The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension: A Multi-center, Double-blind, Placebo-controlled, Phase 3b Study
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Sponsor: Actelion

Selexipag / ACT-293987 
Pulmonary Arterial Hypertension 
Protocol AC-065A308 
 
TRITON 
The efficacy and safety of initial triple versus initial dual oral combination therapy 
in patients with newly diagnosed pulmonary arterial hypertension: A multi-center, 
double-blind, placebo-controlled, Phase 3b study 
 
 
Study Phase: 
3b 
EudraCT Number: 
2015-003438-28 
Status and version: 
Final Version 6 
Date: 
4 December 2018 
Actelion 
document 
number 
(Doc No.): 
D-18.392 
 
Confidentiality statement 
The information contained in this document, especially unpublished data, is the property of the sponsor of 
this study, Actelion Pharmaceuticals Ltd. It is therefore provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an Ethics Committee or Institutional 
Review Board. It is understood that this information will not be disclosed to others without written 
authorization from Actelion Pharmaceuticals Ltd, except to the extent necessary to obtain informed consent 
from those persons to whom the study treatment may be administered. 
 
NCT02558231

SPONSOR CONTACT DETAILS 
SPONSOR 
 
ACTELION Pharmaceuticals Ltd 
Gewerbestrasse 16 
CH-4123 Allschwil 
Switzerland 
 
+41 61 565 65 65 
Clinical Trial Physician  
Maziar Assadi Gehr, MD 
 
 
Fax 
 
e-mail 
 
MEDICAL HOTLINE 
Toll phone number:  
+41 61 227 05 63 
Country-specific toll and toll-free phone numbers 
for the Medical Hotline can be found in the 
Investigator Site File 
 
 
 
ACTELION CONTRIBUTORS TO THE PROTOCOL 
Clinical Trial Scientist 
, Associate Director 
 
Clinical Trial Statistician 
Nicolas Martin, Expert Statistician 
 
Clinical Trial Physician 
Maziar Assadi Gehr, Global Medical Affairs 
Physician 
 
Drug Safety Physician 
, Associate Director 
 
 
 
COORDINATING INVESTIGATOR 
Name / Title 
Address 
Marius Hoeper, MD 
University of Hannover, Medical School 
 
, Germany 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
NCT02558231

CONTRACT RESEARCH ORGANIZATIONS INFORMATION 
 
CENTRAL LABORATORY 
 
ACM Global Central Laboratory 
23 Hospital Fields Road 
York YO10 4DZ, UK 
 
CENTRAL 
RANDOMIZATION 
 
Almac Clinical Technologies LLC 
25 Fretz Road 
Souderton, PA 18964, USA 
 
CRO 
 
Chiltern International 
171 Bath Road 
Slough, Berkshire SL1 4AA, UK 
 
Biostatistics 
Datamap GmbH 
Munzinger Strasse 5a 
79111 Freiburg, Germany 
 
Home Phlebotomy 
Global Care Clinical Trials Ltd 
2201 Waukegan Road 
Suite 270 
Bannockburn, IL 60015, USA 
 
A list of site-specific contact details for Contract Research Organizations (CROs) can 
be found in the Investigator Site File. 
 
 
 
NCT02558231

SIGNATURE PAGE FOR ACTELION PHARMACEUTICALS LTD 
Hereinafter called Actelion 
 
Treatment name / number 
Selexipag / ACT-293987 
Indication 
Pulmonary arterial hypertension 
Protocol number, study acronym, study title 
AC-065A308, TRITON: The efficacy and safety of initial triple versus initial dual oral 
combination therapy in patients with newly diagnosed pulmonary arterial hypertension: A 
multi-center, double-blind, placebo-controlled, Phase 3b study. 
 
I approve the design of this study. 
 
 
 
 
 
PPD
PP
D
PPD
PPD
NCT02558231

INVESTIGATOR SIGNATURE PAGE 
 
Treatment name / number 
Selexipag / ACT-293987 
Indication 
Pulmonary arterial hypertension 
Protocol number, study acronym, study title 
AC-065A308, TRITON: The efficacy and safety of initial triple versus initial dual oral 
combination therapy in patients with newly diagnosed pulmonary arterial hypertension: A 
multi-center, double-blind, placebo-controlled, Phase 3b study. 
I agree to the terms and conditions relating to this study as defined in this protocol including 
appendices, the electronic Case Report Form (CRF), and any other protocol-related 
documents. I fully understand that any changes instituted by the investigator(s) without 
previous agreement with the sponsor would constitute a protocol deviation, including any 
ancillary studies or procedures performed on study subjects (other than those procedures 
necessary for the wellbeing of the subjects). 
I agree to conduct this study in accordance with the latest versions of the Declaration of 
Helsinki principles, International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines, and applicable regulations and laws. I will obtain approval by an 
Institutional Review Board or Independent Ethics Committee (IRB/IEC) prior to study start 
and signed informed consent from all subjects included in this study. If an amendment to 
the protocol is necessary, I will obtain approval by an IRB/IEC and ensure approval by 
regulatory authorities (if applicable) have been obtained before the implementation of 
changes described in the amendment. I will allow direct access to source documents and 
study facilities to sponsor representative(s), particularly monitor(s) and auditor(s), and 
agree to inspection by regulatory authorities or IRB/IEC representative. I will ensure that 
the study treatment(s) supplied by the sponsor are being used only as described in this 
protocol. I confirm herewith that the sponsor is allowed to enter and utilize my professional 
contact details and function in an electronic database for internal purposes and for 
submission to regulatory authorities worldwide. 
 
Country 
Site 
number 
Town 
Date 
 
Signature 
Principal 
Investigator 
 
 
 
 
 
 
NCT02558231

TABLE OF CONTENTS 
SPONSOR CONTACT DETAILS ......................................................................................2 
ACTELION CONTRIBUTORS TO THE PROTOCOL .....................................................2 
COORDINATING INVESTIGATOR.................................................................................2 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION ...................................3 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................13 
PROTOCOL SYNOPSIS AC-065A308 ............................................................................16 
1 
BACKGROUND .........................................................................................................29 
1.1 
Indication ......................................................................................................29 
1.2 
Study treatments ...........................................................................................29 
1.2.1 
Macitentan ........................................................................................29 
1.2.1.1 
Nonclinical results ...................................................................30 
1.2.1.2 
Clinical pharmacology ............................................................30 
1.2.1.3 
Clinical efficacy ......................................................................30 
1.2.1.4 
Summary of safety profile .......................................................31 
1.2.2 
Tadalafil ............................................................................................31 
1.2.2.1 
Nonclinical results ...................................................................31 
1.2.2.2 
Clinical pharmacology ............................................................31 
1.2.2.3 
Clinical efficacy ......................................................................31 
1.2.2.4 
Summary of safety profile .......................................................32 
1.2.3 
Selexipag ...........................................................................................32 
1.2.3.1 
Nonclinical results ...................................................................33 
1.2.3.2 
Clinical pharmacology ............................................................33 
1.2.3.3 
Clinical efficacy ......................................................................33 
1.2.3.4 
Summary of safety profile .......................................................33 
1.3 
Purpose and rationale of the study ................................................................34 
2 
STUDY OBJECTIVES ...............................................................................................35 
2.1 
Primary objective ..........................................................................................35 
2.2 
Secondary objectives ....................................................................................35 
2.3 
Exploratory objectives ..................................................................................35 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................36 
3.1 
Study design .................................................................................................36 
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3.2 
Study design rationale ..................................................................................38 
3.3 
Study committees .........................................................................................39 
4 
SUBJECT POPULATION ..........................................................................................40 
4.1 
Subject population description .....................................................................40 
4.2 
Rationale for the selection of the study population ......................................40 
4.3 
Inclusion criteria ...........................................................................................40 
4.4 
Exclusion criteria ..........................................................................................41 
4.5 
Criteria for women of childbearing potential ...............................................43 
4.5.1 
Definition of childbearing potential ..................................................43 
4.5.2 
Acceptable methods of contraception ...............................................43 
4.6 
Medical history .............................................................................................44 
5 
TREATMENTS ..........................................................................................................45 
5.1 
Study treatment .............................................................................................45 
5.1.1 
Investigational treatment: description and rationale .........................45 
5.1.2 
Comparator treatment: description and rationale ..............................45 
5.1.3 
Study treatment administration .........................................................45 
5.1.4 
Treatment assignment .......................................................................47 
5.1.5 
Blinding ............................................................................................48 
5.1.6 
Unblinding ........................................................................................48 
5.1.6.1 
Unblinding for final analyses ..................................................48 
5.1.6.2 
Unblinding for interim analyses ..............................................48 
5.1.6.3 
Unblinding for suspected unexpected serious adverse reactions
 .......................................................................................48 
5.1.6.4 
Emergency procedure for unblinding ......................................49 
5.1.7 
Study treatment supply .....................................................................49 
5.1.7.1 
Study treatment packaging and labeling .................................49 
5.1.7.2 
Study treatment distribution and storage .................................50 
5.1.7.3 
Study treatment dispensing .....................................................50 
5.1.7.4 
Study treatment return and destruction ...................................50 
5.1.8 
Study treatment accountability and compliance with study 
treatment ...........................................................................................50 
5.1.8.1 
Study treatment accountability ................................................50 
5.1.8.2 
Study treatment compliance ....................................................51 
5.1.9 
Study treatment dose adjustments and interruptions ........................51 
5.1.10 
Premature discontinuation of study treatment ..................................52 
5.1.11 
Study-specific criteria for interruption / premature 
discontinuation of study treatment ....................................................52 
5.2 
Previous and concomitant therapy ................................................................56 
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5.2.1 
Definitions ........................................................................................56 
5.2.2 
Reporting of previous/concomitant therapy in the eCRF .................57 
5.2.3 
Allowed concomitant therapy ...........................................................57 
5.2.4 
Forbidden concomitant therapy ........................................................57 
5.2.5 
Rescue therapy ..................................................................................58 
6 
STUDY ENDPOINTS ................................................................................................58 
6.1 
Efficacy endpoints ........................................................................................58 
6.1.1 
Primary efficacy endpoint .................................................................58 
6.1.2 
Secondary efficacy endpoints ...........................................................59 
6.1.3 
Exploratory efficacy endpoints .........................................................59 
6.2 
Safety endpoints ...........................................................................................60 
6.3 
Biomarker endpoints .....................................................................................60 
7 
STUDY ASSESSMENTS ...........................................................................................60 
7.1 
Screening/baseline assessments ....................................................................61 
7.1.1 
Eligibility criteria ..............................................................................61 
7.1.2 
Demographic and baseline characteristics ........................................61 
7.1.3 
Medical history .................................................................................61 
7.1.4 
Previous therapies .............................................................................61 
7.2 
Efficacy assessments ....................................................................................61 
7.2.1 
RHC ..................................................................................................61 
7.2.2 
6-minute walk test, Borg dyspnea index ...........................................62 
7.2.3 
WHO functional class .......................................................................62 
7.2.4 
Circulating biomarkers of right ventricular function and 
structure ............................................................................................62 
7.2.5 
Other efficacy assessments ...............................................................62 
7.3 
Safety assessments ........................................................................................62 
7.3.1 
(Serious) adverse events ...................................................................63 
7.3.2 
Contraception methods and pregnancy testing .................................63 
7.3.3 
Vital signs .........................................................................................63 
7.3.4 
Body weight ......................................................................................63 
7.3.5 
Physical examination ........................................................................63 
7.3.6 
Concomitant therapies ......................................................................63 
7.3.7 
Laboratory assessments ....................................................................63 
7.3.7.1 
Type of laboratory ...................................................................63 
7.3.7.2 
Laboratory tests .......................................................................64 
8 
SCHEDULE OF VISITS ............................................................................................66 
8.1 
Screening period ...........................................................................................66 
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8.2 
Treatment period ...........................................................................................67 
8.2.1 
Day 1 (randomization) visit ..............................................................67 
8.2.2 
Day 8 visit .........................................................................................68 
8.2.3 
Day 15 visit .......................................................................................68 
8.2.4 
Weekly phone calls during up-titration ............................................68 
8.2.5 
Week 12 visit ....................................................................................68 
8.2.6 
Week 26 visit ....................................................................................69 
8.2.7 
Month 12, 18, 24, 30, etc. visits ........................................................69 
8.2.8 
EOMOP visit .....................................................................................69 
8.2.9 
EOT visit ...........................................................................................70 
8.2.10 
Unscheduled visits ............................................................................70 
8.3 
Safety follow-up ...........................................................................................70 
8.3.1 
EOS visit ...........................................................................................70 
9 
STUDY COMPLETION AND POST-STUDY TREATMENT/MEDICAL 
CARE ..........................................................................................................................71 
9.1 
Study completion ..........................................................................................71 
9.2 
Premature withdrawal of subjects from study ..............................................71 
9.3 
Premature termination or suspension of the study ........................................72 
9.4 
Medical care of subjects after study completion/withdrawal from 
study ..............................................................................................................72 
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................73 
10.1 
Adverse events ..............................................................................................73 
10.1.1 
Definitions of adverse events ............................................................73 
10.1.2 
Intensity of adverse events ................................................................73 
10.1.3 
Relationship to study treatment ........................................................74 
10.1.4 
Adverse events associated to study design or 
protocol-mandated procedures ..........................................................74 
10.1.5 
Reporting of adverse events ..............................................................74 
10.1.6 
Follow-up of adverse events .............................................................75 
10.2 
Serious adverse events ..................................................................................75 
10.2.1 
Definitions of serious adverse events ...............................................75 
10.2.1.1 
Serious adverse events .............................................................75 
10.2.2 
Reporting of serious adverse events .................................................75 
10.2.3 
Follow-up of serious adverse events .................................................76 
10.2.4 
After the [30-day] follow-up period .................................................76 
10.2.5 
Reporting procedures ........................................................................76 
10.3 
Pregnancy .....................................................................................................77 
10.3.1 
Reporting of pregnancy ....................................................................77 
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10.3.2 
Follow-up of pregnancy ....................................................................77 
10.4 
Study safety monitoring ................................................................................77 
11 STATISTICAL METHODS .......................................................................................77 
11.1 
Analysis sets .................................................................................................78 
11.1.1 
Screened Analysis Set .......................................................................78 
11.1.2 
Full Analysis Set ...............................................................................78 
11.1.3 
Modified Full Analysis Set ...............................................................78 
11.1.4 
Per-protocol Set ................................................................................78 
11.1.5 
Safety Set ..........................................................................................78 
11.1.6 
Usage of the analysis sets .................................................................78 
11.2 
Variables .......................................................................................................79 
11.2.1 
Primary efficacy variable ..................................................................79 
11.2.2 
Secondary efficacy variables ............................................................79 
11.2.3 
Other efficacy variables ....................................................................79 
11.2.4 
Safety variables .................................................................................79 
11.3 
Description of statistical analyses .................................................................79 
11.3.1 
Overall testing strategy .....................................................................79 
11.3.2 
Analysis of the primary efficacy variable .........................................80 
11.3.2.1 
Hypotheses and statistical model ............................................80 
11.3.2.2 
Handling of missing data .........................................................80 
11.3.2.3 
Main analysis ...........................................................................80 
11.3.2.4 
Supportive/sensitivity analyses ...............................................81 
11.3.2.5 
Subgroup analyses ...................................................................81 
11.3.3 
Analysis of the secondary efficacy variables ....................................81 
11.3.4 
Analysis of the other efficacy variables ............................................82 
11.3.5 
Analysis of the safety variables ........................................................82 
11.3.5.1 
Adverse events ........................................................................83 
11.3.5.2 
Laboratory variables ................................................................83 
11.3.5.3 
Vital signs and body weight ....................................................84 
11.3.6 
Analysis of other variable(s) .............................................................84 
11.4 
Interim analyses ............................................................................................84 
11.5 
Sample size ...................................................................................................85 
11.5.1 
Sample size justification ...................................................................85 
11.5.2 
Sample size sensitivity ......................................................................87 
12 DATA HANDLING ....................................................................................................88 
12.1 
Data collection ..............................................................................................88 
12.2 
Maintenance of data confidentiality .............................................................88 
12.3 
Database management and quality control ...................................................88 
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13 PROCEDURES AND GOOD CLINICAL PRACTICE .............................................89 
13.1 
Ethics and Good Clinical Practice ................................................................89 
13.2 
Independent Ethics Committee / Institutional Review Board ......................89 
13.3 
Informed consent ..........................................................................................90 
13.4 
Compensation to subjects and investigators .................................................91 
13.5 
Protocol adherence/compliance ....................................................................91 
13.6 
Protocol amendments ...................................................................................91 
13.7 
Essential documents and retention of documents .........................................91 
13.8 
Monitoring ....................................................................................................92 
13.9 
Investigator Site File .....................................................................................93 
13.10 
Audit .............................................................................................................94 
13.11 
Inspections ....................................................................................................94 
13.12 
Reporting of study results and publication ...................................................94 
14 REFERENCES ............................................................................................................95 
 
 
LIST OF TABLES 
 
Table 1 
Visit and assessment schedule ......................................................................27 
Table 2 
Double-blind up-titration scheme up to the Week 12 visit ...........................47 
Table 3 
Mean and SD for PVR, log-transformed PVR and change from baseline on 
log-scale ........................................................................................................86 
Table 4 
Sample sizes needed for 90% power at final analysis, and stopping value for 
futility at interim analysis (two-sided α = 0.05, SD = 0.5, information 
time = 0.33) ...................................................................................................87 
 
 
LIST OF FIGURES 
 
Figure 1 
Study periods (subject level) .........................................................................37 
Figure 2 
Planned duration (study level) ......................................................................38 
 
 
LIST OF APPENDICES 
 
Appendix 1 Actelion guidelines for RHC .........................................................................98 
Appendix 2 Actelion guidelines for 6MWT ...................................................................100 
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Appendix 3 Borg dyspnea index .....................................................................................105 
Appendix 4 WHO Functional Classification of pulmonary hypertension ......................106 
Appendix 5 Central laboratory alert thresholds ..............................................................106 
 
 
NCT02558231

LIST OF ABBREVIATIONS AND ACRONYMS 
6MWD  
6-minute walk distance 
6MWT  
6-minute walk test 
AE  
Adverse event 
ALT  
Alanine aminotransferase 
ANCOVA  
Analysis of covariance 
AST  
Aspartate aminotransferase 
ATS  
American Thoracic Society 
BMI  
Body mass index 
BP  
Blood pressure 
CEC  
Clinical Events Committee 
CFR  
Code of Federal Regulations 
cGMP  
Cyclic guanosine monophosphate 
CI  
Confidence interval 
CL  
Confidence limit 
CO  
Cardiac output 
CRA  
Clinical Research Associate 
CRF  
Case Report Form 
CRO  
Contract Research Organization 
CYP3A4  
Cytochrome P450 3A4 
DLCO  
Diffusing capacity of the lung for carbon monoxide 
d/sSAP  
Diastolic/systolic systemic arterial pressure 
ECG  
Electrocardiogram 
eCRF  
Electronic case report form 
EMA  
European Medicines Agency 
EOMOP  
End of main observation period 
EOS  
End of study 
EOT  
End of treatment 
ERA  
Endothelin receptor antagonist 
FAS  
Full Analysis Set 
FC  
Functional class 
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FDA  
Food and Drug Administration 
FEV1  
Forced expiratory volume in 1 second 
FVC  
Forced vital capacity 
GCP  
Good Clinical Practice 
GMR  
Geometric mean ratio 
HIV  
Human immunodeficiency virus 
HR  
Heart rate 
IB  
Investigator’s Brochure 
ICF  
Informed Consent Form 
ICH  
International Council for Harmonisation 
IDMC  
Independent Data Monitoring Committee 
IEC  
Independent Ethics Committee 
ILSDRB  
Independent Liver Safety Data Review Board 
IRB  
Institutional Review Board 
IRT  
Interactive Response Technology 
ISF  
Investigator Site File 
LVEDP  
Left ventricular end-diastolic pressure 
MedDRA  
Medical Dictionary for Regulatory Activities 
m/d/sPAP  
Mean/diastolic/systolic pulmonary artery pressure 
mRAP  
Mean right atrial pressure 
MTD  
Maximum tolerated dose 
NAION  
Non-arteritic ischemic optic neuropathy 
NT-proBNP  
N-terminal pro B-type natriuretic peptide 
PAH  
Pulmonary arterial hypertension 
PAWP  
Pulmonary arterial wedge pressure 
PDE-5  
Phosphodiesterase-5 
PDE-5i  
Phosphodiesterase-5 inhibitor 
PH  
Pulmonary hypertension 
PI  
Principal investigator 
PPS  
Per-protocol Set 
PVOD  
Pulmonary veno-occlusive disease 
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PVR  
Pulmonary vascular resistance 
RHC  
Right heart catheterization 
SAC  
Statistical Analysis Center 
SAE  
Serious adverse event 
SAP  
Statistical Analysis Plan 
SBP  
Systolic blood pressure 
SC  
Steering Committee 
SD  
Standard deviation 
SIV  
Site initiation visit 
SmPC  
Summary of Product Characteristics 
SOC  
System organ class 
SOP  
Standard Operating Procedure 
SUSAR  
Suspected unexpected serious adverse reaction 
ULN  
Upper limit of the normal range 
USPI  
US package insert 
VO2  
Volume of oxygen uptake 
WHO  
World Health Organization 
WU  
Wood Units 
 
 
NCT02558231

PROTOCOL SYNOPSIS AC-065A308 
TITLE 
The efficacy and safety of initial triple versus initial dual oral 
combination therapy in patients with newly diagnosed pulmonary 
arterial hypertension: A multi-center, double-blind, placebo-
controlled, Phase 3b study 
ACRONYM 
TRITON 
OBJECTIVES 
Primary objective 
To compare the effect on pulmonary vascular resistance (PVR) of an 
initial triple oral regimen (macitentan, tadalafil, selexipag) versus an 
initial dual oral regimen (macitentan, tadalafil, placebo) in newly 
diagnosed, treatment-naïve subjects with pulmonary arterial 
hypertension (PAH).  
Secondary objectives 
To compare an initial triple oral regimen (macitentan, tadalafil, 
selexipag) with an initial dual oral regimen (macitentan, tadalafil, 
placebo) in newly diagnosed, treatment-naïve subjects with PAH, with 
respect to cardio-pulmonary hemodynamics (other than PVR), 
exercise capacity, disease severity, disease progression events, safety, 
and tolerability.  
Exploratory objectives 
To compare an initial triple oral regimen (macitentan, tadalafil, 
selexipag) with an initial dual oral regimen (macitentan, tadalafil, 
placebo) in newly diagnosed, treatment-naïve subjects with PAH, with 
respect to additional disease severity endpoints. 
DESIGN 
This is a prospective, multi-center, double-blind, randomized, 
placebo-controlled, parallel group, Phase 3b, efficacy and safety study 
comparing a triple oral regimen (macitentan, tadalafil, selexipag) with 
a dual oral regimen (macitentan, tadalafil, placebo) in newly 
diagnosed, treatment-naïve subjects with PAH.  
 
 
 
 
 
 
 
NCT02558231

PERIODS 
1 Signed written informed consent is required prior to any study-mandated procedure (right heart 
catheterization [RHC] data obtained at the study site before informed consent signature but 
within 28 days prior to Day 1 are acceptable).  
2 Increase in tadalafil dose on Day 8 ± 3.  
3 For simplification, most visits between Day 1 and end of main observation period (EOMOP; 
as defined below) are not displayed. The complete visits and assessments are shown in Table 1.  
4 If double-blind treatment (selexipag/placebo) is discontinued before Week 26: The Week 26 
assessments should be done either at Week 26 or before start of rescue therapy (prostacyclin, 
prostacyclin analog, or prostacyclin receptor agonist), whichever is first.  
5 The EOMOP is the data cutoff for the main efficacy and safety analyses, followed by data 
cleaning and unblinding of the treatment group allocation. The EOMOP visit is planned 
26 ± 1 weeks after enrollment of the last subject. This timepoint will be announced by Actelion 
approximately 6 months in advance. The EOMOP visit is not required if within ± 2 weeks of a 
patient’s Week 26 visit or Month 12, 18, 24, 30, etc. visit.  
6 All 3 study treatments are provided until the end of treatment (EOT) visit, which is planned 
approximately 4 months after the EOMOP visit. In order to allow sufficient time for the 
investigator to arrange any post-study therapy, Actelion will announce EOT approximately 
10 months in advance, and unblind the treatment group allocation (selexipag or placebo) 
approximately 1 month prior to EOT. In case of premature discontinuation of all 3 study 
treatments, the EOT visit should be performed within 1 week but the subject should be followed 
up according to the schedule of assessments until end of study (EOS; as defined below).  
7 EOS is defined as the last data collection for a subject. The EOS visit for all subjects (regardless 
of whether they are receiving 3, 2, 1, or no study treatment) is planned approximately 5 months 
after the EOMOP visit. For all randomized patients, follow-up for disease progression 
(including death) will continue until EOS. 
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PLANNED 
DURATION 
The study duration will be approximately 4 years, based on an 
assumed enrollment period of 3 years. 
SITE(S) / 
COUNTRY(IES) 
The study will be conducted at approximately 75 sites in 
approximately 20 countries.  
SUBJECTS / 
GROUPS 
Approximately 238 subjects will be randomized in a 1:1 ratio to the 
two treatment groups (approximately 119 subjects per group), 
stratified by region (North America versus rest of world) and WHO 
functional class (FC) at baseline (I/II versus III/IV). 
INCLUSION 
CRITERIA 
1. Signed informed consent prior to any study-mandated procedure. 
2. Male or female ≥ 18 and ≤ 75 years of age at screening. 
3. Initial PAH diagnosis < 6 months prior to Day 1.  
4. RHC performed between Day −28 and Day 1 (RHC data obtained 
at the study site within this time frame, but before the study, 
i.e., before signed informed consent, are acceptable), meeting all 
the following criteria:  
• Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg. 
• Pulmonary artery wedge pressure or left ventricular 
end-diastolic pressure ≤ 15 mmHg. 
• PVR ≥ 480 dyn·sec/cm5 (≥ 6 Wood Units). 
• Negative vasoreactivity test mandatory in idiopathic, heritable, 
and drug/toxin induced PAH (at this or a previous RHC).  
5. Symptomatic PAH belonging to one of the following subgroups:  
• Idiopathic. 
• Heritable. 
• Drug or toxin induced. 
• Associated with one of the following: 
- Connective tissue disease. 
- HIV infection. 
- Congenital heart disease with simple systemic-to-pulmonary 
shunt (atrial septal defect, ventricular septal defect, patent 
ductus arteriosus) ≥ 1 year after surgical repair.  
6. 6-minute walk distance (6MWD) ≥ 50 m at screening.  
7. Women of childbearing potential must: 
• Have a negative serum pregnancy test at the screening visit and 
a negative urine pregnancy test at the Day 1 visit, and 
• Agree to perform monthly pregnancy tests up to EOS, and 
• Agree to use reliable contraception from screening up to 
1 month following discontinuation of the last study treatment. 
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Reliable contraception must be started at least 11 days prior to 
Day 1. 
EXCLUSION 
CRITERIA 
1. Any PAH-specific drug therapy (e.g., any endothelin receptor 
antagonist [ERA], phosphodiesterase-5 inhibitor (PDE-5i), 
soluble guanylate cyclase stimulator, prostacyclin, prostacyclin 
analog, or prostacyclin receptor agonist) at any time prior to 
Day 1 (administration for vasoreactivity testing is permitted; 
previous PAH-specific drugs used intermittently for the 
treatment of digital ulcers or Raynaud’s phenomenon are 
permitted if stopped > 6 months prior to Day 1).  
2. Cardio-pulmonary rehabilitation program based on exercise 
(planned, or started ≤ 12 weeks prior to Day 1).  
3. Body mass index (BMI) > 40 kg/m2 at screening. 
4. Presence of three 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. 
• Coronary artery disease, i.e., any of the following:  
- History of stable angina or 
- More than 50% stenosis in a coronary artery (by coronary 
angiography) or 
- History of myocardial infarction or 
- History of or planned coronary artery bypass grafting 
and/or coronary artery stenting. 
5. Acute myocardial infarction ≤ 12 weeks prior to screening. 
6. Cerebrovascular events (e.g., transient ischemic attack, stroke) 
≤ 12 weeks prior to screening. 
7. Known permanent atrial fibrillation. 
8. Systolic blood pressure < 90 mmHg at screening or Day 1. 
9. Ongoing or planned treatment with organic nitrates and/or 
doxazosin. 
10. Presence of one or more of the following signs of relevant lung 
disease at any time up to screening: 
• Diffusing capacity of the lung for carbon monoxide (DLCO) 
< 40% of predicted UNLESS computed tomography reveals 
no or mild interstitial lung disease. 
• Forced vital capacity (FVC) < 60% of predicted. 
NCT02558231

• Forced expiratory volume in one second (FEV1) < 60% of 
predicted. 
Pulmonary function tests may be performed either with or 
without the use of bronchodilators, as per local clinical practice. 
11. Known or suspected pulmonary veno-occlusive disease.  
12. Documented severe hepatic impairment (with or without 
cirrhosis) according to National Cancer Institute organ 
dysfunction working group criteria, defined as total bilirubin 
> 3 × upper limit of the normal range (ULN) accompanied by 
aspartate aminotransferase (AST) > ULN (assessed at screening); 
and/or Child-Pugh Class C.  
13. Serum AST and/or alanine aminotransferase (ALT) > 3 × ULN 
(assessed at screening).  
14. Severe renal impairment (estimated creatinine clearance 
≤ 30 mL/min/1.73 m2) assessed at screening.  
15. Ongoing or planned dialysis. 
16. Hemoglobin < 100 g/L assessed at screening. 
17. Known or suspected uncontrolled thyroid disease (hypo- or 
hyperthyroidism).  
18. Loss of vision in one or both eyes because of non-arteritic 
ischemic optic neuropathy. 
19. Treatment with strong inducers of cytochrome P450 3A4 
(CYP3A4) (e.g., carbamazepine, rifampin, rifampicin, rifabutin, 
rifapentin, phenobarbital, phenytoin, and St. John’s wort) 
≤ 28 days prior to Day 1.  
20. Treatment with strong inhibitors of CYP3A4 (e.g., ketoconazole, 
itraconazole, 
voriconazole, 
clarithromycin, 
telithromycin, 
nefazodone, ritonavir, and saquinavir) and/or strong inhibitors of 
CYP2C8 (e.g., gemfibrozil) ≤ 28 days prior to Day 1.  
21. Treatment with another investigational drug (planned, or taken 
≤ 12 weeks prior to Day 1). 
22. Hypersensitivity to any of the 3 study treatments or any excipient 
of 
their 
formulations 
(lactose, 
magnesium 
stearate, 
microcrystalline cellulose, hydroxypropyl cellulose, povidone, 
corn starch, sodium starch glycolate type A, polyvinyl alcohol, 
polysorbate 80, titanium dioxide, talc, xanthan gum, lecithin 
from soya, croscarmellose sodium, hypromellose, sodium 
laurylsulfate, triacetin, iron oxide yellow, iron oxide red, iron 
oxide black, d-mannitol, propylene glycol, carnauba wax).  
NCT02558231

23. Pregnancy, breastfeeding, or intention to become pregnant 
during the study.  
24. Concomitant life-threatening disease with a life expectancy 
< 12 months. 
25. Alcohol abuse. 
26. Any factor or condition likely to affect protocol compliance of 
the subject, as judged by the investigator.  
STUDY 
TREATMENTS 
Investigational treatment 
• Macitentan, open-label, oral tablet, 10 mg once daily (preferably 
always in the morning or always in the evening; to be recorded in 
the electronic Case Report Form [eCRF]).  
• Tadalafil, open-label, oral tablet, 20 mg one or two tablets once 
daily (preferably always in the morning or always in the evening; 
to be recorded in the eCRF).  
• Selexipag oral tablet, 200 µg, one to eight tablets twice daily (in 
the morning and in the evening). A once-daily regimen is 
recommended in patients with moderate hepatic impairment 
(Child-Pugh class B) due to the increased exposure to selexipag 
and its active metabolite. 
Comparator treatment 
• Macitentan, open-label, oral tablet, 10 mg once daily (preferably 
always in the morning or always in the evening; to be recorded in 
the eCRF).  
• Tadalafil, open-label, oral tablet, 20 mg one or two tablets once 
daily (preferably always in the morning or always in the evening; 
to be recorded in the eCRF).  
• Matching placebo to selexipag oral tablet, 200 µg, one to eight 
tablets twice daily (in the morning and in the evening). A 
once-daily regimen is recommended in patients with moderate 
hepatic impairment (Child-Pugh class B) due to the increased 
exposure to selexipag and its active metabolite. 
NCT02558231

CONCOMITANT 
THERAPY 
Forbidden concomitant therapy: 
• Any PAH-specific drug (e.g., ERA, PDE-5i [also if used for 
erectile dysfunction], soluble guanylate cyclase stimulator, 
prostacyclin, prostacyclin analog, or prostacyclin receptor agonist) 
other than the 3 study treatments up to EOT, except if used as 
rescue therapy. If another PAH-specific drug is started (and the 
corresponding study treatment is stopped), subjects remain in the 
study, irrespective of whether they are receiving 3, 2, 1, or no study 
treatments.  
• Organic nitrates (other medications with vasodilatory effects must 
be used with caution).  
• Doxazosin. 
• Strong inducers of CYP3A4 (e.g., carbamazepine, rifampin, 
rifampicin, rifabutin, rifapentin, phenobarbital, phenytoin, and 
St. John’s wort) during treatment with macitentan and/or tadalafil. 
• Strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
voriconazole, 
clarithromycin, 
telithromycin, 
nefazodone, 
ritonavir, and saquinavir) during treatment with macitentan and/or 
tadalafil. 
• Strong inhibitors of CYP2C8 (e.g., gemfibrozil) during treatment 
with selexipag/placebo. 
• Any investigational drug other than the 3 study treatments.  
• Cardio-pulmonary rehabilitation programs based on exercise 
between Screening and the Week 26 visit. 
ENDPOINTS 
Primary efficacy endpoint 
The primary endpoint is the ratio of Week 26 to baseline PVR.  
Secondary efficacy endpoints 
1. Change in 6MWD from baseline to Week 26. 
2. Change in N-terminal pro B-type natriuretic peptide (NT-proBNP) 
from baseline to Week 26. 
3. Absence of worsening in WHO FC from baseline to Week 26. 
4. Change in RHC variables other than PVR (mPAP, cardiac index, 
total pulmonary resistance, mean right atrial pressure, venous 
oxygen saturation) from baseline to Week 26. 
5. Time from randomization to the first disease progression event up 
to EOMOP + 7 days (adjudicated by the Clinical Events 
Committee [CEC]), defined as any of the following:  
a. Death (all causes; adjudicated for PAH relationship).  
b. Hospitalization for worsening PAH.  
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c. Initiation of prostacyclin, a prostacyclin analog, or a 
prostacyclin receptor agonist for worsening PAH.  
d. Clinical worsening defined as a post-baseline decrease in 
6MWD by > 15% from the highest 6MWD obtained at or 
after baseline, accompanied by WHO FC III or IV (both 
conditions confirmed at two consecutive post-baseline 
visits separated by 1–21 days).  
 
Safety endpoints 
• Treatment-emergent adverse events (AEs). 
• AEs leading to premature discontinuation of any of the 3 study 
treatments. 
• Treatment-emergent serious AEs. 
• Treatment-emergent deaths. 
• Treatment-emergent marked laboratory abnormalities. 
• Change from baseline in laboratory variables. 
• Change from baseline in vital signs. 
ASSESSMENTS 
See Table 1.  
STATISTICAL 
METHOD-
OLOGY 
Analysis sets: 
The Safety Set includes all subjects who received at least one dose of 
any of the 3 study treatments. 
The Full Analysis Set (FAS) includes all randomized subjects. 
The Modified Full Analysis Set (Modified FAS) includes all subjects 
from the FAS who received at least one dose of each of the 3 study 
treatments. 
The Per-protocol Set includes all subjects from the FAS who received 
at least one dose of double-blind study treatment and who have no 
major protocol deviation. 
Primary endpoint: 
The primary efficacy endpoint is the ratio of Week 26 to baseline 
PVR. A geometric mean ratio (GMR) of Week 26 to baseline 
PVR < 1 corresponds to a reduction in PVR from baseline.  
Statistical hypotheses: 
The null hypothesis is that the GMR of Week 26 to baseline PVR is 
equal in the dual and triple therapy groups. The alternative hypothesis 
NCT02558231

is that these GMRs are different, with a difference of –0.223 expressed 
on a log scale.  
Type I and II errors and power: 
The overall type I error (α) is set to 0.05 (two-sided). The type II error 
is set to 0.10 and therefore the power to 90%. 
Primary analysis: 
Following the intent-to-treat principle, the primary analysis will be 
conducted on the FAS. 
The ratio of Week 26 to baseline PVR will be log-transformed (base 
e) and analyzed using an analysis of covariance with factors for 
treatment group, region (as stratified at randomization), WHO FC (as 
stratified) and a continuous covariate for baseline log PVR. The 
treatment group difference (on log-scale) and its 95% confidence 
interval (CI) will be estimated based on the model.  
The triple versus dual ratio of GMRs and its 95% CI will be obtained 
by exponentiation. The null hypothesis will be rejected if the 95% CI 
around the ratio of the GMRs excludes 1. 
For subjects with a post-baseline PVR measurement obtained before 
Week 26, the (last) post-baseline PVR measurement will be carried 
forward. For subjects without a post-baseline PVR measurement, the 
baseline PVR will be carried forward (i.e., the ratio of Week 26 to 
baseline is set to one). Subjects with missing baseline PVR 
measurement will be excluded from analysis. 
Secondary analyses: 
To control for multiplicity across the primary and selected secondary 
efficacy endpoints, statistical analyses will be performed in the 
following sequence: change from baseline to Week 26 in 6MWD, 
change from baseline to Week 26 in NT-proBNP, time from 
randomization to first disease progression event, and absence of 
worsening from baseline to Week 26 in WHO FC. The changes from 
baseline to Week 26 in other RHC variables will be excluded from 
this hierarchical testing strategy as they include too many variables. 
Secondary efficacy variables will be analyzed for the FAS at α = 0.05 
(two-sided) using 95% CIs. 
Safety analysis: 
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All safety analyses will be performed on the Safety Set using 
descriptive statistics. Additional safety analyses will be performed for 
the subset of subjects who received at least one dose of double-blind 
study treatment. 
Interim analysis: 
This study uses a group sequential design, and one interim analysis is 
planned when 33% of planned enrolled subjects in each arm have 
completed their Week 26 assessment or prematurely discontinued the 
study.  
This interim analysis is intended to test for futility (non-binding), in 
order to prevent continuing treating subjects with triple combination 
therapy if it is unlikely to show a clinical benefit for the subjects.  
However, as the interim analysis is designed to assess the efficacy of 
the triple versus the dual combination, it is not considering all safety 
aspects. Thus, an Independent Data Monitoring Committee (IDMC) 
will review efficacy, safety and tolerability data at regular intervals 
prior to and after the interim analysis.  
Sample size calculations: 
An integrated analysis of two bosentan studies (BENEFIT, 
AC-052-366, and EARLY, AC-052-364) and one macitentan study 
(the hemodynamic sub-study of SERAPHIN, AC-055-302) suggested 
that the within group standard deviation (SD) of the log-transformed 
ratio of Week 26 to baseline PVR is 0.41 (90% CI: 0.39–0.43). This 
is in line with published PVR data from studies of dual or triple 
combination therapy. For this trial, a more conservative SD = 0.5 on 
the log-scale was assumed. 
Four studies of initial dual therapy reported reductions (calculated) of 
PVR from baseline of 40% (n = 22; 95% CI: 27%–50%), 51% 
(n = 23; 95% CI: 42%–58%), 45% (n = 52; 95% CI: 38%–51%), and 
54% (n=16; 95% CI: 48%–60%). 
One observational study of initial triple therapy reported a reduction 
(calculated) of PVR of 68% (n = 18; 95% CI: 62%–74%). 
Assuming 50% PVR reduction in the dual therapy group, 60% 
reduction in the triple therapy group (corresponding to a ratio of 
geometric means of 0.80, i.e., 20% difference in favor of triple 
therapy), and an overall type I error level of 5%, around 238 subjects 
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would provide an overall 90% power at final analysis using a group 
sequential design and Pocock boundary, with interim analysis 
performed when 33% (i.e., 79 subjects) have completed the Week 26 
PVR assessment. 
STUDY 
COMMITTEES 
• Steering Committee.  
• CEC.  
• IDMC.  
• Independent Liver Safety Data Review Board.  
NCT02558231

Table 1 
Visit and assessment schedule 
PERIODS 
Name 
SCREE
-NING 
TREATMENT 
FOLLOW-
UP 
 
Duration 
28 days  
30 days 
VISITS 
Name 
Scree-
ning 6 
Random-
ization 
 
 
 
 
 
 
End of main 
observation 
period 
(EOMOP) 5,14 
End of 
Treatment 
(EOT) 5 
Unscheduled 
visits 1, 2, etc 
3, 15 
End of 
Study 
(EOS) 1, 5 
 
Time 
Day −28 
to Day 1 
Day 1 
Day 8 (± 
3 days) 1 
Day 15 
(± 3 
days)  
Weekly 
phone 
calls 2 
Week 
12 
(± 1 
week) 
Week 
26 
(± 1 
week)  
Month 12, 
18, 24, 30, 
etc 
(± 2 
weeks) 13 
Will be 
announced 11 
Will be 
announced 
11 
Any time 
between Day 
1 and EOS 3 
30–35 days 
after EOT 
1,5 
Informed consent 10 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility & demographics  X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Right heart catheterization X 10 
 
 
 
 
 
X 
 
 
 
X 
 
Physical examination 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Vital signs (BP, HR) 
X 
X 7 
 
X 
 
X 
X 
X 
X 
X 
X 
 
WHO FC 15 
X 
X 7 
 
 
 
X 
X 
X 
X 
X 
X 
 
6MWD 15, Borg dysp. index X 
X 7 
 
 
 
X 
X 
X 
X 
X 
X 
 
Laboratory tests general 17 
X 16 
X 7 
 
 
 
X 
X 
X 
X 
X 
X 
 
Liver and hemoglobin tests 9 X 16 
X 7 
Monthly 13 (± 1 week) 
X 
X 
 
Pregnancy test 8 
X 
X 
Monthly 13 (± 1 week) 
X 
X 
X 
Contraceptive methods docu X 4 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood sampling biomarkers X 
 
 
 
 
 
X 
 
 
 
 
 
Study treatm. dispensing 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
 
Study treatment return 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Previous/concom. therapies X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
AEs, SAEs 12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NCT02558231

1 Visit or phone call. 
2 Weekly phone calls during the up-titration phase of double-blind study treatment.  
3 Unscheduled visits may be performed at any time during the study and may include any of the indicated assessments, based on investigator judgment. 
4 Reliable contraception must be started at least 11 days prior to Day 1. 
5 EOMOP, EOT, EOS: See definitions under ‘Periods’ above.  
6 It is permitted to re-screen subjects once, if the reason for non-eligibility was transient (e.g., abnormal laboratory test, insufficient wash-out period of a 
forbidden medication). All screening assessments should then be repeated at the time of re-screening.  
7 Only needed if screening assessment > 7 days before Day 1.  
8 In women of childbearing potential only. Serum pregnancy tests at Screening, Week 12, Week 26, monthly (± 1 week) throughout the study, at 
EOMOP, EOT, and if pregnancy is suspected at any time during the study. Urine pregnancy tests at the Day 1 visit and if a monthly serum test is 
missed. At EOS either serum or urine pregnancy testing. 
9 Monthly (± 1 week) central laboratory testing of liver aminotransferases, total and direct bilirubin, and hemoglobin is mandatory throughout the 
study. For monthly testing, blood drawing is performed either at the study site, at a satellite laboratory close to where the subject lives, or by a 
phlebotomy service at the subject’s home.  
10 Signed informed consent required before any study-mandated procedure. However, RHC data obtained at the study site within 28 days prior to Day 1 
but before the study (i.e., before signed informed consent) are acceptable.  
11 Actelion will announce EOMOP approximately 6 months in advance and EOT approximately 10 months in advance. The treatment group allocation 
(unblinding) will be disclosed approximately 1 month prior to EOT.  
12 All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after discontinuation of the last of the 3 study treatments 
must be reported.  
13 For this clinical trial, a month is defined as 30 days.  
14 The EOMOP visit is not required if within ± 2 weeks of a patient’s Week 26 visit or Month 12, 18, 24, 30, etc. visit.  
15 If any post-baseline decrease in 6MWD by > 15% from the highest 6MWD obtained at or after screening is observed, accompanied by WHO FC III or 
IV, then both the 6MWD and WHO FC must be reassessed at an unscheduled visit after 1–21 days.  
16 As an alternative to central laboratory tests, eligibility of subjects at Screening may be determined using local laboratory tests as long as the central 
laboratory kit is used in parallel. All local laboratory data including the normal ranges must be entered on dedicated eCRF pages. 
17 Laboratory tests general: Hematology, clinical chemistry including liver and hemoglobin tests, coagulation tests, and NT-proBNP. 
 
6MWD = 6-minute walk distance; AE = adverse event; BP = blood pressure; eCRF = electronic case report form; EOMOP = end of main observation 
period; EOS = end of study; EOT = end of treatment; FC = functional class; HR = heart rate; NT-proBNP = N-terminal prohormone of brain 
natriuretic peptide; RHC = right heart catheterization; SAE = serious adverse event; WHO = World Health Organization.  
 
NCT02558231

PROTOCOL 
1 
BACKGROUND 
1.1 Indication 
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 artery pressure (PAP) and in pulmonary vascular resistance (PVR) 
potentially leading to right heart failure and death [Benza 2010, Kylhammar 2014, 
Oudiz 2013]. The complex pathogenesis of PAH involves dysfunction of three key 
pathways: the endothelin pathway, the nitric oxide pathway, and the prostacyclin pathway 
[Humbert 2004].  
PAH is hemodynamically defined as a resting mean pulmonary artery 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 updated clinical classification of pulmonary hypertension (PH; Nice 2013) 
[Simonneau 2013] classifies the numerous conditions that are known to lead 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 (idiopathic), in a familial 
setting (heritable), as the result of the use of certain drugs and toxins, or it can be associated 
with a connective tissue disease, HIV infection, portal hypertension, congenital heart 
disease, or schistosomiasis.  
1.2 Study treatments 
Three PAH-specific drugs are used as study treatments in this trial: macitentan, tadalafil, 
and selexipag. Macitentan is an endothelin receptor antagonist (ERA) and acts via the 
endothelin pathway, tadalafil is a phosphodiesterase type 5 (PDE-5) inhibitor and acts via 
the nitric oxide pathway, and selexipag is an prostacyclin receptor agonist and acts via the 
prostacyclin pathway, i.e., when administered together, these drugs tackle all three key 
PAH therapeutical pathways mentioned in Section 1.1.  
1.2.1 Macitentan 
Macitentan is approved in the US, the European Union, and an increasing number of other 
countries for the treatment of PAH.  
More detailed information on macitentan can be found in the Investigator’s Brochure (IB) 
[Macitentan IB].  
NCT02558231

1.2.1.1 Nonclinical results 
Macitentan is an orally active, non-peptide, potent dual endothelin receptor A and B 
antagonist. Macitentan showed dose dependent efficacy in nonclinical models of 
hypertension and PH. In nonclinical safety studies, no effects on normal physiological 
functions or ECG variables, including cardiac repolarization, were observed, with the 
exception of a decrease in arterial blood pressure (BP) 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 
without affecting male or female fertility. Teratogenicity is considered to be an ERA class 
effect. 
1.2.1.2 Clinical pharmacology 
During the Phase 1 program, more than 200 healthy subjects and about 30 subjects with 
renal and hepatic impairment were treated with macitentan. Macitentan was well tolerated 
in all studies. The most frequently reported adverse event (AE) was headache.  
1.2.1.3 Clinical efficacy 
Efficacy was established in a long-term study in PAH patients with predominantly WHO 
functional class (FC) II–III symptoms treated for an average of 2 years [Pulido 2013]. 
Patients had idiopathic or heritable PAH (57%), PAH caused by connective tissue disorders 
(31%), and PAH caused by congenital heart disease with repaired shunts (8%), and were 
treated with macitentan monotherapy or in combination with PDE-5 inhibitors (PDE-5i) or 
inhaled prostanoids.  
The trial demonstrated that macitentan 10 mg reduces the risk of morbidity/mortality in 
patients with symptomatic PAH, with a hazard ratio versus placebo of 0.55, 97.5% 
confidence limits (CLs): 0.32, 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 other therapy for PAH.  
The placebo-corrected mean change in 6-minute walk distance (6MWD) from baseline to 
Month 6 showed an increase of 22.0 m (97.5% CLs: 3.2, 40.8) with macitentan 10 mg. The 
WHO FC improved from baseline to Month 6 in 13% of the patients in the placebo group, 
as compared with 22% of those in the group that received 10 mg of macitentan (P = 0.006) 
[Pulido 2013].  
A hemodynamic sub-study showed a placebo-corrected mean reduction of PVR from 
baseline to Month 6 of 38.5% (97.5% CLs: 25.7, 49.0) with macitentan 10 mg 
[Pulido 2013].  
NCT02558231

1.2.1.4 Summary of safety profile 
The safety of macitentan has been evaluated in a long-term placebo-controlled trial of 742 
patients with symptomatic PAH [Pulido 2013, Macitentan 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 are nasopharyngitis (14.0%), 
headache (13.6%), and anaemia (13.2%). The majority of adverse reactions are 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%).  
1.2.2 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.  
1.2.2.1 Nonclinical results 
Tadalafil is a selective inhibitor of PDE-5, the enzyme responsible for the degradation of 
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 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.  
Nonclinical studies have shown that the effect of tadalafil is more potent on PDE-5 than 
on other phosphodiesterases.  
For the nonclinical toxicology of tadalafil see the prescribing information [Adcirca SmPC, 
Adcirca USPI, local prescribing information].  
1.2.2.2 Clinical pharmacology 
In clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the 
hypotensive effect of nitrates. Tadalafil must not be used in patients taking any form of 
organic nitrates.  
For other pharmacodynamics effects, interactions, and the pharmacokinetics of tadalafil 
see the SmPC and USPI [Adcirca SmPC, Adcirca USPI, local prescribing information].  
1.2.2.3 Clinical efficacy 
Tadalafil was evaluated in a Phase 3, randomized, double-blind, 16-week 
placebo-controlled study conducted in 405 patients with PAH. Allowed background 
therapy included bosentan (maintenance dosing up to 125 mg twice daily). Subjects were 
randomly assigned to 1 of 5 treatment groups (tadalafil 2.5, 10, 20, 40 mg, or placebo) in 
NCT02558231

a 1:1:1:1:1 ratio. The mean age of all subjects was 54 years (range 14–90 years) with the 
majority of subjects being Caucasian (81%) and female (78%). PAH etiologies were 
predominantly idiopathic PAH (61%) and related to collagen vascular disease (24%). More 
than half (53%) of the subjects in the study were receiving concomitant bosentan therapy. 
The majority of subjects had a WHO FC III (65%) or II (32%). The mean baseline 6MWD 
was 343 meters. 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 meters (95% confidence interval [CI]: 15–50 meters; p = 0.0004). Placebo-
adjusted changes in 6MWD at 16 weeks were evaluated in subgroups. In patients taking 
only tadalafil 40 mg (i.e., without concomitant bosentan), the placebo-adjusted mean 
change in 6MWD was 44 meters. In patients taking tadalafil 40 mg and concomitant 
bosentan therapy, the placebo adjusted mean change in 6MWD was 23 meters. There was 
less clinical worsening (defined as death, lung transplantation, atrial septostomy, 
hospitalization because of worsening PAH, initiation of new PAH therapy [prostacyclin or 
prostacyclin analog, ERA, PDE-5i], or worsening WHO FC) in the tadalafil 40 mg group 
compared to the placebo group and the groups that used lower doses of tadalafil.  
Patients (N = 357) from the placebo-controlled study entered a non-controlled long-term 
extension study. Of these, 311 patients have been treated with tadalafil for at least 6 months 
and 182 for 1 year (median exposure 356 days; range 2 days to 415 days). The survival rate 
in the extension study was 96.5 per 100 patient years.  
1.2.2.4 Summary of safety profile 
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. Adverse reaction data are limited in patients over 
75 years of age. 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 once daily 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 11%, 
placebo 16%). Of the patients who completed the pivotal study, 357 entered a long-term 
extension study. Doses studied were 20 mg and 40 mg once daily.  
1.2.3 Selexipag 
Selexipag is approved for the treatment of PAH in the US, the European Union, and an 
increasing number of other countries. 
More detailed information on selexipag can be found in the IB [Selexipag IB].  
NCT02558231

1.2.3.1 Nonclinical results 
Selexipag is an orally available non-prostanoid prostacyclin receptor agonist. Whilst active 
by itself, selexipag is hydrolyzed to an active metabolite with prolonged terminal half-life 
and a high selectivity for the prostacyclin receptor. Selexipag and its metabolite possess 
anti-fibrotic, anti-proliferative, and anti-thrombotic activity. Oral selexipag is effective in 
an animal model of PAH, improving hemodynamic and structural factors leading to 
increased survival. Selexipag seems to induce minimal or no tachyphylaxis in rats.  
1.2.3.2 Clinical pharmacology 
For interactions as well as the pharmacodynamics and pharmacokinetics of selexipag see 
the IB [Selexipag IB].  
1.2.3.3 Clinical efficacy 
In the multicenter, double-blind, placebo-controlled event-driven Phase 3 clinical trial 
GRIPHON, conducted in 1156 patients with PAH, selexipag demonstrated a clinically and 
statistically significant 40% risk reduction compared to placebo in the occurrence of a first 
morbidity/mortality event up to end of treatment (EOT) + 7 days (hazard ratio for selexipag 
versus placebo 0.60, 99% CI: 0.46–0.78, 1-sided unstratified log-rank P < 0.0001). Results 
of all supportive analyses on the primary endpoint were consistent with that of the main 
analysis, and the observed treatment effect was also consistent across subgroups (PAH 
etiology, region, ethnicity, gender, age, WHO FC, and – most important in the setting of 
the present triple combination study – baseline PAH background medication) [Sitbon 2015, 
Selexipag IB].  
The secondary endpoints of change from baseline to Week 26 in 6MWD measured at 
trough, and of time to first PAH-related death or hospitalization due to PAH, showed a 
statistically significant effect favoring selexipag over placebo. The secondary endpoints of 
absence of worsening in WHO FC from baseline to Week 26 and of time to death of all 
causes up to study closure did not show a difference between selexipag and placebo 
[Selexipag IB].  
1.2.3.4 Summary of safety profile 
In the GRIPHON trial, patients were treated for up to 4.2 years. The most frequently 
reported AEs in the selexipag group were those associated with prostacyclin treatment: 
headache (65% vs 32% in placebo group), diarrhea (42% vs 18%), nausea (33% vs 18%), 
jaw pain (26% vs 6%), vomiting (18% vs 9%), pain in extremity (17% vs 8%), and myalgia 
(16% vs 6%). A total of 43.8% and 47.1% of patients in the selexipag and placebo groups, 
respectively, had at least 1 serious adverse event (SAE). The great majority of SAEs were 
consistent with the underlying PAH condition. PAH worsening and right ventricular failure 
were the most frequently reported SAEs, and both were reported at lower frequencies in 
the selexipag group (14.4% and 5.9%, respectively) compared to the placebo group (22.0% 
NCT02558231

and 7.1%, respectively). A total of 31.7% of patients in the selexipag group and 37.1% in 
the placebo group had at least one AE leading to discontinuation of study treatment. Other 
than prostacyclin-associated AEs, most of the AEs that led to discontinuation of study 
treatment were SAEs associated with underlying PAH disease.  
Overall, 
in 
the 
GRIPHON 
study, 
the 
nature 
and 
incidence 
of 
typical 
prostacyclin-associated AEs (i.e., headache, flushing, diarrhea, nausea, vomiting, jaw pain, 
myalgia and arthralgia) on selexipag was largely in line with that observed with 
prostacyclin and prostacyclin analogs [Sitbon 2015, Selexipag IB].  
Hypotension was reported more frequently in the selexipag group compared to the placebo 
group (5.9% and 3.8%, respectively). In the selexipag group 9.7% of patients had systolic 
blood pressure (SBP) ˂ 90 mmHg on at least one occasion, compared to 6.7% in the 
placebo group. A decrease from baseline of > 40 mmHg in SBP was reported for 2.3% and 
3.0% of patients in selexipag and placebo groups, respectively.  
Bleeding was not observed more frequently in selexipag-treated patients compared to 
placebo, including in those patients treated concomitantly with anticoagulants. Anemia was 
reported more frequently in the selexipag group and a small reduction in hemoglobin was 
observed at most post-baseline visits.  
Hyperthyroidism was reported more frequently in the selexipag group compared to the 
placebo group. Corresponding laboratory changes were a small reduction in 
thyroid-stimulating hormone at most post-baseline visits. A possible association between 
thyroid disorders and PAH is described in the literature [reviewed in Marvisi 2013]. 
Previously published investigations showed that prostaglandins may influence thyroid 
function by a direct effect on specific prostaglandin membrane receptors [Chadha 2009].  
Importantly, in the GRIPHON study there were no additional safety and tolerability 
findings in those patients receiving selexipag on top of both an ERA and a PDE-5i.  
1.3 Purpose and rationale of the study 
Recent guidelines for the treatment of PAH [Galiè 2013] recommended sequential 
combination therapy in patients with an inadequate clinical response to initial 
monotherapy. However, based on the recent results of the AMBITION study 
[Galiè 2015a], initial dual combination therapy with an ERA and a PDE-5i is emerging as 
a potential new standard of care in newly diagnosed PAH patients [Galiè 2015b]. 
To date, only one pilot study has investigated initial triple combination therapy 
[Sitbon 2014], showing dramatic improvements in all relevant variables such as WHO FC, 
6MWD, mPAP, cardiac index, and PVR. Although the study was small (n = 18), non-
controlled, and used different drugs than in the present study (in particular, intravenous 
NCT02558231

epoprostenol as the drug acting on the prostacyclin pathway), it suggests that initial triple 
therapy in PAH may be beneficial and safe.  
With the availability of selexipag, it is possible to investigate a triple oral therapy regimen. 
Data from the GRIPHON trial suggest that selexipag is efficacious and safe irrespective of 
whether or not subjects are already receiving other PAH drugs [Sitbon 2015, Selexipag IB]. 
In fact, the majority of the patient population in GRIPHON was prevalent and thus already 
being treated with an ERA and/or a PDE-5i at baseline.  
The above-mentioned triple therapy data from the GRIPHON trial [Sitbon 2015, Selexipag 
IB] and the pilot study [Sitbon 2014] provide a rationale for the present study. The purpose 
is to investigate whether an initial triple oral treatment regimen combining an ERA, a 
PDE-5i, and selexipag adds significant efficacy benefit while being safe and well tolerated, 
as compared to an initial dual oral treatment regimen with an ERA and a PDE-5i 
[Galiè 2015a].  
Given the extensive and long-term controlled efficacy and safety data available with all 
3 study treatments (including triple combination used in many subjects in the GRIPHON 
study) and the careful follow-up of subjects mandated by this protocol, the benefit/risk 
assessment supports the current study.  
2 
STUDY OBJECTIVES 
2.1 Primary objective 
The primary objective of the study is to compare the effect on PVR of an initial triple oral 
regimen (macitentan, tadalafil, selexipag) versus an initial dual oral regimen (macitentan, 
tadalafil, placebo) in newly diagnosed, treatment-naïve subjects with PAH.  
2.2 Secondary objectives 
The secondary objective of the study is to compare an initial triple oral regimen 
(macitentan, tadalafil, selexipag) with an initial dual oral regimen (macitentan, tadalafil, 
placebo) in newly diagnosed, treatment-naïve subjects with PAH, with respect to 
cardio-pulmonary hemodynamics (other than PVR), exercise capacity, disease severity, 
disease progression events, safety, and tolerability.  
2.3 Exploratory objectives 
The exploratory objective of the study is to compare an initial triple oral regimen 
(macitentan, tadalafil, selexipag) with an initial dual oral regimen (macitentan, tadalafil, 
placebo) in newly diagnosed, treatment-naïve subjects with PAH, with respect to additional 
disease severity endpoints.  
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3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
This is a prospective, multi-center, double-blind, randomized, placebo-controlled, parallel 
group, Phase 3b, efficacy and safety study comparing a triple oral regimen (macitentan, 
tadalafil, selexipag) with a dual oral regimen (macitentan, tadalafil, placebo) in newly 
diagnosed, treatment-naïve subjects with PAH.  
This study uses a group sequential design, with one interim analysis planned when 
approximately one third of the subjects have completed their Week 26 PVR assessment 
(primary endpoint) or prematurely discontinued the study.  
Approximately 238 subjects will be randomized in a 1:1 ratio to the two treatment groups 
(approximately 119 subjects per group), stratified by region (North America versus rest of 
world) and WHO FC at baseline (I/II versus III/IV). The study will be conducted at 
approximately 75 sites in approximately 20 countries. Randomization will proceed until 
the required number of subjects has been reached. It will be competitive across 
participating sites. Actelion may replace sites with no subject enrollment.  
The study periods at the subject level are summarized in Figure 1. Figure 2 illustrates the 
planned duration of the study and the duration of the subjects’ participation in the study.  
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Figure 1 
Study periods (subject level) 
 
1 Signed written informed consent is required prior to any study-mandated procedure (right 
heart catheterization [RHC] data obtained at the study site before informed consent 
signature but within 28 days prior to Day 1 are acceptable).  
2 Study treatment initiation scheme: See Section 5.1.3.  
3 For simplification, most visits between Day 1 and end of main observation period 
(EOMOP; as defined below) are not displayed. The complete visits and assessments are 
shown in Table 1.  
4 If double-blind treatment (selexipag/placebo) is discontinued before Week 26: The Week 
26 assessments should be done either at Week 26 or before start of rescue therapy 
(prostacyclin, prostacyclin analog, or prostacyclin receptor agonist), whichever is first.  
5 The EOMOP is the data cutoff for the main efficacy and safety analyses, followed by data 
cleaning and unblinding of the treatment group allocation. The EOMOP visit is planned 26 
± 1 weeks after enrollment of the last subject. This timepoint will be announced by Actelion 
approximately 6 months in advance. The EOMOP visit is not required if within ± 2 weeks 
of a patient’s Week 26 visit or Month 12, 18, 24, 30, etc. visit.  
6 All 3 study treatments are provided until the EOT visit, which is planned approximately 
4 months after the EOMOP visit. In order to allow sufficient time for the investigator to 
arrange any post-study therapy, Actelion will announce EOT approximately 10 months in 
advance, and unblind the treatment group allocation (selexipag or placebo) approximately 
1 month prior to EOT. In the event of premature discontinuation of all 3 study treatments, 
the EOT visit should be performed within 1 week but the subject should be followed up 
according to the schedule of assessments until end of study (EOS; as defined below).  
7 EOS is defined as the last data collection for a subject. The EOS visit for all subjects 
(regardless of whether they are receiving 3, 2, 1, or no study treatment) is planned 
approximately 5 months after the EOMOP visit. For all randomized patients, follow-up for 
disease progression (including death) will continue until EOS. 
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Figure 2 
Planned duration (study level) 
 
 
* See Figure 1 for abbreviations and definitions 
No sub-studies are planned.  
3.2 Study design rationale 
The rationale for the selected treatment groups is described in Section 1.3. The 
double-blind design is required to minimize any bias. Stratification by region and baseline 
WHO FC is justified by the fact that these variables had a major impact on PVR (primary 
endpoint) in previous trials, in particular in the hemodynamic sub-study of Actelion’s 
SERAPHIN trial (AC-055-302) with macitentan.  
The use of a group sequential design is justified by the absence of prior data on the potential 
clinical benefit of a triple versus a dual oral combination therapy. The interim analysis is 
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therefore designed as a futility analysis to prevent continuing the trial and exposing subjects 
to unnecessary burden if it is unlikely to demonstrate a relevant treatment difference.  
A maximum of 28 days for screening is considered an acceptable balance between granting 
sufficient time to conduct all assessments and not delaying treatment start for too long.  
Initiating all 3 study treatments within 2 weeks is a pragmatic balance between a true initial 
triple therapy approach and the need to carefully monitor subject safety during this phase. 
The rules for up-titration of selexipag [Section 5.1.3] are very similar to those used in the 
GRIPHON trial [Sitbon 2015, Selexipag IB].  
The primary endpoint (PVR) is determined at Week 26 because it is expected that during 
the first 26 weeks the 3 study treatments have sufficient time to exert a treatment effect.  
It is planned that Actelion will provide all 3 study treatments until approximately 
10 months after the last subject has been enrolled (EOT). All subjects should continue the 
study until EOS, irrespective of whether they are receiving 3, 2, 1, or no study treatments 
up to EOT, and irrespective of any other PAH therapy administered. Consequently, the 
total study duration for a subject will vary between approximately 11 months and 
approximately 4 years, depending on the timepoint at which the subject is enrolled and the 
enrollment rate (assumed enrollment period is 3 years). The reasons for keeping subjects 
in the study beyond Week 26 (primary endpoint) are (1) to allow investigators to make 
informed decisions regarding any post-study therapy once the result of the primary analysis 
and study treatment allocation for each patient is known (approximately 1 month prior to 
EOT), (2) to assess some of the secondary and exploratory efficacy and safety endpoints 
requiring longer observation periods. One of the aims of this study is to explore various 
disease severity and clinical outcome endpoints. A traditional clinical worsening endpoint 
does not appear feasible in a triple combination setting (too few events).  
3.3 Study committees 
The following study committees will be established, each governed by a separate charter: 
o Steering Committee (SC) - to advise on the study protocol, oversee the conduct of 
the study, contribute to interpretation of the results, and support publications.  
o Clinical Events Committee (CEC) - to adjudicate the disease progression events.  
o IDMC - to safeguard the interests of subjects by monitoring safety, tolerability, and 
efficacy data obtained in the study and making appropriate recommendations based 
on the reported data, thus ensuring that the study is being conducted at the highest 
scientific and ethical standards. The IDMC will be fully operational prior to 
enrollment of the first subject into the study.  
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o Independent Liver Safety Data Review Board (ILSDRB) - to provide advice 
regarding serious hepatic events of the study subjects. The ILSDRB is an external 
expert committee of hepatologists.  
4 
SUBJECT POPULATION 
4.1 Subject population description 
The target population is subjects with PAH [Simonneau 2013], as detailed in Sections 4.3 
and 4.4.  
4.2 Rationale for the selection of the study population 
The minimum PVR is 480 dyn·sec/cm5 (6 WU) in order to exclude mild PAH in a study 
investigating an aggressive treatment approach, i.e., initial triple therapy. Furthermore, 
with the change in PVR from baseline to Week 26 being the primary endpoint, subjects 
with an elevated baseline PVR may have a higher chance of a PVR improvement.  
The minimum 6MWD is 50 m in order to ensure a baseline value is available, which is 
needed for several of the secondary and exploratory efficacy endpoints. This avoids 
imputation of missing values in subjects who can hardly walk or not walk at all.  
The upper age limit is set to 75 years in order to exclude subjects with a potentially 
uncertain or atypical PAH diagnosis due to co-morbidities. For the same reason, subjects 
with conditions such as permanent atrial fibrillation, lung diseases indicative of PH 
etiologies other than PAH, and presence of multiple risk factors for heart failure with 
preserved ejection fraction are excluded.  
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 3 study 
treatments [Macitentan IB, Adcirca SmPC, Adcirca USPI, and Selexipag 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 subject:  
1. Signed informed consent prior to any study-mandated procedure. 
2. Male or female ≥ 18 and ≤ 75 years of age at screening. 
3. Initial PAH diagnosis < 6 months prior to Day 1.  
4. RHC performed between Day −28 and Day 1 (RHC data obtained at the study site 
within this time frame, but before the study, i.e., before signed informed consent, are 
acceptable), meeting all the following criteria:  
• mPAP ≥ 25 mmHg. 
• PAWP or LVEDP ≤ 15 mmHg. 
NCT02558231

• PVR ≥ 480 dyn·sec/cm5 (≥ 6 WU). 
• Negative vasoreactivity test mandatory in idiopathic, heritable, and drug/toxin 
induced PAH (at this or a previous RHC).  
5. Symptomatic PAH belonging to one of the following subgroups [Simonneau 2013]:  
• Idiopathic. 
• Heritable. 
• Drug or toxin induced. 
• Associated with one of the following: 
− Connective tissue disease. 
− HIV infection. 
− Congenital heart disease with simple systemic-to-pulmonary shunt (atrial septal 
defect, ventricular septal defect, patent ductus arteriosus) ≥ 1 year after surgical 
repair. 
6. 6MWD ≥ 50 m at screening.  
7. Women of childbearing potential [defined in Section 4.5.1] must: 
• Have a negative serum pregnancy test at the screening visit and a negative urine 
pregnancy test at the Day 1 visit, and 
• Agree to perform monthly pregnancy tests up to EOS, and 
• Agree to use reliable contraception [defined in Section 4.5.2] from screening up to 
1 month following discontinuation of the last study treatment. Reliable 
contraception must be started at least 11 days prior to Day 1.  
4.4 Exclusion criteria 
Subjects must not fulfill any of the following exclusion criteria. It is not permitted to waive 
any of the criteria for any subject:  
1. Any PAH-specific drug therapy (e.g., any ERA, PDE-5i, soluble guanylate cyclase 
stimulator, prostacyclin, prostacyclin analog, or prostacyclin receptor agonist) at any 
time prior to Day 1 (administration for vasoreactivity testing is permitted; previous 
PAH-specific drugs used intermittently for the treatment of digital ulcers or Raynaud’s 
phenomenon are permitted if stopped > 6 months prior to Day 1).  
2. Cardio-pulmonary rehabilitation program based on exercise (planned, or started 
≤ 12 weeks prior to Day 1).  
3. Body mass index (BMI) > 40 kg/m2 at screening. 
4. Presence of three 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. 
• Coronary artery disease, i.e., any of the following:  
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− History of stable angina or 
− More than 50% stenosis in a coronary artery (by coronary angiography) or 
− History of myocardial infarction or 
− History of or planned coronary artery bypass grafting and/or coronary artery 
stenting.  
5. Acute myocardial infarction ≤ 12 weeks prior to screening. 
6. Cerebrovascular events (e.g., transient ischemic attack, stroke) ≤ 12 weeks prior to 
screening. 
7. Known permanent atrial fibrillation. 
8. SBP < 90 mmHg at screening or Day 1. 
9. Ongoing or planned treatment with organic nitrates and/or doxazosin. 
10. Presence of one or more of the following signs of relevant lung disease at any time up 
to screening: 
• Diffusing capacity of the lung for carbon monoxide (DLCO) < 40% of predicted 
UNLESS computed tomography reveals no or mild interstitial lung disease. 
• Forced vital capacity (FVC) < 60% of predicted. 
• Forced expiratory volume in one second (FEV1) < 60% of predicted. 
Pulmonary function tests may be performed either with or without the use of 
bronchodilators, as per local clinical practice. 
11. Known or suspected pulmonary veno-occlusive disease (PVOD).  
12. Documented severe hepatic impairment (with or without cirrhosis) according to 
National Cancer Institute organ dysfunction working group criteria, defined as total 
bilirubin > 3 × upper limit of the normal range (ULN) accompanied by aspartate 
aminotransferase (AST) > ULN (assessed at screening); and/or Child-Pugh Class C.  
13. Serum AST and/or alanine aminotransferase (ALT) > 3 × ULN (assessed at 
screening).  
14. Severe renal impairment (estimated creatinine clearance ≤ 30 mL/min/1.73 m2) 
assessed at screening.  
15. Ongoing or planned dialysis. 
16. Hemoglobin < 100 g/L assessed at screening. 
17. Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism).  
18. Loss of vision in one or both eyes because of non-arteritic ischemic optic neuropathy 
(NAION). 
19. Treatment 
with 
strong 
inducers 
of 
cytochrome 
P450 
3A4 
(CYP3A4; 
e.g., carbamazepine, rifampin, rifampicin, rifabutin, rifapentin, phenobarbital, 
phenytoin, and St. John’s wort) ≤ 28 days prior to Day 1.  
20. Treatment with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) 
and/or strong inhibitors of CYP2C8 (e.g., gemfibrozil) ≤ 28 days prior to Day 1.  
NCT02558231

21. Treatment with another investigational drug (planned, or taken ≤ 12 weeks prior to 
Day 1). 
22. Hypersensitivity to any of the 3 study treatments or any excipient of their formulations 
(lactose, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, 
povidone, corn starch, sodium starch glycolate type A, polyvinyl alcohol, polysorbate 
80, titanium dioxide, talc, xanthan gum, lecithin from soya, croscarmellose sodium, 
hypromellose, sodium laurylsulfate, triacetin, iron oxide yellow, iron oxide red, iron 
oxide black, d-mannitol, propylene glycol, carnauba wax).  
23. Pregnancy, breastfeeding, or intention to become pregnant during the study.  
24. Concomitant life-threatening disease with a life expectancy < 12 months.  
25. Alcohol abuse.  
26. Any factor or condition likely to affect protocol compliance of the subject, as judged 
by the investigator.  
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. 
− Premature ovarian failure confirmed by a specialist. 
− XY genotype, Turner syndrome, uterine agenesis. 
− Postmenopausal, defined as 12 consecutive months with no menses without an 
alternative medical cause (ICH M3 definition). 
4.5.2 Acceptable methods of contraception 
Women of childbearing potential as defined in Section 4.5.1 must use reliable 
contraception from screening up to 1 month following discontinuation of the last study 
treatment. Reliable contraception must be started at least 11 days prior to Day 1. The 
methods of contraception used (including non-pharmacological methods) must be recorded 
in the electronic Case Report Form (eCRF) at every visit.  
Europe and other areas outside of Australia and North America 
Use of at least one of the following methods is regarded as reliable contraception:  
1. Oral, implantable, transdermal, or injectable hormonal contraceptives or intrauterine 
devices, or  
2. True abstinence from intercourse with a male partner only when this is in line with the 
preferred lifestyle of the subject, or  
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3. Permanent female sterilization (tubal occlusion/ligation at least 6 weeks prior to 
screening), or  
4. Sterilization of the male partner, with documented post-vasectomy confirmation of the 
absence of sperm in the ejaculate.  
Rhythm methods, use of a condom by the male partner alone, use of a female condom or 
diaphragm alone are not considered acceptable methods of contraception for this study.  
Australia 
In females of childbearing potential, pregnancy should be excluded before the start of 
treatment and prevented thereafter by the use of two reliable methods of contraception. If 
necessary, patients should discuss with their doctor or gynecologist which methods would 
be most suitable for them. Given the teratogenic nature of macitentan, women should not 
become pregnant for 3 months after discontinuation of the drug. 
North America 
For North America, use of one of the following options is regarded as reliable 
contraception:  
 
4.6 Medical history 
Relevant medical history as defined in Section 7.1.3 must be recorded in the eCRF.  
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5 
TREATMENTS 
5.1 Study treatment 
Study treatments are macitentan, tadalafil, and selexipag/placebo. Details and references 
are provided in Section 1.2. 
5.1.1 Investigational treatment: description and rationale 
The investigational group will receive the following: 
o Macitentan oral tablet, 10 mg once daily (preferably always in the morning or 
always in the evening; to be recorded in the eCRF).  
o Tadalafil oral tablet, 20 mg one or two tablets once daily (preferably always in the 
morning or always in the evening; to be recorded in the eCRF).  
o Selexipag oral tablet, 200 µg, one to eight tablets twice daily (in the morning and 
in the evening). Exceptions from the twice daily dosing regimen are described in 
Section 5.1.3.  
The doses are in accordance with the IB for macitentan [Macitentan IB], the product 
labeling for tadalafil [Adcirca SmPC, Adcirca USPI], and the IB for selexipag 
[Selexipag IB].  
5.1.2 Comparator treatment: description and rationale 
The comparator group will receive the following: 
o Macitentan oral tablet, 10 mg once daily (preferably always in the morning or 
always in the evening; to be recorded in the eCRF).  
o Tadalafil oral tablet, 20 mg one or two tablets once daily (preferably always in the 
morning or always in the evening; to be recorded in the eCRF).  
o Matching placebo to selexipag oral tablet, 200 µg, one to eight tablets twice daily 
(in the morning and in the evening). Exceptions from the twice daily dosing 
regimen are described in Section 5.1.3.  
The doses are in accordance with the IB for macitentan [Macitentan IB], the product 
labeling for tadalafil [Adcirca SmPC, Adcirca USPI], and the IB for selexipag 
[Selexipag IB].  
5.1.3 Study treatment administration 
The 3 study treatments are administered as follows:  
o Day 1: Start of open-label macitentan 10 mg once daily and open-label tadalafil 
20 mg once daily.  
o Day 8 ± 3: Tadalafil dose increase to 40 mg once daily (in subjects with mild or 
moderate renal impairment, defined as creatinine clearance > 30 and 
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≤ 80 mL/min/1.73 m2, tadalafil up-titration to 40 mg once daily should be based on 
individual tolerability [Adcirca SmPC, Adcirca USPI]).  
o Day 15 ± 3: Start of double-blind selexipag or placebo, see details below. 
Double-blind treatment should be started even in subjects who had to previously 
discontinue one or both of the other study treatments.  
The starting dose of double-blind selexipag or placebo on Day 15 ± 3 is 200 µg twice daily 
(in the morning and in the evening). The dose is up-titrated in increments of 200 µg twice 
daily, usually at weekly intervals [see Table 2], until either a maximum dose of 1600 µg 
twice daily is reached or adverse pharmacological effects that cannot be tolerated or 
medically managed are experienced, whichever is first. In the event of adverse effects 
typical of prostanoid therapy, it is recommended not to discontinue double-blind treatment 
because these effects are usually transient or manageable with symptomatic treatment. If a 
dose that cannot be tolerated is reached, the dose should be reduced to the previous dose 
level.  
The goal of the titration is to identify the individually appropriate dose for each subject (the 
maximum tolerated dose [MTD]) to be used during the maintenance treatment period, i.e., 
after titration has been completed. The MTD is defined as the first dose used after the Week 
12 visit. Later dose changes are at the discretion of the investigator, i.e., dose adjustments 
of selexipag/placebo (up to the maximum dose of 1600 µg twice daily) are allowed at any 
time after reaching the MTD. The date and dose at every dose change are recorded on a 
dedicated page in the eCRF.  
A once-daily regimen (one to eight tablets once in the morning or in the evening) is 
recommended in patients with moderate hepatic impairment (Child-Pugh class B) due to 
the increased exposure to selexipag and its active metabolite. 
In case of concomitant administration of a moderate inhibitor of CYP2C8 (e.g., 
clopidogrel, deferasirox, teriflunomide), the dosing frequency of selexipag/placebo should 
be reduced to once daily because of drug-drug interactions. A drug-drug interaction study 
showed that clopidogrel had no relevant effect on the exposure to selexipag but increased 
the exposure to the active metabolite approximately 2.7-fold at steady-state. The dosing 
frequency should be reverted to twice daily when co-administration of the moderate 
CYP2C8 inhibitor is stopped [Selexipag IB]. 
In case of concomitant administration of a moderate inducer of CYP2C8 (e.g., rifampicin), 
dose adjustment of selexipag/placebo may be required because of drug-drug interactions. 
A drug-drug interaction study showed that rifampicin did not lead to a relevant change in 
exposure to selexipag, whereas exposure to the active metabolite decreased by half 
[Selexipag IB]. 
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Table 2 
Double-blind up-titration scheme up to the Week 12 visit 
Duration (Study Days, all ± 3) Dose regimen1, 2, 3 
Day 15 to Day 21 
200 µg twice daily 
(1 tablet twice daily) 
Day 22 to Day 28 
400 µg twice daily 
(2 tablets twice daily) 
Day 29 to Day 35 
600 µg twice daily 
(3 tablets twice daily) 
Day 36 to Day 42 
800 µg twice daily 
(4 tablets twice daily) 
Day 43 to Day 49 
1000 µg twice daily 
(5 tablets twice daily) 
Day 50 to Day 56 
1200 µg twice daily 
(6 tablets twice daily) 
Day 57 to Day 63 
1400 µg twice daily 
(7 tablets twice daily) 
Day 64 to Week 12 visit 
1600 µg twice daily 
(8 tablets twice daily) 
1 Or maximum tolerated dose. The indicated doses are target doses if previous dose level was tolerated or if 
tolerability issues were addressed by down-titration.  
2 When titrating up or down, it is recommended to take the first new dose in the evening.  
3 Exceptions from the twice daily dosing regimen are described in Section 5.1.3. 
 
For all 3 study treatments, tablets are to be taken orally, with or without food. Tolerability 
may be improved when taken with food. The tablets should not be split, crushed or chewed, 
and are to be swallowed with some water. If a dose has been missed, the subject must take 
it as soon as possible (unless the next dose is within the next 6 hours), and then take the 
next dose at the next scheduled time. 
5.1.4 Treatment assignment 
At Screening, subjects will be assigned a study-specific subject number by the Interactive 
Response Technology (IRT) system. This number is kept throughout the study and is the 
main subject identifier. Note: In case of re-screening, the original number will also be used 
the second time.  
At the randomization visit, after having confirmed the eligibility of the subject and prior to 
the start of study treatment, the subject will be randomized. The IRT system will assign a 
randomization number to the subject (in addition to the subject number mentioned above), 
and assign the treatment container 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), Almac.  
Randomization will be done in a 1:1 ratio. Stratification will be by region (North America 
versus rest of world) and WHO FC at baseline (I/II versus III/IV).  
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5.1.5 Blinding 
The study will be performed in an open-label fashion for macitentan and tadalafil.  
The study will be performed in a double-blind fashion for selexipag and its matching 
placebo. Selexipag and its matching placebo are indistinguishable and all treatment kits 
will be packaged in the same way.  
The investigator and study staff, the subjects, the monitors, Actelion staff, and CROs 
involved in the conduct of the study will remain blinded to the study treatment until 
database closure. Actelion staff responsible for clinical trial supply distribution will need 
to be unblinded to ensure adequate distribution of study treatment. These persons will be 
clearly identified, their unblinding will be documented in the trial master file and they will 
not take part in any Clinical Trial Team meetings after study set-up has been completed.  
Until the time of unblinding for final data analysis, the randomization list is kept strictly 
confidential, and accessible only to authorized persons who are not involved in the conduct 
of the study.  
5.1.6 Unblinding 
5.1.6.1 Unblinding for final analyses 
Full randomization information will be made available for data analysis only after database 
closure (following EOMOP) in accordance with Actelion Standard Operating Procedures 
(SOPs). The treatment group allocation (selexipag or placebo) will be provided to study 
sites approximately 1 month prior to EOT.  
5.1.6.2 Unblinding for interim analyses 
A formal interim analysis is planned. In addition, an IDMC will review efficacy, safety and 
tolerability data at regular time intervals. The access to randomization information will in 
any case be limited to the independent Statistical Analysis Center (SAC) which will prepare 
all outputs for the interim analysis and the analyses required for the IDMC. The SAC will 
be represented by an independent statistician.  
5.1.6.3 Unblinding for suspected unexpected serious adverse reactions 
When a reported SAE qualifying as a suspected unexpected serious adverse reaction 
(SUSAR) for any of the administered study treatments occurs for a subject participating in 
the study, Actelion Global Drug Safety will request the unblinding of the treatment 
assignment only if the reported SAE is assessed as related to blinded study medication 
(selexipag or placebo) and if this event is not listed in Selexipag IB reference safety 
information section [Selexipag IB] or does not represent an event that is PAH disease 
related [see Section 10.2.5]. The randomization code will not be communicated to the site 
staff or to the Actelion study team; unblinded SUSAR information will be anonymized and 
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provided to Actelion Global Drug Safety, regulatory authorities, and IRBs/IECs only. 
SUSARs will be reported to investigators in a blinded fashion with regard to blinded study 
medication.  
No systematic unblinding of treatment assignment of blinded study medication is required 
if the reported SUSAR qualifies for the open-label study medication(s), macitentan or 
tadalafil.  
5.1.6.4 Emergency procedure for unblinding 
The investigator, study staff, and sponsor staff must remain blinded to the subject’s study 
treatment assignment. The identity of the study treatment may be revealed only if the 
subject experiences a medical event, the management of which requires knowledge of the 
treatment assignment. In this case, the investigator can receive the unblinded 
randomization code for study treatment allocation through the IRT. In these situations, the 
decision to unblind resides solely with the investigator. Whenever possible and if it does 
not interfere with or delay any decision in the best interest of the subject, the investigator 
is requested to discuss the intended unblinding with Actelion.  
The occurrence of any unblinding during the study must be clearly justified and explained 
by the investigator. In all cases, Actelion must be informed as soon as possible before or 
after the unblinding. 
The circumstances leading to unblinding must be documented in the Investigator Site File 
(ISF) and eCRF. 
5.1.7 Study treatment supply 
Manufacturing, labeling, packaging, and supply of study treatments will be conducted 
according to Good Manufacturing Practice, Good Clinical Practice (GCP), and any local 
or national regulatory requirements. 
All study treatment supplies will be used only in accordance with this protocol, and not for 
any other purpose.  
5.1.7.1 Study treatment packaging and labeling 
5.1.7.1.1 Study treatment packaging 
Study treatment is provided as tablets for all 3 study treatments. All 3 study treatments are 
provided in childproof kits.  
5.1.7.1.2 Study treatment labeling 
Study treatment is labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located.  
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5.1.7.2 Study treatment distribution and storage 
The investigator is responsible for 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 subjects enrolled in the study and in accordance with the protocol. 
Study treatments must be kept in a locked cabinet or room, which can be accessed only by 
the pharmacist, the investigator, or another duly designated person.  
Study treatment supplies must be stored according to the conditions specified on the 
container labels.  
5.1.7.3 Study treatment dispensing 
The subjects will receive sufficient study treatment to cover the period up to the next 
scheduled visit. Subjects will be asked to return all used, partially used, and unused study 
treatment (including the kits) at each visit. The protocol-mandated study treatment 
dispensing/return procedures may not be altered without prior written approval from 
Actelion. An accurate record of the date and amount of study treatment dispensed to each 
subject must be available for inspection at any time.  
5.1.7.4 Study treatment return and destruction 
On an ongoing basis and/or on termination of the study, the monitor will collect used and 
unused treatment kits, which will be sent to the warehouse, where Actelion or a deputy will 
check treatment reconciliation. In certain circumstances, used and unused study treatment 
containers may be destroyed at the site once study treatment accountability is finalized and 
has been checked by Actelion or the deputy, and written permission for destruction has 
been obtained from Actelion.  
5.1.8 Study treatment accountability and compliance with study treatment 
5.1.8.1 Study treatment accountability 
The inventory of study treatment dispensed and returned (i.e., study treatment 
accountability) must be performed by the study staff on the day of the subject visit and 
before dispensing further study treatment. It is recorded on the investigational medicinal 
product dispensing and accountability log and checked by the Clinical Research Associate 
(CRA) during site visits and at the end of the study. The study treatment accountability log 
will include at least the following information for each study treatment unit (kit) dispensed 
to the subject, for each of the 3 study treatments: 
• Dispensed kit number 
• Date dispensed / Number of tablets dispensed (pre-populated in eCRF) 
• Date returned / Number of tablets returned 
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All study treatment supplies, including partially used or empty kits must be retained at the 
site for review by the CRA.  
If the subject forgets to bring the remaining study treatment to a study visit, he/she must be 
instructed to not take any tablets from the remaining study treatment and to bring it at the 
next visit.  
5.1.8.2 Study treatment compliance 
Study treatment compliance is based on study treatment accountability. Study treatment 
compliance must be calculated at each visit using the formula below, separately for the 
3 study treatments:  
Compliance = 
[(number of tablets dispensed - number of tablets returned) / total number of tablets that 
should have been taken during the respective period between 2 visits] × 100 
During the study, compliance is expected to be between 80% and 120%. If out of range 
value(s) are noticed for any of the 3 study treatments (from study treatment accountability), 
they will be considered as a protocol deviation. The investigator must check with the 
subject the reasons for this non-compliance and discuss actions to be taken to avoid 
recurrence at the next visit.  
Compliance of selexipag will not be assessed for the period up to the Week 12 visit.  
5.1.9 Study treatment dose adjustments and interruptions 
Any of the 3 study treatments may be temporarily interrupted if required due to an AE, a 
tolerability issue, a diagnostic or therapeutic procedure, a laboratory abnormality, or for 
administrative reasons. Interruptions of study treatments should be kept as short as 
possible. Interruptions must be for less than 4 consecutive weeks; longer interruptions must 
lead to permanent discontinuation of the respective study treatment(s). Study-specific 
criteria for interruption of study treatment are described in Section 5.1.11.  
Dose adjustments are permitted for tadalafil (e.g., reduction from 40 to 20 mg once daily) 
and double-blind selexipag or placebo. No dose adjustment is possible for macitentan.  
Any interruption of 3 days or more of blinded selexipag/placebo treatment will require new 
up-titration. Subjects will start with one tablet (200 µg) twice daily. If this dose is well 
tolerated, the dose will be up-titrated by the investigator in 200 µg increments up to the 
subject’s maximum dose achieved before interruption. The frequency of dose increments 
will be based on the medical judgment of the investigator, considering the subject’s 
tolerability to selexipag/placebo prior to its interruption.  
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If study treatment intake is interrupted or the dose adjusted by the subject for any reason, 
she/he must immediately inform the investigator.  
Study treatment dose adjustments / interruptions must be recorded in the eCRF.  
5.1.10 Premature discontinuation of study treatment 
The decision to prematurely discontinue any of the 3 study treatments may be made by the 
subject, the investigator, or Actelion. The main reason for discontinuation of study 
treatment and whether it is the decision of the subject, the investigator, or Actelion is 
documented in the eCRF. However, the subject is not obliged to provide a reason. 
A subject has the right to prematurely discontinue any of the 3 study treatments at any time 
by withdrawal from study treatment only or by withdrawal from any further participation 
in the study (i.e., premature withdrawal from the study, see Section 9.2).  
The investigator should discontinue study treatments for a given subject if, on balance, 
he/she believes that continued administration would be contrary to the best interests of the 
subject.  
Any of the 3 study treatments may be discontinued in response to an AE, lack of efficacy 
(including disease progression, treatment failure, worsening of subject’s condition), a 
protocol deviation (including eligibility failure, non-compliance with study requirements), 
a diagnostic or therapeutic procedure, a laboratory abnormality, or for administrative 
reasons.  
Study-specific criteria for discontinuation of study treatment are described in 
Section 5.1.11.  
A subject who prematurely discontinues all study treatments and withdraws consent to 
participate in any further study assessments is considered as withdrawn from the study. 
Subjects who die or are lost to follow-up are also considered as withdrawn from the study. 
Withdrawal from the study and follow-up medical care of subjects withdrawn from the 
study is described in Sections 9.2 and 9.4, respectively.  
5.1.11 Study-specific criteria for interruption / premature discontinuation of study 
treatment 
For more details see the prescribing information or other background information for the 3 
study treatments [Macitentan IB, Adcirca SmPC, Adcirca USPI, local prescribing 
information for tadalafil, Selexipag IB].  
A) Pregnancy 
If a female subject becomes pregnant after study start (i.e., signing of informed consent) 
and up to 1 month following discontinuation of the last study treatment, a Pregnancy Form 
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must be completed [see Section 10.3]. Therapy with all study treatments must be 
discontinued and the investigator should arrange for any PAH-specific therapy as needed 
[ESC Guidelines]. In the event of pregnancy with abortion, the investigator should discuss 
the impact on study treatment with Actelion.  
B) Liver aminotransferases abnormalities 
Interruption of study treatment 
Study treatment with macitentan must be interrupted in the following case: 
• Aminotransferases (i.e., 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 one 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 of macitentan can be considered.  
Reintroduction of macitentan 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.  
Liver aminotransferase levels must be checked within 3 days after reintroduction, then 
again after a further 2 weeks and thereafter at monthly intervals.  
Permanent discontinuation of study treatment 
Study treatment with macitentan must be stopped and its reintroduction is not to be 
considered in any of the following cases: 
• Aminotransferases ≥ 8 × ULN.  
• Aminotransferases ≥ 3 × ULN and associated clinical symptoms of liver injury, 
e.g., nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue, flu 
like syndrome (arthralgia, myalgia, fever). However, the investigator may consider 
reintroduction of macitentan treatment (as described in the paragraph ‘Interruption of 
study treatment’ above) if he/she judges the symptom(s) to be unrelated to the elevated 
aminotransferase levels.  
• Aminotransferases ≥ 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.  
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Other diagnoses (e.g., viral hepatitis, mononucleosis, toxoplasmosis, cytomegalovirus) 
and/or etiologies (e.g., acetaminophen-related liver toxicity) should be considered and 
ruled out by performing the appropriate tests.  
All liver aminotransferases abnormalities leading to study treatment interruption or 
discontinuation must be recorded as AEs [see Section 10].  
An ILSDRB provides ongoing assessment and advice regarding serious hepatic events that 
require further evaluation during the study.  
C) Severe hepatic impairment 
If liver impairment is suspected, a clinical assessment of severity (e.g., Child-Pugh score) 
should be performed. If the investigator becomes aware that a patient has developed 
moderate hepatic impairment (e.g., Child-Pugh B) at any time during the study, then it is 
the responsibility of the investigator to evaluate the benefit/risk of keeping the patient on 
any or all of the 3 study treatments.  
If a patient develops severe hepatic impairment (e.g., Child-Pugh C), the study drugs 
macitentan, tadalafil, and selexipag/placebo must be discontinued.  
Assessment of Child-Pugh score is not a mandatory study assessment.  
D) Severe renal impairment 
Study treatment with tadalafil must be discontinued in the event of severe renal impairment 
(estimated creatinine clearance ≤ 30 mL/min/1.73 m2).  
E) Pulmonary edema due to PVOD 
If a subject develops pulmonary edema due to PVOD consider discontinuation of the 
3 study treatments, and consult the background information [Macitentan IB, 
Adcirca SmPC, Adcirca USPI, local prescribing information for tadalafil, Selexipag IB] 
regarding the risk of pulmonary edema.  
F) Vision disorder 
Study treatment with tadalafil must be discontinued in case of loss of vision in one or both 
eyes because of NAION.  
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G) Hemoglobin abnormalities 
In case of hemoglobin decrease from baseline∗ of > 20 g/L during study treatment with 
macitentan, 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, indirect bilirubin. 
Study treatment with macitentan should be temporarily interrupted if clinically mandated 
based on the investigator’s judgment, or in any of the following situations (unless clearly 
unrelated to macitentan, e.g., hemoglobin decrease due 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, 
− The need for transfusion. 
Reintroduction of study treatment with macitentan may be considered if hemoglobin 
recovers, i.e., 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 
macitentan outweigh the potential risks.  
H) Start of a CYP3A4 or CYP2C8 inducer or inhibitor 
Study treatment with macitentan and tadalafil must be discontinued if a strong CYP3A4 
inducer or inhibitor is started during study treatment with macitentan and/or tadalafil.  
Selexipag/placebo treatment must be discontinued if a strong CYP2C8 inhibitor (e.g., 
gemfibrozil) is started. 
In case of concomitant administration of a moderate inhibitor of CYP2C8 (e.g., 
clopidogrel, deferasirox, teriflunomide), the dosing frequency of selexipag/placebo should 
be reduced to once daily because of drug-drug interactions. A drug-drug interaction study 
showed that clopidogrel had no relevant effect on the exposure to selexipag but increased 
the exposure to the active metabolite approximately 2.7-fold at steady-state. The dosing 
frequency should be reverted to twice daily when co-administration of the moderate 
CYP2C8 inhibitor is stopped [Selexipag IB]. 
In case of concomitant administration of a moderate inducer of CYP2C8 (e.g., rifampicin), 
dose adjustment of selexipag/placebo may be required because of drug-drug interactions. 
∗ Baseline hemoglobin: last value obtained prior to first intake of macitentan study treatment. 
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A drug-drug interaction study showed that rifampicin did not lead to a relevant change in 
exposure to selexipag, whereas exposure to the active metabolite decreased by half 
[Selexipag IB].  
I) Start of doxazosin and/or organic nitrates 
Study treatment with tadalafil must be discontinued if doxazosin and/or any organic nitrate 
is started during treatment.  
J) Start of another PAH-specific drug 
Subjects remain in the study irrespective of whether they are receiving 3, 2, 1, or no study 
treatments, even if another PAH drug is started.  
Study treatment with macitentan must be discontinued if another ERA is started 
concurrently during macitentan treatment. 
Study treatment with tadalafil must be discontinued if another PDE-5i or soluble guanylate 
cyclase stimulator is started concurrently during tadalafil treatment.  
Study treatment with double-blind selexipag/placebo must be discontinued if another 
prostacyclin, prostacyclin analog, or prostacyclin receptor agonist is started during 
treatment, e.g., as rescue therapy. Details are described in Section 5.2.5. 
K) Hyperthyroidism or hypothyroidism 
In the event of clinical suspicion or manifestation of hyperthyroidism or hypothyroidism, 
thyroid function markers including thyroid stimulating hormone, free triiodothyronine 
(T3), and free thyroxine (T4) levels must be monitored by the investigator/delegate and 
appropriate measures according to local clinical practice should be implemented. 
5.2 Previous and concomitant therapy 
5.2.1 Definitions 
A previous therapy is any treatment for which the end date is prior to the start of study (i.e., 
signing of informed consent).  
A study-concomitant therapy is any treatment that is administered at any time between the 
start of study (i.e., signing of informed consent) and EOS.  
A study treatment-concomitant therapy is any treatment that is administered at any time 
between the start of the first study treatment (Day 1) and discontinuation of the last study 
treatment (EOT).  
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5.2.2 Reporting of previous/concomitant therapy in the eCRF 
All concomitant therapy (including contraceptives and traditional and alternative 
medicines, i.e., plant-, animal-, or mineral-based medicines, and also cardio-pulmonary 
rehabilitation programs based on exercise) will be recorded in the eCRF. Previous therapy 
will be recorded in the eCRF if discontinued less than 28 days prior to the start of study 
(i.e., signing of informed consent).  
For both previous and concomitant therapy, the generic name, start/end dates of 
administration (as well as whether it was ongoing at key timepoints such as EOS), route of 
administration, dose, and indication will be recorded in the eCRF.  
Single-dose administration of a drug for vasoreactivity testing during RHC should NOT be 
recorded in the eCRF.  
5.2.3 Allowed concomitant therapy 
Single-dose administration of a drug for vasoreactivity testing during RHC.  
Cardio-pulmonary rehabilitation programs based on exercise, started after the Week 26 
visit. 
5.2.4 Forbidden concomitant therapy 
o Any PAH-specific drug (e.g., ERA, PDE-5i [also if used for erectile dysfunction], 
soluble guanylate cyclase stimulator, prostacyclin, prostacyclin analog, or 
prostacyclin receptor agonist) other than the 3 study treatments up to EOT, except 
if used as rescue therapy [see Section 5.2.5]. If another PAH-specific drug is started 
(and the corresponding study treatment is stopped), subjects remain in the study, 
irrespective of whether they are receiving 3, 2, 1, or no study treatments. See also 
Section 5.1.11, paragraph J.  
o Organic nitrates (other medications with vasodilatory effects must be used with 
caution).  
o Doxazosin. 
o Strong inducers of CYP3A4 (e.g., carbamazepine, rifampin, rifampicin, rifabutin, 
rifapentin, phenobarbital, phenytoin, and St. John’s wort) during treatment with 
macitentan and/or tadalafil. 
o Strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, 
clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) during 
treatment with macitentan and/or tadalafil. 
o Strong inhibitors of CYP2C8 (e.g., gemfibrozil) during treatment with 
selexipag/placebo. 
o Any investigational drug other than the 3 study treatments. 
o Cardio-pulmonary rehabilitation programs based on exercise between Screening 
and the Week 26 visit. 
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PAH-specific drugs other than the 3 study treatments are forbidden in order to minimize 
confounding effects on the outcome. Organic nitrates and doxazosin are forbidden in order 
to comply with the prescribing information of tadalafil, strong CYP3A4 inducers and 
inhibitors are forbidden during treatment with macitentan and/or tadalafil in order to 
comply with the background information for macitentan and tadalafil [Macitentan IB, 
Adcirca SmPC, Adcirca USPI, local prescribing information for tadalafil]. Strong CYP2C8 
inhibitors are forbidden during treatment with selexipag/placebo because of drug-drug 
interactions (as described in Selexipag IB).  
Section 5.1.11 describes actions to be taken if a subject takes a forbidden concomitant 
therapy.  
5.2.5 Rescue therapy 
In the event of documented worsening of PAH, it is permitted to use prostacyclin, 
prostacyclin analogs, or prostacyclin receptor agonists as rescue therapy, in parallel to 
discontinuation of double-blind study treatment. Start of rescue therapy and 
discontinuation of double-blind selexipag or placebo may overlap in order to ensure 
sustained efficacy during the transition. Subjects starting rescue therapy remain in the study 
until EOS, irrespective of whether they are receiving any of the 3 study treatments.  
6 
STUDY ENDPOINTS 
6.1 Efficacy endpoints 
A traditional morbidity/mortality endpoint (as defined in Actelion’s SERAPHIN and 
GRIPHON trials) does not appear feasible due to the expected low event rates in the setting 
of the present study (subjects receiving at least two PAH-specific drugs). Therefore, the 
trial is designed as a pilot study (with PVR as the primary endpoint) that will explore 
various disease severity and clinical outcome endpoints.  
For the purpose of this study, baseline is defined as the last available assessment from the 
screening and Day 1 visits.  
6.1.1 Primary efficacy endpoint 
The primary endpoint is the ratio of Week 26 to baseline PVR.  
RHC is the standard approach for the initial confirmation of the presence of PH, for 
establishing the specific diagnosis (e.g., PAH), determining the severity of PH, and for 
guiding therapy. PVR as determined by RHC is needed to obtain an objective judgment on 
the hemodynamic response to treatment and to improve management. Likewise, PVR is 
associated with disease severity and correlates with mortality. An increase in PVR leads to 
right ventricular overload, hypertrophy, dilatation, and eventually to right ventricular 
failure and death.  
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6.1.2 Secondary efficacy endpoints 
1. Change from baseline to Week 26 in 6MWD. 
2. Change from baseline to Week 26 in N-terminal pro B-type natriuretic peptide 
(NT-proBNP). 
3. Absence of worsening from baseline to Week 26 in WHO FC. 
4. Changes from baseline to Week 26 in RHC variables other than PVR (mPAP, cardiac 
index, total pulmonary resistance, mean right atrial pressure (mRAP), venous oxygen 
saturation). 
5. Time from randomization to the first disease progression event up to EOMOP + 7 days 
(adjudicated by the CEC), defined as any of the following:  
a. Death (all causes; adjudicated for PAH relationship).  
b. Hospitalization for worsening PAH.  
c. Initiation of prostacyclin, a prostacyclin analog, or a prostacyclin receptor 
agonist for worsening PAH.  
d. Clinical worsening defined as a post-baseline decrease in 6MWD by > 15% 
from the highest 6MWD obtained at or after baseline, accompanied by WHO 
FC III or IV (both conditions confirmed at two consecutive post-baseline visits 
separated by 1–21 days). 
6.1.3 Exploratory efficacy endpoints 
1. Changes in NT-proBNP, 6MWD, and WHO FC from baseline to all regular collection 
timepoints up to EOMOP.  
2. Unsatisfactory clinical response defined as % of subjects meeting at least one of the 
following three conditions [adapted from McLaughlin 2013], analyzed at every 
scheduled visit from Week 26 up to EOMOP: 
a. WHO FC III or IV.  
b. 6MWD ≤ 440 m AND NT-proBNP ≥ 3 × ULN.  
c. Clinical worsening event as defined under secondary efficacy endpoint 5, at 
any time up to the respective visit.  
3. Number of treatment goals (score 0 = no or 1 = yes per goal, i.e., total score 0–5, with 
5 representing the best treatment outcome) met at Week 26 [adapted from McLaughlin 
2013]: 
o WHO FC I or II.  
o Cardiac index > 3 L/min/m2.  
o mRAP < 8 mmHg.  
o 6MWD > 440 m.  
o NT-proBNP < 3 × ULN.  
4. Number of treatment goals as defined in exploratory efficacy endpoint 3 but using 
> 2.5 L/min/m2 as an alternative cutoff for cardiac index.  
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5. Number of treatment goals as defined in exploratory efficacy endpoint 3 but using 
< 1800 pg/mL as an alternative cutoff for NT-proBNP [Nickel 2012].  
6.2 Safety endpoints 
The following safety endpoints will be used: 
o Treatment-emergent AEs. 
o AEs leading to premature discontinuation of any of the 3 study treatments. 
o Treatment-emergent SAEs. 
o Treatment-emergent deaths. 
o Treatment-emergent marked laboratory abnormalities. 
o Change from baseline in laboratory variables. 
o Change from baseline in vital signs. 
The safety endpoints will be analyzed for the following time periods: 
o From Day 1 until EOMOP.  
o From Day 1 until start of double-blind treatment (selexipag/placebo).  
o From start until discontinuation of macitentan study treatment (or until EOMOP, 
whichever is first) + 30 days safety follow up. 
o From start until discontinuation of tadalafil study treatment (or until EOMOP, 
whichever is first) + 30 days safety follow up. 
o From start until discontinuation of double-blind treatment (or until EOMOP, 
whichever is first) + 30 days safety follow up.  
o From EOMOP until EOT plus 30 days safety follow-up.  
o The 30 days safety follow-up.  
6.3 Biomarker endpoints 
Based on nonclinical data [Gomez-Arroyo 2015], it is hypothesized that selexipag may 
have a beneficial effect on circulating biomarkers involved in right ventricular function and 
structure. Therefore, changes in such biomarkers from baseline to Week 26 will be 
explored. The list of biomarkers to be measured after the end of the study will be based on 
the latest scientific evidence regarding right ventricular function and structure at the time 
of laboratory analysis. No genetic testing of any kind will be performed  
[see Section 7.3.7.2].  
7 
STUDY ASSESSMENTS 
Signed written informed consent is to be obtained prior to any study-mandated procedure.  
All study assessments (at scheduled or unscheduled visits) are performed by qualified study 
staff members (medical, nursing, or specialist technical staff), and are recorded in the eCRF 
(except the central laboratory assessments, see Section 7.3.7).  
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If the principal investigator (PI) delegates any study procedure/assessment for a subject to 
an external facility, he/she should inform Actelion to whom these tasks are delegated. The 
set-up and oversight will be agreed upon with Actelion. The supervision of any external 
facilities remains the responsibility of the PI.  
Calibration certificates for the temperature monitoring device for the study treatment 
storage area must be available prior to screening of the first subject at the site.  
7.1 Screening/baseline assessments 
Table 1 summarizes which assessments are performed at which visit.  
For subjects who fail screening, only data related to eligibility criteria, demographics and 
baseline characteristics are collected in the eCRF.  
7.1.1 Eligibility criteria 
Inclusion and exclusion criteria as listed in Sections 4.3 and 4.4.  
7.1.2 Demographic and baseline characteristics 
• Age, gender, height, weight. 
• Race (if allowed by local regulations). 
• PAH etiology (classification), date of initial PAH diagnosis. 
7.1.3 Medical history 
The subject’s relevant medical history up to start of study (i.e., signing of informed 
consent) must be recorded in the eCRF and should include, but is not limited to: 
• Any chronic medical conditions (e.g., diabetes). 
• Any acute medical conditions in the past 6 months. 
• Any other medically important conditions. 
7.1.4 Previous therapies 
Previous therapies must be recorded in the eCRF [see Section 5.2.1].  
7.2 Efficacy assessments 
Table 1 summarizes which assessments are performed at which visit.  
7.2.1 RHC 
The rationale for using RHC (and PVR as the primary endpoint) is provided in  
Section 6.1.1.  
For the RHC methodology to be used see the Actelion guidelines for RHC [Appendix 1].  
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The following variables are determined and entered in the eCRF: 
• PVR 
• Systolic pulmonary artery pressure (sPAP) 
• Diastolic pulmonary artery pressure (dPAP) 
• mPAP 
• PAWP or LVEDP 
• mRAP 
• Cardiac output (CO) 
• Cardiac index 
• Heart rate (HR) during RHC 
• Venous oxygen saturation 
• Systolic systemic artery pressure (sSAP) 
• Diastolic systemic artery pressure (dSAP) 
• Date of the RHC 
7.2.2 6-minute walk test, Borg dyspnea index 
The 6-minute walk test (6MWT) [ATS Statement 2002] is a non-encouraged test which 
measures the distance covered over a 6-minute walk. The ‘Actelion guidelines for 6MWT’ 
[Appendix 2] must be followed. For subjects who have never performed a 6MWT 
previously, a training test is recommended before the qualifying test for inclusion.  
The Borg dyspnea index is evaluated after each 6MWT. It rates dyspnea on a scale from 
‘0’ to ‘10’ [Appendix 3].  
7.2.3 WHO functional class 
WHO FC [Appendix 4] is a classification which reflects disease severity based on 
symptoms.  
7.2.4 Circulating biomarkers of right ventricular function and structure 
Laboratory testing of circulating biomarkers of right ventricular function and structure is 
included in Section 7.3.7.2.  
7.2.5 Other efficacy assessments 
Other efficacy assessments are detailed in Section 6.1.  
7.3 Safety assessments 
Table 1 summarizes which assessments are performed at which visit.  
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7.3.1 (Serious) adverse events 
The definitions, reporting and follow-up of AEs, SAEs and pregnancies are described in 
Section 10.  
7.3.2 Contraception methods and pregnancy testing 
For women of childbearing potential [Section 4.5.1], contraception methods and monthly 
pregnancy testing must be recorded in the eCRF.  
7.3.3 Vital signs 
Systolic and diastolic blood pressure and HR are measured non-invasively in the same 
position (e.g., supine) throughout the study.  
7.3.4 Body weight 
Body weight is used for the calculation of BMI (calculated as body weight in kg divided 
by height in m2) and of hemodynamic indices.  
7.3.5 Physical examination 
Physical examination (i.e., inspection, percussion, palpation, and auscultation) is 
performed during the study. The observations should be reported according to body system 
in the eCRF as either normal or abnormal. If abnormal, this should be specified on the 
corresponding eCRF page. Clinically relevant findings (other than those related to PAH) 
that are present at study start (i.e., signing of informed consent) must be recorded on the 
Medical History eCRF page. Findings made after study start which meet the definition of 
an AE [Section 10.1.1] must be recorded on the AE page of the eCRF.  
7.3.6 Concomitant therapies 
Concomitant therapies must be recorded in the eCRF [see Section 5.2].  
7.3.7 Laboratory assessments 
7.3.7.1 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 data will be loaded into 
the clinical database, i.e., no entry into the eCRF is required for central laboratory data.  
Eligibility of subjects at Screening may alternatively be determined using local laboratory 
tests as long as the central laboratory kit is used in parallel. Local laboratory results alone 
may be sufficient in other exceptional situations (e.g., subject is hospitalized in a different 
hospital due to a medical emergency). Local laboratory data including the normal ranges 
must be entered on dedicated eCRF pages. The investigator/delegate will provide Actelion 
with the name, professional degree, and curriculum vitae of the director of the local 
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laboratory, a copy of the laboratory’s certification, and the normal ranges for each 
laboratory test that is evaluated locally. These laboratory references must be updated 
whenever necessary. 
Under specific circumstances (e.g., if the subject lives far from the site and cannot return 
every month for liver and hemoglobin testing), laboratory samples may be collected at a 
laboratory close to where the subject lives (satellite laboratory) or by a phlebotomy service 
at the subject’s home, and sent to the central laboratory for analysis. In such a case, the 
satellite laboratory or phlebotomy service must be provided with the central laboratory 
sampling kits. Shipment of the samples will be organized by the satellite laboratory. If this 
process is implemented, the satellite laboratory must be identified prior to randomization 
of the subject. The supervision of the satellite laboratory remains the responsibility of the 
PI. The supervision of the phlebotomy service is the responsibility of Actelion.  
If a central laboratory sample is lost or cannot be analyzed, the investigator/delegate will 
collect an additional sample as soon as possible to repeat the 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 study site. In the event of specific laboratory 
abnormalities (pre-defined threshold values), the central laboratory will alert Actelion and 
the concerned study site [Appendix 5].  
All laboratory reports must be signed and dated by the investigator or delegate within 
3 working days of receipt and filed with the source documentation. The 
investigator/delegate must indicate on the laboratory report whether abnormal values are 
considered clinically relevant or not. Clinically relevant laboratory findings that are known 
at the time of signature of informed consent must be recorded on the medical history page 
of the eCRF. Any clinically relevant laboratory abnormalities detected after signature of 
informed consent must be reported as an AE or SAE as appropriate [see Section 10], 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. Further laboratory analyses should be performed as 
clinically indicated and according to the judgment of the investigator.  
Details about the collection, sampling, storage, shipment procedures, and reporting of 
results and abnormal findings can be found in the laboratory manual.  
7.3.7.2 Laboratory tests 
In Table 1 and Section 8, the following are summarized as ‘general’ laboratory tests: 
Hematology, clinical chemistry including liver and hemoglobin tests, coagulation tests, and 
NT-proBNP. 
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Hematology 
Rules for additional investigations and study treatment interruption in case of hemoglobin 
abnormalities are provided in Section 5.1.11.  
• Hemoglobin 
• Hematocrit 
• Erythrocyte count (reticulocyte count) 
• Leukocyte count with differential counts 
• Platelet count 
Clinical chemistry 
Rules for study treatment interruption in case of liver enzymes abnormalities or severe 
renal impairment are provided in Section 5.1.11.  
The Cockcroft-Gault formula is used for estimation of the creatinine clearance: Estimated 
creatine clearance rate = (140 – age) × (weight in kg) × (1.23 for men and 1.04 for women), 
divided by serum creatinine in μmol/L.  
• Aminotransferases (AST/ALT), alkaline phosphatase, total and direct bilirubin, lactate 
dehydrogenase 
• Creatinine, urea 
• Uric acid (serum urate) 
• Glucose 
• Sodium, potassium, chloride, calcium 
• Protein, albumin 
Coagulation tests 
• International Normalized Ratio 
• Prothrombin time 
• Activated partial thromboplastin time 
Pregnancy test 
Monthly (± 1 week) pregnancy tests are done for women of childbearing potential [as 
defined in Section 4.5.1]. For details, see Table 1, including footnotes. 
Pregnancy reporting requirements are described in Section 10.3. Also see Section 5.1.11.  
Biomarkers of myocardial stress and of right ventricular function and structure 
• 
NT-proBNP 
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• 
Circulating biomarkers involved in right ventricular function and structure (blood 
samples will be stored at the central laboratory or a specialized laboratory for up to 
two years after the last subject’s last visit and destroyed after that date. The list of 
biomarkers to be measured after the end of the study will be based on the latest 
scientific evidence regarding right ventricular function and structure at the time of 
laboratory analysis. No genetic testing of any kind will be performed).  
8 
SCHEDULE OF VISITS 
For a tabulated summary of all visits and assessments described here see Table 1. For a 
description of the assessment methods see Section 7.  
For this clinical trial, a month is defined as 30 days. 
All assessments except the central laboratory results must be recorded in the eCRF.  
Monthly (± 1 week) central laboratory testing of liver aminotransferases, total and direct 
bilirubin, and hemoglobin is mandatory throughout the study. For monthly testing, blood 
drawing is performed either at the study site, at a satellite laboratory close to where the 
subject lives, or by a phlebotomy service at the subject’s home.  
In women of childbearing potential [Section 4.5.1], serum pregnancy tests are performed 
at Screening, Week 12, Week 26, monthly (± 1 week) throughout the study, at EOMOP, 
EOT, and if pregnancy is suspected at any time during the study. Urine pregnancy tests are 
performed at the Day 1 visit and if a monthly serum test is missed. At EOS either serum or 
urine pregnancy tests are performed. To ensure compliance, at each visit, the study 
personnel must remind women of childbearing potential to perform monthly pregnancy 
tests and to use reliable contraception as defined for this study [Section 4.5.2]; the 
reminders must be documented in the hospital chart.  
8.1 Screening period 
It is the responsibility of the investigator to obtain written informed consent (Informed 
Consent Form [ICF]) from each patient participating in the study after adequate 
explanation of the objectives, methods, and potential benefits and hazards of the study. The 
ICF must be signed and dated by both parties prior to any study assessment or procedure. 
However, RHC data obtained at the study site within 28 days prior to Day 1 but before the 
study (i.e., before signed informed consent) are acceptable.  
Assessments of the screening period must be performed between Day −28 and the Day 1 
(enrollment/randomization) visit. Reliable contraception [defined in Section 4.5.2] must be 
started at least 11 days prior to Day 1.  
It is permitted to re-screen subjects once, if the reason for non-eligibility was transient (e.g., 
abnormal laboratory test, insufficient wash-out period of a forbidden medication). All 
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screening assessments should then be repeated at the time of re-screening (including 
signature of the ICF if the first ICF was signed more than 28 days prior to Day 1 [i.e., 
randomization]). 
The screening period includes recording of the following [see Table 1]: 
• Check of eligibility (inclusion and exclusion criteria) 
• Demographics 
• Medical history 
• RHC 
• Physical examination 
• Vital signs (BP, HR) 
• WHO FC 
• 6MWD, Borg dyspnea index 
• Central laboratory tests (general, serum pregnancy test, and biomarkers); eligibility 
of subjects at Screening may alternatively be determined using local laboratory tests 
as long as the central laboratory kit is used in parallel 
• Contraceptive methods used 
• Previous therapies 
• AEs, SAEs 
8.2 Treatment period 
For monthly central laboratory testing requirements during the treatment phase see footnote 
9 of the Visit and assessment schedule [Table 1].  
8.2.1 Day 1 (randomization) visit 
The Day 1 (randomization) visit includes recording of the following [see Table 1]: 
• Vital signs (BP, HR) * 
• WHO FC * 
• 6MWD, Borg dyspnea index * 
• Central laboratory tests (general) * 
• Urine pregnancy test 
• Contraceptive methods used 
• Concomitant therapies 
• AEs, SAEs 
* Only required if the respective assessment from the screening period was obtained more 
than 7 days prior to the Day 1 visit.  
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At the end of this visit, subjects are randomized to one of the two treatment groups. 
Macitentan and tadalafil study treatments are dispensed to the subjects. Treatment is 
initiated as described in Section 5.1.  
8.2.2 Day 8 visit 
The Day 8 (± 3 days) visit may be performed as a phone call and includes recording of the 
following [see Table 1]: 
• AEs, SAEs 
At the end of this visit, the dose of tadalafil is increased as described in Section 5.1.  
8.2.3 Day 15 visit 
The Day 15 (± 3 days) visit includes recording of the following [see Table 1]: 
• Physical examination 
• Vital signs (BP, HR) 
• Contraceptive methods used 
• Concomitant therapies 
• AEs, SAEs 
At the end of this visit, double-blind selexipag/placebo is dispensed to the subjects. The 
subjects initiate treatment and up-titration (on top of ongoing study treatment with 
macitentan and tadalafil) as described in Section 5.1.  
8.2.4 Weekly phone calls during up-titration 
Weekly phone calls are performed during the up-titration phase of double-blind study 
treatment. They include instructing the subjects regarding the dose of double-blind study 
treatment and recording of the following [see Table 1]: 
• AEs, SAEs 
8.2.5 Week 12 visit 
The Week 12 (± 1 week) visit includes recording of the following [see Table 1]: 
• Physical examination 
• Vital signs (BP, HR) 
• WHO FC 
• 6MWD, Borg dyspnea index 
• Central laboratory tests (general, serum pregnancy test) 
• Contraceptive methods used 
• Concomitant therapies 
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• AEs, SAEs 
At this visit, study treatments are dispensed and returned as described in Section 5.1.  
8.2.6 Week 26 visit 
The Week 26 (± 1 week) visit includes recording of the following [see Table 1]: 
• RHC 
• Physical examination 
• Vital signs (BP, HR) 
• WHO FC 
• 6MWD, Borg dyspnea index 
• Central laboratory tests (general, serum pregnancy test, and biomarkers) 
• Contraceptive methods used 
• Concomitant therapies 
• AEs, SAEs 
At this visit, study treatments are dispensed and returned as described in Section 5.1.  
8.2.7 Month 12, 18, 24, 30, etc. visits 
The Month 12, 18, 24, 30, etc. (± 2 weeks) visits include recording of the following [see 
Table 1]: 
• Physical examination 
• Vital signs (BP, HR) 
• WHO FC 
• 6MWD, Borg dyspnea index 
• Central laboratory tests (general, serum pregnancy test) 
• Contraceptive methods used 
• Concomitant therapies 
• AEs, SAEs 
At these visits, study treatments are dispensed and returned as described in Section 5.1.  
8.2.8 EOMOP visit 
The EOMOP visit [see Section 3.1] includes recording of the following [see Table 1]: 
• Physical examination 
• Vital signs (BP, HR) 
• WHO FC 
• 6MWD, Borg dyspnea index 
• Central laboratory tests (general, serum pregnancy test) 
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• Contraceptive methods used 
• Concomitant therapies 
• AEs, SAEs 
At this visit, study treatments are dispensed and returned as described in Section 5.1.  
8.2.9 EOT visit 
The EOT visit [Section 3.1] includes recording of the following [see Table 1]: 
• Physical examination 
• Vital signs (BP, HR) 
• WHO FC 
• 6MWD, Borg dyspnea index 
• Central laboratory tests (general, serum pregnancy test) 
• Contraceptive methods used 
• Concomitant therapies 
• AEs, SAEs 
At this visit, all study treatments are returned by the subjects, as described in Section 5.1.  
8.2.10 Unscheduled visits 
Unscheduled visits may be performed at any time during the study. Depending on the 
reason for the unscheduled visit (e.g., AE), appropriate assessments will be performed 
based on the judgment of the investigator and the results will be recorded in the eCRF. 
After an unscheduled visit, the regular scheduled study visits must continue according to 
the visit and assessment schedule in Table 1.  
If any post-baseline decrease in 6MWD by > 15% from the highest 6MWD obtained at or 
after screening is observed, accompanied by WHO FC III or IV, then both the 6MWD and 
WHO FC must be reassessed at an unscheduled visit after 1–21 days.  
8.3 Safety follow-up 
All subjects undergo a 30 days safety follow-up prior to EOS.  
8.3.1 EOS visit 
The EOS visit may be performed as a phone call. It is performed at the end of the safety 
follow-up, i.e., 30–35 days after EOT.  
The EOS visit includes recording of the following [see Table 1]: 
• Pregnancy test (serum or urine) 
• Contraceptive methods used 
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• AEs, SAEs 
9 
STUDY COMPLETION AND POST-STUDY TREATMENT/MEDICAL 
CARE 
9.1 Study completion 
Sites will be informed once the planned total subject enrollment is met. Subjects in 
screening (i.e., signed informed consent available but not yet randomized) at that point in 
time will be allowed to be randomized if they are eligible. No additional subjects may be 
screened. All subjects still in the study will be invited for their EOMOP visit 26 weeks 
after enrollment of the last subject, and for their EOT visit approximately 4 months after 
EOMOP.  
The end of the study as a whole is the date of the last subject’s EOS visit.  
9.2 Premature withdrawal of subjects from study 
Subjects may voluntarily withdraw from the study for any reason at any time. Subjects are 
considered withdrawn if they state an intention to withdraw further participation in all 
components of the study (i.e., withdrawal of consent), die, or are lost to follow-up. If a 
subject withdraws consent, no further data will be collected in the eCRF from the date of 
withdrawal onward.  
The investigator may withdraw a subject from the study (without regard to the subject’s 
consent) if, on balance, he/she believes that continued participation in the study would be 
contrary to the best interests of the subject. Withdrawal from the study may also result from 
a decision by Actelion for any reason, including premature termination or suspension of 
the study [see Section 9.3].  
Subjects are considered as lost to follow-up if all reasonable attempts by the 
investigator/delegate to communicate with the subject fail. The site must take preventive 
measures to avoid a subject being lost to follow-up (e.g., document different attempts of 
contact such as via telephone, home address, email address, or a person to be contacted in 
case the subject cannot be reached). The following methods must be used: at least three 
telephone calls must be placed to the last available telephone number and one registered 
letter must be sent by post to the last available home address. Additional methods may be 
acceptable if they are compliant with local rules/regulations (e.g., site staff visit to the 
subject’s home), respecting the subject’s right to privacy. If the subject is still unreachable 
after all contact attempts listed above, he/she will be considered to be lost to follow-up. 
This is documented in the eCRF.  
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If premature withdrawal from the study occurs for any reason, the reason along with who 
made the decision (subject, investigator, or Actelion) is recorded in the eCRF. However, 
the subject is not obliged to provide a reason. 
If a subject is withdrawn from the study because of withdrawal of consent, the investigator 
should make efforts to schedule a last appointment/phone call to assess the safety and well-
being of the subject, collect unused study treatment and discuss follow-up medical care. 
Data obtained during this last appointment/phone call will be recorded in the subjects’ 
medical records but it will not be reported in the eCRF or SAE Form, unless the subject 
agrees with such reporting. The investigator must provide follow-up medical care for all 
subjects who are prematurely withdrawn from the study, or must refer them for appropriate 
ongoing care, as described in Section 9.4.  
9.3 Premature termination or suspension of the study 
Actelion reserves the right to terminate the study at any time globally (e.g., based on the 
outcome of the interim analysis) or locally. Investigators can terminate the participation of 
their site in the study at any time.  
If a study is prematurely suspended or terminated, Actelion will promptly inform the 
investigators, the IRBs/IECs, and regulatory authorities, as appropriate, and provide the 
reasons for the suspension or termination.  
If the study is suspended or prematurely terminated for any reason, the investigator in 
agreement with Actelion must promptly inform all enrolled subjects, and ensure their 
appropriate treatment and follow-up, as described in Section 9.2. Actelion may inform the 
investigator of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the subjects’ interests.  
In addition, if the investigator suspends or terminates a study without prior agreement from 
Actelion, the investigator must promptly inform Actelion and the IRB/IEC, and provide 
both with a detailed written explanation of the termination or suspension.  
If the IRB/IEC suspends or terminates its approval/favorable opinion of a study, the 
investigator must promptly notify Actelion and provide a detailed written explanation of 
the termination or suspension.  
Any suspension or premature termination of the study must be discussed with the IDMC 
and SC.  
9.4 Medical care of subjects after study completion/withdrawal from study 
At the subjects’ EOT, the investigator/delegate will explain to subjects what standard 
treatment/medical care is necessary and available according to local regulations. Such care 
may include commercial PAH-specific drugs.  
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10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
10.1 Adverse events 
10.1.1 Definitions of adverse events 
An AE is any adverse change, i.e., any unfavorable and unintended sign, including an 
abnormal laboratory finding, symptom, or disease that occurs in a subject during the course 
of the study, whether or not considered by the investigator as related to study treatment. 
A treatment-emergent AE is any AE temporally associated with the use of study treatment 
(from study treatment initiation until 30 days after last 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 start of the study (i.e., signing of informed consent). 
• Abnormal assessments, e.g., change on physical examination, ECG findings, if they 
represent a clinically significant finding that was not present at study start or worsened 
during the course of the study. 
• Laboratory test abnormalities if they represent a clinically significant finding, 
symptomatic or not, which was not present at study start or worsened during the course 
of the study or led to dose reduction, interruption or permanent discontinuation of study 
treatment. 
Overdose, misuse, and abuse of the study treatment should be reported as an AE and, in 
addition, study treatment errors must be documented in the study treatment log of the 
eCRF. 
10.1.2 Intensity of adverse events 
The intensity of clinical AEs is graded on a three-point scale – mild, moderate, severe – 
and is reported on specific AE pages of the eCRF. 
If the intensity of an AE worsens during study treatment administration, only the worst 
intensity should be reported on the AE page. If the AE lessens in intensity, no change in 
the severity is required. 
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If the intensity of an AE with an onset date between informed consent signature and start 
of study treatment and which is ongoing at the start of treatment worsens after the start of 
study treatment, a new AE page must be completed. The onset date of this new AE 
corresponds to the date of worsening in intensity. 
The three categories of intensity are defined as follows: 
 Mild 
The event may be noticeable to the subject. It does not influence daily activities, and 
usually does not require intervention. 
 Moderate 
The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed. 
 Severe 
The event may cause noticeable discomfort, and usually interferes with daily activities. 
The subject may not be able to continue in the study, and treatment or intervention is 
usually needed. 
A mild, moderate, or severe AE may or may not be serious [see Section 10.3.1]. 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 severity assessment, determines the regulatory reporting 
obligations. 
10.1.3 Relationship to study treatment 
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the study treatments, and reported as either related or 
unrelated to macitentan, tadalafil, or blinded study treatment (selexipag/placebo). The 
determination of the likelihood that the study treatments caused the AE will be provided 
by an investigator who is a qualified physician.  
10.1.4 Adverse events associated to study design or protocol-mandated procedures 
An AE is defined as related to study design or 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.  
10.1.5 Reporting of adverse events 
All AEs occurring after study start (i.e., signing of informed consent) and up to EOS must 
be recorded on specific AE pages of the eCRF. 
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10.1.6 Follow-up of adverse events 
AEs still ongoing more than 30 days after study treatment discontinuation must be followed 
up until they are no longer considered clinically relevant. 
10.2 Serious adverse events 
10.2.1 Definitions of serious adverse events 
10.2.1.1 Serious adverse events 
An SAE is defined by the ICH guidelines as any AE fulfilling at least one of the following 
criteria: 
• Fatal. 
• Life-threatening: refers to an event in which the subject was at risk of death at the time 
of the event. It does not refer to an event that hypothetically might have caused death 
had it been more severe. 
• Requiring inpatient 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 
subject, and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definitions above. 
The following reasons for hospitalization are exempted from being reported: 
• Hospitalization for cosmetic elective surgery, or social and/or convenience reasons. 
• Hospitalization for pre-planned (i.e., planned prior to signing informed consent) 
surgery or standard monitoring of a pre-existing disease or medical condition that did 
not worsen, e.g., hospitalization for coronary angiography in a subject with stable 
angina pectoris. 
However, complications that occur during hospitalization are AEs or SAEs (for example if 
a complication prolongs hospitalization). 
10.2.2 Reporting of serious adverse events 
All SAEs occurring after study start (i.e., signing of informed consent) up to EOS must be 
reported on AE pages in the eCRF and on an SAE form, regardless of the 
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investigator-attributed causal relationship with study treatment or study-mandated 
procedures. 
10.2.3 Follow-up of serious adverse events 
SAEs still ongoing at the EOS visit must be followed up until resolution or stabilization, 
or until the event outcome is provided, e.g., death. 
10.2.4 After the [30-day] follow-up period 
New SAEs occurring after the 30-days follow-up period must be reported to the Actelion 
drug safety department 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 any of the 3 
study treatments.  
10.2.5 Reporting procedures 
All SAEs must be reported by the investigator to the Actelion drug safety department 
within 24 hours of the investigator’s first knowledge of the event. 
All SAEs must be recorded on an SAE form, irrespective of the study treatment received 
by the subject, and whether or not this event is considered by the investigator to be related 
to any of the study treatments (macitentan, tadalafil, or selexipag/placebo).  
The SAE forms must be faxed to the Actelion drug safety department (contact details are 
provided on the SAE form). The investigator must complete the SAE form in English, and 
must assess the causal relationship of the event to study treatment. 
Follow-up information about a previously reported SAE must also be reported within 
24 hours of receiving it. The Actelion drug safety department may contact the investigator 
to obtain further information. 
If the subject is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE relevant information and 
documentation. 
The reference safety document to assess expectedness of a suspect serious adverse reaction 
and reported by the sponsor to regulatory authorities, IRBs/IECs, and investigators are the 
background information for the 3 study treatments [reference safety information section of 
Macitentan IB, Adcirca USPI, reference safety information section of Selexipag IB].  
The following events that are anticipated to occur in subjects with PAH will be considered 
as ‘disease-related’ and will not be subject to unblinding (as applicable) and regulatory 
reporting: signs and symptoms of PAH worsening/exacerbation/progression, abdominal 
pain, anorexia, chest pain, cyanosis, diaphoresis, dizziness, pre-syncope, syncope, dyspnea, 
orthopnea, fatigue, hemoptysis, heart failure, hypoxia, palpitations, collapse, systemic 
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arterial hypotension, and tachycardia. Like all other SAEs, these SAEs must be reported 
on an SAE form by the investigator to the Actelion drug safety department within 24 hours 
of the investigator’s first knowledge of the event, and be reported on the AE page of the 
eCRF.  
10.3 Pregnancy 
If a female subject becomes pregnant, the instructions in Section 5.1.11 must be followed. 
The investigator must counsel the subject and discuss the risks of continuing with the 
pregnancy and the possible effects on the fetus.  
10.3.1 Reporting of pregnancy 
Irrespective of the treatment received by the subject, any pregnancy occurring after study 
start (i.e., signing of informed consent) and up to 1 month following discontinuation of the 
last of the 3 study treatments must be reported within 24 hours of the investigator’s 
knowledge of the event.  
Pregnancies must be reported on the Actelion Pregnancy form, which is faxed to the 
Actelion drug safety department (see contact details provided on the Actelion Pregnancy 
form), and on the AE page in the eCRF.  
10.3.2 Follow-up of pregnancy 
Any pregnancy must be followed to its conclusion and its outcome must be reported to the 
Actelion drug safety department. 
Any AE associated with the pregnancy occurring during the follow-up period after study 
treatment discontinuation must be reported on separate AE pages in the eCRF. Any SAE 
occurring during the pregnancy must be reported on an SAE form as described in 
Section 10.3.1. 
10.4 Study safety monitoring 
Clinical study safety information (AEs, SAEs, laboratory values, vital signs, and 
project-specific laboratories/examinations as required) is monitored and reviewed on a 
continuous basis by the Actelion Clinical Team (in charge of ensuring subjects’ safety as 
well as data quality) by periodically monitoring clinical studies activities from protocol 
conception to database closure. In addition, an IDMC is monitoring safety data [see Section 
3.3]. 
11 STATISTICAL METHODS 
All statistical analyses will be conducted by Actelion or by designated CRO supervised by 
Actelion. 
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A Statistical Analysis Plan (SAP) will provide full details of the analyses, data displays, 
and algorithms to be used for data derivations. 
11.1 Analysis sets 
11.1.1 Screened Analysis Set 
This analysis set includes all subjects who were screened. 
11.1.2 Full Analysis Set 
The Full Analysis Set (FAS) includes all randomized subjects. Subjects are evaluated 
according to the study treatment they have been assigned to (which may be different from 
the study treatment they have received). 
11.1.3 Modified Full Analysis Set 
The Modified Full Analysis Set (Modified FAS) includes all subjects from the FAS who 
received at least one dose of each of the 3 study treatments (macitentan, tadalafil, and 
double-blind selexipag or placebo). Subjects are evaluated according to the study treatment 
they have been assigned to (which may be different from the study treatment they have 
received).  
11.1.4 Per-protocol Set 
The Per-protocol Set (PPS) includes all subjects from the FAS who received at least one 
dose of double-blind study treatment and who have no major protocol deviation. Major 
protocol deviations will be described in the SAP. Subjects are evaluated according to the 
study treatment they have been assigned to (which may be different from the study 
treatment they have received). 
11.1.5 Safety Set 
The Safety Set includes all subjects who received at least one dose of any of the 3 study 
treatments.  
11.1.6 Usage of the analysis sets 
The primary efficacy analysis will be performed on the FAS based on treatment as 
randomized. Secondary and exploratory efficacy analyses will also be performed on the 
FAS. The Modified FAS and PPS will be used for sensitivity analyses. 
Safety analyses will be performed on the Safety Set based on treatment as received. 
Subject listings will be based on the Safety Set, unless otherwise specified. Subject 
disposition will be described for the Screened Analysis Set. 
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11.2 Variables 
11.2.1 Primary efficacy variable 
The primary efficacy variable is the ratio of Week 26 to baseline PVR. In the analyses this 
variable will be log-transformed, as log-transformed ratios follow a normal distribution 
more closely. In addition, the mean change from baseline on log scale can be transformed 
into a geometric mean ratio (GMR) of Week 26 to baseline PVR. A GMR < 1 corresponds 
to a reduction in PVR from baseline, which reflects a positive treatment effect.  
Baseline is defined as the last measurement obtained before or on Day 1 (before 
randomization). 
11.2.2 Secondary efficacy variables 
See Section 6.1.2.  
11.2.3 Other efficacy variables 
See Section 6.1.3.  
11.2.4 Safety variables 
See Section 6.2.  
11.3 Description of statistical analyses 
11.3.1 Overall testing strategy 
The analysis of the primary endpoint, i.e., PVR, will be tested according to the sequential 
group design of this trial. The first look, i.e., the futility interim analysis (non-binding), 
will be performed at information time 0.33 (i.e., when 33% of the planned enrolled subjects 
in each arm have completed their Week 26 visit) and the final one at the end of the study 
(i.e., when all subjects have completed their Week 26 visit). The overall type I error will 
be preserved at a 5% level. 
To control for multiplicity across the primary and selected secondary efficacy endpoints, 
statistical analyses for secondary endpoints will be performed in the following sequence: 
change from baseline to Week 26 in 6MWD, change from baseline to Week 26 in 
NT-proBNP, time from randomization to first disease progression event, and absence of 
worsening from baseline to Week 26 in WHO FC. The changes from baseline to Week 26 
in other RHC variables will be excluded from this hierarchical testing strategy as they 
include too many variables. 
Secondary efficacy variables will be analyzed for the FAS at α = 0.05 (two-sided) using 
95% CIs. 
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11.3.2 Analysis of the primary efficacy variable 
11.3.2.1 Hypotheses and statistical model 
The null hypothesis (H0) is that the GMR of Week 26 to baseline PVR is equal in the dual 
and triple therapy groups. The alternative hypothesis (H1) is that these GMRs are different, 
with a difference of –0.223 expressed on a log scale.  
If the GMR of Week 26 to baseline PVR in the triple therapy group is statistically 
significantly lower than in the dual therapy group, then triple therapy is considered superior 
to dual therapy. 
11.3.2.2 Handling of missing data 
For subjects with a post-baseline PVR measurement obtained before Week 26, the (last) 
post-baseline PVR measurement will be carried forward. For subjects without a 
post-baseline PVR measurement, the baseline PVR will be carried forward (i.e., the ratio 
of Week 26 to baseline set to one). Subjects with missing baseline PVR measurement will 
be excluded from analysis. 
Since subjects are treated with two or three PAH medications, their PVR is expected to 
decrease. Subjects that do not complete 26 weeks of treatment will generally have less 
decrease in PVR as compared to subjects that complete 26 weeks of treatment. On a subject 
level, the last observation carried forward approach is expected to be conservative. 
11.3.2.3 Main analysis 
Following the intent-to-treat principle, the primary analysis will be conducted on the FAS. 
The same method will be considered for the primary efficacy endpoint at time of interim 
analysis and at final analysis. The only difference will be the significance level as indicated 
further below.  
The ratio of Week 26 to baseline PVR will be log-transformed (base e) and analyzed using 
an analysis of covariance (ANCOVA) with factors for treatment group, region (as stratified 
at randomization), baseline WHO FC (as stratified) and a continuous covariate for baseline 
log PVR. The treatment group difference (triple minus dual) and its corresponding CI will 
be estimated based on the model.  
For each treatment group, the GMR of Week 26 to baseline PVR will be obtained by 
exponentiating the least squares means from the model. The triple versus dual treatment 
group ratio of GMRs and its corresponding CI will be obtained by exponentiating the 
treatment group difference and its corresponding CI from the model.  
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The null hypothesis will be rejected if the corresponding CI around the ratio of GMRs 
excludes 1. Triple therapy will be considered superior to dual therapy if the corresponding 
CI is entirely below 1. 
11.3.2.4 Supportive/sensitivity analyses 
Supportive analyses will be performed for the Modified FAS as well as for the PPS. 
Additional sensitivity analyses will be described in the SAP. 
11.3.2.5 Subgroup analyses 
Subgroup analyses will be performed by region and WHO FC at baseline (I/II versus 
III/IV). Additional subgroups analyses will be described in the SAP. 
11.3.3 Analysis of the secondary efficacy variables 
To control for multiplicity across the primary and selected secondary efficacy endpoints, 
statistical analyses will be performed in the following sequence: change from baseline to 
Week 26 in 6MWD, change from baseline to Week 26 in NT-proBNP, time from 
randomization to first disease progression event, and absence of worsening from baseline 
to Week 26 in WHO FC. The changes from baseline to Week 26 in other RHC variables 
will be excluded from this hierarchical testing strategy as they include too many variables. 
Secondary efficacy variables will be analyzed for the FAS at α = 0.05 (two-sided) using 
95% CIs. 
Change from baseline to Week 26 in NT-proBNP (log-transformed) will be analyzed using 
an ANCOVA with factors for treatment group, region, baseline WHO FC, and a covariate 
for baseline NT-proBNP (log-transformed). 
Change from baseline to Week 26 in 6MWD will be analyzed using an ANCOVA with the 
same factors and a continuous covariate for baseline 6MWD. 
Absence of worsening from baseline to Week 26 in WHO FC will be analyzed using a 
logistic regression model with factors for treatment group, region, and baseline WHO FC. 
Subjects in WHO FC IV at baseline will be excluded from the latter analysis. A sensitivity 
analysis will be performed including subjects in WHO FC IV at baseline (for whom 
worsening will be defined as death or hospitalization due to PAH).  
Changes from baseline to Week 26 in RHC variables other than PVR will be analyzed 
using an ANCOVA with factors for treatment group, region, baseline WHO FC, and a 
continuous covariate for the baseline value of the variable. 
Time from randomization to first disease progression event (censored at EOMOP plus 
7 days) will be described by Kaplan-Meier plots and analyzed by the logrank test and a 
Cox model with factors for treatment group, region and baseline WHO FC. These analyses 
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will also be performed in the subset of subjects from the FAS who received at least one 
dose of double-blind study treatment. In that case the variable is defined as time from first 
double-blind study treatment intake to first disease progression event (censored at end of 
double-blind study treatment plus 7 days, or EOMOP plus 7 days, whichever is first). 
The components of the first occurrence of disease progression events will be tabulated by 
treatment group. If for a given subject two components occur on the same day then the 
worst will be tabulated (according to the hierarchy: death, hospitalization, initiation of 
therapy for worsening PAH, and clinical worsening). 
Analysis of efficacy variables between EOMOP and EOT (i.e., after the main observation 
period) will be described in the SAP.  
11.3.4 Analysis of the other efficacy variables 
Changes from baseline to all regular collection timepoints in NT-proBNP 
(log-transformed) will be analyzed using a mixed model for repeated measurements with 
factors for treatment group, visit and treatment by visit interaction and a continuous 
covariate for baseline NT-proBNP (log-transformed). An unstructured covariance matrix 
will be used to account for the correlation between measurements of the same subject. 
Changes from baseline to all regular visits in 6MWD will be analyzed using the same 
model, but with a covariate for baseline 6MWD. 
Absence of worsening from baseline to all regular visits in WHO FC will be summarized 
by treatment group using descriptive statistics. Subjects in WHO FC IV at baseline will be 
excluded from this analysis. 
Unsatisfactory clinical response will be summarized by treatment group using descriptive 
statistics. This analysis will also be performed excluding subjects who already have an 
unsatisfactory ‘response’ at baseline (i.e., WHO FC III or IV or a baseline 6MWD ≤ 440 m, 
accompanied by NT-proBNP ≥ 3 × ULN). 
The number of treatment goals met at Week 26 (0–5) will be compared between treatment 
groups using the Cochran-Mantel-Haenszel test, stratified by baseline WHO FC and 
6MWD (≤ 440 m versus > 440 m). This analysis will also be performed excluding subjects 
who already had one or more goals met at baseline. 
Analysis of efficacy variables between EOMOP and EOT (i.e., after the main observation 
period) will be described in the SAP.  
11.3.5 Analysis of the safety variables 
All safety analyses will be performed on the Safety Set using descriptive statistics. Where 
indicated, safety analyses will also be performed on the subset of subjects who received at 
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least one dose of double-blind study treatment (i.e., selexipag or placebo). All safety data 
will be listed, with flags for quantitative abnormalities. AEs in subjects who were screened 
but not randomized will be listed. Safety analysis periods are described in Section 6.2.  
11.3.5.1 Adverse events 
A treatment-emergent AE is any AE temporally associated with the use of any of the 
3 study treatments. The number and percentage of subjects experiencing treatment 
emergent AEs and SAEs at least once will be tabulated by treatment group and by: 
• 
MedDRA system organ class (SOC) and individual preferred term within each SOC, 
in descending order of incidence. 
• 
Frequency of subjects 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 
severity and relationship to study treatment (relationship separately by study treatment).  
AEs leading to premature discontinuation of any of the 3 study treatments and AEs with 
outcome death 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, for AEs leading to premature discontinuation of study 
treatment, and for AEs with outcome death. 
Additionally, AE and SAE tables will be provided for the subset of subjects who received 
at least one dose of double-blind study treatment. In these tables only AEs with onset 
between the first and last day of double-blind study treatment will be included. AEs 
specifically related to double-blind study treatment will be tabulated as described above. 
AEs leading to premature discontinuation of double-blind study treatment and AEs on 
double-blind study treatment with outcome death will be summarized similarly. AEs and 
SAEs with onset between randomization and first day of double-blind study treatment will 
also be summarized.  
For AEs occurring more than 30 days after discontinuation of one or more of the study 
treatments, a dedicated analysis will be described in the SAP. 
11.3.5.2 Laboratory variables 
Descriptive summary statistics by visit and treatment group will be provided for observed 
values and absolute changes from baseline, in both hematology and blood chemistry 
laboratory tests. In order to minimize missing data and to allow for unscheduled visits, all 
recorded assessments up to EOT plus 30 days will be assigned to the most appropriate visit 
timepoint according to the best fitting time window for that assessment. 
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Actelion internal guidelines will be used for the definitions of marked abnormalities and 
for the standardization of numeric values obtained from different laboratories and/or using 
different normal ranges. Standard numeric laboratory variables are transformed to standard 
units. All laboratory data transferred are taken into account regardless of whether they 
correspond to scheduled (per protocol) or unscheduled assessments.  
Marked laboratory abnormalities will be summarized for each laboratory variable by 
treatment group providing their incidence and frequency. Absolute values and changes 
from baseline of laboratory values during the course of the study will be summarized using 
the usual location and scale summary statistics by treatment group. 
For laboratory variables measured see Section 7.3.7.2.  
The number and percentage of subjects with treatment-emergent laboratory abnormalities 
will be tabulated by treatment group. 
11.3.5.3 Vital signs and body weight  
Vital signs, HR, and body weight will be summarized at each study visit using the usual 
location and scale summary statistics by treatment group for both absolute values and 
changes from baseline. Subjects for whom no post-baseline value is available are excluded 
from the analysis of the changes from baseline in the Safety Set. 
11.3.6 Analysis of other variable(s) 
The individual maintenance dose for selexipag (or placebo) —defined as the dose to which 
a subject was exposed for the longest duration during the maintenance period— will be 
summarized using descriptive statistics. 
11.4 Interim analyses 
A formal interim analysis is planned at information time of 0.33, i.e., when 33% of planned 
enrolled subjects in each arm have completed their Week 26 visit assessment or 
prematurely discontinued the study.  
This interim analysis is intended to test for futility (non-binding), in order to prevent 
continuing treating subjects with triple combination therapy if it is unlikely to show a 
clinical benefit for the subjects.  
However, as the interim analysis is designed to assess the efficacy of the triple versus the 
dual combination, it is not considering all safety aspects. Thus, an IDMC will review the 
efficacy, safety and tolerability data at regular intervals prior to and after the interim 
analysis.  
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Access to randomization information will be limited to the independent SAC which will 
prepare all unblinded outputs for the interim analysis and for the regular IDMC reviews. 
The SAC will be represented by an independent statistician.  
The interim analysis will be formally performed on the primary efficacy endpoint. 
However, to ensure adequate and sufficient data for the interpretation and decision making, 
descriptive statistics will also be provided for other efficacy endpoints, selected safety 
variables (adverse events, selected laboratory abnormalities), exposure, and demographic 
data.  
11.5 Sample size 
11.5.1 Sample size justification 
Table 3 shows published PVR data from studies of initial dual therapy (bosentan and 
epoprostenol [Humbert 2004, Kemp 2012, Sitbon 2017]) and initial triple therapy 
(bosentan, epoprostenol and sildenafil [Sitbon 2014]). In addition, unpublished data from 
initial dual therapy were included [Sitbon 2015, unpublished]. 
The four studies of initial dual therapy reported reductions (calculated) of PVR from 
baseline ranging from 40% to 54% [Sitbon 2017]. The observational study of initial triple 
therapy reported a reduction (calculated) of PVR of 68% (95% CI: 62%–74%) 
[Sitbon 2014].  
For the anticipated treatment difference (triple versus dual therapy group) it should be 
noted that the data from Table 3 are from different studies that may not be fully comparable 
and that the information on initial triple therapy is limited (n = 18). Taking into account 
those limitations (as well as the possibly less pronounced PVR reduction in subjects that 
do not complete 26 weeks of treatment) it is anticipated that the reduction in PVR from 
baseline in the dual therapy group is approximately 50% (GMR = 0.50), whereas the PVR 
reduction in the triple therapy is approximately 60% (GMR = 0.40), corresponding to a 
ratio of geometric means of 0.80 (20% difference in favor of triple therapy). This 
corresponds to a treatment difference on log scale of −0.223 (i.e., log(0.40)  
–log(0.50)). 
An integrated analysis of two bosentan studies (BENEFIT, AC-052-366, and EARLY, AC-
052-364) and one macitentan study (the hemodynamic sub-study of SERAPHIN, AC-055-
302) suggested that the within group standard deviation (SD) of the log-transformed ratio 
of Week 26 to baseline PVR is 0.41 (90% CI: 0.39–0.43). This is in line with the published 
PVR data where SD ranged from 0.38 to 0.44. For this trial, a more conservative SD = 0.5 
on the log-scale was assumed. 
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Considering a one-step analysis, i.e., no interim analysis, to detect a treatment difference 
of −0.223 with an SD of 0.5 (both on log-scale), a total of 212 subjects (106 per group) 
would be needed for 90% power (two-sided α = 0.05). 
However, this trial is considering an early stopping for futility, which impacts the overall 
number of subjects. Under the same hypothesis, and considering a group sequential design, 
with a Pocock boundary, and a non-binding interim analysis performed at information time 
0.33, the number of subjects needed to demonstrate this difference (i.e., –0.223) at the final 
analysis is increased to 238 subjects.  
The interim analysis is to be performed when 33% of the planned total number of subjects 
have completed the Week 26 PVR assessment or prematurely discontinued the study. 
Under those assumptions and considering the current selected boundary, it is expected that 
the study should be stopped if a reduction compared to placebo (on log scale) lower than 
or equal to 0.042 is observed (assuming equal SD of 0.5). In other words, H1 (reduction of 
approximately 0.223 on a log scale compared to placebo) is to be rejected if a 
p-value ≥ 0.706 is observed at interim analysis [Table 4].  
Table 3 
Mean and SD for PVR, log-transformed PVR and change from 
baseline on log-scale 
 
 
N 
Mean 
dyn.s-1cm-5 
SD 
dyn.s-1cm-5 
SD 
(log-
scale) 
Mean 
(log-
scale) 
GMR 
(% red)2 
[95% CI] 
Dual Therapy 
 
 
 
 
 
 
 
Humbert 2004 
Baseline 
22 
1511 
605.1 
0.39 
7.25 
 
 
Week 16 
22 
947 
487.8 
0.49 
6.74 
 
 
CFB1 
22 
- 
- 
0.44 
−0.51 
0.60 (40%)  
[27%–50%] 
Kemp 2012 
Baseline 
23 
1493 
398 
0.26 
7.27 
 
 
Month 4 
23 
784 
364 
0.44 
6.57 
 
 
CFB 
23 
- 
- 
0.38 
−0.71 
0.49 (51%) 
[42%–58%] 
Sitbon 2015 
(unpublished) 
Baseline 
52 
1076 
385 
0.35 
6.92 
 
 
Month 4 
52 
620 
292 
0.45 
6.33 
 
 
CFB 
52 
- 
- 
0.41 
−0.59 
0.55 (45%) 
[38%–51%] 
Sitbon 2017 
Baseline 
16 
808 
312 
NC3 
NC3 
 
 
Week 16 
16 
384 
184 
NC3 
NC3 
 
 
CFB 
16 
- 
- 
NC3 
NC3 
0.46 (54%) 
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N 
Mean 
dyn.s-1cm-5 
SD 
dyn.s-1cm-5 
SD 
(log-
scale) 
Mean 
(log-
scale) 
GMR 
(% red)2 
[95% CI] 
[48%–60%] 
Triple Therapy 
 
 
 
 
 
 
 
Sitbon 2014 
Baseline 
18 
1718 
627 
0.35 
7.39 
 
 
Month 4 
18 
564 
260 
0.44 
6.24 
 
 
CFB 
18 
- 
- 
0.40 
−1.15 
0.32 (68%) 
[62%–74%] 
The means and SDs for untransformed PVR were taken from the publications, whereas the means and SDs for 
log-transformed PVR were calculated from those. 
1 Change from baseline. For the SD on log scale a correlation of 0.5 was assumed between baseline and post-baseline.  
2 Geometric Mean Ratio to baseline (percentage reduction from baseline). 
CFB = change from baseline; CI = confidence interval; GMR = geometric mean ratio; PVR = pulmonary vascular 
resistance; SD = standard deviation. 
3 NC = “Not Calculated” as treatment effect is directly provided in reference. 
 
11.5.2 Sample size sensitivity 
Table 4 shows the sample sizes when the assumptions about PVR reduction from baseline 
(50% in the dual therapy group versus 60% in the triple therapy group) are not entirely met. 
For the dual therapy group 40% to 60% reduction was considered and for the triple therapy 
group an additional 10% to 15% reduction was assumed. 
Table 4 
Sample sizes needed for 90% power at final analysis, and stopping 
value for futility at interim analysis (two-sided α = 0.05, SD = 0.5, 
information time = 0.33) 
PVR 
reduction 
in dual 
therapy 
group 
PVR 
reduction 
in triple 
therapy 
group 
Treatment 
effect 
GMR 
(% red)(2) 
Number 
of 
subjects  
Number of 
subjects at 
interim 
analysis  
Stop for futility if 
PVR reduction in 
triple therapy 
group ≤ (1) 
Stop for futility if 
p-value ≥  
40% 
55% 
0.75 (25%) 
144 
48 
43.21% 
0.704 
40% 
50% 
0.83 (17%) 
357 
119 
42.06% 
0.703 
50% 
65% 
0.70 (30%) 
91 
31 
53.19% 
0.713 
50% 
60% 
0.80 (20%) 
238 
79 
52.06% 
0.706 
60% 
75% 
0.63 (37%) 
54 
18 
63.34% 
0.705 
60% 
70% 
0.75 (25%) 
144 
48 
62.21% 
0.704 
Retained scenario (dual: 50% / triple: 60%) appears in bold. PVR = pulmonary vascular resistance, SD = standard 
deviation. 
(1) Lowest PVR reduction in the triple combination below which, for the corresponding dual therapy PVR reduction, the 
difference with the dual therapy implies rejection of H1. 
(2) Geometric Mean Ratio (GMR) of triple therapy over dual therapy (percentage reduction). 
 
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It can be seen that the proposed sample size of 238 subjects is robust to most deviations 
from the assumptions. Calculations were done using software EAST version 6.4. 
12 DATA HANDLING 
12.1 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. 
Case Report Form (CRF) 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 
staff will be trained to enter and edit the data via a secure network, with secure access 
features (username, password, and identification – an electronic password system). A 
complete electronic audit trail will be maintained. The investigator/delegate will approve 
the data (i.e., confirm the accuracy of the data recorded) using an electronic signature 
(according to 21 CFR Part 11). 
Subject Screening data will be completed for all subjects (i.e., eligible and non-eligible) 
through the IRT system and eCRF. 
For each subject enrolled, regardless of study treatment initiation, an eCRF must be 
completed and signed by the investigator/delegate. This also applies to those subjects who 
fail to complete the study. If a subject withdraws from the study, the reason is noted in the 
eCRF. However, the subject is not obliged to provide a reason. 
12.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On eCRFs or 
other documents (e.g., documents attached to SAE reports) submitted to Actelion and any 
external service providers, subjects must be identified only by number, and never by name 
or initials, hospital numbers, or any other identifier. The investigator/delegate must keep a 
subject identification code list, at the site, showing the screening/randomization number, 
the subject’s name, date of birth, and address or any other locally accepted identifiers. 
Documents identifying the subjects (e.g., signed ICFs) must not be sent to Actelion, and 
must be kept in strict confidence by the investigator/delegate. 
12.3 Database management and quality control 
Electronic CRFs will be used for all subjects. The investigator/delegate will have access to 
the site eCRF data until the database is closed. Thereafter, they will have read-only access. 
The eCRF must be kept current to reflect subject status at any timepoint during the course 
of the study.  
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While entering the data, the investigator/delegate will be instantly alerted to data queries 
by validated programmed checks. Additional data review will be performed by Actelion 
on an ongoing basis to look for unexpected patterns in data and study monitoring. If 
discrepant data are detected, a query specifying the problem and requesting clarification 
will be issued and visible to the investigator/delegate via the eCRF. All electronic queries 
visible in the system either require a data correction (when applicable) and a response from 
the investigator/delegate to clarify the queried data directly in the eCRF, or simply a data 
correction in the eCRF. The investigator/delegate must, on request, supply Actelion with 
any required background data from the study documentation or clinical records. This is 
particularly important when errors in data transcription are suspected. In the case of 
regulatory authority queries, it is also necessary to have access to the complete study 
records, provided that subject confidentiality is protected. 
This process will continue until database closure. 
Laboratory samples will be processed through a central laboratory and the results will be 
loaded electronically into the clinical database [for exceptions see Section 7.3.7.1]. 
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 SOP. After database closure, the investigator will receive the eCRFs of the 
subjects pertaining to her/his site (including all data changes made) on electronic media. 
13 PROCEDURES AND GOOD CLINICAL PRACTICE 
13.1 Ethics and Good Clinical Practice 
Actelion and the investigators will ensure that the study is conducted in full compliance 
with the latest versions of ICH-GCP Guidelines, the principles of the “Declaration of 
Helsinki”, and with the laws and regulations of the country in which the research is 
conducted. 
13.2 Independent Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document provided to the subject 
(such as Subject Information Leaflet used to obtain informed consent) to an IRB or IEC. 
Approval from the committee 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 subject information leaflet after receipt of the 
approval must also be submitted as amendments by the investigator to the IRB/IEC in 
accordance with local procedures and regulations [see Section 13.6]. 
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A list of members participating in the IRB/IEC 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 study staff member was 
present during a meeting, it must be clear that this person did not vote. 
13.3 Informed consent 
It is the responsibility of the investigator/delegate to obtain informed consent according to 
ICH-GCP guidelines and local regulations from each individual participating in this study 
and/or legal representative. The investigator/delegate must explain to subjects that they are 
completely free to refuse to enter the study, or to withdraw from it at any time for any 
reason and without having to provide any justification. 
The ICF will be provided in each country’s local language(s). 
Site staff authorized to participate to the consent process and/or to obtain consent from the 
subject and/or legal representative will be listed on Actelion Delegation of Authority form. 
A study physician must always be involved in the consent process. 
The subject and/or legal representative must sign, personally date and time (if appropriate) 
the ICF before any study-related procedures (i.e., any procedures required by the protocol) 
begin. The ICF must also be signed, personally dated and timed (if the first study-mandated 
procedure was performed on the same day informed consent was obtained) by the 
authorized site staff listed on Actelion Delegation of Authority form. 
A copy of the signed and dated ICF is given to the subject and/or legal representative; the 
original is filed in the site documentation.The informed consent process must be fully 
documented in the subject’s medical records. This must include the study reference, the 
subject number, the date and, if applicable, time when the subject was first introduced to 
Actelion clinical study, the date and, if applicable, time of consent, who participated in the 
consent discussion, who consented the subject, and any additional person present during 
the consent process (e.g., subject family member), a copy of the signed ICF given to the 
subject / legal representative. 
In the case that the site would like to recruit subjects who are considered as vulnerable 
(e.g., subject cannot read or write, does not speak or understand the ICF language), 
additional measures must be implemented in order to ensure subject’s rights are respected 
and the consent obtained is legally valid. Actelion, the regulatory authorities (if applicable), 
and the IRB/IEC must be informed prior to the recruitment. The consent process (e.g., 
involvement of an impartial witness) must be fully described, submitted to, and approved 
by the IRB/IEC, according to procedures and before subjects are recruited. 
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13.4 Compensation to subjects and investigators 
Actelion provides insurance in order to indemnify (with both legal and financial coverage) 
the investigator/site against claims arising from the study, except for claims that arise from 
malpractice and/or negligence. 
The compensation of the subject in the event of study-related injuries will comply with 
applicable regulations. 
13.5 Protocol adherence/compliance 
The investigator must conduct the study in compliance with the approved version of the 
protocol and must not implement any deviation/change from the protocol, except when 
deviation is necessary to eliminate an immediate hazard to the subject. 
If a protocol deviation occurs, the investigator/delegate will inform Actelion or its 
representative, in a timely manner. The investigator/delegate must document and explain 
any deviation from the approved protocol. Deviations considered to be a violation of GCP 
must be reported to the IRB/IEC and regulatory authorities according to Actelion or 
(overruling) local requirements. 
13.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. A 
protocol amendment must be submitted to IRB/IEC and regulatory authorities, according 
to their requirements. 
13.7 Essential documents and retention of documents 
The investigator/delegate must maintain adequate records necessary for the reconstruction 
and evaluation of the study. A number of attributes are considered of universal importance 
to source data and the records that hold those data. These include that the data and records 
are accurate, legible, contemporaneous, original (or certified copy), attributable, complete, 
consistent, enduring, and available when needed. 
These records are to be classified into two different categories of documents: ISF and 
subject clinical source documents. 
These records must be kept by the investigator for as long as is necessary to comply with 
Actelion’s requirements (i.e., as specified in the clinical study agreement), and national 
and/or international regulations, whichever would be the longest period. If the investigator 
cannot guarantee this archiving requirement at the site for any or all of the documents, 
special arrangements, respecting the data confidentiality, must be made between the 
investigator and Actelion to store these documents outside the site, so that they can be 
retrieved in case of a regulatory inspection. No study document should be destroyed 
without prior written approval from Actelion. Should the investigator wish to assign the 
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study records to another party, or move them to another location, Actelion must be notified 
in advance. 
If the site is using an electronic/computerized system to store subject medical records, it 
can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 or 
equivalent standard) and if the monitor has been provided personal and restricted access to 
study subjects only, to verify consistency between electronic source data and the eCRF 
during monitoring visits. 
If the site is using an electronic/computerized system to store subject medical records but 
it could not be confirmed that the system is validated or if the monitor could not be provided 
access to the system, the site is requested to print the complete set of source data needed 
for verification by the monitor. 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 subject’s data. The 
printouts will be considered as the official clinical study records and must be filed either 
with the subject medical records or with the subject’s eCRF. 
In order to verify that the process the site uses to prepare certified copies is reliable, the 
monitor 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 monitor does not need 
to verify this process for all data of all subjects but at least for some of them (e.g., first 
subject; regular check during the study of critical data like inclusion/exclusion criteria, 
endpoints for some subjects) as per Actelion’s instructions. If it were not possible for the 
monitor 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. 
13.8 Monitoring 
Prior to study start, a site initiation visit (SIV) will be performed after the required essential 
study documents are approved by Actelion. The study treatment will be shipped to the site 
upon approval of the required essential documents. 
The PI must ensure that all site personnel involved in the study are present during the SIV 
and will dedicate enough time to it. Site Information Technology support should also be 
available during the initiation visit. 
The SIV must be completed before the site can start the screening of study subjects. 
Following the SIV, a copy of the completed initiation visit report and follow-up letter will 
be provided to the PI and filed in the ISF. 
During the study, the monitor 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 
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entered in the eCRFs and other protocol-related documents. Actelion monitoring standards 
require full verification that informed consent has been provided, verification of adherence 
to the inclusion/exclusion criteria, documentation of SAEs, and the recording of the main 
efficacy, safety, and tolerability endpoints. Additional checks of the consistency of the 
source data with the eCRFs will be performed according to the study-specific monitoring 
plan. The frequency of the monitoring visits will be based on subject recruitment rate and 
critical data collection times. 
The PI must ensure that the eCRF is completed after a subject’s visit (site visit or phone 
call), and that all requested subject files (e.g., ICFs, medical notes/charts, other 
documentation verifying the activities conducted for the study) are available for review by 
the monitor. The required site personnel must be available during monitoring visits and 
allow adequate time to meet with the monitor to discuss study related issues. 
The investigator agrees to cooperate with the monitor(s) to ensure that any issues detected 
in the course of these monitoring visits are resolved. If the subject is hospitalized or dies in 
a hospital other than the study site, the investigator is responsible for contacting that 
hospital in order to document the SAE, in accordance with local regulations. 
A close-out visit will be performed for any initiated site when there are no more active 
subjects and all follow-up issues have been resolved. In case a site does not enroll any 
subjects, the close-out visit may be performed prior to study database closure at the 
discretion of Actelion. 
13.9 Investigator Site File 
Each site will be provided with an ISF prior to the initiation visit. It will contain all the 
essential documents that are required to always be up-to-date and filed at site as per ICH 
E6 GCP Section 8. 
The ISF will include a table of content listing the essential documents. All study-related 
documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the monitor regarding the filing of the 
study documents outside the ISF. It should be clearly documented where each document is 
filed. This note to file should be present in the specific tab of the document in the ISF. 
The ISF must be stored in a secure and access-restricted area during and after the study. It 
must be kept by the site for as long as needed to comply with any applicable rules and 
regulations, ICH-GCP, as well as instructions from Actelion. If the site needs to transfer 
the ISF to another location and/or if site facility can no longer store the ISF, the PI must 
inform Actelion immediately. 
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If the PI will change, or if the site will relocate, the monitor must be notified as soon as 
possible. 
13.10 Audit 
Actelion’s Global Quality Management representatives may audit the investigator site 
(during the study or after its completion). The purpose of this visit will be to determine the 
investigator’s adherence to ICH-GCP, the protocol, and applicable regulations; adherence 
to Actelion’s requirements (e.g., SOPs) will also be verified. Prior to initiating this audit, 
the investigator will be contacted by Actelion to arrange a time for the audit. 
The investigator and staff must cooperate with the auditor(s) and allow access to all study 
documentation (e.g., subject records) and facilities. 
13.11 Inspections 
Regulatory authorities and/or IRB/IEC may also conduct an inspection of Actelion’s 
clinical study (during the study or after its completion). 
Should an inspection be announced by a regulatory authority and/or IRB/IEC, the 
investigator must inform Actelion immediately (usually via the monitor) that such a request 
has been made. 
The investigator and staff must cooperate with inspector(s) and allow access to all study 
documentation (e.g., subject records) and study facilities. 
13.12 Reporting of study results and publication 
Study results will be documented in a clinical study report that will be signed by Actelion 
representatives and the coordinating investigator (or PI for single-center studies). 
The coordinating investigator and the SC, if any, will have the opportunity to review the 
analysis of the data and to discuss the interpretation of the study results with Actelion prior 
to publication. 
Actelion will post results from this clinical study on Actelion’s Clinical Trial Register and 
on external/national registries, as required by local law.  
Actelion’s Policy on Disclosure of Clinical Research Information can be found at: 
http://www.actelion.com/documents/corporate/policies-charters/policy-clinical-research-
information.pdf 
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 publication in a peer-reviewed journal. 
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Authorship will be determined in accordance with the International Committee of Journal 
Editors (ICMJE) criteria, and be based on: 
• substantial contributions to the conception or design of the study, or the acquisition, 
analysis, or interpretation of data; and 
• drafting of the publication or critical review for important intellectual content; and 
• providing final approval of the version to be published; and 
• agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved. 
The list of authors of any publication of study results may include representatives of 
Actelion and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted to 
Actelion for review at least 30 days prior to submission for publication or presentation. 
Upon review, Actelion may provide comments, and may also request alterations and/or 
deletions for the sole purpose of protecting its confidential information and/or patent rights. 
Neither the institution nor the investigator should permit publication during such a review 
period. 
Actelion’s Policy on Scientific Publications can be found at: 
http://www.actelion.com/documents/corporate/policies-charters/policy-scientific-
publications.pdf 
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