and day of the first dose of OL study treatment or the medication end date, 
whichever is earliest, if year of the start of medication and year of the first dose of OL 
study treatment and year of the medication end date are the same.
Completely missing end dates will not be imputed and will be flagged as concomitant unless 
medication start date is after EOT (rule will be applied to all participants).
All other imputation rules for medication start and end dates will follow rules in SAP Part 1.
Hospitalizations
If the admission date of a hospitalization is missing the day only, it will be set to:
!
The day of first dose of OL study treatment, if the month/year of the admission is the same 
as month/year of the first dose of OL study treatment and month/year of the discharge date 
is different


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!
The day of first dose of OL study treatment or day of discharge date, whichever is earliest, 
if month/year of the admission and month/year of the first dose of OL study treatment and 
month/year of the discharge date are the same
If the admission date of a hospitalization is missing both the day and month, it will be set to:
!
Month and day of the first dose of OL study treatment or the discharge date, whichever is 
earliest, if year of the admission and year of the first dose of OL study treatment and year 
of the discharge date are the same.
If participant is hospitalized due to an AE, AE onset date is available and partial admission date 
was imputed to earlier date than AE onset date or is missing then AE onset date will be imputed 
as hospitalization start date instead. In case there are more AEs for the same hospitalization, the 
earliest AE onset date after OL treatment start date will be used.
Completely missing admission dates without corresponding AE will be imputed as min (first dose 
of OL study treatment, discharge date).
All other imputation rules for hospitalization admission and discharge dates will follow rules in 
SAP Part 1.
M/M Components Event Date
All imputation rules for M/M event dates will follow rules in SAP Part 1.
5.2.
Participant Disposition
The number of participants in the following disposition categories will be summarized throughout 
the study by DB treatment group and overall as described in Section 4.2 for each of the analysis 
set (OLS, LTFDCS and CSS):
!
Participants entering the OL period
!
Participants receiving OL study treatment
!
Participants receiving M/T FDC DB study treatment
!
Participants receiving M/T FDC DB and OL study treatment
!
Participants completing DB study treatment [except for OLS]
!
Participants who discontinued DB study treatment prematurely [except for OLS]
!
Reasons for premature discontinuation of DB study treatment [except for OLS]
!
Participants ongoing in OL study treatment [only for analyses at time of final DB 
analysis/submission]
!
Participants completing OL study treatment
!
Participants who discontinued OL study treatment prematurely
!
Reasons for premature discontinuation of OL study treatment


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!
Participants completing the DB study period [except for OLS]
!
Participants who terminated study DB period prematurely [except for OLS]
!
Reasons for premature termination of study DB period [except for OLS]
!
Participants ongoing in OL study period [only for analyses at time of final DB 
analysis/submission]
!
Participants completing the OL study period
!
Participants who terminated study OL period prematurely
!
Reasons for premature termination of study OL period
Listings of participants will be provided for the following categories:
!
Participants who discontinued OL study treatment prematurely, based on OLS
!
Participants who terminated OL study prematurely, based on FAS
A participant will be counted as completing DB study treatment if CRF question “Did the subject 
take study drug until this visit?” at Visit 8 is answered as “Yes”. Otherwise the participant will be 
considered to have discontinued DB study treatment prematurely.
A participant will be counted as completing the study DB period if the participant underwent Week 
16 visit/Visit 8.
A participant entering the OL treatment period is defined as a participant receiving at least one 
dose of OL study treatment in the OL period.
A participant entering the OL period (with or without being treated in OL treatment period) is 
defined as a participant who underwent at least one visit between Visit 9 and Visit 14 (included). 
A participant will be counted as completing the study OL period if the participant underwent week 
120 Visit/Visit 14. 
5.3.
Primary Endpoint Analysis
Not applicable.
5.4.
Secondary Endpoints Analysis
Not applicable.
5.5.
Other Efficacy Endpoints Analysis
All other efficacy endpoints for the OL period will be analyzed for the OLS and LTFDCS. Selected 
efficacy endpoints will be analyzed for the FAS. Listings with data for each endpoint will be 
produced for the FAS, and as indicated also for OLS. Listing for OLS will contain all data from 
the OL period and OL baseline (where applicable). Listing for FAS will contain all data collected 


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throughout the study (DB and OL period). Each value will be flagged as assessed during DB or 
OL period. 
It is allowed per protocol for participants to continue study treatment after the 24-month OL period 
is completed. EOLT visit in this case will be beyond 24 months. Therefore, the analyses specified 
below will include mainly data up to 24 months but also data beyond 24 months. The selection of 
assessments used for the summaries of efficacy is described for each endpoint in the sections 
below. All collected assessments will be presented in the corresponding listings.
5.5.1.
Change from Baseline in 6MWD
5.5.1.1.
Definition
This endpoint is change from baseline, by visit, in exercise capacity as measured by the 6MWD 
(in meters), defined as: 
Post-baseline 6MWD (m) at scheduled timepoint −6MWD (m) at baseline.
Assignment to visit windows is described in Section 5.1.1. For analyses based on OLS and 
LTFDCS, only assessment up to EOT+7 days will be summarized. For analyses based on FAS, all 
available data will be included.
5.5.1.2.
Analysis Methods
Absolute values at baseline and by visit, as well as absolute changes from baseline to all scheduled 
timepoints will be summarized by treatment on the OLS, FAS and LTFDCS using descriptive 
statistics. 
For the LTFDCS and FAS, a plot of the mean changes (± SE) in 6MWT from baseline overtime 
will be displayed. A reference line is included at zero change and baseline is added to the time axis 
to visualize an initial change from zero. When based on FAS, a reference line is displayed to 
separate DB from OL-treatment period.
In addition, for the FAS, the following analyses of the change from baseline in 6MWT will be 
performed considering all the observed values (from scheduled or unscheduled assessments) and 
the actual assessment day: 
!
Spaghetti plots will be presented by treatment arm to explore the longitudinal pattern of 
observed values. 
!
A parametric longitudinal mixed-effects model, with a (fixed-effects) mean structure that 
is quadratic over time (based on analysis visit, with time corresponding to the target
assessment day of the corresponding analysis visit) and with a random intercept and a 
random slope will be considered for the change from baseline to each post-baseline 
assessment. The model will include time, time-by-treatment interaction term, time-by-
time-by-treatment quadratic interaction term, treatment and the baseline value. Random 
intercept and slope at the level of the participant will be considered. Estimates by treatment 


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arm at analysis visits Week 8, Week 16, Week 42, Week 68, Week 94 and Week 120 will 
be presented along with 95% confidence intervals from the model. Graphical presentation 
of model estimates along with 95% confidence regions will be overlayed to the observed 
values of the change from baseline. In case of missing data, no imputation will be 
performed and only observed data will be summarized.
All available 6MWD data will also be listed as described in Section 5.5.
Supportive data collected on Borg dyspnea index (including the type of Borg scale used by the 
participant) or oxygen saturation will be listed only.
5.5.2.
Change from Baseline in WHO FC
5.5.2.1.
Definition
The change from baseline, by visit, in WHO FC will be categorized as worsening or no worsening 
that is assessed in the following way:
!
Worsening: X=0 if (difference between post-baseline WHO-FC and baseline WHO-FC) >0
!
No worsening: X=1 if (difference between post-baseline WHO-FC and baseline WHO-FC)
≤0.
WHO-FC assessments will be assigned to visit windows as described in Section 5.1.1. For analyses 
based on OLS and LTFDCS, only assessment up to EOT+7 days will be summarized. For analyses 
based on FAS, all available data will be included.
5.5.2.2.
Analysis Methods
The proportion of participants who improved or remained stable (absence of worsening from 
baseline) in WHO FC (ie, a change ≤0) will be summarized by visit and treatment, on the OLS, 
FAS and LTFDCS.
In addition, at the time of OL final analysis and based on the FAS, a marginal weighted 
longitudinal generalized estimating equation will be considered for the absence of worsening at 
each post-baseline assessment. The model will include time (based on analysis visit, with time 
corresponding to the target assessment day of the corresponding analysis visit), time-by-treatment 
interaction term, and treatment. Estimates by treatment arm at analysis visits Week 8, Week 16, 
Week 42, Week 68, Week 94, and Week 120 will be presented along with 95% confidence 
intervals from the model. 
In case of missing data, no imputation will be performed and only observed data will be 
summarized.


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5.5.3.
Time to First M/M Event Occurring Between Baseline and EOT + 7 
days and Between Baseline and Week 120 visit
5.5.3.1.
Definition
Time to first M/M event is defined as any of the following:
!
Death (all causes).
!
Non-planned PAH-related hospitalization.
!
Initiation of intravenous or subcutaneous prostacyclin or prostacyclin analog for worsening 
PAH.
!
Clinical worsening defined as:
∀
Deterioration in exercise testing, confirmed by two 6MWTs performed on different days 
within 2 weeks, showing at least 15% decrease in 6MWD from baseline (ie, Day 1 in 
DB). 
AND
∀
Worsening of PAH symptoms, defined as at least 1 of the following:
∀
Increase in WHO FC.
∀
Appearance or worsening of signs/symptoms of right heart failure that do not respond 
to optimized oral diuretic therapy. 
The sponsor will identify participants with a mortality event, and/or a morbidity event (including 
clinical worsening) through end of study. The adjudication package will be reviewed by two CEC 
members (CEC 1 and CEC 2) and a CEC adjudicator, if applicable (see details in the CEC Charter). 
All cases reviewed and confirmed by the CEC will be included in the analysis of the endpoint. The 
onset date as assessed in the CEC review will be used. In case a partial or missing date is recorded 
by the CEC, then rules as specified in Section 5.1.4 will be applied.
The time to M/M event is defined as the time from baseline (Day 1) to the first occurrence of a 
M/M event confirmed by the CEC up to either EOT + 7 days or Week 120 visit. For participants 
without Week 120 Visit, Week 120 Visit is imputed by minimum (cut-off date, EOS date). Only 
events up to and including the cutoff date are considered.
Participants without the event (confirmed by the CEC) in the corresponding period are right 
censored 
!
at minimum (EOT+7 days, EOS, cutoff date) for analysis up to EOT+7 days
!
at (imputed) Week 120 visit for analysis up to Week 120 visit.  
5.5.3.2.
Analysis Methods
LTFDCS will be used to assess this endpoint up to EOT+7 days. The FAS will be used to assess 
this endpoint up to EOT+7 days and up to Week 120 visit. The time to occurrence of the first CEC 


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confirmed M/M event will be estimated by Kaplan-Meier method, providing estimates for each 
treatment arm and corresponding 95% two-sided CLs at Week 16 (Day 113), Month 6 (Day 183), 
Month 12 (Day 365), Month 18 (Day 548), Month 24 (Day 730). 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 participants 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 participants at risk and 
KM estimates of the survival function for time to event variables. The graph of the estimates 
survival function of the time to first M/M event 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 
participants remain at risk of an event. The graphical presentation follows the recommendations 
from (Pocock 2002).
Based on OLS (up to EOT+7 days), LTFDCS (up to EOT+7 days) and FAS (up to EOT+7 days
and up to Week 120 visit), causes of M/M events confirmed by CEC will also be summarized in 
frequency tables as first event and also all events per participant. If a participant experiences 
several first events as assessed by the CEC (i.e. multiple events with the same onset date), the 
cause of the first event corresponds to the most severe event documented, using the following 
hierarchy: 1) Death, 2) Non-planned PAH-related hospitalization, 3) Initiation of IV or 
Subcutaneous prostacyclin or prostacyclin analog for worsening PAH, 4) Clinical worsening.
5.5.4.
Time to Death Due to PAH or Hospitalization for PAH Occurring 
Between Baseline and EOT + 7 days or Between Baseline and Week 
120 Visit
5.5.4.1.
Definition
Time to death due to PAH or hospitalization for PAH is defined as:
!
Death due to PAH, or onset of a TEAE that led to permanent discontinuation of study 
treatment with a fatal outcome due to PAH occurring within 4 weeks of study treatment 
discontinuation. 
OR
!
Non-planned PAH-related hospitalization.
The PAH relatedness for death or hospitalization will be based on the investigator’s assessment of 
the event as reported on the eCRFs. The following eCRF forms will be used:
!
The “Death Information” form for death due to PAH (“Was death due to PAH?” eCRF question 
answered as “Yes”), 
!
The “Adverse Event” form for onset of TEAE leading to study treatment discontinuation (DB 
or OL) with fatal outcome due to PAH occurring within 4 weeks of study treatment 
discontinuation (date of DB or OL study treatment discontinuation is picked as the last date 
with dose administered on the “Study Drug Administration” form). The death due to PAH 
information will be based on the “Death Information” form,


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!
The “Suspected M/M event” form for non-planned PAH-related hospitalization.
The time to death/hospitalization due to PAH event is determined as the time from baseline (Day 
1) to the first occurrence of an event specified above up to either EOT+7 days or Week 120 visit. 
For participants without Week 120 Visit, Week 120 Visit is imputed by minimum (cut-off date, 
EOS date). Only events up to and including the cutoff date are considered.
Participants without the endpoint event in the corresponding period are right-censored:
!
at minimum (EOT+7 days, EOS, date of death for reason not related to PAH, cutoff date) 
for analysis up to EOT+7 days
!
at minimum ([imputed] Week 120 visit, date of death for reason not related to PAH) for 
analysis up to Week 120 visit.
5.5.4.2.
Analysis Methods
LTFDCS will be used to assess this endpoint up to EOT+7 days. The FAS will be used to assess 
this endpoint up to EOT+7 days and up to Week 120 visit. The time to death/hospitalization due 
to PAH will be estimated by Kaplan-Meier method as detailed in Section 5.5.3.2.
Based on OLS (up to EOT+7 days), LTFDCS (up to EOT+7 days) and FAS (up to EOT+7 days 
and up to Week 120 visit), death and hospitalizations due to PAH will be summarized in a 
frequency table as first event and also all events per participant. If a participant experiences several 
events, all events are counted separately unless the participant experiences the events at the same 
time (eg. if a participant dies during hospitalization, this is counted only as one event, the most 
serious one).
5.5.5.
Time to Death (All Causes) Occurring Between First Dose in double-
blind period and last available survival follow-up
5.5.5.1.
Definition
Time to death (all causes) is defined as any death event reported by the investigator in the CRF.
The time to death is determined as the time from first dose of study treatment in DB to the 
participant’s death up to last available follow-up date as collected in the Survival Follow up eCRF 
form. 
Participants without the endpoint event between first dose of study treatment in DB and up to study 
closure are right censored last available follow-up date. Participants without the endpoint event 
who withdrew consent are right-censored at EOS date.
5.5.5.2.
Analysis Methods
FAS will be used to analyze this endpoint. At the time of final DB analysis/submission, this 
endpoint includes all survival data collected up to the cut-off date. At the time of OL final analysis, 
this endpoint includes all survival data collected at the time of OL database lock.


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The time to death will be estimated by Kaplan-Meier method as detailed in Section 5.5.3.2, 
providing estimates at 6-monthly intervals [Months 6 (Day 183), 12 (Day 365), 18 (Day 548), 24 
(Day 730), 30 (Day 913), 36 (Day 1095), …].
Reasons for death will also be summarized in a frequency table.
5.5.6.
Change from Baseline in NT-proBNP
5.5.6.1.
Definition
NT-proBNP samples will be processed through the central laboratory, and the results will be sent 
electronically to the sponsor. Results will be reported in conventional units (ng/L). NT-proBNP 
values will be assigned to visit windows as described in Section 5.1.1. For OLS and LTFDCS, 
only assessment up to EOT+7 days will be summarized. For the FAS all available assessments are 
included.
Change from baseline, by visit, in NT-proBNP will be calculated as:
!
Post-baseline NT-proBNP value at scheduled timepoint−NT-proBNP value at baseline.
!
Percent of baseline calculated as: 
	
  
 
  
 
 
 	

× 100
5.5.6.2.
Analysis Methods
Absolute values at baseline and by visit as well as absolute changes from baseline to all scheduled 
timepoints will be summarized by treatment on the OLS, LTFDCS, and FAS using descriptive 
statistics. Percent of baseline will also be summarized at each scheduled post-baseline timepoint 
using geometric means and two-sided 95% confidence intervals of the geometric means, assuming 
normal distribution of the log transformed NT-proBNP.
Based on the FAS, a plot of percent of baseline NT-proBNP over time will be displayed by means 
of geometric mean and 95% CL. A reference line is included at 100% and baseline is added to the 
time axis to visualize an initial change.
In case of missing data, no imputation will be performed and only observed data will be 
summarized.
5.5.7.
Number Per Year of All-cause and PAH-related Hospitalizations and 
In-patient Hospital Days, From Baseline up to EOLT
5.5.7.1.
Definition
All hospitalizations starting between Day 1 (for LTFDCS) or OL Day 1 (for OLS)and up to EOLT
visit will be used for number per year of hospitalizations and in-patient hospital days. The 
following medical encounters are considered hospitalizations:
!
Intensive care unit
!
Hospice/palliative care unit


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!
Hospital in-patient department
!
Long-term care facility
!
Rehabilitation centers
Hospitalizations will be identified as PAH-related based on the investigator’s assessment of the 
hospitalization.
Participant’s time on study (in years) for hospitalization endpoints will be derived as follows:
(EOLT visit date – (Day 1 or OL Day 1 for LTFDCS and OLS, respectively) + 1)/365.25,
Participant-years on study in a treatment group will be computed as the total participant’s time on 
study for all participants in the treatment group.
The number of days for a hospitalization will be counted as:
Min(hospitalization discharge date, EOLT visit date)∀hospitalization admission date+1.
In case of missing discharge date of a hospitalization that is not ongoing, the number of days for 
the hospitalization will be imputed as a median hospitalization length in the geographical region. 
If the median hospitalization length in the geographical region cannot be computed or the 
hospitalization is ongoing, the length of the hospitalization will be computed from the admission 
date up to the EOLT date.
In case participant was not enrolled in OL then EDBT visit will be used in place of EOLT visit.
5.5.7.2.
Analysis Methods
This endpoint will be analyzed for OLS and LTFDCS.
The total number of hospitalizations will be added up by DB treatment group for OLS and overall 
for LTFDCS. This number will then be divided by participant-years on study in the DB treatment
group for OLS (or overall for LTFDCS) to obtain the number per year of hospitalizations.
The same approach as for the number per year of hospitalizations will be done for the number per 
year of in-patient hospitalization days.
5.5.8.
Number per Year of Emergency Room Visits From Baseline up to 
EOLT
5.5.8.1.
Definition
All emergency room (ER) medical encounters between Day 1 (for LTFDCS) or OL Day 1 (for 
OLS) and up to EOLT visit will be used for the number per year of ER visits. If an ER visit results 
in a hospital admittance (ie, participant has other hospitalization, as defined in Section 5.5.7.1
reported on the same day), such an encounter will not be considered for this endpoint.


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ER visits will be identified as PAH-related based on the investigator’s assessment of the encounter.
Participant’s time on study and participant-years on study in a treatment group are derived in the 
same way as described in Section 5.5.7.1.
5.5.8.2.
Analysis Methods
This endpoint will be analyzed for the OLS and LTFDCS. The total number of ER visits will be 
added up by DB treatment group for OLS and overall for LTFDC and divided by participant-years 
on study in the DB treatment group for OLS (or overall for LTFDCS) to obtain the number per 
year of ER visits.
5.6.
Safety Analyses
All safety analyses will be based on the CSS based on actual DB treatment received in the DB 
period, unless otherwise specified. Summaries will be displayed overall and by DB treatment 
group as described in Section 4.2.
For all continuous safety variables, descriptive statistics will include the n, mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be summarized using 
frequency counts and percentages.
Treatment-emergent period
The combined treatment-emergent period is defined from first intake of M/T FDC treatment
[ie, loose combination of macitentan and tadalafil] in DB or OL treatment period up to EOT 
(EOT-DB or EOT-OL) + 30 days. For participants who completed the 24-months of OL treatment 
and who are eligible for continued access program (post-trial access program or other open-label 
extension study), the observation period will be shorter as these participants are not required to 
perform the 30 days safety follow up period.
5.6.1.
Extent of Exposure
The number and percentage of participants who receive M/T FDC treatment (as loose combination 
of macitentan and tadalafil or as fixed dose combination) will be summarized for OLS and CSS. 
Descriptive statistics for duration of M/T FDC treatment (N, mean, SD, median, and range 
(minimum, maximum)) will be summarized. 
Duration of M/T FDC treatment will be summarized in the following duration categories: 
<4 weeks, 4-<16 weeks, 16-<42 weeks, 42-<68 weeks, 68-<94 weeks, 94-<120 weeks and
≥120 weeks overall and for each DB treatment group and presented graphically in a histogram.
Cumulative duration of M/T FDC treatment ≥4 weeks, ≥16 weeks, ≥42 weeks, ≥68 weeks, 
≥94 weeks and ≥120 weeks will be summarized.
M/T FDC treatment duration (weeks) is defined as (date of EOT – date of first dose of M/T FDC 
treatment +1)/7. M/T FDC treatment duration with interruptions (weeks) is calculated as (date of 


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EOT – date of first dose of M/T FDC treatment – days without study treatment administration + 
1)/7.
For the OLS, M/T FDC treatment duration (weeks) is defined as (date of EOT-OL – date of first 
dose of OL study treatment +1)/7. M/T FDC treatment duration with interruptions (weeks) is 
calculated as (date of EOT-OL – date of first of first dose of OL study treatment – days in OL 
without study treatment administration + 1)/7.
Individual participant listings will be provided for exposure data broken down by actual DB 
treatment group, stratum, site, and participant number. In case interim analysis results in early 
stopping of the DB period for efficacy, a listing of all DB and OL exposure is provided for 
participants in the FAS who enter OL period after premature discontinuation of DB study 
treatment.
M/T FDC treatment compliance will be summarized descriptively. See Appendix 7 for further 
details.
5.6.2.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the latest version of Medical Dictionary for Regulatory Activities (MedDRA) at the time of DBL. 
For each adverse event, the number and percentage of participants who experience at least 
1 occurrence of the given event will be summarized overall and by actual DB treatment group. No 
formal testing between treatment groups will be done.
If severity of AE is missing the worst severity, ie, “Severe” will be imputed. If AE relationship to 
the study treatment is missing, “Related” will be imputed. If seriousness information of AE is 
missing the “Serious” will be imputed.
The same summary tables as described for the DB period in the SAP Part 1 section 6.1 will be 
done for the combined DB-OL period. AEs leading to premature study treatment discontinuation 
will include AEs that led to premature DB or OL study treatment discontinuation.
In order to account for differences in the duration of treatment exposure among participants, 
incidence rates of any treatment emergent AE, any treatment-emergent SAE, any AE leading to 
discontinuation, treatment-emergent AEs of special interest (AESI) and treatment-emergent fatal 
AEs will be presented as a rate adjusted for subject-years exposure (SYE). 
Based on the CSS, the subject-observation time will be calculated, for each participant, as follows:
!
For participants without event: by considering the treatment duration as EOT – Date of 
first dose of M/T FDC + 1
!
For participants with event: by considering the M/T FDC treatment duration up to the start 
date of first event (min [date of first event, EOT] – Date of first dose of M/T FDC + 1).


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The SYE will be calculated by first summing the subject-observation time for all participants and 
then dividing it by 365.25 days.
Then the Exposure Adjusted Incidence Rate (EAIR) for an event category, per 100 subject-years 
will be calculated by dividing the number of subjects with at least one event by the SYE and 
multiplying by 100:
Exposure Adjusted Incidence Rate (EAIR) = 100 * Number of participants with the event/SYE.
The exposure adjusted incidence rate is interpreted as the number of events occurring in 100 
subject-years (SY). It is based on the assumption that the occurrences of a specific event are 
following an independent Poisson process, so the events occur with a constant rate over time. 
Hence the 95% confidence limit (CL) of the adjusted incidence rate will be computed using a 
Poisson regression model with log of time at risk as an offset. 
The following information will be displayed:
n = The number of participants with at least one event. Participants with multiple events 
will be counted only once.
T = The total of the participants time on M/T FDC treatment (in years). It is the duration 
of treatment.
Exposure Adjusted Rate = The exposure adjusted event incidence rate per 100-SY
including 95% CL. It is interpreted as the number of events occurring in 100-SY.
In addition to the summary tables, specific AE type listings will be provided for participants who
experienced at least 1:
!
AE
!
SAE
!
AE leading to premature discontinuation of OL study treatment
!
AESI (one listing for each AESI type as defined in SAP Part 1)
All AEs throughout the study will be included in the listings for all participants in the CSS, the 
listing on all AEs will also be provided based on the FAS. The listings will contain information 
about tadalafil and macitentan dose at the onset of the AE as well as the day of the last dose intake 
prior to the onset of the AE.
Separate summaries are provided on AEs with an onset during the first week of combination 
treatment when participants who are not on an allowable dose of PDE-5i (40 mg tadalafil, 60–120 
mg sildenafil, or 10 mg vardenafil daily) undergo the tadalafil 20 mg titration phase (week 1 of 
M/T FDC). All treatment emergent AEs up to the day prior to start of tadalafil 40 mg (or up to 
FDC day 7 if no up-titration was mandated) are included in the analysis. Participants from the CSS 
are grouped by prior stratum and DB treatment group


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The following displays are provided for AEs with an onset during the first week of combination 
treatment (tadalafil 20 mg titration phase):
!
Overall summary table of TEAEs, containing number of participants with at least one: AE, 
AE related to study treatment, SAE, SAE related to study treatment, AE leading to 
premature discontinuation of study treatment, Fatal AE)
!
TEAE table by SOC and PT within each SOC, in descending order of incidence in the
overall group
!
Listing of AEs
Deaths will be displayed by actual DB treatment received. For treatment-emergent deaths and all 
deaths, frequencies for the following parameters will be included in the summary table:
!
Number of participants who died
!
Cause of death
!
Relationship to study treatment (related to study treatment/relationship unknown)
The summary will be based on the Death Information CRF page, and relationship to the study 
treatment will be mapped through corresponding AE, if available. A listing of participants who 
died during the study will be provided based on CSS and FAS. The listing will contain information 
about the last tadalafil and macitentan dose as well as the day of the last dose intake.
5.6.3.
Additional Safety Assessments
5.6.3.1.
Clinical Laboratory Tests
Clinical laboratory tests will be displayed for the participants included in the CSS.
The analysis of the clinical laboratory tests will be the done in the same way as described in the 
SAP Part 1 in section 6.2 including the same definitions of marked liver and hemoglobin 
abnormalities. The following marked liver categories are added to the ones already defined in SAP 
part 1: ALT and/or AST >= 3xULN and <5xULN; ALT and/or AST >= 5xULN and <8xULN; 
ALT and/or AST >= 3xULN and bilirubin >= 2xULN at any time (and both, ALT or AST and 
bilirubin increased compared to baseline). All tables and figures defined for the DB treatment-
emergent period will be repeated for the combined DB and OL treatment-emergent period. 
In addition, a plot of the mean change from baseline (± SE) for parameters hemoglobin, leukocyte 
count, and platelet count over time will be displayed. A reference line is included at zero change 
and baseline is added to the time axis to visualize an initial change from zero.
All laboratory data throughout the study will be included in the listings for all participants in the 
CSS and the FAS.
5.6.3.2.
Vital Signs and Physical Examination Findings
Vital signs parameters will be displayed for the participants included in the CSS.


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The analysis of the vital signs parameters will be the done in the same way as described in the SAP 
Part 1 in section 6.3 including the definition of markedly abnormal vital signs. A further category
of markedly abnormal vital signs is added as follows: ‘Increase in body weight from baseline > 5 
kg’. All tables and figures defined for DB treatment-emergent period will be repeated for the 
combined DB and OL treatment-emergent period. 
All vital signs data throughout the study will be included in the listings for all participants in the 
CSS and the FAS. 
5.7.
Other Analyses
5.7.1.
Biomarkers
Optional biomarker assessments are described in section 7.2.2.7 of the protocol.
The biomarker analysis will be performed after study closure and will not be included in the CSR.
5.7.2.
Health Economics
Please refer to Sections 5.5.7 and 5.5.8 for the definition and analysis of health economics 
endpoints.
5.7.3.
Definition of Subgroups
Summary of 6MWD, WHO FC and time to M/M event, will be performed by prior-strata 
subgroups (prior-ERA stratum, prior-PDE-5i stratum, treatment naïve stratum) on the FAS. 
Based on the CSS, summary tables of treatment-emergent AE (by SOC and PT), SAE (by PT),
and AESI (by SOC and PT) are provided for the following subgroups: Region (US, non-US), Prior-
strata (treatment naïve, not treatment naïve), Age group, Sex, and Race. Overall summary table of 
treatment-emergent AEs (containing number of participants with at least one: AE, AE related to 
study treatment, SAE, SAE related to study treatment, AE leading to premature discontinuation of 
study treatment, Fatal AE) are provided for the following subgroups: Age group, Sex, and Race. 
Subgroups are defined in SAP Part 1.


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6.
DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
6MWD
6-minute walk distance
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
anatomic and therapeutic class
BMI
body mass index
CEC
Clinical event committee
CL
confidence limit
CRF
case report form
CSR
Clinical Study Report
CSS
Combination safety set 
DB
Double-blind
DMC
Data Monitoring Committee
DPS
Data Presentation Specifications
eCRF
electronic case report form
EDBT
End of Double-blind Treatment 
EAIR
Exposure Adjusted Incidence Rate
EOLT
End of Open-label Treatment 
EOS
End-Of-Study
EOT
End-Of-Treatment
ER
Emergency Room
ERA
Endothelin receptor antagonist
FAS
full analysis set
FC
Functional Class
FDC
Fixed dose combination
KM
Kaplan-Meier
LTFDCS
Long-term M/T FDC set 
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
M/M
Morbidity /Mortality
M/T
Macitentan / Tadalafil 
NT pro-BNP
N-terminal pro B-type natriuretic peptide
OL
Open-label
OLS
Open label Set 
PAH
Pulmonary arterial hypertension
PD
Protocol deviation
PDE-5
Phosphodiesterase type-5
PDE-5i
Phosphodiesterase type-5 inhibitor
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SE
standard error
S-FU
Safety follow-up 
SMQs
standardised MedDRA queries
SOC
System organ class
SS
Safety set
SY
Subject-Year
SYE
Subject-Years Exposure
TEAE
treatment-emergent adverse event
US NCI
United States National Cancer Institute
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary


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6.2.
Appendix 2 Changes to Protocol-Planned Analyses
It is clarified that the available OL data are analyzed together with the double-blind data at the 
time of final DB analysis/submission. An overall cut-off date will be applied for the analyses run 
at that time. 
The protocol defines the baseline value for the combination treatment period as the last valid 
assessment obtained prior to the first intake of macitentan and tadalafil (double-blind or 
open-label). As there is no definition of “valid”, the baseline definition was changed as follows:
For the CSS analysis population, baseline is defined as the last assessment prior to the first intake 
of M/T FDC study treatment either in DB or OL period. The first M/T FDC intake can be either 
LC of macitentan and tadalafil or M/T FDC.
The time to first M/M event is also analyzed as a separate endpoint up to Week 120 visit in order 
to include events collected after premature EDBT/EOLT. 
It is clarified that the protocol endpoint time to death (all causes) from randomization until OL
database lock is the time to death from first dose of study treatment up to last available survival 
follow-up at the time of OL database lock. The protocol endpoint time to death (all causes) from 
randomization until DB database lock is the time to death from first dose of study treatment up to 
last available survival follow-up at the time of final DB analysis/submisson (ie, up to the cut-off 
date). Both analyses are described in Section 5.5.5 of this SAP. ‘Randomization’ is changed to 
‘first dose in double-blind’ to align with other efficacy endpoints which are analyzed from baseline 
(ie, first dose in DB period).


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6.3.
Appendix 3 Demographics and Baseline Characteristics
The number of participants will be summarized and listed by strata group and DB treatment group, 
and overall as described in Section 4.2. In addition, the distribution of participants by stratum and 
geographical region will be presented unless otherwise noted.
Table 7 presents a list of the demographic variables that will be summarized by DB treatment
group and overall for all the analysis sets (OLS and CSS). 
Table 7 – Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum]).
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2)
Categorical Variables
Age (18-25 years, 26-50 years, 51-64 years, and >=65 years)
Frequency distribution with the 
number and percentage of 
participants in each category.
Sex (male, female)
Racea (American Indian or Alaska Native, Asian [if Asian, Japanese or 
Other Asian], Black or African American, Native Hawaiian or other Pacific 
Islander, White, Multiple, not reported)
Ethnicity (Hispanic or Latino, not Hispanic or Latino, not reported)
Region (US, non-US)
Geographical region (North America, Latin America, Asia, Eastern Europe, 
South and Western Europe, Oceania, Africa)
BMI ([underweight <18.5 kg/m2, normal 18.5-<25 kg/m2, overweight 25-
<30 kg/m2, obese >=30 kg/m2])
aIf multiple race categories are indicated, the Race is recorded as ‘Multiple’
Countries will be assigned to geographical region based on the Standard Country or Area Codes 
for Statistical Use (M49) standard (unstats.un.org).  
Demography variables will be summarized as collected at the DB screening with an exception of 
body weight and BMI, these will be re-derived for baseline as applicable for each analysis set.
The following baseline characteristics variables will be summarized for all the analysis sets (OLS, 
LTFDCS and CSS):
!
WHO FC (I, II, III, IV), re-derived for baseline as applicable for each analysis set.
!
PAH etiology (idiopathic, heritable, drug- and toxin- induced, PAH associated with other 
conditions [connective tissue disease, HIV infection, portal hypertension, congenital heart 
disease, schistosomiasis], long-term responders to calcium channel blockers, with overt 
features of venous/capillaries involvement)
!
Time since diagnosis (in years). For each participant time since diagnosis will be derived as:
∀
(Date of the first study treatment administration as applicable for each analysis set–date 
of diagnosis+1)/365.25.
!
Baseline RHC results (this will include a summary of the PVR results as calculated by the 
central reader [WCC] together with the proportion of assessments based on Fick cardiac 


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output [CO] and thermodilution CO, the CO results as well as the mPAP, PAWP and LVEDP
values from the central reader), re-derived for baseline as applicable for each analysis set.
!
Baseline 6MWD (in meters), re-derived for baseline as applicable for each analysis set.
Demographics and baseline characteristics will also be listed on the OLS.


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6.4.
Appendix 4 Protocol Deviations
In general, the following list of major protocol deviations (PD) may have the potential to impact 
participants’ rights, safety or well-being, or the integrity and/or result of the clinical study. 
Participants with major protocol deviations will be identified prior to database lock and the number 
and percentage of participants with major protocol deviations during the OL period will be 
summarized by category and PD criterion based on the OLS. A listing of all major PDs is provided 
for the FAS. PD will be flagged as occurring during DB or OL period.
!
Developed withdrawal criteria but not withdrawn
!
Entered but did not satisfy criteria
!
Received a disallowed concomitant treatment
!
Received wrong treatment or incorrect dose
!
Other


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6.5.
Appendix 5 Prior and Concomitant Medications
Prior medications are analyzed as part of the SAP Part 1. 
Concomitant medications will be coded using the latest version of World Health Organization 
Drug Dictionary (WHO-DD) at the DBL. 
For the CSS, study treatment-concomitant medications are defined as any therapy used on or after 
the same day as the first dose of M/T FDC study treatment (ie, loose combination of macitentan 
and tadalafil) in DB or OL period, including those that started before and continue on after the first 
dose of M/T FDC study treatment in DB or OL period, up to EOT (EOT-DB or EOT-OL).
Summaries of concomitant medications will be presented by ATC level 4 term and standardized 
medication name, overall and by DB treatment group for CSS. The proportion of participants who 
receive each concomitant medication will be summarized as well as the proportion of participants 
who receive at least 1 concomitant medication. In addition, study treatment-concomitant 
medications categorized as PAH-specific medications will be presented in the same fashion, by 
category. See SAP Part 1 for list of medications in the category.
In addition, for the CSS, PAH-specific medications at baseline will be summarized by category, 
ATC level 4 and DB treatment group. Medication at baseline is any medication taken during the 
first day of M/T FDC study treatment (ie, loose combination of macitentan and tadalafil).
PAH-specific medications initiated after end of M/T FDC study treatment up to EOS will be 
summarized by category, ATC level 4 and DB treatment group. 
Medications and Procedures will be listed for CSS and for FAS.


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6.6.
Appendix 6 Medical History
Not applicable for this SAP. Medical history is analyzed in the SAP Part 1 section 4.1


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6.7.
Appendix 7 Treatment Compliance
Compliance will be summarized descriptively for the OL study treatment overall and by DB 
treatment group for the OLS, from first OL study treatment up to EOT-OL. 
Compliance = [(number of OL treatment tablets dispensed at all visits−number of OL treatment
tablets returned at all visits)/Total number of OL treatment tablets that should have been taken 
from the first dose of OL study treatment to EOT-OL] × 100.
The total number of OL treatment tablets that should have been taken will be calculated knowing 
that 3 tablets should be taken each day during the OL titration phase (OL Day 1 to OL Day 14) 
and then 1 tablet each day during the OL maintenance phase (OL Day 15 to EOT-OL).
The number of tablets dispensed will be derived based on the kit types dispensed. Each kit type 
contains a fixed number of tablets of each type (including placebo tablets). The number of tablets 
returned will be based on the information collected in the eCRF.
The number and percentage of participants who have:
!
<80%
!
80–100%
!
>100–120%
!
>120%
overall study treatment compliance will be summarized overall and by actual DB treatment group.


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6.8.
Appendix 8 Adverse Events of Special Interest
Adverse events of special interest are defined in the Attachment 2 of SAP Part 1.


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6.9.
Appendix 9 Medications of Special Interest
Concomitant medications of special interest are defined in Attachment 1 of SAP Part 1.


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6.10.
Appendix 10 Laboratory Toxicity Grading
Not applicable. Marked laboratory abnormalities as detailed in section 14.4 of the protocol and in 
SAP Part 1 section 6.2.


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6.11.
Appendix 11 Estimands Examples
Not applicable.


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7.
REFERENCES
(EDMS-RIM-263896, 3.0) Clinical Protocol AC-077A301: A DUE, Version 6. Prospective, multi-center, double-
blind, randomized, active-controlled, triple dummy, parallel-group, group-sequential, adaptive Phase 3 clinical study 
to compare the efficacy and safety of macitentan and tadalafil monotherapies with the corresponding fixed dose 
combination in subjects with pulmonary arterial hypertension (PAH), followed by an open-label treatment period 
with macitentan and tadalafil fixed dose combination therapy. Actelion Pharmaceuticals Ltd. (27 Apr 2021).
(EDMS-RIM-264821, 3.0) Clinical Protocol COVID-19 Appendix AC-077A301: A-DUE. Prospective, multi-
center, double-blind, randomized, active-controlled, triple dummy, parallel-group, group-sequential, adaptive Phase 
3 clinical study to compare the efficacy and safety of macitentan and tadalafil monotherapies with the corresponding 
fixed dose combination in subjects with pulmonary arterial hypertension (PAH), followed by an open-label 
treatment period with macitentan and tadalafil fixed dose combination therapy. Actelion Pharmaceuticals Ltd. (27
Apr 2021).
(unstats.un.org) Standard country or area codes for statistical use (M49). United Nations Statistics Division website. 
https://unstats.un.org/unsd/methodology/m49/overview/. Accessed 23 March 2020.
(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.