Conditions: Pulmonary Arterial Hypertension
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 247
Healthy volunteers: no

Brief summary:
The objective of this clinical trial is to compare the efficacy and safety of an initial triple oral treatment regimen (macitentan, tadalafil, selexipag) versus an initial dual oral treatment regimen (macitentan, tadalafil, placebo) in newly diagnosed, treatment-naïve patients with pulmonary arterial hypertension.

Detailed description:

Arms:
arm 1: Macitentan, tadalafil, and selexipag arm 2: Macitentan, tadalafil, and placebo

Interventions: intervention 1: Macitentan intervention 2: Tadalafil intervention 3: Selexipag
Intervention descriptions: intervention 1: Used open-label in both arms, 10 mg tablet, 1 tablet u.i.d. intervention 2: Used open-label in both arms, 20 mg tablet, 1-2 tablets u.i.d. intervention 3: Used double-blind in the triple oral treatment arm, 200 microgram tablet, 1-8 tablets b.i.d.

Protocol document:
SAP_002.pdf: 
TPL-000241 v02 
STATISTICAL ANALYSIS PLAN FOR CSR 
VERSION 3 
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 (TRITON) 
Purpose of Analysis 
Clinical Study Report 
Investigational Drug 
Selexipag / ACT-293987 
Protocol Number 
AC-065A308/TRITON 
Actelion Document Number 
D-19.253
Document Status/Version Number 
Final 3.0
Date 
20 August 2019
Author(s) 
, CRO Trial Statistician 
, Actelion Trial Statistician 
, Statistician 
Reviewer 
, Head of Global Post Approval 
Studies 
Reviewer 
, Clinical Trial Scientist  
Reviewer 
Reviewer 
, Senior Expert Statistician 
, Senior Drug Safety 
Physician 
Confidential 
Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or 
otherwise disclosed without the consent of Actelion Pharmaceuticals Ltd. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
NCT02558231


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................9 
1 
INTRODUCTION .......................................................................................................12 
1.1 
Study documents ...........................................................................................12 
2 
STUDY DESIGN AND FLOW ..................................................................................12 
2.1 
Study design .................................................................................................12 
2.2 
Study visit and assessment schedule ............................................................15 
3 
OBJECTIVES .............................................................................................................16 
3.1 
Primary objective(s) .....................................................................................16 
3.2 
Secondary objective(s) .................................................................................16 
3.3 
Other objective(s) .........................................................................................16 
4 
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL .................................................................................................16 
4.1 
Changes to the analyses planned in the study protocol ................................16 
4.2 
Changes in the conduct of the study / data collection ..................................17 
4.3 
Clarifications concerning endpoint definitions and related variables or 
statistical methods .........................................................................................17 
5 
DEFINITIONS OF VARIABLES ..............................................................................17 
5.1 
Screened failures ...........................................................................................17 
5.2 
Subject characteristics ..................................................................................17 
5.2.1 
Demographics ...................................................................................17 
5.2.2 
Baseline disease characteristics ........................................................17 
5.2.3 
Other baseline characteristics ...........................................................18 
5.2.4 
Medical history .................................................................................18 
5.2.5 
Previous and concomitant therapies .................................................18 
5.2.5.1 
Previous therapies ....................................................................18 
5.2.5.2 
Baseline-concomitant therapies ...............................................18 
5.2.5.3 
Study-treatment-concomitant therapies ...................................19 
5.3 
Study treatment exposure .............................................................................19 
5.3.1 
Exposure to study drugs ....................................................................19 
5.3.1.1 
Exposure to macitentan (days) ................................................19 
5.3.1.2 
Exposure to tadalafil (days) .....................................................19 
5.3.1.3 
Exposure to selexipag/placebo (days) .....................................19 
5.3.1.4 
Exposure to combinations (days) ............................................21 
5.3.2 
Study treatment discontinuation .......................................................21 


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5.3.3 
Study treatment adjustments or interruptions ...................................21 
5.4 
Study discontinuation ...................................................................................21 
5.5 
Efficacy variables .........................................................................................21 
5.5.1 
Primary efficacy variable ..................................................................21 
5.5.2 
Secondary efficacy variables ............................................................22 
5.5.2.1 
Change from baseline to Week 26 in six-minute walk distance
 .................................................................................................22 
5.5.2.2 
Change from baseline to Week 26 in NT-proBNP ..................22 
5.5.2.3 
Absence of worsening from baseline to Week 26 in WHO FC
 .................................................................................................22 
5.5.2.4 
Change from baseline to Week 26 in hemodynamic variables 
other than PVR ........................................................................22 
5.5.2.5 
Time to the first disease progression event up to EOMOP + 7 
days ..........................................................................................23 
5.5.3 
Other efficacy variables ....................................................................23 
5.5.3.1 
Changes of secondary efficacy endpoints from baseline to 
EOMOP ...................................................................................23 
5.5.3.2 
Unsatisfactory clinical response ..............................................23 
5.5.3.3 
Number of treatment goals met at Week 26 ............................24 
5.5.3.4 
Improvement of WHO FC from baseline to Week 26 ............25 
5.5.3.5 
Hospitalizations up to EOMOP ...............................................25 
5.6 
Safety variables .............................................................................................26 
5.6.1 
Adverse events ..................................................................................26 
5.6.1.1 
Treatment-emergent adverse events ........................................26 
5.6.1.2 
Frequency of treatment-emergent adverse events ...................26 
5.6.1.3 
Intensity of treatment-emergent adverse events ......................27 
5.6.1.4 
Relationship of treatment-emergent adverse events ................27 
5.6.2 
Deaths ...............................................................................................27 
5.6.3 
Serious adverse events ......................................................................27 
5.6.4 
Non-serious adverse events ..............................................................27 
5.6.5 
Adverse events leading to discontinuation of study treatment .........27 
5.6.6 
Other significant adverse events .......................................................27 
5.6.7 
Vital signs and body weight ..............................................................28 
5.6.8 
Electrocardiogram .............................................................................28 
5.6.9 
Laboratory .........................................................................................28 
5.6.9.1 
Hematology tests .....................................................................28 
5.6.9.2 
Biochemistry tests ...................................................................29 
5.6.9.3 
Coagulation tests .....................................................................29 
5.6.9.4 
Pregnancy tests ........................................................................29 
5.6.9.5 
Biomarkers ..............................................................................29 
5.6.9.6 
Schedule of assessments ..........................................................29 


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6 
DEFINITION OF PROTOCOL DEVIATIONS .........................................................29 
7 
ANALYSIS SETS .......................................................................................................30 
7.1 
Definitions of analysis sets ...........................................................................30 
7.1.1 
Screened analysis set ........................................................................30 
7.1.2 
Full analysis set .................................................................................30 
7.1.3 
Modified Full Analysis Set ...............................................................30 
7.1.4 
Per-protocol analysis set ...................................................................30 
7.1.5 
Safety analysis set .............................................................................30 
7.2 
Usage of the analysis sets .............................................................................31 
8 
DEFINITION OF SUBGROUPS ................................................................................31 
9 
GENERAL STATISTICAL METHODOLOGY ........................................................32 
9.1 
Design of the study .......................................................................................32 
9.2 
Statistical methods used for the primary endpoint .......................................32 
9.3 
Analysis of covariance for secondary efficacy parameters ..........................33 
9.4 
Logistic regression for dichotomous outcomes ............................................34 
9.5 
Time to event analyses .................................................................................34 
9.6 
Mixed model repeated measures analyses ....................................................35 
9.7 
Cochran-Mantel-Haenszel test for categorical outcomes .............................36 
9.8 
Multiple imputation method analysis ...........................................................37 
9.9 
Analysis method for counts and rates ...........................................................38 
10 STATISTICAL ANALYSES ......................................................................................38 
10.1 
Overall testing strategy .................................................................................38 
10.1.1 
Type I error adjustment .....................................................................39 
10.1.2 
Type II error (power) ........................................................................39 
10.2 
General rules for data presentations .............................................................39 
10.2.1 
General guidelines for table contents ................................................39 
10.2.2 
General guidelines for table layout and formats ...............................40 
10.2.3 
Analysis of variables between EOMOP and EOT ............................40 
10.3 
Display of subject disposition, protocol deviations and analysis sets ..........40 
10.3.1 
Subject disposition ............................................................................40 
10.3.2 
Protocol deviations ...........................................................................41 
10.3.3 
Analysis sets .....................................................................................41 
10.4 
Analyses of subject characteristics ...............................................................41 
10.4.1 
Demographics ...................................................................................41 
10.4.2 
Baseline disease characteristics ........................................................41 
10.4.3 
Other baseline characteristics ...........................................................41 
10.4.4 
Medical history .................................................................................41 


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10.4.5 
Previous and concomitant therapies .................................................42 
10.5 
Analysis of study treatment exposure ...........................................................42 
10.5.1 
Exposure ...........................................................................................42 
10.5.1.1 
Exposure to macitentan (days) ................................................42 
10.5.1.2 
Exposure to tadalafil (days) .....................................................42 
10.5.1.3 
Exposure to selexipag/placebo (days) .....................................42 
10.5.1.4 
Exposure to combinations (days) ............................................42 
10.5.2 
Study treatment discontinuation .......................................................43 
10.6 
Analyses of the primary and secondary efficacy variables ..........................43 
10.6.1 
Description of the estimand for the primary and first secondary 
efficacy variables ..............................................................................43 
10.6.2 
Analysis of the primary efficacy variable(s) .....................................48 
10.6.2.1 
Hypothesis and statistical model .............................................48 
10.6.2.2 
Primary endpoint PVR ............................................................48 
10.6.2.3 
Main analysis ...........................................................................48 
10.6.2.4 
Supportive/sensitivity analyses ...............................................49 
10.6.2.5 
Subgroup analyses ...................................................................50 
10.6.3 
Analysis of the secondary efficacy variables ....................................50 
10.6.4 
Secondary endpoints .........................................................................51 
10.6.4.1 
Change from baseline to Week 26 in six-minute walk distance
 .................................................................................................51 
10.6.4.2 
Change from baseline to Week 26 in NT-proBNP ..................51 
10.6.4.3 
Time to the first disease progression event .............................52 
10.6.4.4 
Absence of worsening from baseline to Week 26 in WHO FC
 .................................................................................................53 
10.6.4.5 
Change from baseline to Week 26 in hemodynamic variables 
other than PVR ........................................................................53 
10.6.4.6 
Analyses of endpoints after Week 26, EOMOP and EOT visits
 .................................................................................................54 
10.6.4.7 
Subgroup analyses ...................................................................54 
10.7 
Analysis of other efficacy variables .............................................................54 
10.7.1 
Change of NT-proBNP from baseline to all regular collection 
time points up to EOMOP ................................................................54 
10.7.2 
Change of 6MWD from baseline to all regular collection time 
points up to EOMOP .........................................................................55 
10.7.3 
Absence of worsening from baseline in WHO FC to all regular 
collection time points up to EOMOP ................................................55 
10.7.4 
Unsatisfactory clinical response .......................................................55 
10.7.5 
Number of treatment goals met at Week 26 .....................................55 
10.7.6 
Improvement of WHO FC from baseline to Week 26 ......................55 
10.7.7 
Hospitalizations up to EOMOP ........................................................56 


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10.7.7.1 
Time from randomization to first hospitalization (all causes)  
up to EOMOP ..........................................................................56 
10.7.7.2 
Time from randomization to first hospitalization for worsening 
PAH up to EOMOP .................................................................56 
10.7.7.3 
Annualized rate of hospitalization (all causes) up to EOMOP56 
10.7.7.4 
Annualized rate of hospitalization for worsening PAH up to 
EOMOP ...................................................................................56 
10.7.7.5 
Annualized rate of days spent in hospital (all causes) up to 
EOMOP ...................................................................................56 
10.7.7.6 
Annualized rate of days spent in hospital for worsening PAH 
up to EOMOP ..........................................................................56 
10.8 
Analysis of safety variables ..........................................................................57 
10.8.1 
Adverse events ..................................................................................57 
10.8.2 
Deaths, other serious adverse events ................................................58 
10.8.2.1 
Death .......................................................................................58 
10.8.2.2 
Serious adverse events .............................................................58 
10.8.3 
Other adverse event analyses ............................................................58 
10.8.3.1 
Important identified or potential risks .....................................58 
10.8.3.2 
Adverse events related to the addition of selexipag to the dual 
treatment regimen ....................................................................59 
10.8.3.3 
Other adverse events of special interest ..................................59 
10.8.3.4 
Summaries of adverse events for disclosure ...........................59 
10.8.4 
Electrocardiography ..........................................................................60 
10.8.5 
Laboratory tests .................................................................................60 
10.8.5.1 
Marked laboratory abnormalities ............................................60 
10.8.5.2 
Other notable laboratory abnormalities (hepatic safety) .........62 
10.8.6 
Vital signs and body weight ..............................................................62 
10.8.6.1 
Clinically relevant vital signs abnormalities ...........................62 
10.9 
Interim analysis .............................................................................................63 
11 GENERAL DEFINITIONS AND DERIVATIONS ...................................................63 
11.1 
Study treatment start and end date ................................................................63 
11.1.1 
Treatment-emergent assessments or events ......................................63 
11.2 
Study days .....................................................................................................63 
11.3 
Baseline definition ........................................................................................63 
11.4 
Assignment of assessment dates to the most appropriate analysis time 
point (visit windows) ....................................................................................63 
11.4.1 
Visit windows for primary efficacy variable, hemodynamics 
from RHC .........................................................................................64 
11.4.2 
Visit windows for six-minute walk test, WHO FC, NT-
proBNP, regular laboratory (except hemoglobin and liver 
function tests) ....................................................................................64 


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11.4.3 
Visit windows for hemoglobin and liver function tests ....................64 
11.4.4 
Visit windows for vital signs and body weight.................................65 
11.5 
Identification of prohibited medication and medications of special 
interest ..........................................................................................................65 
11.6 
Handling of selexipag/placebo dose titrations over day ...............................69 
12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS ...............69 
12.1 
Imputation of previous/concomitant medication and therapy dates .............70 
12.1.1 
Previous/concomitant medication and therapy start date .................70 
12.1.2 
Previous/concomitant medication and therapy end date ...................70 
12.2 
Imputation of AE start and end dates ...........................................................71 
12.2.1 
AE start date ......................................................................................71 
12.2.2 
AE end date .......................................................................................71 
12.3 
Imputation of other date fields ......................................................................71 
12.3.1 
Date of PAH diagnosis .....................................................................71 
12.4 
Imputation of hospital admission and discharge dates .................................72 
12.4.1 
Hospital admission date ....................................................................72 
12.4.2 
Hospital discharge date .....................................................................72 
13 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES .................................73 
13.1 
Subject disposition ........................................................................................73 
13.2 
Protocol deviations .......................................................................................74 
13.3 
Subject characteristics ..................................................................................74 
13.3.1 
Demographics ...................................................................................74 
13.3.2 
Baseline disease characteristics ........................................................75 
13.3.3 
Other baseline characteristics ...........................................................75 
13.3.4 
Medical history .................................................................................75 
13.3.5 
Previous and concomitant therapies .................................................76 
13.4 
treatment exposure ........................................................................................77 
13.4.1 
Exposure ...........................................................................................77 
13.4.2 
Study treatment discontinuation .......................................................79 
13.5 
Study withdrawal ..........................................................................................79 
13.6 
Primary efficacy analyses .............................................................................80 
13.6.1 
Main analysis ....................................................................................80 
13.6.2 
Supportive/sensitivity analyses .........................................................80 
13.6.3 
Subgroup analyses ............................................................................82 
13.6.4 
Secondary efficacy analyses .............................................................83 
13.7 
Other efficacy analyses .................................................................................90 
13.8 
Safety analyses .............................................................................................93 
13.8.1 
Adverse events ..................................................................................93 
13.9 
Deaths and serious adverse events ................................................................97 
13.9.1 
Deaths ...............................................................................................97 


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13.9.2 
Serious adverse events ......................................................................98 
13.9.3 
Adverse events leading to treatment discontinuation .....................100 
13.9.4 
Other significant adverse events .....................................................101 
13.10 
Summaries of adverse events for disclosure (EudraCT and 
ClinicalTrials.gov) ......................................................................................104 
13.11 
Laboratory tests ..........................................................................................105 
13.12 
Vital signs and body weight .......................................................................106 
14  REFERENCES ..........................................................................................................106 
15  APPENDICES ...........................................................................................................107 
 
LIST OF TABLES 
 
Table 1 
Overview of the different analysis sets and their usage .................................. 31 
Table 2 
Description of the estimand for primary efficacy endpoint (ratio of Week 26 
to baseline PVR)* ........................................................................................... 44 
Table 3 
Description of the estimand for first secondary efficacy endpoint (Change 
from baseline to Week 26 in 6MWD)* ........................................................... 46 
Table 4 
Definition of marked laboratory abnormalities ............................................... 61 
Table 5 
Time windows for 6-minute walk tests, WHO FC and laboratory assessments 
(except hemoglobin and liver function tests) .................................................. 64 
Table 6 
Time windows for hemoglobin and liver function tests ................................. 65 
Table 7 
Time windows for vital signs assessments ..................................................... 65 
Table 8 
Clinical forbidden medications list ................................................................. 66 
Table 9 
New PAH specific therapies ........................................................................... 68 
Table 10 
Handling of selexipag/placebo dose titrations over day ................................. 69 
 
LIST OF FIGURES 
 
Figure 1 
Study periods (subject level) ........................................................................... 14 
Figure 2 
Planned duration (study level) ........................................................................ 15 
 
LIST OF APPENDICES 
Appendix 1  Protocol Synopsis ......................................................................................... 107 
Appendix 2  Document history ......................................................................................... 117 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
6MWD  
Six-minute walk distance 
ADaM  
Analysis data model 
AE  
Adverse event 
ALT  
Alanine aminotransferase 
ANCOVA  
Analysis of covariance 
AST  
Aspartate aminotransferase 
BMI  
Body mass index 
BSA  
Body surface area 
b.i.d.  
Twice daily 
bpm  
Beats per minute 
CEC  
Clinical Events Committee 
CI  
Cardiac index 
CO  
Cardiac output 
CMH  
Cochran-Mantel-Haenszel 
CRF  
Case report form 
CSR  
Clinical study report 
CTD  
Connective tissue disease 
ECG  
Electrocardiography 
eCRF  
Electronic case report form 
EOS  
End-of-study 
EOMOP  
End of main observation period 
EOT  
End-of-treatment 
EudraCT  
European Union Drug Regulating Authorities Clinical Trials 
FAS  
Full analysis set 
FC  
Functional class 
FDA  
Food and Drug Administration 
GMR  
Geometric mean ratio 
IA  
Interim analysis 


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IDMC  
Independent data monitoring committee 
IMD  
Individual maintenance dose 
IMTD  
individual maximum tolerated dose 
ISAC  
Independent statistical analysis center 
KM  
Kaplan-Meier 
LOCF  
Last observation carried forward 
LVEDP  
Left ventricular end diastolic pressure 
MedDRA  
Medical Dictionary for Regulatory Activities 
mFAS  
Modified Full Analysis Set 
MI  
Multiple imputation 
MMRM  
Mixed model repeated measures analysis 
mPAP  
Mean pulmonary arterial pressure  
mRAP  
Mean right atrial pressure 
MTD  
Maximum tolerated dose 
NT-proBNP  
N-terminal pro B-type natriuretic peptide 
PAH  
Pulmonary arterial hypertension 
PCWP  
Pulmonary capillary wedge pressure  
PD  
Protocol deviation 
PDE  
Phosphodiesterase 
PH  
Pulmonary hypertension 
PPS  
Per-protocol analysis set 
PVR  
Pulmonary vascular resistance 
PT  
Preferred Term 
RHC  
Right heart catheterization  
SAE  
Serious adverse event 
SAF  
Safety analysis set 
SAP  
Statistical analysis plan 
SAS  
Statistical analysis system 
SD  
Standard deviation 


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SEM  
Standard error of the mean 
SMQ  
Standardized MedDRA Queries 
SOC  
System organ class 
SI  
Système international d’unités 
TC  
Teleconference 
TPR  
Total pulmonary resistance 
ULN  
Upper limit of the normal range 
WHO  
World Health Organization 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes in detail the derivations of efficacy and safety 
endpoints, the analyses and the presentation of analysis results and data for the clinical 
study report (CSR) of study AC-065A308 (TRITON).  
This SAP also describes the blinded outputs provided on a regular basis for 
independent data monitoring committee (IDMC) open session meetings (see IDMC 
charter). Those blinded outputs for IDMC are a subset of CSR outputs and are flagged 
accordingly in list of outputs provided in Section 13. 
The unblinded analyses for IDMC closed sessions (including futility interim analysis) are 
performed by the Independent Statistical Analysis Center (ISAC) according to ISAC’s own 
analysis plan. The study team remains blinded. The ISAC is responsible for the content of 
these unblinded analyses for the closed reports provided to the IDMC (see IDMC charter). 
Electronic Case Report Form (eCRF) is used for all subjects. Laboratory samples are 
processed through a central laboratory and the results are loaded electronically into the 
clinical database. All data are converted into study data tabulation model datasets and are 
provided by data management. Technical procedures and steps for processing these data 
and for implementing the definitions of variables for the purpose of the statistical analysis 
in analysis data model (ADaM) datasets are covered in the analysis datasets specifications 
document. 
1.1 Study documents  
The following study documents are used for the preparation of the SAP: 
• Protocol AC-065A308, version 6, dated 4 December 2018 [D-18.392] 
• eCRF, version 004, dated 3 May 2017 
• Case report form (CRF) completion guidelines, version 3.0, dated 9 January 2018 
• Data management plan, final version 3, dated 5 January 2018 
• Protocol deviation code list, version 4, dated 10 May 2019 
• Definition of Marked Abnormalities in Laboratory Data (OTH-000005), Version 09, 
dated 1 November 2017 
Any change to any of those documents affecting the biostatistics deliverables will require 
this SAP and related documents to be updated accordingly. 
2 
STUDY DESIGN AND FLOW 
For a detailed description refer to the study protocol [D-18.392]. 
2.1 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 


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(macitentan, tadalafil, selexipag) with a dual oral regimen (macitentan, tadalafil, placebo) 
in newly diagnosed, treatment-naïve subjects with pulmonary arterial hypertension (PAH).  
This study uses a group sequential design, with one interim analysis for futility 
(non-binding) planned when approximately one third of the subjects have completed their 
Week 26 pulmonary vascular resistance (PVR) assessment (primary endpoint) or have 
prematurely discontinued the study. The interim analysis will be performed by the ISAC 
for the IDMC who will provide Actelion with their recommendation to either continue or 
prematurely terminate the study for futility. 
Approximately 238 subjects are randomized in a 1:1 ratio to the two treatment groups 
(approximately 119 subjects per group), stratified by region (North America versus rest of 
the world) and WHO functional class (FC) at baseline (I/II versus III/IV). The study is 
conducted at approximately 75 sites in approximately 20 countries. Randomization 
proceeds until the required number of subjects has been reached. It is 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 (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 study protocol [D-18.392] 
3 For simplification, most visits between Day 1 and EOMOP (as defined below) are not displayed.  
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 week after enrollment of the last subject. This timepoint is 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 announces 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. 
EOMOP = end of main observation period; EOS = end of study; EOT = end-of-treatment; RHC = right heart catheterization. 


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Figure 2 
Planned duration (study level) 
 
*See Figure 1 for abbreviations and definitions 
The database will be partially locked once all subjects have performed their end of main 
observation period (EOMOP) visit (or prematurely discontinued from the study). 
Unblinding will follow the partial database lock. Unless otherwise specified, the analyses 
described in this SAP will be performed on this set of data including all data up to EOMOP. 
Once all subjects have undergone their end-of-treatment (EOT) and end-of-study (EOS) 
visits the database will be fully locked. Some analyses [see Section 13] will be performed 
including all data up to EOS.  
2.2 Study visit and assessment schedule 
Please refer to the protocol [D-18.392] for schedule of visits and assessments. 
Database lock / 
Unblinding 


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3 
OBJECTIVES 
3.1 Primary objective(s) 
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.  
3.2 Secondary objective(s) 
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 exercise 
capacity, cardio pulmonary hemodynamics (other than PVR), disease severity, disease 
progression events, safety, and tolerability.  
3.3 Other objective(s) 
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.  
4 
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN 
THE STUDY PROTOCOL  
4.1 Changes to the analyses planned in the study protocol 
The order of hierarchical testing for secondary endpoints is modified as compared to the 
protocol. The change from Baseline to Week 26 in six-minute walk distance (6MWD) is 
promoted as the first secondary endpoint in the hierarchical testing strategy.  
As a result, statistical analyses for secondary endpoints will be performed in the following 
sequence: 
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. Time from randomization to first disease progression event up to EOMOP + 7 days 
4. Absence of worsening from baseline to Week 26 in WHO FC 
This change is performed following interaction with the Food and Drug Administration 
(FDA; teleconference [TC] on 2 November 2017). The protocol is not amended for this 
purpose due to insufficient time to implement this change prior to the pre-planned interim 
analysis for futility. This will be added at a later stage in a protocol amendment (if any). 


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4.2 Changes in the conduct of the study / data collection 
Following a protocol amendment to increase sample size (protocol version 4 [D-18.392]), 
new countries are participating in the study. The level of randomization stratification factor 
“Europe” is re-labeled as “Rest of World” to include those new countries and ensure that 
it does not affect the original randomization list. 
4.3 Clarifications concerning endpoint definitions and related variables or 
statistical methods 
Clarifications have been added for PVR calculation when pulmonary capillary wedge 
pressure (PCWP) / left ventricular end diastolic pressure (LVEDP) at a given visit is 
missing, as described in Section 10.6.2.2. Sensitivity analyses have been added for primary 
and secondary efficacy analyses. 
In addition, primary efficacy endpoint and first secondary efficacy endpoint have been 
described in terms of estimands [Table 2 and Table 3, respectively]. 
5 
DEFINITIONS OF VARIABLES 
5.1 Screened failures 
Screened subjects are subjects who received a subject number. Screened failures are 
subjects who receive a subject number but are not randomized. If a patient is not 
randomized, the reason is collected in the eCRF. 
5.2 Subject characteristics 
Unless stated otherwise, if a subject is re-screened and baseline, demographics, or other 
characteristics are collected again, the latest assessments from the re-screening are used for 
analysis. 
5.2.1 Demographics 
Demographics are collected at screening and comprise age, sex, race, ethnicity, region, 
height, weight, body mass index (BMI) and body surface area (BSA). 
Although BSA and BMI are computed by the eCRF, the statistical analysis only considers 
the re-calculated values using weight and height.  
5.2.2 Baseline disease characteristics 
Etiology of PAH, association of PAH with other diseases, as well as WHO FC are collected 
at screening. The time since the initial diagnosis of PAH to the randomization date is 
summarized in days. 
A right heart catheterization (RHC) is performed and hemodynamic parameters – PVR 
(dyne.sec.cm-5), mean pulmonary arterial pressure (mPAP; mmHg), systolic/diastolic 
pulmonary arterial pressure (mmHg), systolic/diastolic systemic arterial pressure (mmHg), 


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PCWP (mmHg), LVEDP (mmHg), mean right atrial pressure (mRAP; mmHg), cardiac 
output (CO; L/min), total pulmonary resistance (TPR; dyne.sec.cm-5), cardiac index (CI; 
L/min/m2) – are determined. 
PVR, TPR and CI that are derived by the eCRF are listed only. The results from the 
sponsor-re-calculated PVR in the analysis database are used for analysis [see Section 5.5.1 
for formula used]. In addition, PVR is also reported by the investigator and is listed along 
with the other hemodynamic parameters, and also summarized together with the sponsor-
re-calculated PVR in the baseline characteristics tables. 
If investigator-reported PVR is entered as Wood units, it is converted to dyne.sec.cm-5 for 
analysis. The conversion follows the rule: 
80 dyne.sec.cm-5 = 1 mmHg.min.L-1 (Wood units) 
5.2.3 Other baseline characteristics 
A six-minute-walk test is performed at screening and on the day of randomization. The 
occurrence and reasons for stopping the test prematurely are collected, as well as the need 
for supplemental oxygen. After the test, the Borg dyspnea score is assessed in each subject. 
Baseline vital signs (pulse and systolic/diastolic blood pressure) are assessed at screening 
and on the day of randomization. 
A physical examination is conducted at screening. Existing abnormalities are identified and 
their clinical significance is determined. 
5.2.4 Medical history 
Clinically significant diseases or medical conditions starting prior to the screening visit are 
collected. The start date of the disease or condition is collected together with the end date 
or the information if the condition was ongoing at screening visit or not. The diagnosis is 
coded using the most current version of the MedDRA dictionary at the time of the database 
closure. 
5.2.5 Previous and concomitant therapies 
Previous and concomitant therapies are collected at every visit in the CRF. Missing or 
incomplete medication start and end dates are imputed as described in Section 12.1 in order 
to assign the dates to one of the categories below.  
5.2.5.1 Previous therapies 
A previous therapy is any treatment for which the end date of treatment is prior to Day 1.  
5.2.5.2 Baseline-concomitant therapies 
A baseline-concomitant therapy is any treatment that is ongoing at start of macitentan and 
tadalafil (as per CRF tick box) or that started prior to study treatment and is ongoing at 
Day 1, i.e., not stopped prior to Day 1. 


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5.2.5.3 Study-treatment-concomitant therapies 
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).  
5.3 Study treatment exposure  
In this study, three different study drugs are investigated: macitentan, tadalafil, and 
selexipag/placebo. With the exception of macitentan, doses are not fixed and can be 
titrated. 
5.3.1 Exposure to study drugs 
5.3.1.1 Exposure to macitentan (days) 
Macitentan is given once daily in oral form in a fixed dose. Exposure to macitentan is 
computed as the number of days between first and last dose of macitentan, regardless of 
any treatment interruptions. 
5.3.1.2 Exposure to tadalafil (days) 
Tadalafil treatment is started as a single 20 mg oral dose and subjects are up-titrated to a 
40 mg single dose after one week. Exposure to tadalafil, regardless of dose, is defined as 
the number of days between the first dose (i.e., first intake) and the last dose of tadalafil, 
regardless of treatment interruptions or titrations.  
5.3.1.3 Exposure to selexipag/placebo (days) 
Selexipag/placebo is administered in a double-blind manner, through two dosing periods.  
• A titration period, which starts 15 days after randomization as a twice daily (b.i.d.) 
oral dose of 200 μg and is up-titrated on a weekly basis thereafter until the 1600 μg 
b.i.d. maximum dose or the maximum tolerated dose (MTD) is reached. The 
titration period ends on the day of the Week 12 visit of the subject. 
• A maintenance period, which follows the titration period, during which the dose of 
selexipag/placebo is maintained constant except dose adjustment for safety. The 
maintenance period starts on the day after the Week 12 visit of the subject. 
Both periods combined represent the overall exposure period. 
Overall exposure to selexipag/placebo regardless of dose is defined as the number of days 
between the first dose (i.e., first intake) and the last dose of selexipag/placebo medication, 
regardless of interruptions or titrations. 


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5.3.1.3.1 Selexipag/placebo maximum tolerated dose 
The MTD is defined as the selexipag/placebo dose (b.i.d) taken by the subject on the day 
after the Week 12 visit. It is 0 for patients with study drug discontinuation prior to or at the 
Week 12 visit, whatever the reason is. 
5.3.1.3.2 Selexipag/placebo individual maintenance dose 
For patients who enter the maintenance period, the individual maintenance dose (IMD) is 
defined as the daily selexipag/placebo dose (b.i.d) to which the subject is exposed to for 
the longest time (i.e., maximum number of days) during the maintenance period, i.e., after 
the day of the Week 12 visit. If more than one selexipag/placebo dose corresponds to the 
maximum number of days during the maintenance period, the highest dose (b.i.d) is 
considered. 
For patients with a last selexipag/placebo dose intake prior to the maintenance period, the 
IMD is the maximum selexipag/placebo dose (b.i.d) that did not lead to study drug 
discontinuation or down-titration of selexipag/placebo. 
For patients who received only the lowest selexipag/placebo dose level of 200 μg b.i.d., 
the IMD is 200 μg if selexipag/placebo was not discontinued prematurely (as recorded on 
specific eCRF “Premature Discontinuation of Study Treatment - Selexipag/Placebo” page), 
otherwise it is set to 0 μg. 
For each subject, the following selexipag/placebo doses are analyzed: 
• Maximum and weighted-average selexipag/placebo dose in the titration period 
• Maximum and weighted-average selexipag/placebo dose in the maintenance period 
(for patients who entered this period) 
• Maximum and weighted-average selexipag/placebo dose in the entire treatment 
period 
• Selexipag/placebo MTD [see Section 5.3.1.3.1] 
• Selexipag/placebo IMD [see Section 5.3.1.3.2] 
 
The b.i.d dose (between 200 μg and 1600 μg) is used for analysis.  
Weight-average dose is computed weighting on the amount of time exposed to each study 
drug dose according to the drug log eCRF. 
5.3.1.3.3 Selexipag/placebo individual maximum tolerated dose 
For patients who completed the titration period, individual maximum tolerated dose 
(IMTD) is defined as the last selexipag/placebo dose (b.i.d) taken at the end of titration 
period (i.e., at the day of the Week 12 visit). For patients who did not enter to the 
maintenance period, IMTD is defined as the latest selexipag/placebo dose (b.i.d) that did 
not lead to study drug discontinuation or down-titration of selexipag/placebo.  


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o If the latest daily dose (b.i.d) is 200 mcg with the above reasons, IMTD is defined 
as zero.  
5.3.1.4 Exposure to combinations (days) 
Overall exposure to combinations “at least macitentan + tadalafil” and “at least macitentan 
+ tadalafil + selexipag/placebo” regardless of dose is defined as the number of days 
between the first dose (i.e., first intake) of concomitant combination and the last dose of 
concomitant medication, regardless of interruptions or titrations. 
5.3.2 Study treatment discontinuation  
Each of the three study medications can be discontinued permanently (as recorded on the 
specific eCRF page “Premature Discontinuation of Study Treatment” for each treatment) 
while the remaining treatment(s) are continued.  
The reasons for premature discontinuation of each treatment are collected in the eCRF on 
separate pages. In case the patient has prematurely discontinued study (e.g., if the patient 
died) and did not provide reasons for premature discontinuation of individual study 
treatments, the information from the study discontinuation page is used to determine the 
reason for premature treatment discontinuation. 
5.3.3 Study treatment adjustments or interruptions 
The reasons for study drug adjustments or interruptions are collected on a separate eCRF 
page for each dose level or dose end of the three study treatments, together with the start 
and end date of the treatment and the dose.  
5.4 Study discontinuation 
Study discontinuation includes all subjects, i.e., those who prematurely discontinued and 
those who completed the study as per protocol. 
For subjects who prematurely discontinued the study, the associated reason(s) are entered 
in the eCRF. 
5.5 Efficacy variables 
5.5.1 Primary efficacy variable 
The primary efficacy variable is the ratio of Week 26 to baseline PVR (Week 26 divided 
by baseline). PVR is determined by RHC at screening and Week 26. Although PVR is 
collected in the eCRF as reported by the investigator (and eCRF-derived), the 
sponsor-re-calculated PVR is used for the analysis, applying the following formula: 
PVR (dyne.sec.cm-5) = ( ( mPAP - PCWP [or LVEDP if PCWP is missing] ) / CO) * 80 
PCWP and LVEDP are recorded as two separated fields for this study, and therefore 
LVEDP can be used in case PCWP is missing [see Appendix 1]. 


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5.5.2 Secondary efficacy variables 
5.5.2.1 Change from baseline to Week 26 in six-minute walk distance 
The change from baseline to Week 26 in 6MWD is calculated as Week 26 minus baseline. 
6MWD is determined at the screening visit, randomization visit (if more than seven days 
after screening visit), at Week 12, at Week 26, and then every six months as well as at 
EOMOP and EOT visits. The distance is entered in meters in the eCRF.  
5.5.2.2 Change from baseline to Week 26 in NT-proBNP 
The change from baseline to Week 26 in NT-proBNP is expressed as the ratio of Week 26 
to baseline NT-proBNP (Week 26 divided by baseline). NT-proBNP is determined at the 
screening visit, randomization visit (if more than seven days after screening visit), Week 
12, Week 26, and then every six months as well as at EOMOP and EOT visits. It is 
determined by the central or local laboratory [see also Section 5.6.9]. NT-proBNP values 
are expressed in unit ng/L for analysis.  
5.5.2.3 Absence of worsening from baseline to Week 26 in WHO FC 
WHO FC is determined at the screening visit, randomization visit (if more than seven days 
after screening visit), at Week 12, at Week 26, and then every six months as well as at 
EOMOP and EOT visits. The WHO FC assessment (I to IV) is directly entered in the eCRF.  
5.5.2.3.1 Absence of worsening from baseline to Week 26, Version I 
Worsening of WHO FC at Week 26 is determined in patients who are in WHO FC I, II, or 
III at baseline. Worsening of WHO FC occurs when a worse WHO FC (higher) than 
baseline is observed at the Week 26 visit. After the final WHO FC assessment, worsening 
of PAH status cannot be determined. Worsening of WHO FC cannot be determined in 
patients who already have Class IV at baseline.  
5.5.2.3.2 Absence of worsening from baseline to Week 26, Version II 
An alternate version of the endpoint is generated for patients in WHO FC IV: a worsening 
occurs if the patient has died or has been hospitalized due to PAH (as adjudicated by the 
Clinical Events Committee [CEC]) before Week 26. If the WHO FC has improved at Week 
26, the patient has absence of worsening, regardless of PAH-related hospitalizations. 
To ensure comparability with the endpoint definition in Version 1, the date of worsening 
is assigned to a scheduled visit date where WHO FC was assessed: the assignment of 
assessments to visits is done using the time windowing for WHO FC [see Section 11.4]. 
After the last visit where a WHO FC assessment is planned (usually the EOT visit), the 
endpoint is not determined. 
5.5.2.4 Change from baseline to Week 26 in hemodynamic variables other than PVR 
The change from baseline to Week 26 in hemodynamic variables other than PVR is 
calculated as Week 26 minus baseline. Variables are: 


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• mPAP 
• CI, which is re-derived as the ratio of CO and re-calculated BSA  
• TPR, which is re-derived as 80 × (mPAP/CO)  
• mRAP 
• Venous oxygen saturation  
BSA, TPR and CI are derived by the eCRF and re-calculated by analysis programming. 
Both values are listed; the re-calculated values are used for analysis. 
5.5.2.5 Time to the first disease progression event up to EOMOP + 7 days 
Time from randomization to the first disease progression event up to EOMOP + 7 days as 
adjudicated by the CEC, defined as any of the following:  
a. Death 
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 screening, accompanied (same 
day) by WHO FC III or IV (both conditions confirmed at two consecutive post-
baseline visits separated by 1–21 days). 
All events are adjudicated by the CEC. The start date of the event provided by the CEC is 
used for time-to-event analyses. 
If two events were observed on the same day, e.g., hospitalization due to worsening of 
PAH and initiation of prostacyclin on the same day, the most severe one is considered as 
the first event. The severity is given in descending order from a) to d) above. All events 
will be listed. 
5.5.3 Other efficacy variables 
5.5.3.1 Changes of secondary efficacy endpoints from baseline to EOMOP 
6MWD, NT-proBNP and WHO FC are collected regularly as described in Section 5.5.2. 
Changes from baseline to the scheduled collection time points up to EOMOP are computed.  
Additional hemodynamic parameters collected in the RHC are listed.  
5.5.3.2 Unsatisfactory clinical response 
Unsatisfactory clinical response is computed for Week 26 and all regular visits after Week 
26, i.e., Month 12, Month 18, Month 24, etc. until EOMOP. 


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It is defined as the occurrence of at least one of the following criteria: 
• WHO FC III or IV at the time of the visit 
• Both 6MWD ≤ 440 m and NT-proBNP ≥ 3 × upper limit of normal (ULN; must be at 
the same visit) at the time of the visit. 
• Clinical worsening as defined in Section 5.5.2.5, part d up to and including the 
analysis visit but ignoring all assessments prior to Week 26. 
If one or more of the criteria are not assessed at a study visit, the last value of the respective 
assessment is carried forward (including baseline value) unless a disease progression event 
[see Section 5.5.2.5] has occurred after the last non-missing assessment.  
5.5.3.3 Number of treatment goals met at Week 26 
The number of treatment goals met is derived at Week 26. The number of treatment goals 
achieved is added up and thus achieve a score of 0 to 5 points. Three different versions of 
treatment goals are determined. 
5.5.3.3.1 Treatment goals Version 1 (McLaughlin I) 
• WHO FC I or II  
• CI > 3 L/min/m2 
• mRAP < 8 mmHg 
• 6MWD > 440 m 
• NT-proBNP < 3 × ULN 
5.5.3.3.2 Treatment goals Version 2 (McLaughlin II) 
The cut-off value for CI is changed compared to Version 1: 
• WHO FC I or II 
• CI > 2.5 L/min/m2 
• mRAP < 8 mmHg 
• 6MWD > 440 m 
• NT-proBNP < 3 × ULN 
5.5.3.3.3 Treatment goals Version 3 (Nickel) 
The cut-off value for NT-proBNP is changed compared to Version 1: 
• WHO FC I or II 
• CI > 3 L/min/m2 
• mRAP < 8 mmHg 
• 6MWD > 440 m 
• NT-proBNP < 1800 ng/L 


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5.5.3.3.4 Treatment goals Version 4 (Galiè) 
The cut-off value for CI and NT-proBNP are changed compared to Version 1: 
• WHO FC I or II 
• CI ≥ 2.5 L/min/m2 
• mRAP < 8 mmHg 
• 6MWD > 440 m 
• NT-proBNP < 300 ng/L 
 
If one or more assessment(s) for a treatment goal at Week 26 is missing, the last value of 
the respective assessment is carried forward (including baseline value) unless a disease 
progression event [see Section 5.5.2.5] has occurred after the last non-missing assessment. 
In this case, the treatment goal(s) carried forward are counted as not reached. Missing 
treatment goals after imputation are considered as not met.  
5.5.3.4 Improvement of WHO FC from baseline to Week 26 
Improvement of WHO FC at Week 26 is determined in patients who are in WHO FC II, 
III or IV at baseline. Improvement of WHO FC occurs when the WHO FC at Week 26 visit 
is lower than the one observed at baseline. Improvement of WHO FC cannot be determined 
in patients who already have Class I at baseline. 
5.5.3.5 Hospitalizations up to EOMOP  
The following endpoints related to hospitalizations are defined. All-causes hospitalizations 
refer to any hospitalization as documented in the AE eCRF pages. Hospitalizations for 
worsening PAH are those as adjudicated by the CEC.  
In case of missing or incomplete hospital admission / discharge date, imputations of 
missing date parts are made as described in Section 12.4.  
5.5.3.5.1 Time from randomization to first hospitalization (all causes) up to EOMOP  
The date of first hospitalization is the date of the first admission date as collected in the AE 
eCRF pages (from randomization up to EOMOP visit date). Subjects with no 
hospitalizations will be censored at min (EOS, EOMOP) date.  
5.5.3.5.2 Time from randomization to first hospitalization for worsening PAH up to 
EOMOP  
The date of first hospitalization for worsening PAH is the date of the first worsening PAH 
event date as adjudicated by CEC (Adjudicator 1) from randomization up to EOMOP visit 
date.  
Subjects with no hospitalizations will be censored at min (EOS, EOMOP) date.  


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5.5.3.5.3 Annualized rate of hospitalization (all causes) up to EOMOP  
The number of hospitalizations (all causes) initiated from randomization up to min (EOS, 
EOMOP) visit is annualized by multiplying with 365.25 divided by (min [EOS, EOMOP] 
date - randomization date +1). 
5.5.3.5.4 Annualized rate of hospitalization for worsening PAH up to EOMOP  
The number of hospitalizations for worsening PAH initiated from randomization up to min 
(EOS, EOMOP) visit is annualized by multiplying with 365.25 divided by ( (min [EOS, 
EOMOP] date - randomization date +1). 
5.5.3.5.5 Annualized rate of days spent in hospital (all causes) up to EOMOP  
For each hospitalization (all causes), the number of days spent in hospital up to EOMOP 
is calculated as min (EOS, EOMOP, discharge date) - admission date + 1. For each subject, 
the number of days spent in hospital up to EOMOP is the sum of the number of days spent 
in hospital up to EOMOP. In case the admission date of a new hospitalization occurs prior 
to or on the discharge date of a previous hospitalization, the day is counted only once.  
The number of days spent in hospital (all causes) is annualized by multiplying with 365.25 
divided by ( (min [EOS, EOMOP] date - randomization date +1). 
In case of missing discharge date: if admission date is not missing or if ‘hospitalization 
required’ is ticked ‘yes’, the min (EOS, EOMOP) visit date is used for the analysis up to 
EOMOP. 
5.5.3.5.6 Annualized rate of days spent in hospital for worsening PAH up to EOMOP  
The annualized rate of days spent in hospital for worsening PAH up to EOMOP is defined 
as in Section 5.5.3.5.5 but restricted only to hospitalization for worsening PAH. 
5.6 Safety variables 
5.6.1 Adverse events 
Adverse events (AEs) are collected in the eCRF. In case of missing or incomplete AE start 
and/or stop dates, imputations of missing date parts are made as described in Section 12.2 
to determine date of onset and resolution for analysis. 
5.6.1.1 Treatment-emergent adverse events 
Treatment-emergent AEs are defined as those AEs occurring from the day of treatment 
start of the first of the three study medications (Day 1) up to 30 days after study treatment 
end date of the last of the three study medications. 
5.6.1.2 Frequency of treatment-emergent adverse events 
Treatment-emergent AEs reported more than once within a subject at the Preferred Term 
(PT) level are counted in the frequency table once.  


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5.6.1.3 Intensity of treatment-emergent adverse events 
For treatment-emergent AEs reported more than once within a subject, the worst intensity 
is considered. AEs with missing intensity are considered in any analysis with the worst 
intensity. 
5.6.1.4 Relationship of treatment-emergent adverse events 
Relationship to study treatment is defined as ‘related’ or ‘not related’. For 
treatment-emergent AEs reported more than once within a subject, the worst relationship 
is considered; i.e., AEs reported both as related and unrelated are counted as related.  
AEs with missing relationship are considered in any analysis as related. 
5.6.2 Deaths 
All AEs with outcome ‘death’ are reported. The reason for death is captured on a separate 
eCRF page. 
5.6.3 Serious adverse events 
Serious adverse events (SAEs) are events that are marked as serious in the eCRF. AEs with 
missing seriousness are considered as serious. 
5.6.4 Non-serious adverse events 
For the disclosure of the results to EudraCT and ClinicalTrials.gov, non-serious AEs are 
defined. A non-serious AE is any AE with the question “Serious?” answered “No” by the 
investigator.  
5.6.5 Adverse events leading to discontinuation of study treatment 
AEs with Action ‘Permanently discontinued’ for any of the three study medications are 
considered AEs leading to discontinuation of study treatment. 
5.6.6 Other significant adverse events 
Important identified or potential risks for selexipag are given below. The definitions are 
based on a combination of preferred terms, high level terms, low level terms, system organ 
class (SOC) and SMQs (Standardized MedDRA Queries) which can be updated according 
to MedDRA/SMQs updates or finding of new safety signal(s). Details of the categories 
below will be provided in “AESI definition file” that will be saved and version controlled 
in the Entimo Integrated Clinical Environment (or equivalent system).  
• Hypotension 
• Anemia 
• Hyperthyroidism 
• Major adverse cardiovascular event 
• Acute renal failure and renal function impairment 
• Bleeding events 


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• Light-dependent non-melanoma skin malignancies 
• Ophthalmological effects associated with retinal vascular system 
• Gastrointestinal disturbances denoting intestinal intussusception (manifested as 
ileus or obstruction) 
• Medication errors. 
• Off-label use 
• Pregnancy 
• Pulmonary venoocclusive disease associated with pulmonary oedema 
In addition, symptomatic hypotension AEs are investigated.  
AEs typical of prostanoid treatments are also investigated. They will be retrieved by 
selecting the following MedDRA PTs: Arthralgia, Diarrhoea, Dizziness, Flushing, 
Headache, Pain in jaw, Musculoskeletal pain, Myalgia, Nausea, Pain in extremity, 
Temporomandibular joint syndrome, Vomiting. 
5.6.7 Vital signs and body weight 
Vital signs (weight [kg], BMI [kg/m2], pulse rate [bpm], systolic/diastolic blood pressure 
[mmHg] and the location of measurement) are collected.  
5.6.8 Electrocardiogram 
Electrocardiography (ECG) is not assessed in this trial. 
5.6.9 Laboratory 
A central laboratory is used for all protocol-mandated laboratory tests, including re-tests 
due to laboratory abnormalities and laboratory tests performed at unscheduled visits. 
Central laboratory data are loaded into the clinical database. However, in exceptional cases 
local laboratory results (with the corresponding variables and normal ranges) may also be 
used in parallel and entered into the clinical database via dedicated eCRF pages.  
Local laboratory values will only be used if no corresponding central laboratory value is 
available. 
The following parameters are evaluated: 
5.6.9.1 Hematology tests 
• Hemoglobin 
• Hematocrit 
• Erythrocyte count (reticulocyte count) 
• Leukocyte count with differential counts 
• Platelet count 


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5.6.9.2 Biochemistry tests 
• Aminotransferases (aspartate aminotransferase [AST] / alanine aminotransferase 
[ALT]), alkaline phosphatase, total and direct bilirubin, lactate dehydrogenase 
• Creatinine, urea 
• Creatinine clearance (Cockcroft-Gault formula) 
• Uric acid (serum urate) 
• Glucose 
• Sodium, potassium, chloride, calcium 
• Protein, albumin 
5.6.9.3 Coagulation tests 
• International Normalized Ratio 
• Prothrombin time 
• Activated partial thromboplastin time 
5.6.9.4 Pregnancy tests 
Urine pregnancy tests at the Day 1 visit and monthly outside of scheduled visits after Week 
26. 
5.6.9.5 Biomarkers 
NT-proBNP is analyzed as an efficacy endpoint. 
The analysis of circulating biomarkers involved in right ventricular function and structure 
is described in a separate document. 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 [D-18.392, section 6.3]. 
5.6.9.6 Schedule of assessments 
Liver function tests (AST/ALT) and hemoglobin values are evaluated in monthly intervals 
up to Week 26, while the general laboratory tests take place at Week 12, Week 26, and 
every visit thereafter. 
Serum pregnancy tests occur at all scheduled visits except the Day 1 visit, and monthly 
until Week 26. Urine pregnancy tests occur at the Day 1 visit and monthly outside of 
scheduled visits after Week 26.  
In Sweden, serum pregnancy tests occur at all scheduled visits except the Day 1 visit, and 
monthly until the EOT visit. Urine pregnancy tests occur at the Day 1 visit and EOS visit. 
6 
DEFINITION OF PROTOCOL DEVIATIONS 
Protocol deviations (PDs) are determined by the study team in a blinded fashion. Major 
PDs leading to exclusions from analysis sets are determined prior to unblinding to the 
study. 


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PDs are described in the PD list referred in Section 1.1. 
7 
ANALYSIS SETS 
7.1 Definitions of analysis sets 
7.1.1 Screened analysis set  
This analysis set includes all subjects who were screened and received a subject number. 
7.1.2 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). 
7.1.3 Modified Full Analysis Set 
The modified full analysis Set (mFAS) includes all subjects from the FAS who received at 
least one dose of each of the three 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).  
7.1.4 Per-protocol analysis set  
The per-protocol analysis 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. 
The PPS are defined in a blinded fashion prior to unblinding of the study.  
The major deviations leading to exclusion of PPS are: 
• Deviation at Screening/Re-screening and Randomization: PD102, PD106, PD107, 
PD108, PD111, PD112, PD113, PD114, PD120, PD121, PD131,  
• PD after Randomization: PD214, PD215, PD216, PD220, PD221, PD222, PD210, 
PD226 (only if occurred prior to Week 26). 
PDs are described in the PD list referred in Section 1.1. 
7.1.5 Safety analysis set  
The Safety analysis set (SAF) includes all subjects who received at least one dose of any 
of the three study treatments. The patients are analyzed as actually treated. If the actual 
treatment arm cannot be determined (e.g., if no double-blinded study medication has been 
received or both placebo and selexipag have been received), patients are assigned to the 
selexipag arm if they received at least one dose of selexipag, otherwise to the placebo arm. 
For subjects included in the SAF, the actual treatment is equal to the randomized treatment 
except for subjects randomized to placebo who received at least one dose of selexipag (if 
a wrong kit was received as documented in the comment field of PD226 and if this kit was 
received prior to EOMOP and corresponds to selexipag treatment). 


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Safety analyses specific to one study medication (e.g., treatment emergent adverse events 
related to macitentan) will be restricted to the subset of subjects from the SAF who received 
at least one dose of the corresponding study medication.  
7.2 Usage of the analysis sets 
The usage of the analysis sets is summarized in Table 1. 
Table 1 
Overview of the different analysis sets and their usage 
Analyses/Data Displays 
Screened 
analysis set 
Full analysis 
set 
Modified full 
analysis set2 
Safety 
analysis set 
Per protocol 
set 
Patient disposition 
 
 
 
 
 
Inclusion /exclusion 
criteria 
 
 
 
 
 
Demographics 
 
 
 
 
 
Baseline characteristics 
 
 
 
 
 
Medical history 
 
 
 
 
 
Previous and 
concomitant 
medications 
 
 
 
 
 
Treatment exposure 
 
 
 
 
 
Efficacy: Primary 
endpoint 
 
 
1 
 
 
Efficacy: Secondary 
endpoints 
 
 
1 
 
 
Efficacy: Exploratory 
endpoints 
 
 
 
 
 
Safety endpoints 
 
 
 
 
 
All subject listings 
 
 
 
 
 
1 A sensitivity analysis is run on all patients who took all three study medications up to the Week 26 
visit. 
2 Analyses on the modified full analysis set are shown if the full analysis set and modified full analysis 
set are different by at least 5% in the total number of patients. 
8 
DEFINITION OF SUBGROUPS 
Subgroup analyses are planned on the stratification factors: region (North America versus 
rest of the world) and WHO FC (FC I/II vs FC III/IV). Additional subgroup analyses will 
be conducted for gender (male vs female), age (64 or lower vs ≥ 65 years) and PAH 
etiology (idiopathic PAH, heritable PAH, drug- or toxin-induced PAH, PAH associated 
with connective tissue disease [CTD], PAH associated with Others).  


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9 
GENERAL STATISTICAL METHODOLOGY 
All statistical analyses are run by the contract research organization Datamap GmbH, 
Freiburg, Germany (under Actelion supervision), using statistical analysis system (SAS) 
9.3 or higher on a SUN Solaris system.  
9.1 Design of the study 
The study uses a group sequential design with an interim analysis (IA) for futility, which 
will be conducted when 33% of the patients have completed the primary efficacy endpoint 
assessment (Week 26 PVR assessment) or prematurely discontinued. The IA will be 
conducted by an ISAC for the IDMC who will provide Actelion with their recommendation 
to either continue or prematurely terminate the study for futility [see also Section 10.1 and 
IDMC charter]. 
The main efficacy analysis will be conducted when all patients have completed the primary 
efficacy endpoint assessment.  
Safety and secondary efficacy data are collected afterwards until the patients reach the EOT 
visit (4 months after EOMOP visit). Further safety data is collected until EOS (5 months 
after EOMOP visit). All data collected after Week 26 visit up to EOMOP visit will be 
analyzed using descriptive methods but not be used for inferential statistics. 
This SAP also describes the blinded outputs provided on a regular basis for IDMC open 
session meetings (see IDMC charter). Those blinded outputs for IDMC are a subset of CSR 
outputs and are flagged accordingly in a list of outputs provided in Section 13. 
The unblinded analyses for IDMC closed sessions (including futility interim analysis) are 
performed by the ISAC according to ISAC’s own analysis plan. The study team remains 
blinded. The ISAC is responsible for the content of these unblinded analyses for the closed 
reports provided to the IDMC (see IDMC charter). 
9.2 Statistical methods used for the primary endpoint 
The primary endpoint will be analyzed on the FAS. The primary efficacy endpoint is the 
ratio of Week 26 to baseline PVR using re-calculated PVR and a last observation carried 
forward (LOCF) approach, i.e., the last observation including baseline is carried forward 
towards Week 26. 
To obtain the ratio of Week 26 to baseline, PVR is log-transformed (base e). The change 
of log-transformed PVR values is analyzed using an analysis of covariance (ANCOVA) 
model with treatment arm and stratification factors region and WHO FC as factors and 
baseline log-transformed PVR as covariate. The estimated least squares mean is computed 
for the treatment group difference (triple therapy - dual therapy) on a log scale. The point 
estimates for treatment group difference and 95% confidence intervals are exponentiated 
and displayed, thus representing the ratio of geometric means of the relative treatment 
effect on PVR.  


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Superiority of the triple combination is achieved if the complete confidence interval for the 
geometric means ratio is below 1. This is equivalent to the upper limit of the confidence 
interval for treatment mean difference of values on a log scale being smaller than zero.  
Distributional assumptions are assessed graphically. Single-slope assumptions in both 
treatment groups are assessed by investigating treatment-by-covariate interaction added to 
the ANCOVA model. 
The following SAS code is used for analysis: 
PROC MIXED DATA=dataset; 
CLASS treatment stratum1 stratum2; 
MODEL logpvrratio=treatment stratum1 stratum2 baselogpvr; 
LSMEANS treatment /PDIFF CL ALPHA=0.05; 
RUN; 
9.3 Analysis of covariance for secondary efficacy parameters 
ANCOVA models for change from baseline to Week 26 are similar to the model used for 
the primary endpoint. They include the randomization strata (region and WHO FC) and 
treatment groups as factors as well as the baseline value as covariate. The 95% confidence 
intervals are computed for treatment group difference. 
Distributional assumptions are assessed graphically. Single-slope assumptions in both 
treatment groups are assessed by investigating treatment-by-covariate interaction added to 
the ANCOVA model. 
SAS code, similar to the following is used for analysis: 
PROC MIXED DATA=dataset; 
WHERE visitvariable = ‘Week 26 Visit’; 
CLASS treatment stratum1 stratum2; 
MODEL value=treatment stratum1 stratum2 baseline; 
LSMEANS treatment /PDIFF CL ALPHA=0.05; 
RUN; 
6MWD, and hemodynamic variables from RHC are analyzed in this fashion (main analysis 
for those endpoints). 
The main analysis for NT-proBNP is the same as for PVR, as described in Section 9.2. 


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9.4 Logistic regression for dichotomous outcomes 
Logistic regression models for dichotomous outcomes include the treatment group, the 
baseline stratification variables (region and WHO FC) unless stated otherwise. The odds 
ratio with 95% Wald confidence intervals are computed for treatment group difference. 
SAS code, similar to the following is used for analysis: 
PROC LOGISTIC DATA=dataset; 
WHERE visitvariable = ‘Week 26 Visit’; 
CLASS treatment stratum1 stratum2 ; 
MODEL value (event=‘Yes’) =treatment stratum1 stratum2 /CLODDS=WALD 
ALPHA=0.05; 
RUN; 
Absence of worsening from baseline to Week 26 is analyzed in this fashion. In case of too 
few events, an exact logistic regression may be used. 
9.5 Time to event analyses 
All event and censoring times are on a day/date scale.  
Kaplan-Meier (KM) type analyses are planned for analyses of time-to event endpoints to 
obtain product-limit survival estimates as well as median survival times. To assess 
treatment effect, stratified log-rank test for treatment group difference stratified for the 
randomization strata is computed. Furthermore, a Cox (proportional hazard) regression 
model with randomization strata and treatment arm as factors is computed. The hazard ratio 
for treatment arms is computed together with the corresponding 95% confidence interval.  
Furthermore, 95% confidence intervals are computed for the KM estimators using 
Greenwood’s formula. Proportional hazard assumption is assessed graphically. 
SAS code, similar to the following, is used for analysis: 


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* Obtain KM estimates *; 
PROC LIFETEST DATA=dataset METHOD=km STDERR; 
BY treatment; 
TIME day*censor(1); 
RUN; 
 
* Log Rank Test *; 
PROC LIFETEST DATA=dataset METHOD=km; 
TIME day*censor(1); 
STRATA stratum1 stratum2/GROUP=treatment TEST=logrank; 
RUN; 
 
* Cox Regression *; 
PROC PHREG DATA=dataset; 
CLASS treatment (ref=“Placebo”); 
MODEL day*censor(1)=treatment /RL; 
STRATA stratum1 stratum2; 
RUN; 
Time to the first disease progression event and time to first hospitalization (without stratum 
1 and stratum 2) is analyzed in this fashion. 
9.6 Mixed model repeated measures analyses  
For mixed model repeated measures analyses (MMRM) up to Week 26 (sensitivity 
analyses for 6MWD and NT-proBNP), the dependent variable is analyzed using treatment 
arm, randomization strata, visit and visit by treatment interaction term as factors. The 
baseline value of the dependent variable is used as a continuous covariate. Repeated 
measures of the response variable within the same subject are considered correlated with 
an unstructured covariance matrix. Fixed-effect tests are computed using the Kenward-
Rogers method to determine the degrees of freedom for the denominator. Treatment group 
differences are computed using appropriate contrasts for the treatment and treatment by 
visit interaction terms. The 95% confidence intervals are computed together with the 
treatment contrasts. Distributional assumptions are assessed graphically. 


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SAS code, similar to the following, is used for analysis. Note that the treatment contrasts 
depend on the number of visits included in the model and thus may be replaced by an 
equivalent SLICE statement to allow for a variable number of visits included in the model. 
PROC MIXED DATA=dataset; 
CLASS treatment visit stratum1 stratum2 subj_id; 
MODEL value = treatment visit stratum1 stratum2 treatment*visit baseline /DDFM=KR; 
REPEATED visit / SUBJECT=subj_id /TYPE=UN; 
ESTIMATE ‘Selexipag - Placebo, overall’  
 treatment 1 -1 /C L ALPHA=0.05; 
ESTIMATE ‘Selexipag - Placebo, Month 1’  
 treatment 1 -1 
 treatment*visit 1 0 0 0 0 -1 0 0 0 0 /CL ALPHA=0.05; 
ESTIMATE ‘Selexipag - Placebo, Month 2’  
 treatment 1 -1 
 treatment*visit 0 1 0 0 0 0 -1 0 0 0 /CL ALPHA=0.05; 
… 
RUN; 
Change of 6MWD from baseline to all regular collection time points (up to Week 26) are 
analyzed in this fashion.  
Change of NT-proBNP is analyzed on a log scale and the results will be exponentiated to 
obtain geometric means and geometric mean ratios at each visit (up to Week 26). 
9.7 Cochran-Mantel-Haenszel test for categorical outcomes 
The Cochran-Mantel-Haenszel (CMH) test assesses treatment arm differences adjusting 
for stratification variables in categorical outcomes. Outcomes with more than one category, 
e.g., number of treatment goals met, must be on an ordinal scale. Mean CMH scores are 
computed for each treatment arm and the results are tested. 
SAS code, similar to the following, is used for analysis. Note that the order of variables in 
the TABLES statement is critical to compute the proper CMH statistic. The CMH test 
statistic for ‘Row mean scores differ’ is used for analysis.  


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PROC FREQ DATA=dataset; 
TABLES stratum1*stratum2*treatment*outcome /CMH; 
RUN; 
The number of treatment goals met is analyzed in this fashion. 
9.8 Multiple imputation method analysis 
Multiple imputation (MI) analysis (under missing at random assumption) replaces each 
missing endpoint by a set of 50 plausible values, each set with a different value for the SAS 
variable _imputation_. 
A linear regression model is fitted using observations with observed values by treatment 
group for the endpoint and baseline covariates. Based on the fitted regression model, a new 
regression model is simulated from the Bayesian posterior predictive distribution of the 
regression parameters and is used to impute the missing values. For each missing value, a 
predicted value is computed from the regression model. Then, a set of five observations, 
whose corresponding predicted values are closest to the predicted values, is generated. The 
missing value is then replaced by a value drawn randomly from these five observations. 
Each imputation is then analyzed using the statistical model for the complete endpoint; the 
estimates are back transformed to normal scale (if applicable) and the results from the 
50 imputations are aggregated using Rubin’s rule. 
PROC MI DATA=dataset OUT=mi_dataset nimpute=50 seed=<random 515448>; 
BY treatment; * Selexipag should be first ** ; 
VAR base endpoint; 
MONOTONE REGPREDMEANMATCH (endpoint=base) 
RUN; 
 
PROC MIXED data=mi_dataset …. /* as for the primary endpoint */; 
by _imputation_; 
CLASS …/* statements as for the primary endpoint */; 
RUN; 
 
PROC MIANALYZE PARMS=mixed_out; 
CLASS treatment; 
MODELEFFECTS treatment difference; 
RUN; 
 


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9.9 Analysis method for counts and rates 
For the annualized rate of events (e.g., hospitalization) up to EOMOP, a generalized linear 
model with Poisson distribution and log of time at risk as an offset is assumed.  
For each treatment group, the 95% confidence limit of the annualized event rate will be 
computed and in addition the 95% confidence limits of the relative reduction in mean 
annualized event rate for selexipag compared to placebo will be computed using SAS 
PROC GENMOD as below. 
PROC GENMOD DATA=dataset; 
CLASS treatment (ref=‘Placebo’) ;  
MODEL Nevent = treatment / dist=poisson link=log offset=ltime; 
ESTIMATE “Selexipag rate” intercept 1 treatment 1 0 / exp ; 
ESTIMATE “Placebo rate” intercept 1 treatment 0 1 / exp ; 
ESTIMATE “Selexipag versus Placebo” intercept 0 treatment 1 -1 / exp ; 
RUN; 
 
“ltime” is the logarithm of the time (subject years) from randomization up to min (EOS, 
EOMOP).  
Nevent represents the annualized rate of hospitalization for a subject 
10 STATISTICAL ANALYSES 
10.1 Overall testing strategy 
The primary efficacy endpoint of the study is the ratio of Week 26 to baseline PVR. The 
design of the study is group sequential with an interim analysis allowing the trial to be 
stopped for futility (non-binding).  
The interim analysis will be conducted at information time 0.33 [see Section 9.1]. A 
Pocock-type alpha spending function is used to preserve an overall type I error rate of 5% 
and a power of 90% for an assumed treatment group difference of −0.223 in PVR on a log 
scale and a standard deviation of 0.5 on the log scale [D-18.392, section 11.5].  
At the interim analysis, the trial can be stopped for futility if a p-value of 0.706 or greater 
is observed, equivalent to a treatment group difference of 0.042 or lower on the log scale. 
The futility boundary is non-binding. 
The overall type I error rate is preserved at 5%. See also Section 10.1.1. 


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The order of hierarchical testing is modified as compared to the protocol. This change is 
performed following interaction with the FDA (TC on 2 November 2017 [see Section 4.1]). 
The following endpoints will be tested in a hierarchical manner:  
1. Primary efficacy endpoint 
2. Change from baseline to Week 26 in 6MWD  
3. Change from baseline to Week 26 in NT-proBNP. 
4. Time from randomization to first disease progression event up to EOMOP + 7 days 
5. Absence of worsening from baseline to Week 26 in WHO FC 
10.1.1 Type I error adjustment 
The interim analysis (non-binding) can only stop the trial for futility. It is not allowed to 
stop the trial for proof of efficacy.  
At the final analysis, the overall type I error rate will be preserved over the hierarchy of 
endpoints as long as all p-values of the previous tests in the hierarchy are smaller than the 
significance level (< 0.05). If a test in the hierarchy fails to reject H0, all subsequent tests 
fail as well, regardless of the size of the p-value.  
10.1.2 Type II error (power)  
Assuming a treatment group difference of −0.223 in change from baseline to Week 26 in 
log PVR and a standard deviation of 0.5, the sample size was increased from 212 subjects 
(in a scenario without interim analysis) to 238 to maintain 90% power for the final analysis. 
10.2 General rules for data presentations 
10.2.1 General guidelines for table contents 
Summary statistics for continuous variables include number of non-missing observations 
(n), mean, standard deviation (SD), standard error of the mean (SEM), median, first and 
third quartiles, minimum and maximum. For discrete variables, the number of patients in 
the respective category and the relative frequency (percentage) are shown. Missing values 
are shown as a separate category and included in the computation of percentages. 
Percentages are shown with one decimal place. 
All summaries are presented by treatment arm in the respective population. Patient 
disposition, demographics, baseline characteristics and exposure summaries are presented 
with a ‘Total’ treatment column to convey a summary of the total population assessed in 
this study. 
Summaries of continuous variables are shown with the same precision (i.e., number of 
decimals) as the original value for minimum and maximum; precision + 1 (i.e., one more 
decimal than source data) for mean, median, and quartiles; precision + 2 for SD. P-values 
are presented with four decimals. P-values smaller than 0.0001 are presented as ‘< 0.0001’. 


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Individual patient listings are ordered by site, treatment arm, patient number and 
assessment date.  
Time-to-event variables are conducted on study days as time variable. KM estimates are 
expressed in summary tables as a fraction of 1. 
10.2.2 General guidelines for table layout and formats 
Treatment groups are labeled ‘Selexipag’ and ‘Placebo’ respectively. The order of the 
treatment groups is ‘Selexipag’ first, then ‘Placebo’, then ‘Total’, if applicable.  
If categories on a nominal scale are displayed (such as reasons for premature 
discontinuation, AE PTs, etc.), the categories are sorted in descending total order. For 
example, a table displaying the incidence of treatment-emergent AEs by SOC and PT is 
sorted by descending total for the SOCs and then sorted by descending total of PTs within 
SOCs. 
The guidelines in the Biostatistics Standards document of the Actelion Standardization 
Project Standard Outputs are followed. 
10.2.3 Analysis of variables between EOMOP and EOT 
The main analyses will be done at the Week 26 visit. After the last subject has completed 
the Week 26 assessment, the EOMOP will be declared, each subject will undergo EOMOP 
assessments, the study will be unblinded and all subjects will undergo EOT/EOS 
assessments. The main analysis will cover data up to Week 26. Efficacy summaries (unless 
otherwise specified) will include all data up to EOMOP; efficacy data collected after 
EOMOP will be listed. Safety summaries will include all data up to EOMOP and separately 
specific summaries will include all data up to EOT/EOS (these summaries are identified in 
the list of outputs Section 13). 
10.3 Display of subject disposition, protocol deviations and analysis sets 
10.3.1 Subject disposition 
The following information will be presented on the screened analysis set: 
• Number of subjects screened for inclusion and reason for screen failures 
• Number of subjects randomized 
• Number of subjects treated with each of the three medication (macitentan, tadalafil, 
selexipag/placebo)  
• Number of subjects who discontinued each of the three study medications up to EOMOP 
and separately overall (i.e., up to study closure). A patient completed treatment up to 
EOMOP if study medication was not discontinued during study or discontinuation 
occurred after the EOMOP visit 
• Reasons for each of the three study treatment discontinuations 
• Number of subjects who completed the study  


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• Reasons for study discontinuations 
10.3.2 Protocol deviations 
The number and percentage of subjects with major PDs leading to exclusion from any 
analysis set will be summarized by category (overall and by country), as defined in 
Section 6, on the FAS. All PDs up to EOMOP will be summarized. Important PDs (i.e., 
major PDs) up to EOMOP will be summarized separately. All PDs will be listed and major 
PDs flagged. PDs occurring from EOMOP until EOS will be listed.  
10.3.3 Analysis sets 
The number and percentage of subjects included in each analysis set will be summarized 
for the screened set. The reasons for exclusion from any analysis set will be presented. 
10.4 Analyses of subject characteristics 
Subject characteristics will be summarized for the FAS, mFAS and the PPS. 
10.4.1 Demographics 
Demographics as described in Section 5.2.1 will be summarized. Age is analyzed as a 
continuous variable and as a categorical variable with categories < 18, 18–64, and 
≥ 65 years. Regions (randomization strata) are North America versus rest of the world, with 
countries as sub-categories. 
10.4.2 Baseline disease characteristics 
Etiology of PAH, time since PAH diagnosis, as well as baseline WHO FC will be 
summarized. WHO FC will be summarized also with categories I/II and III/IV combined 
(randomization strata). 
PVR (as reported by the investigator in the eCRF and re-calculated for analysis) as well as 
other parameters from the baseline RHC will be summarized. 
10.4.3 Other baseline characteristics 
6MWD, Borg dyspnea score, and baseline vital signs will be summarized as continuous 
variables. 
Results from the physical examination will be listed. 
10.4.4 Medical history 
Medical history ongoing at the screening visit will be summarized by MedDRA SOC and 
PT. A second summary will be prepared by MedDRA PT only. 
All clinically significant diseases or medical conditions starting prior to the screening visit 
will be listed, regardless if ongoing at start of study or not. 


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10.4.5 Previous and concomitant therapies 
For study reporting purposes, all previous and study-concomitant therapies will be reported 
in the subject listings.  
Baseline concomitant and study-treatment concomitant therapies will be summarized by 
therapeutic organ class and PT up to EOMOP and overall. A second summary will be 
prepared by PT only. 
10.5 Analysis of study treatment exposure  
10.5.1 Exposure 
All exposure analyses will be conducted on the SAF, including all data up to EOMOP and 
separately for the overall treatment period.  
10.5.1.1 Exposure to macitentan (days) 
Exposure to macitentan in days will be summarized descriptively. Furthermore, the number 
and percentage of subjects being exposed at least 1, 15, 30, 60, 90, 180, 270, 365, 548, 730, 
and 913 days will be given in categories. 
10.5.1.2 Exposure to tadalafil (days) 
Exposure to tadalafil in days, regardless of dose, will be summarized descriptively. 
Furthermore, the number and percentage of subjects being exposed at least 1, 15, 30, 60, 
90, 180, 270, 365, 548, 730, and 913 days will be given in categories. 
10.5.1.3 Exposure to selexipag/placebo (days) 
Exposure to selexipag/placebo in days, regardless of dose, will be summarized 
descriptively. Furthermore, the number and percentage of subjects being exposed at least 
1, 15, 30, 60, 90, 180, 270, 365, 548, 730, and 913 days will be given in categories. 
Exposure will be summarized graphically as inverse cumulative distribution function. 
The maximum and weighted-average selexipag dose (b.i.d) will be summarized as a 
continuous variable for  
• the titration period 
• the maintenance period (for patients entering the maintenance period) 
• the entire treatment period. 
The selexipag/placebo MTD and IMD will be summarized presenting the number and 
percentage of subjects with each dose level. Selexipag/placebo MTD and IMD will be also 
summarized as a continuous variable. 
10.5.1.4 Exposure to combinations (days) 
Concomitant exposure to “At least macitentan + tadalafil” and “At least macitentan + 
tadalafil + selexipag/placebo” in days, regardless of dose, will be summarized 


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descriptively. Furthermore, the number and percentage of subjects being exposed at least 
1, 15, 30, 60, 90, 180, 270, 365, 548, 730, and 913 days will be given in categories. 
10.5.2 Study treatment discontinuation  
The reason for premature discontinuation of each treatment will be summarized separately 
for each of the three study medications in a similar fashion as for the subject disposition.  
10.6 
Analyses of the primary and secondary efficacy variables 
10.6.1 Description of the estimand for the primary and first secondary efficacy 
variables 
This section describes the estimands for primary and first secondary variables (PVR and 
6MWD respectively).  
 


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Table 2 
Description of the estimand for primary efficacy endpoint (ratio of Week 26 to baseline PVR)* 
A) Population: All randomized patients (FAS) from targeted population, defined through protocol inclusion/exclusion criteria 
B) Variable: Ratio of Week 26 to baseline PVR 
C) Intercurrent events and strategies: See below description for main estimator and sensitivity estimators 
D) Population-level summary measure: Ratio of geometric means (triple over dual therapy) for ratio of Week 26 to baseline PVR 
Estimators 
Details of planned analyses and handling of intercurrent events 
Main 
estimator  
Handling of intercurrent events: 
• Discontinuation of treatment from either macitentan, tadalafil or selexipag/placebo: treatment-policy strategy; all post-
treatment data are used. 
• Death: hypothetical strategy; LOCF 
• Study discontinuation for other reason than death: hypothetical strategy; LOCF 
LOCF corresponds to BOCF if no post-baseline assessment available: PVR is measured at baseline and Week 26 [Section 
10.6.2.2]. 
Analysis: Change from baseline to Week 26 in log PVR is analyzed using an ANCOVA model with treatment arm and 
stratification variables as factors and baseline log PVR as covariate. Ratio of geometric means (triple over dual therapy) is 
obtained by exponentiation [see Section 9.2]. 
Sensitivity 
estimator#1 
Handling of intercurrent events: 
• Discontinuation of treatment from either macitentan, tadalafil or selexipag/placebo: treatment-policy strategy; all post-
treatment data are used. 
• Death: hypothetical strategy; Week 26 is imputed using the largest ratio of baseline at Week 26 (largest worsening) in all subjects 
in the same treatment group and analysis set, such that this value is multiplied by the subject’s baseline to obtain the imputed 
Week 26 value.  
• Study discontinuation for other reason than death: hypothetical strategy; if the subject is alive up to the Week 26 assessment and 
does not have a post-baseline value, then the median of the ratio of baseline at Week 26 from all subjects in the same treatment 
group and analysis set will be used to impute the Week 26 value, such that this value is multiplied by the subject’s baseline to 
obtain the imputed Week 26 value [see Section 10.6.2.4]. LOCF is used in case the patient is alive and has a post-baseline value 
before Week 26. 
Analysis: Same as for main estimator. 
Sensitivity 
estimator#2 
Handling of intercurrent events: Multiple imputation methodology, with missing at random assumptions for intercurrent 
events leading to missing Week 26 assessment [see Section 9.8]. 
Analysis: Same as for main estimator performed on each imputed complete dataset, and treatment effect is summarized using 
the Rubin’s rule [see Section 9.8]. 


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Sensitivity 
estimator#3 
Handling of intercurrent events: Same as for main estimator. 
Analysis: Same as for main estimator but without stratification variables as factors. 
Sensitivity 
estimator#4 
Handling of intercurrent events: 
• Discontinuation of treatment from either macitentan, tadalafil or selexipag/placebo: treatment-policy strategy; all post-
treatment data are used. 
• Death: hypothetical strategy; LOCF. 
• Study discontinuation for other reason than death: hypothetical strategy; LOCF. 
• Administration of prostanoids rescue medication: All PVR assessments performed before administration of prostanoids rescue 
medication are used, then LOCF is applied. 
Analysis: Same as for main estimator. 
*Supportive analyses will be performed by running main estimator analysis on the Per-protocol analysis set (PPS; FAS patients without any major protocol 
deviations leading to exclusion from PPS [see Section 7.1.4]), on modified FAS (FAS patients who received at least one dose of each of the three study 
treatments [see Section 7.1.3]), on modified FAS with restrictions (modified FAS patients who received all three study treatments at least until the Week 26 
assessments [see Section 10.6.2.4]) and on FAS without any imputation (analysis performed on observed data). 
ANCOVA = analysis of covariance; BOCF = baseline observation carried forward; FAS = Full analysis set; LOCF = last observation carried forward; PPS = Per-
protocol analysis set; PVR = pulmonary vascular resistance. 
 
 


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Table 3 
Description of the estimand for first secondary efficacy endpoint (Change from baseline to Week 26 
in 6MWD)* 
A) Population: All randomized patients (FAS) from targeted population, defined through protocol inclusion/exclusion criteria  
B) Variable: Change from baseline to Week 26 in 6MWD 
C) Intercurrent events and strategies: See below description for main estimator and sensitivity estimators 
D) Population-level summary measure: Difference in means (triple minus dual therapy) for change from baseline to Week 26 in 6MWD 
Estimators 
Details of planned analyses and handling of intercurrent events 
Main 
estimator  
Handling of intercurrent events: 
• Discontinuation of treatment from either macitentan, tadalafil or selexipag/placebo: treatment-policy strategy; all post-
treatment data are used. 
• Death: hypothetical strategy; LOCF 
• Study discontinuation for other reason than death: hypothetical strategy; LOCF 
LOCF corresponds to BOCF if no post-baseline assessment available: 6MWD is measured at baseline, Week 12 and Week 26 
[Section 10.6.4.1]. 
Analysis: Change from baseline to Week 26 in 6MWD is analyzed using an ANCOVA model with treatment arm and 
stratification variables as factors and baseline 6MWD as covariate [see Section 10.6.4.1]. 
Sensitivity 
estimator#1 
Handling of intercurrent events: 
• Discontinuation of treatment from either macitentan, tadalafil or selexipag/placebo: treatment-policy strategy; all post-
treatment data are used. 
• Death: hypothetical strategy; the Week 26 assessment is imputed by 0 meter.  
• Study discontinuation for other reason than death: hypothetical strategy; LOCF  
Analysis: Same as for main estimator. 
Sensitivity 
estimator#2 
Handling of intercurrent events: Multiple imputation methodology, with missing at random assumptions for intercurrent 
events leading to missing Week 26 assessment [see Section 9.8]. 
Analysis: Same as for main estimator performed on each imputed complete dataset, and treatment effect summarized using the 
Rubin’s rule [see Section 9.8]. 
Sensitivity 
estimator#3 
Handling of intercurrent events: Same as for main estimator. 
Analysis: Same as for main estimator, but without stratification variables as factors. 
Sensitivity 
estimator#4 
Handling of intercurrent events: Same as for main estimator. 
Analysis: MMRM to also consider Week 12 assessment in model to compute population-level summary measure [see Section 
10.6.4.1]. 


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Sensitivity 
estimator#5 
Handling of intercurrent events: 
• Discontinuation of treatment from either macitentan, tadalafil or selexipag/placebo: treatment-policy strategy; all post-
treatment data are used. 
• Death: hypothetical strategy; LOCF. 
• Study discontinuation for other reason than death: hypothetical strategy; LOCF. 
• Administration of prostanoids rescue medication: All 6MWD assessments performed before administration of prostanoids 
rescue medication are used, then LOCF is applied. 
Analysis: Same as for main estimator. 
*Supportive analyses will be performed by running main estimator analysis on the Per-protocol analysis set (PPS; FAS patients without any major protocol 
deviations leading to exclusion from PPS [see Section 7.1.4]), on modified FAS (FAS patients who received at least one dose of each of the three study 
treatments [see Section 7.1.3]), on modified FAS with restrictions (modified FAS patients who received all three study treatments at least until the Week 26 
assessments [see Section 10.6.3]) and on FAS without any imputation (analysis performed on observed data). 
6MWD = six-minute walk distance; ANCOVA = analysis of covariance; BOCF = baseline observation carried forward; FAS = Full analysis set; LOCF = last 
observation carried forward; MMRM = mixed model repeated measures analyses (PPS = Per-protocol analysis set; PVR = pulmonary vascular resistance. 


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10.6.2 Analysis of the primary efficacy variable(s) 
The primary efficacy variable is the ratio of Week 26 to baseline PVR (Week 26 divided by 
baseline). PVR will be summarized descriptively at baseline and Week 26 together with its 
change from baseline and its ratio of baseline for the FAS, mFAS and PPS.  
Change from baseline on the log-transformed PVR values will be analyzed using an 
ANCOVA model [see Section 9.2]. 
10.6.2.1 Hypothesis and statistical model 
For inferential analysis, ratio of Week 26 to baseline PVR is log-transformed, as 
log-transformed ratios follow a normal distribution more closely. In addition, the mean 
change from baseline to Week 26 on log scale can be transformed into a geometric mean 
ratio (GMR) of Week 26 to baseline PVR.  
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 (triple therapy minus dual therapy).  
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. 
10.6.2.2 Primary endpoint PVR 
The following imputation is based on the clinical assumption that study treatment does not 
affect PCWP/LVEDP.  
If PVR cannot be calculated due to missing PCWP/LVEDP but mPAP and CO are 
available for the same visit, one of the following is applied:  
1. If PCWP/LVEDP is missing both at baseline and post-baseline, the treatment group 
medians is imputed (based on the FAS).  
2. If PCWP/LVEDP is missing either at baseline or at post-baseline, the patient’s 
available PCWP/LVEDP is imputed.  
• Baseline: If, after this PCWP/LVEDP imputation, baseline PVR cannot still be 
computed for a patient, this patient is excluded from the analyses.  
• Post-baseline: For subjects with a post-baseline PVR measurement obtained before 
Week 26, the (last) post-baseline PVR measurement is carried forward. For subjects 
without a post-baseline PVR measurement, the baseline PVR is carried forward 
(i.e., the ratio of Week 26 to baseline set to one). 
10.6.2.3 Main analysis 
The main analysis will be the analysis of the primary efficacy endpoint [see Section 5.5.1] 
using the algorithm described in Section 9.2 on the FAS.  


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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 LOCF approach is expected to be conservative. 
10.6.2.4 Supportive/sensitivity analyses 
The main analysis will be repeated on the primary endpoint using the mFAS (if at least 5% 
different from the FAS) and PPS as a supportive/sensitivity analysis.  
An additional sensitivity analysis will be run on the patients in the mFAS who received all 
three required study treatments at least until the Week 26 assessments. 
To assess the impact of missing values and their imputation, the following sensitivity 
analyses will be run on the FAS: 
• In patients with a post-baseline PVR measurement obtained before Week 26, the 
post-baseline PVR measurement will be carried forward. This imputation will be 
performed unless one of the following occurs: 
– If a subject dies without a prior Week 26 PVR assessment, then the Week 26 PVR 
is imputed using the largest (worst value) ratio of baseline PVR at Week 26 in all 
subjects in the same treatment group and analysis set, such that this value is 
multiplied by the subject’s baseline PVR to obtain the imputed Week 26 value. 
– If the subject is alive up to the Week 26 PVR assessment and does not have a 
post-baseline value, then the median of the ratio of baseline PVR at Week 26 from 
all subjects in the same treatment group and analysis set will be used to impute the 
Week 26 PVR value, such that this value is multiplied by the subject’s baseline 
PVR to obtain the imputed Week 26 value. 
• An analysis applying main ANCOVA without any imputation described in 
Section 10.6.2.2 (observed cases).  
• An analysis on change from baseline to Week 26 (main ANCOVA analysis without 
PVR log-transformation) 
• An analysis applying main ANCOVA without stratification factors  
• To assess the robustness of the model towards possible treatment-arm-related 
drop-out patterns, a multiple imputations analysis for the primary endpoint will be 
conducted: Each missing value is replaced by a set of plausible values that represent 
the uncertainty about the right value to impute. Each one of the multiply imputed data 


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sets is analyzed then by using the same model as for the primary analysis, and the 
results are displayed [see Section 9.8]. 
• To include the intercurrent event ‘administration of rescue therapy’, the Week 26 PVR 
values of subjects who received a prostanoids pulmonary hypertension (PH) therapy 
(as defined in Table 9 of Section 11.5) prior to PVR assessment at Week 26 will be 
imputed using LOCF (including baseline) of the value prior to prostanoids PH therapy 
initiation (i.e., values obtained after or on prostanoids PH therapy initiation date are 
considered as missing). In subjects who did not receive prostanoids PH therapy prior 
to Week 26 PVR assessment, the same imputation rules as in the main analysis are 
used. 
In addition, the change from baseline in PVR at Week 26 versus baseline PVR is displayed 
in a scatter plot. Imputed values are flagged.  
10.6.2.5 Subgroup analyses 
Descriptive summaries will be repeated for the individual randomization strata (North 
America versus rest of the world and WHO FC I/II versus WHO FC III/IV), and also for 
age (64 or lower versus ≥ 65 years), gender and PAH etiology (idiopathic PAH, heritable 
PAH, drug- or toxin-induced PAH, PAH associated with CTD, PAH associated with 
Others). The main ANCOVA analysis on the FAS will be also repeated on subgroups. 
Subgroups will be shown on a forest plot and will display estimates, 95% CI and p-value 
for treatment by subgroup interaction. 
10.6.3 Analysis of the secondary efficacy variables 
To control for multiplicity across the primary and selected secondary efficacy endpoints, 
statistical analyses for secondary endpoints will be performed in the following sequence: 
1. Change from baseline to Week 26 in 6MWD 
2. Change from baseline to Week 26 in NT-proBNP 
3. Time from randomization to first disease progression event up to EOMOP + 7 days 
4. 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 at α = 0.05 (two-sided). 
All analyses for secondary efficacy variables are presented on the FAS, mFAS (if at least 
5% different from the FAS) and PPS. 
An additional sensitivity analysis is run on the patients in the mFAS who received all three 
required study treatments at least until the Week 26 assessments. 


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10.6.4 Secondary endpoints  
10.6.4.1 Change from baseline to Week 26 in six-minute walk distance 
6MWD will be summarized by a scheduled analysis time window [see Table 5]. 
Change from baseline to Week 26 in 6MWD will be analyzed using an ANCOVA model 
with factors for treatment arm and stratification factors (region, WHO FC) and baseline 
6MWD as a covariate, as described Section 9.3.  
For the main analysis, in case of a missing Week 26 assessment, for subjects with a 
post-baseline 6MWD measurement obtained before Week 26, the (last) post-baseline 
6MWD measurement will be carried forward. For subjects without a post-baseline 6MWD 
measurement, the baseline 6MWD will be carried forward. Patients without a baseline 
value will be excluded from analysis.  
To assess the impact of missing values and their imputation, the following sensitivity 
analyses will be run on the FAS: 
• In patients with a post-baseline 6MWD measurement obtained before Week 26, the 
post-baseline 6MWD measurement will be carried forward. This imputation will be 
performed unless the following occurs: 
– If a subject dies without a prior Week 26 6MWD assessment, then the Week 
26 6MWD is imputed by 0 meter. 
• An analysis applying main ANCOVA without any imputation of missing Week 26 
assessments (observed cases).  
• An analysis applying main ANCOVA without stratification factors  
• To assess the robustness of the model towards possible treatment-arm-related 
drop-out patterns, a multiple imputations analysis will be conducted: each missing 
value is replaced by a set of plausible values that represent the uncertainty about the 
right value to impute. Each one of the multiply imputed data sets is analyzed then by 
using the same model as the main analysis, and the results are displayed [see 
Section 9.8]. 
• An MMRM done on the FAS after LOCF imputation for missing Week 12/Week 26 
assessments [see Section 9.6]. 
• To include the intercurrent event ‘administration of rescue therapy’, the Week 26 
6MWD values of subjects who received prostanoids PH therapy (as defined in Table 9 
of Section 11.5) prior to 6MWD assessment at Week 26 will be imputed using LOCF 
(including baseline) of the value prior to prostanoids PH therapy initiation (i.e., values 
obtained after or on prostanoids PH therapy initiation date are considered as missing). 
In subjects who did not receive prostanoids PH therapy prior to Week 26 6MWD 
assessment, the same imputation rules as in the main analysis are used.  
10.6.4.2 Change from baseline to Week 26 in NT-proBNP 
NT-proBNP will be summarized by scheduled analysis time window [see Table 5]. 


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NT-proBNP values are log-transformed (base e) and change from baseline to Week 26 in 
log-transformed NT-proBNP will be analyzed using an ANCOVA model with factors for 
treatment arm and stratification factors (region, WHO FC) and baseline log-transformed 
NT-proBNP as a covariate.  
For display, point estimates and bounds of the 95% confidence intervals are exponentiated, 
yielding a GMR similar to the primary endpoint analysis. 
For the main analysis, in case of a missing Week 26 assessment, for subjects with a 
post-baseline NT-proBNP measurement obtained before Week 26, the (last) post-baseline 
NT-proBNP measurement is carried forward. For subjects without a post-baseline 
NT-proBNP measurement, the baseline NT-proBNP is carried forward. Patients without 
baseline value will be excluded from analysis.  
To assess the impact of missing values and their imputation, the following sensitivity 
analyses will be run on the FAS: 
• In patients with a post-baseline NT-proBNP measurement obtained before Week 26, 
the post-baseline NT-proBNP measurement will be carried forward. This imputation 
will be performed unless one of the following occurs: 
– If a subject dies without a prior Week 26 NT-proBNP assessment, then the 
Week 26 NT-proBNP is imputed using the largest ratio of baseline NT-proBNP at 
Week 26 in all subjects in the same treatment group and analysis set, such that 
this value is multiplied by the subject’s baseline NT-proBNP to obtain the 
imputed Week 26 value. 
– If the subject is alive up to the Week 26 NT-proBNP assessment and does not 
have a post-baseline value then the median of the ratio of baseline NT-proBNP at 
Week 26 from all subjects in the same treatment group and analysis set will be 
used to impute the Week 26 NT-proBNP value, such that this value is multiplied 
by the subject’s baseline NT-proBNP to obtain the imputed Week 26 value. 
• An analysis applying main ANCOVA without any imputation of missing Week 26 
assessments (observed cases). 
10.6.4.3 Time to the first disease progression event  
The time from randomization to the first disease progression event up to EOMOP + 7 days 
will be analyzed using KM estimates and KM plots, as described in Section 9.5.  
Patients will be censored at min (EOS, EOMOP + 7) days for the main analysis (FAS).  
A log rank test for treatment difference will be computed, stratified by randomization strata 
(region and WHO FC at baseline). Additionally, a Cox regression model will be fitted using 
region (North America versus rest of the world) and WHO FC at baseline as factors. 
The components of the first occurrence of disease progression events will be tabulated. If 
for a given subject two components occur on the same day then the worst is tabulated 


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according to the hierarchy stated in Section 5.5.2.5: death, hospitalization, initiation of 
therapy for worsening PAH, and clinical worsening. 
For sensitivity analyses, patients will be censored at EOMOP + 7 days or day of last drug 
intake of any of the three study medications + 7 days, whichever is the earliest (sensitivity 
analysis #1, FAS); at EOMOP + 7 days or end of double-blind study treatment + 7 days, 
whichever is the earliest (sensitivity analysis #2, restricted to patients in the FAS who 
received at least one dose of double-blind study treatment); and at EOS (sensitivity analysis 
#3, FAS). 
10.6.4.4 Absence of worsening from baseline to Week 26 in WHO FC 
The absence of worsening of WHO FC from baseline to Week 26 will be summarized as a 
categorical variable and analyzed using a logistic regression model, as described in Section 
9.4. The main analysis will be restricted to patients with WHO FC I–III at baseline (using 
the definition in Section 5.5.2.3.1), and a sensitivity analysis will be performed including 
all patients (also those with WHO FC IV at baseline using the definition of Section 
5.5.2.3.2).  
In case of a missing Week 26 assessment, for subjects with a post-baseline WHO FC 
measurement obtained before Week 26, the (last) post-baseline WHO FC measurement 
will be carried forward. For subjects without a post-baseline WHO FC measurement, the 
baseline WHO FC will be carried forward. Patients without baseline value will be excluded 
from analysis.  
To assess the impact of missing values and their imputation, the following sensitivity 
analyses will be run on the FAS: 
• In patients with a post-baseline WHO FC measurement obtained before Week 26, the 
post-baseline WHO FC measurement will be carried forward. This imputation will be 
performed unless the following occurs: 
– If a subject dies without prior Week 26 WHO FC assessment, then the Week 26 
WHO FC is imputed by class IV. 
• An analysis without any imputation of missing Week 26 assessments (observed 
cases). 
WHO FC at baseline and at Week 26 will also be displayed in a shift table, using the 
same imputation rules as for the main analysis.  
10.6.4.5 Change from baseline to Week 26 in hemodynamic variables other than PVR 
The change from baseline to Week 26 in variables from RHC other than PVR (mPAP, CI, 
TPR, mRAP, venous oxygen saturation) will be summarized on the FAS. Analysis will be 
performed after LOCF imputation and repeated without imputation (observed cases). 
The change from baseline to Week 26 in RHC parameters other than PVR will be analyzed 
on the FAS using an ANCOVA model with factors for treatment arm and stratification 


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factors (region, WHO FC) and respective baseline value as covariate, as described in 
Section 9.3.  
10.6.4.6 Analyses of endpoints after Week 26, EOMOP and EOT visits 
Due to the design of the study, EOMOP for all subjects will be announced once the last 
subject has been enrolled, i.e., approximately 26 weeks in advance; all subjects will 
undergo the EOMOP visit. The study will be unblinded shortly after the last subject’s 
EOMOP visit. 
All summaries and statistical models will use data up to EOMOP or EOMOP + 7 as stated. 
Assessments made after the period will be listed only. 
10.6.4.7 Subgroup analyses 
Descriptive summaries will be repeated on the FAS for 6MWD for the individual 
randomization strata (North America versus rest of the world and WHO FC I/II versus 
WHO FC III/IV), age (64 or lower versus ≥ 65 years), gender, and PAH etiology (idiopathic 
PAH, heritable PAH, drug- or toxin-induced PAH, PAH associated with CTD, PAH 
associated with Others).  
The main 6MWD ANCOVA analysis on the FAS will be also repeated on subgroups. In 
addition, subgroups will be shown on a forest plot and will display estimates, 95% CI and 
p-value for treatment by subgroup interaction added in the model. 
10.7 Analysis of other efficacy variables 
All analyses for other efficacy variables will be presented on the FAS. 
Patient data up to EOMOP (for visit-based data) or EOMOP + 7 days (for time-to-event 
data), respectively, will be used for summaries and analyses. Assessments collected after 
EOMOP will be listed. Sensitivity analysis up to EOS will be performed only after all 
patients’ EOS. 
10.7.1 Change of NT-proBNP from baseline to all regular collection time points up 
to EOMOP 
NT-proBNP will be log transformed (base e). Changes from baseline to Week 26 in 
log-transformed values will be analyzed using the MMRM model, as described in 
Section 9.6. Note that log-transformed baseline NT-proBNP will be used as a covariate. 
Treatment contrasts and the corresponding 95% confidence intervals will be computed for 
each regular collection visit up to Week 26. The treatment differences and confidence 
interval boundaries are exponentiated and will be thus displaying a GMR. Data after Week 
26 will be reported with descriptive statistics only. 


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10.7.2 Change of 6MWD from baseline to all regular collection time points up to 
EOMOP 
Changes from baseline to Week 26 in 6MWD will be analyzed in an MMRM model, as 
described in Section 9.6 (also described as sensitivity analysis for 6MWD secondary 
endpoint). Baseline 6MWD will be used as the continuous covariate. Treatment contrasts 
and the corresponding 95% confidence intervals will be computed for each regular visit 
where 6MWD was collected up to Week 26. Data after Week 26 will be reported with 
descriptive statistics only. 
10.7.3 Absence of worsening from baseline in WHO FC to all regular collection 
time points up to EOMOP 
The absence of worsening of WHO FC to all scheduled study visits where WHO FC is 
assessed up to EOMOP will be summarized as a categorical variable for patients in WHO 
FC I–III at baseline using the definition of Section 5.5.2.3.1.  
Subjects in WHO FC IV at baseline will be excluded from the analysis. A sensitivity 
analysis will be performed including subjects in WHO FC IV at baseline (for whom 
worsening is defined as death or hospitalization due to PAH), as described in 
Section 5.5.2.3.2. 
10.7.4 Unsatisfactory clinical response 
Unsatisfactory clinical response will be summarized for all regular visits from Week 26 
onwards. The number and percentage of patients with unsatisfactory response will be 
displayed along with the - criteria for unsatisfactory response for each visit up to EOMOP.  
Patients fulfilling one or more unsatisfactory response criteria at baseline will be also 
included in the analysis. 
10.7.5 Number of treatment goals met at Week 26 
The number of treatment goals met will be summarized at Week 26 for all three definitions 
of the number of treatment goals met [see Section 5.5.3.3] along with the number of 
patients who met each individual treatment goal. The summary will be done both ways, 
considering the number of treatment goals as a continuous and a categorical variable.  
The number of treatment goals met will be tested for treatment arm difference using a CMH 
test adjusting for baseline WHO FC (randomization stratum) and baseline 6MWD 
(≤ 440 m vs > 440 m).  
The number of treatment goals at baseline and at Week 26 will also be summarized as a 
shift table. 
10.7.6 Improvement of WHO FC from baseline to Week 26 
The improvement of WHO FC from baseline to Week 26 will be summarized as a 
categorical variable and analyzed using a logistic regression model, as described in 


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Section 9.4. The main analysis will be restricted to patients with WHO FC II–IV at baseline 
(using the definition in Section 5.5.3.3). In case of a missing Week 26 assessment, for 
subjects with a post-baseline WHO FC measurement obtained before Week 26, the (last) 
post-baseline WHO FC measurement will be carried forward. For subjects without a 
post-baseline WHO FC measurement, the baseline WHO FC will be carried forward. 
Patients without baseline value will be excluded from analysis.  
10.7.7 Hospitalizations up to EOMOP 
All hospitalization data will be listed. 
10.7.7.1 Time from randomization to first hospitalization (all causes) up to EOMOP 
The time from randomization to the first hospitalization (all causes) up to EOMOP will be 
analyzed using KM estimates and KM plots, as described in Section 9.5. 
A log rank test for treatment difference will be computed without stratification variables 
and a Cox regression model will be fitted without stratification variables. 
10.7.7.2 Time from randomization to first hospitalization for worsening PAH up to 
EOMOP  
The time from randomization to the first hospitalization for worsening PAH up to EOMOP 
will be analyzed using KM estimates and KM plots, as described in Section 9.5. 
A log rank test for treatment difference will be computed without stratification variables 
and a Cox regression model will be fitted without stratification variables. 
10.7.7.3 Annualized rate of hospitalization (all causes) up to EOMOP  
The annualized rate of hospitalization (all causes) up to EOMOP will be summarized 
descriptively. In addition, a Poisson regression model as described in Section 9.9 will be 
used for exploratory statistical analysis.  
10.7.7.4 Annualized rate of hospitalization for worsening PAH up to EOMOP  
The annualized rate of hospitalization for worsening PAH up to EOMOP will be 
summarized descriptively. In addition, a Poisson regression model as described in 
Section 9.9 will be used for exploratory statistical analysis.  
10.7.7.5 Annualized rate of days spent in hospital (all causes) up to EOMOP  
The annualized rate of days spent in hospital (all causes) up to EOMOP will be summarized 
using descriptive statistics.  
10.7.7.6 Annualized rate of days spent in hospital for worsening PAH up to EOMOP  
The annualized rate of days spent in hospital for worsening PAH up to EOMOP will be 
summarized using descriptive statistics. 


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10.8 Analysis of safety variables 
This section describes the analyses of the safety variables defined in Section 5.6. All 
analyses of safety variables will be based on the SAF. Safety analyses specific to one study 
medication (e.g., treatment-emergent AEs related to macitentan) will be restricted to the 
subset of subjects from the SAF who received at least one dose of the corresponding study 
medication.  
10.8.1 Adverse events 
All AEs captured from signature of informed consent up to EOS will be reported in the 
subject listings.  
All AEs will be coded using the MedDRA dictionary valid at the time of database closure.  
In general, AEs will be summarized by presenting, for each treatment group, the number 
and percentage of patients having any AE, having an AE in each primary SOC, and having 
each individual AE (PT). A second summary will present a summary of each individual 
AE at the PT level. 
The following summaries will be provided for AEs 
• Incidence of AEs from informed consent signature until initiation of first study drug 
(Day −1) 
• Incidence of treatment-emergent AEs up to EOMOP and separately for the overall 
study period 
• Incidence of treatment-emergent AEs related to each of the three study medications, 
separately for each study medication up to EOMOP and separately for the overall 
study period 
• Incidence of treatment-emergent AEs by maximum intensity (summary only at the PT 
level) up to EOMOP 
• Incidence of treatment-emergent AEs leading to discontinuation of each of the three 
study medications, separately for each study medication up to EOMOP and separately 
for the overall study period. 
A table of the most frequent PTs (incidence rate of at least 5% in any treatment arm) up to 
EOMOP. 
Additionally, the incidence of AEs will be analyzed for the following time periods 
• AEs with onset between Day 1 until EOMOP (or EOS whichever is earlier) 
• AEs with onset between Day 1 and before start of double-blind treatment 
(selexipag/placebo). For subjects who did not receive double-blind treatment, AEs with 
onset between Day 1 and Day 14 (included) will be displayed 
• AEs with onset between first and last day (+ 30 days) of macitentan treatment (or 
EOMOP, whichever is earlier) 


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• AEs with onset between first and last day (+ 30 days) of tadalafil treatment (or EOMOP, 
whichever is earlier) 
• AEs with onset between first and last day (+ 30 days) of double-blind treatment (or 
EOMOP, whichever is earlier) 
• AEs with onset between EOMOP and EOT + 30 days. The summary will be restricted 
to subset of subjects from the SAF with ongoing treatment at time of EOMOP visit.  
• AEs with onset after EOT (30 day safety follow-up) 
• AEs with onset during the titration period of double-blind treatment versus AEs with 
onset during the maintenance period of double-blind treatment (up to last day in the 
maintenance period or EOMOP, whichever is earlier) 
• AEs with onset between first and last day (+ 3 days) of double-blind treatment (or 
EOMOP, whichever is earlier). 
10.8.2 Deaths, other serious adverse events 
10.8.2.1 Death 
Study deaths will be summarized by SOC and PT up to EOMOP and separately for the 
overall study period. A listing of primary reasons for death and all AEs leading to death 
will be provided.  
10.8.2.2 Serious adverse events 
Treatment-emergent SAEs will be displayed by SOC and PT as well as by PT alone up to 
EOMOP and separately for the overall study period. A summary will be created for 
treatment-emergent SAEs related to each of the three study medications, separately.  
Listings will be provided for all SAEs, SAEs prior to the first dose (i.e., first intake) of 
study medication, SAEs occurring more than 30 days after the last dose of study 
medication. 
A separate summary of treatment-emergent SAEs will be provided for patients who have 
received at least one dose of double-blind study medication. 
Listing of all SAEs with onset date after start of a new PAH specific therapy (as defined in 
Table 9 of Section 11.5) will be provided.  
10.8.3 Other adverse event analyses 
10.8.3.1 Important identified or potential risks  
Important identified or potential-risk AEs treatment emergent to selexipag will be 
displayed by the individual category up to EOMOP. 


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10.8.3.2 Adverse events related to the addition of selexipag to the dual treatment 
regimen 
Additional tables will be prepared to investigate safety signals that may be related to the 
addition of selexipag to the dual treatment regimen. For those tables, only AEs with onset 
during exposure to selexipag/placebo are tabulated:  
• Incidence of AEs during selexipag/placebo exposure up to EOMOP 
• Incidence of SAEs during selexipag/placebo exposure up to EOMOP  
• Incidence of AEs during selexipag/placebo exposure related to selexipag/placebo up 
to EOMOP  
• Incidence of AEs during selexipag/placebo exposure leading to discontinuation of 
selexipag/placebo up to EOMOP  
• Incidence of AEs during selexipag/placebo exposure leading to death up to EOMOP. 
10.8.3.3 Other adverse events of special interest 
The incidence of treatment-emergent symptomatic hypotension AEs will be displayed by 
PT up to EOMOP. 
The incidence of AEs typical of prostanoids treatment (as defined in Section 5.6.6) with 
onset date between start of double-blind treatment and last day (+ 3 days) of double-blind 
treatment (or EOMOP, whichever is earlier) will be displayed by PT. 
10.8.3.4 Summaries of adverse events for disclosure 
For the disclosure of the results to EudraCT and ClinicalTrials.gov (and not for the purpose 
of the CSR), treatment-emergent (S)AEs will be summarized displaying, for each treatment 
group, counts and percentages of subjects with at least a treatment-emergent event plus the 
number of events (counted exactly the number of times they occurred also within a subject) 
by SOC and individual PT. The summary table will be presented in descending order 
according to the incidence in the selexipag treatment group (i.e., SOC and individual PT 
within each SOC, with the highest number of occurrences appearing first). Equal frequency 
of different individual PTs will be sorted in alphabetical order of the individual PT.  
The following summaries will be prepared according to the guidelines stated above: 
• Summary of treatment-emergent SAEs up to EOMOP [see Section 10.8.2.2] 
• Summary of treatment-emergent SAEs judged to be treatment related by the 
investigator up to EOMOP [see Section 10.8.2.2] 
• Summary of treatment-emergent SAEs with fatal outcome up to EOMOP 
• Summary of treatment-emergent SAEs with fatal outcome judged to be treatment 
(related by the investigator up to EOMOP 
• Summary of non-serious AEs with an incidence of 5% or higher in any treatment 
group up to EOMOP. 


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10.8.4 Electrocardiography 
ECG is not assessed in this trial. 
10.8.5 Laboratory tests 
Central lab values will be used for analysis; local lab values will be used only if no central 
lab value is available for the laboratory test. In some cases the same sample can be assessed 
twice by the central laboratory. If the results are different, the highest value will be used 
for display in summary tables.  
The data will be assigned to the most appropriate analysis time point using time windows, 
as described in Table 5. 
Laboratory values will be summarized by visit in their respective SI unit together with the 
respective changes from baseline for all scheduled study visits up to EOMOP. Laboratory 
test assessments within 30 days of the last dose of study medication will be used for 
summaries.  
All laboratory values will be listed.  
10.8.5.1 Marked laboratory abnormalities  
Actelion internal guidelines (OTH-000005) will be used for the definitions of marked 
abnormalities. Standard numeric laboratory variables will be transformed to standard units. 
All laboratory data transferred will be taken into account regardless of their correspondence 
to scheduled or unscheduled assessments.  


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Table 4 
Definition of marked laboratory abnormalities  
Parameter (SI unit) 
LL 
Marked 
LLL 
Alert 
HH 
Marked 
HHH 
Alert 
Hemoglobin (g/L) 
 baseline within ULN 
 
 baseline above ULN 
 
< 100 
 
< 100 
 
< 80 
 
< 80 
 
> 20 above 
ULN 
> 20 above 
baseline 
 
> 40 above 
ULN 
> 40 above 
baseline 
Hematocrit (L/L) 
 males 
 females 
 
< 0.32 
< 0.28 
 
< 0.20 
< 0.20 
 
> 0.60 
> 0.55 
 
> 0.65 
> 0.65 
Platelets (109/L) 
< 75 
< 50 
> 600 
> 999 
Leucocytes (109/L) 
< 3 
< 2 
> 20 
> 100 
Neutrophils (109/L) 
< 1.5 
< 1.0 
- 
- 
Eosinophils (109/L) 
- 
- 
> 5 
- 
Lymphocytes (109/L) 
< 0.8 
< 0.5 
> 4 
> 20 
ALT  
- 
- 
> 3 ULN 
> 5 ULN 
AST 
- 
- 
> 3 ULN 
> 5 ULN 
Alkaline Phosphatase 
- 
- 
> 2.5 ULN 
> 5 ULN 
Total Bilirubin 
- 
- 
> 2 ULN 
> 5 ULN 
INR 
- 
- 
> 1.5 ULN 
> 2.5 ULN 
Creatinine 
 baseline within ULN 
 baseline above ULN 
 
- 
- 
- 
- 
- 
 
> 1.5 ULN 
> 1.5 baseline 
 
> 3 ULN 
> 3 baseline 
Glucose (mmol/L) 
< 3 
< 2.2 
> 8.9 
> 13.9 
Calcium (mmol/L) 
< 2 
< 1.75 
> 2.9 
> 3.1 
Sodium (mmol/L) 
- 
< 130 
> 150 
> 155 
Potassium (mmol/L) 
< 3.2 
< 3 
> 5.5 
> 6 
Uric Acid (μmol/L) 
- 
- 
> 590 
> 720 
Albumin 
< 30 
< 20 
- 
- 
Creatinine Clearance/eGFR 
(mL/min) 
< 60 
< 30 
- 
- 
BUN 
- 
- 
> 2.5 ULN 
> 5 ULN 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; eGFR = estimated 
glomerular filtration rate; INR = international normalized ratio; ULN = upper limit of normal. 
The number and percentage of subjects with treatment-emergent (i.e., within 30 days of 
last dose) post-baseline laboratory abnormalities will be tabulated by treatment group up 
to EOMOP. 


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For subjects with laboratory abnormality at baseline, the post-baseline value will be 
counted as a post-baseline abnormality only if the post-baseline category is worse than the 
baseline category.  
10.8.5.2 Other notable laboratory abnormalities (hepatic safety) 
The incidence of the following notable treatment-emergent laboratory values post baseline 
will be tabulated up to EOMOP:  
• ALT ≥ 3*ULN 
• AST ≥ 3*ULN 
• ALT or AST ≥ 3*ULN 
• ALT or AST ≥ 3*ULN + < 5*ULN 
• ALT or AST ≥ 5*ULN + < 8*ULN 
• ALT or AST ≥ 8*ULN 
• ALT or AST ≥ 3*ULN + total bilirubin > 2*ULN (at the same time as ALT or AST 
≥ 3*ULN) 
An e-DISH plot of the maximum treatment-emergent post-baseline ALT by concomitant 
post-baseline bilirubin (in multiples of ULN) will be presented to detect possible cases of 
drug-induced liver toxicity up to EOMOP. In case of missing concomitant bilirubin (in 
multiples of ULN), the closest non-missing bilirubin value (in multiple of ULN) to the peak 
ALT value (within 14 days) will be used.  
10.8.6 Vital signs and body weight 
Vital signs assessments within 30 days of the last dose of study medication will be used 
for summaries up to EOMOP. All data, regardless if from scheduled or unscheduled visits 
will be used. The data will be assigned to the most appropriate analysis time point using 
time windows as described in Table 7. 
Weight, BMI, pulse rate, systolic and diastolic blood pressure will be summarized together 
with the respective changes from baseline for all scheduled study visits. 
10.8.6.1 Clinically relevant vital signs abnormalities 
The incidence of the following notable treatment-emergent blood pressure values post 
baseline will be tabulated up to EOMOP:  
• Systolic blood pressure < 90 mmHg 
• Diastolic blood pressure < 50 mmHg 
• Decrease of > 40 mmHg in systolic blood pressure from baseline 
• Decrease of > 20 mmHg in diastolic blood pressure from baseline 
• All four notable criteria fulfilled 
 
All treatment-emergent post-baseline assessments from scheduled and unscheduled visits 
will be used to determine notable blood pressure values. 


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For the first two criteria above, subjects with vital signs abnormality at baseline and post-
baseline (e.g., systolic blood pressure < 90 mmHg at baseline and post-baseline) are not 
counted as having a post baseline abnormality.  
10.9 Interim analysis 
An interim analysis for futility (non-binding) will be conducted when 33% of the patients 
have completed their Week 26 visit or discontinued prematurely.  
The unblinded analyses for IDMC closed sessions (including futility interim analysis) are 
performed by the ISAC according to ISAC’s own analysis plan (and following stopping 
rules mentioned in protocol section 11.5). The study team remains blinded. The ISAC is 
responsible for the content of these unblinded analyses for the closed reports provided to 
the IDMC (see IDMC charter). 
11 GENERAL DEFINITIONS AND DERIVATIONS 
11.1 Study treatment start and end date 
The study treatments are macitentan, tadalafil and selexipag/placebo, which are scheduled 
to start at different time points after randomization. Each of the three study treatments may 
be discontinued while the other treatments are continued.  
The first dose (i.e., first intake) of any of the three study treatments is considered study 
treatment start date.  
The last dose (i.e., last intake) of any of the three study treatments is considered study 
treatment end date. 
11.1.1 Treatment-emergent assessments or events 
Treatment-emergent assessments or events are assessments made or events experienced 
within the next full 30 days after the last dose of study medication, i.e., if the day of the 
last dose is on Day x, all events up to Day x + 30 + 1 are considered treatment emergent. 
11.2 Study days 
Study days are relative to the date of first study medication. The date of first study 
medication is Day 1. There is no Day 0, i.e., the Day before Day 1 is Day −1. 
11.3 Baseline definition 
The last value prior to first dose (i.e., first intake) of study medication is considered 
baseline. All assessments made on the first day of study drug intake (Day 1) are considered 
as prior to study drug intake for the determination of baseline. 
11.4 Assignment of assessment dates to the most appropriate analysis time 
point (visit windows) 
To allow for unscheduled assessments and to minimize the impact of missed assessments 
at regular study visits, all values obtained up to 30 days after last dose of study medication 
are assigned the most appropriate analysis time point using a time window. All 


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unscheduled visits, the EOMOP and EOT visits are realigned using windowing rules, if 
they were within 30 days after the last dose of study drug. 
Not all assessments are conducted at every study visit. Therefore, different visit windows 
are used for different assessments. 
11.4.1 Visit windows for primary efficacy variable, hemodynamics from RHC 
The primary efficacy variable, PVR, and other hemodynamic assessments are determined 
by RHC at screening and Week 26.  
In case more than one pre-baseline RHC is obtained, the assessments from the latest RHC 
prior to first dose (i.e., first intake) of study are used for baseline. 
In case more than one post-baseline RHC is obtained, the assessments from the RHC 
closest to Week 26 are used. If two assessments are equally close, the earliest of the two 
assessments is used. 
11.4.2 Visit windows for six-minute walk test, WHO FC, NT-proBNP, regular 
laboratory (except hemoglobin and liver function tests) 
These assessments are obtained at Week 12, Week 26 and every study visit thereafter. They 
are mapped to the most appropriate time point using Table 5. 
Table 5 
Time windows for 6-minute walk tests, WHO FC and laboratory 
assessments (except hemoglobin and liver function tests) 
Visit label 
Target Day 
Lower limit of study 
day 
Upper limit of study 
day 
Baseline 
1 
Latest assessment before or at Day 1 
Week 12 
84 
2 
133 
Week 26 
182 
134 
197 
Month 12 
365 
198 
456 
Month 18 
548 
457 
638 
Month 24 
730 
639 
821 
Month 30 
913 
822 
1003 
Month 36 
1095 
1004 
1186 
… 
 
 
 
11.4.3 Visit windows for hemoglobin and liver function tests 
These assessments are obtained monthly up to Week 26 and every study visit thereafter. 
They are mapped to the most appropriate time point using Table 6. 


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Table 6 
Time windows for hemoglobin and liver function tests 
Visit label 
Target Day 
Lower limit of study 
day 
Upper limit of study 
day 
Baseline 
1 
Latest assessment before or at Day 1 
Month 1 
30 
2 
45 
Month 2 
60 
46 
75 
Month 3 
90 
76 
115 
Month 4 
120 
116 
135 
Month 5 
150 
136 
166 
Week 26 
182 
167 
197 
Month 12 
365 
198 
456 
Month 18 
548 
457 
638 
Month 24 
730 
639 
821 
Month 30 
913 
822 
1003 
Month 36 
1095 
1004 
1186 
… 
 
 
 
11.4.4 Visit windows for vital signs and body weight 
Vital signs assessments are mapped to the most appropriate time point using Table 7.  
Table 7 
Time windows for vital signs assessments 
Visit label 
Target Day 
Lower limit of study 
day 
Upper limit of study 
day 
Baseline 
1 
Latest assessment before or at Day 1 
Day 15 
15 
2 
50 
Week 12 
84 
51 
133 
Week 26 
182 
134 
197 
Month 12 
365 
198 
456 
Month 18 
548 
457 
638 
Month 24 
730 
639 
821 
Month 30 
913 
822 
1003 
Month 36 
1095 
1004 
1186 
… 
 
 
 
11.5 Identification of prohibited medication and medications of special 
interest  
The search criteria laid out in Table 8 are used to identify prohibited and special-interest 
drug classes. 


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Table 8 
Clinical forbidden medications list 
Drug class 
Generic 
name/active 
ingredient 
Rule 
Id 
(within 
category) 
SDG Level 1 
SDG Level 2 
SDG 
Level 3 
SDG 
Scope 
Drug Name 
List of 
ATC 
codes 
Ingredients 
Prostacyclin analogs 
Epoprostenol 
1 
 
 
 
 
 
 
Epoprostenol 
Treprostinil 
2 
 
 
 
 
 
 
Treprostinil 
Iloprost 
3 
 
 
 
 
 
 
Iloprost 
Beraprost 
4 
 
 
 
 
 
 
Beraprost 
Prostacyclin receptor 
agonist 
Selexipag 
1 
 
 
 
 
 
 
Selexipag 
Ralinepag 
Endothelin receptor 
antagonist 
Bosentan 
1 
 
 
 
 
 
 
 
Ambrisentan 
2 
 
 
 
 
 
 
 
Macitentan 
3 
 
 
 
 
 
 
 
Phosphodiesterase-5 
inhibitor (PDE-5i) 
 
 
Phosphodiesterase 
(PDE) inhibitors 
Phosphodiesterase 
type 5 inhibitors 
 
narrow 
+ 
broad 
 
 
 
Soluble guanylate 
cyclase stimulator 
Riociguat 
1 
 
 
 
 
 
 
Riociguat 
Nitric oxide 
2 
 
 
 
 
 
 
Nitric oxide 
Strong inducers of 
CYP3A4 
 
 
CYP3A 
interacting 
substances 
CYP3A inducers 
Strong 
CYP3A 
inducers 
 
 
 
 
Strong inhibitors of 
CYP3A4 
 
 
CYP3A 
interacting 
substances 
CYP3A inhibitors 
Strong 
CYP3A 
inhibitors 
 
 
 
 
Another investigational 
drug 
 
1 
 
 
 
 
Investigational 
antineoplastic 
drugs 
 
 
 
2 
 
 
 
 
Investigational 
drug 
 
 
Organic nitrates 
 
1 
 
 
 
 
 
C01DA   


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2 
 
 
 
 
 
 
Eritrityl 
tetranitrate 
Glyceryl 
trinitrate 
Isosorbide 
dinitrate 
Isosorbide 
mononitrate 
Methylpropyl
propanediol 
dinitrate 
Organic 
nitrates 
Pentaerithrity
l tetranitrate 
Propatylnitrat
e 
Tenitramine 
Trolnitrate 
Doxazosin 
 
 
 
 
 
 
 
 
Doxazosin 
Strong CYP2C8 
inhibitors 
 
 
CYP2C8 
interacting 
substances 
CYP2C8 
inhibitors 
Strong 
CYP2C8 
inhibitors 
 
 
 
 
The search criteria laid out in Table 9 are used to identify new PAH specific therapies. 
 


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Table 9 
New PAH specific therapies 
Category 
Subcategory 
Ingredient names 
Antihypertensives for pulmonary arterial 
hypertension 
ERAs 
Ambrisentan, Bosentan 
 
PDE-5 Inhibitors 
Sildenafil, Vardenafil, Udenafil 
 
sGC stimulator 
Riociguat  
Prostanoids  
 
Epoprostenol, Treprostinil, Iloprost, Beraprost, selexipag 
Categories are identified by searching the coded WHODRUG preferred terms for occurrence of any of the ingredient names. E.g., ‘Sildenafil’ 
and ‘Sildenafil Citrate’ will both be assigned to PDE-5 inhibitors. 
ERA = endothelin receptor antagonist; PDE-5 = phosphodiesterase-5; sGC = soluble guanylate cyclase. 


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11.6 Handling of selexipag/placebo dose titrations over day 
In the protocol [D-18.392], it is recommended that dose changes (up- or down-titration) 
shall be conducted over one day of the b.i.d. regimen of selexipag/placebo, i.e., the dose 
taken in the evening is higher or lower than the dose taken in the morning. In the eCRF, 
overlapping intervals of dosages are recorded in such a case: the end date of the old regimen 
is the same date as the start date of the new regimen. To account for the actual daily dose 
the following handling convention was used: 
1. The end date of the old dose regimen is reduced by one day 
2. The start date of the new dose regimen is increased by one day 
3. A record with an intermediate dose is created for the day of dose change 
An example from the selexipag/placebo dosage log is shown in Table 10. 
Table 10 
Handling of selexipag/placebo dose titrations over day 
Dose start  
Dose end 
Regimen 
Total daily dose 
As recorded in the eCRF 
01Sep2016 
16Sep2016 
200 mcg b.i.d. 
400 mcg 
16Sep2016 
30Sep2016 
400 mcg b.i.d. 
800 mcg 
Handling rule for analysis 
01Sep2016 
15Sep2016 
200 mcg b.i.d. 
400 mcg  
16Sep2016 
16Sep2016 
--- 
600 mcg 
17Sep2016 
30Sep2016 
400 mcg b.i.d. 
800 mcg 
b.i.d. = twice daily; eCRF = electronic Case Report Form. 
12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS 
Missing and incomplete date and time fields should be avoided as much as possible. 
However, in some cases complete dates cannot be obtained with reasonable effort. In those 
cases, imputation of incomplete dates or incomplete date parts is employed.  
1. Dates are split in three parts: year, month and day. Year is the top level, month is 
medium level and day is low level. If a part expected to contain a number is numeric 
but the value is outside a valid range, the complete date is handled as missing. For 
example, if date = 44Nov2000 the whole date is considered to be missing. 
2. If a part expected to contain a number is not numeric, i.e., contains values such as, 
for example, ND, NA, --, ??, 2?, it is considered as missing.  
3. If a part is missing, all other parts of a lower level are considered to be missing. 
This means that a ddmmyy date ‘21ND99’ is considered as ‘----99’. 
4. Missing parts are changed into acceptable non-missing values in a way depending 
on the type of date to be replaced. 


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In the following sections, ‘lower limit’ and ‘upper limit’ refer to the minimum or 
maximum, respectively, of a possible date. For example, if the day is missing, the lowest 
limit is the first day of the given month and the upper limit is the last day of the given 
month. If the day and month are missing, the lower limit refers to the first day of the given 
year and the upper limit to the last day of the given year. The earliest and the latest of 
different dates refer to the first or last date, respectively, when ordered in sequence. 
12.1 Imputation of previous/concomitant medication and therapy dates 
12.1.1 Previous/concomitant medication and therapy start date 
Date is incomplete 
Date is missing 
Lower limit except when: 
Not tagged as ongoing at start of macitentan or 
tadalafil AND 
Medication stop date not collected or with the 
upper limit after the study drug start AND  
The treatment start day falls in the range of 
possible dates. 
In which case it is the study drug start day 
No replacement, the medication is 
considered to have started before 
the study 
12.1.2 Previous/concomitant medication and therapy end date 
Date is incomplete 
Date is missing 
Upper limit except when: 
Medication start is before study drug start or 
missing AND  
Upper limit is after the study drug start AND  
Not tagged as ongoing at start of macitentan or 
tadalafil AND 
Not tagged as ongoing at last visit 
In which case it is 1 day before study drug start 
No 
replacement 
(considered 
ongoing) 


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12.2 Imputation of AE start and end dates 
12.2.1 AE start date 
Date is incomplete 
Date is missing 
If the end date of the AE is not before the start of 
study drug, and if the study drug start falls in the 
range of possible dates, it is the study drug start 
date. In all the other cases, it is the lower limit. 
The earlier of the end date of the AE 
and the start of study drug. 
12.2.2 AE end date 
Date is incomplete 
Date is missing 
The upper limit 
No 
replacement, 
the 
AE 
is 
considered as ongoing in the 
analysis 
12.3 Imputation of other date fields 
12.3.1 Date of PAH diagnosis 
Date is incomplete 
Date is missing 
Day missing: 15th of the month 
Day and month missing: 30 June 
If the resulting date is later than the date of 
screening visit date and the lower limit is not later 
than the screening visit date, then the date is 
substituted with the date of screening visit. 
No replacement 
 


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12.4 Imputation of hospital admission and discharge dates 
12.4.1 Hospital admission date 
Date is incomplete 
Date is missing 
If the onset of the AE leading to hospitalization 
falls in the range of possible dates, it is the onset 
date of the AE. In all the other cases, it is the lower 
limit. 
The onset date of the AE leading to 
hospitalization. 
12.4.2 Hospital discharge date 
Date is incomplete 
Date is missing 
The upper limit 
The hospitalization is considered as 
ongoing.  
 


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13 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES 
This section lists all outputs (i.e., listings, tables and figures) produced to display the results 
of the analyses defined in the sections above.  
The table, listing and figure naming conventions have three components: Type (T, L, F), 
Name (free text, not longer than ten characters), Suffix (for example, for analysis sets, or 
subgroups, not longer than four characters). Multiple suffixes can be added; 
components/suffixes are separated by ‘_’. 
Key deliverables are marked as being of priority. Outputs marked as ‘***’ will be also 
created on blinded combined groups for IDMC open sessions. 
Mock layouts refer to specifications in the AC-065A308 ‘Layouts for TLFs’ document. 
13.1 Subject disposition 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output  
Mock layout 
Rerun 
after 
EOS 
DISP 
T 
Subject disposition 
SCR 
x*** 
DISP001 
x 
SCRF 
T 
Reasons for screening failure 
SCR 
*** 
DISP002  
 
SCRF 
L 
Listing of reasons for screening 
failure 
SCR 
 
LSTCSR011 
(from standard 
catalog) 
 
PWDS 
T 
Reasons for premature 
discontinuation of study up to 
EOMOP 
FAS 
x*** 
DISP004 
x# 
ANA 
T 
Overview of analysis sets  
FAS 
x*** 
ANA001 
 
ANA-
EX 
T 
Exclusions from analysis sets 
FAS 
 
ANA002 
 
RAN 
L 
Listing of randomization 
information 
FAS 
 
LSTRAN 
(from standard 
catalog) 
 
VIS 
L 
Listing of study visits 
SCR 
 
LSTVIS001 
x 
*T = Summary table, L = Listing, **SCR = Screened analysis set, FAS = Full analysis set, ***Created on blinded 
combined groups for IDMC open sessions, # without ‘up to EOMOP’ in the title 
 


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13.2 Protocol deviations 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock 
layout 
Rerun 
after 
EOS 
PD 
T 
Summary 
of 
protocol 
deviations 
leading 
to 
an 
exclusion 
from 
the 
Per 
Protocol Set 
FAS 
*** 
PD001 
 
PD 
L 
Listing of protocol deviations 
leading to an exclusion from 
the Per Protocol Set 
FAS 
 
LSTPD001 
 
PDALL 
T 
Summary 
of 
protocol 
deviations up to EOMOP 
FAS 
 
PD001 
 
PD-IMP 
T 
Summary 
of 
important 
protocol deviations up to 
EOMOP 
FAS 
x 
PD001 
 
PD-EXC 
T 
Summary 
of 
protocol 
deviations 
leading 
to 
an 
exclusion from Per Protocol 
Set, by country 
FAS 
 
PD001 
 
PDALL 
L 
Listing 
of 
all 
protocol 
deviations  
SCR 
 
LSTPD001 
x 
*T = Summary table, L = Listing, **SCR = Screened analysis set, FAS = Full analysis set, ***Created on blinded 
combined groups for IDMC open sessions 
13.3 Subject characteristics 
13.3.1 Demographics 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
DEM 
T 
Summary of demographics 
FAS, 
mFAS, P 
x 
(FAS***) 
DEM001 
DEM 
L 
Listing of demographics  
SCR 
 
LSTDEM001 
*T = Summary table, L = Listing, **SCR = Screened analysis set, FAS = Full analysis set, mFAS = Modified full 
analysis set, P = Per-protocol analysis set, ***Created on blinded combined groups for IDMC open sessions 


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13.3.2 Baseline disease characteristics 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
BAS 
T 
Summary 
of 
disease 
baseline 
characteristics  
FAS, 
mFAS, P 
x 
(FAS***) 
BAS001 
BAS 
L 
Listing 
of 
disease 
baseline 
characteristics  
SCR 
 
LSTDEM003 
BAS-
RHC 
T 
Summary of baseline values of 
efficacy endpoints from right-heart 
catheterization  
FAS, 
mFAS, P 
x 
(FAS***) 
BAS002 
*T = Summary table, L = Listing, **SCR = Screened analysis set, FAS = Full analysis set, mFAS = Modified full 
analysis set, P = Per-protocol analysis set, ***Created on blinded combined groups for IDMC open sessions 
13.3.3 Other baseline characteristics 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
BAS-O 
T 
Summary 
of 
other 
baseline 
characteristics  
FAS, 
mFAS, P 
x 
(FAS***) 
BAS003 
PHYS 
L 
Listing of physical examination 
results 
SCR 
*** 
LSTDEM002 
*T = Summary table, L = Listing, **SCR = Screened analysis set, FAS = Full analysis set, mFAS = Modified full 
analysis set, P = Per-protocol analysis set, ***Created on blinded combined groups for IDMC open sessions 
13.3.4 Medical history 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
MH-SOC 
T 
Summary of medical history ongoing 
at screening visit, by primary system 
organ class and preferred term 
FAS, 
mFAS 
x 
(FAS***) 
LAYMH001 
(from standard 
catalog) 
MH-PT 
T 
Summary of medical history ongoing 
at screening visit, by preferred term 
FAS, 
mFAS 
 
LAYMH002  
MHHEP-
PT 
T 
Summary of medical history ongoing 
at screening visit, by preferred term 
and subjects with and without post-
baseline hepatic lab abnormality 
FAS  
 
LAYMH002  


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Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
MH 
L 
Listing of medical history  
SCR 
 
LSTCSR043 
(from standard 
catalog) 
*T = Summary table, L = Listing, **SCR = Screened analysis set, FAS = Full analysis set, mFAS = Modified full 
analysis set, ***Created on blinded combined groups for IDMC open sessions 
13.3.5 Previous and concomitant therapies 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
CM-BSL-
SOC 
T 
Summary 
of 
therapies 
concomitant to baseline by 
Anatomical 
Therapeutic 
Chemistry (ATC) Class and 
Preferred 
Term 
[Add 
footnote: 
A 
baseline-
concomitant therapy is any 
treatment that is started prior 
to study treatment and is 
ongoing at Day 1.] 
FAS, 
mFAS 
(FAS***) 
LAYCMED001 
(from standard 
catalog) 
 
CM-BSL-
PT 
T 
Summary 
of 
therapies 
concomitant to baseline by 
Preferred 
Term 
[Add 
footnote: 
A 
baseline-
concomitant therapy is any 
treatment that is started prior 
to study treatment and is 
ongoing at Day 1.] 
FAS, 
mFAS 
*** 
LAYCMED002 
 


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Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
CM-
BSLHEP-
PT 
T 
Summary 
of 
therapies 
concomitant to baseline by 
Preferred Term and subjects 
with 
and 
without 
post-
baseline 
hepatic 
lab 
abnormality [Add footnote: A 
baseline-concomitant 
therapy is any treatment that 
is started prior to study 
treatment and is ongoing at 
Day 1.] 
FAS  
 
LAYCMED002 
 
CM-SOC 
T 
Summary 
of 
therapies 
concomitant 
to 
study 
treatment up to EOMOP by 
Anatomical 
Therapeutic 
Chemistry (ATC) Class and 
Preferred Term  
FAS, 
mFAS 
*** 
LAYCMED001 
(from standard 
catalog) 
 
CM-PT 
T 
Summary 
of 
therapies 
concomitant 
to 
study 
treatment up to EOMOP by 
Preferred Term  
FAS, 
mFAS 
*** 
LAYCMED002 
 
CM 
L 
Listing of 
subjects 
with 
previous and concomitant 
therapies 
SCR 
 
LSTCSR044 
(from standard 
catalog) 
x 
*T = Summary table, L = Listing, **SCR = Screened analysis set, FAS = Full analysis set, mFAS = Modified full 
analysis set, ***Created on blinded combined groups for IDMC open sessions 
 
13.4 Study treatment exposure  
13.4.1 Exposure 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
EXP-M 
T 
Exposure to macitentan up to 
EOMOP 
S 
x*** 
EXP001 
x# 


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Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
EXP-M 
F 
Exposure to macitentan up to 
EOMOP 
S 
*** 
FIGLINE001 
(from 
standard 
catalog) 
x# 
EXP-T 
T 
Exposure to tadalafil up to 
EOMOP 
S 
x*** 
EXP001 
x# 
EXP-T 
F 
Exposure to tadalafil up to 
EOMOP 
S 
*** 
FIGLINE001 
(from 
standard 
catalog) 
x# 
EXP-S 
T 
Exposure to double-blind study 
treatment 
(selexipag/placebo) 
up to EOMOP 
S 
x*** 
EXP0001 
x# 
EXP-S 
F 
Exposure to double-blind study 
treatment 
(selexipag/placebo) 
up to EOMOP 
S 
*** 
FIGLINE001 
(from 
standard 
catalog) 
x# 
EXP-MT 
T 
Exposure 
to 
concomitant 
macitentan and tadalafil up to 
EOMOP 
S 
 
EXP0001 
x# 
EXP-MT 
F 
Exposure 
to 
concomitant 
macitentan and tadalafil up to 
EOMOP 
S 
 
FIGLINE001 
(from 
standard 
catalog) 
x# 
EXP-
MTS 
T 
Exposure 
to 
concomitant 
macitentan and tadalafil and 
selexipag/placebo 
up 
to 
EOMOP 
S 
 
EXP0001 
x# 
EXP-
MTS 
F 
Exposure 
to 
concomitant 
macitentan and tadalafil and 
selexipag/placebo 
up 
to 
EOMOP 
S 
 
FIGLINE001 
(from 
standard 
catalog) 
x# 


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Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
DOS-S 
T 
Maximum 
and 
weighted-
average double-blind treatment 
daily dose up to EOMOP 
S 
*** 
EXP004 
x# 
DOS-
TM 
T 
Individual maintenance dose 
and maximum tolerated dose of 
double-blind study treatment up 
to EOMOP 
S 
x*** 
EXP005 
x# 
DOS 
L 
Study 
medication 
dosing 
records 
S 
 
LSTDOS001 
x 
*T = Summary table, L = Listing, F=Figure, **S = Safety analysis set, ***Created on blinded combined groups for 
IDMC open sessions, # without ‘up to EOMOP’ in the title 
13.4.2 Study treatment discontinuation 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
PWDT 
T 
Reasons for premature 
discontinuation of study 
treatment up to EOMOP 
S 
x*** 
DISP003 
x# 
PWDT 
L 
Listing of reasons for 
premature discontinuation of 
study and study treatment 
S 
 
LSTDSP001 
x 
*T = Summary table, L = Listing, ** S = Safety analysis set, ***Created on blinded combined groups for IDMC open 
sessions, # without ‘up to EOMOP’ in the title 
13.5 Study withdrawal 
See Section 13.1. 


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13.6 Primary efficacy analyses 
13.6.1 Main analysis 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
MAIN 
T 
Analysis of covariance: PVR ratio 
of Week 26 to baseline 
FAS  
x 
MAIN001 
*T = Summary table, **FAS = Full analysis set 
13.6.2 Supportive/sensitivity analyses 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
MAIN 
T 
Analysis of covariance: PVR 
ratio of Week 26 to baseline 
mFAS1, 
P  
 
MAIN001 
MAIN-
COMP 
T 
Analysis of covariance: PVR 
ratio of Week 26 to baseline in 
subjects who took all three study 
medications until Week 26 
mFAS  
 
MAIN001 
PVR-
SUM 
T 
Summary and change from 
baseline to Week 26 of PVR  
FAS 
x*** 
SUM001 
MAIN-
IMP2 
T 
Analysis of covariance: PVR 
ratio of Week 26 to baseline 
(alternative imputation) 
FAS 
x 
MAIN001 
MAIN-
NOADJ 
T 
Analysis of covariance: PVR 
ratio of Week 26 to baseline 
(without adjustment) 
FAS 
x 
MAIN001 
MAIN-
NOLOG 
T 
Analysis of covariance: Change 
from Baseline to Week 26 in 
PVR (no log-transformation) 
FAS 
x 
MAIN001 
MAIN-
NOIMP 
T 
Analysis of covariance: PVR 
ratio of Week 26 to baseline 
(observed cases) 
FAS  
x 
MAIN001 
MAIN-MI 
T 
Multiple imputation analysis of 
the primary endpoint 
FAS 
x 
MI001 


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Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
MAIN-
IMP3 
T 
Analysis of covariance: PVR 
ratio of Week 26 to baseline 
(alternative imputation 2) 
FAS 
x 
MAIN001 
MAIN 
F 
Scatter plot of change from 
baseline in PVR (Recalculated 
and LOCF) at Week 26 versus 
baseline 
FAS 
 
FIGSCAT001 
(from standard 
catalog) 
*T = Summary table, F = Figure, ** FAS = Full analysis set, mFAS = Modified full analysis set, P = Per-protocol 
analysis set, 1 only if mFAS is ≥ 5% different from FAS, ***Created on blinded combined groups for IDMC open 
sessions 


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13.6.3 Subgroup analyses 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
PVR-
SUB 
T 
Summary and change from 
baseline to Week 26 of PVR 
by subgroups 
[region, WHO FC, age, 
gender, PAH etiology], one 
page per subgroup, show 
visits baseline and Week 26 
FAS 
 
SUM001 
 
MAIN-
SUB 
T 
Analysis of covariance: PVR 
ratio of Week 26 to baseline 
by subgroups 
[region, WHO FC, age, 
gender, race, PAH etiology], 
one page per subgroup 
FAS  
 
MAIN001 
 
MAIN-
SUB 
F 
Forest plot of Analysis of 
covariance: PVR ratio of 
Week 26 to baseline by 
subgroups 
[region, WHO FC, age, 
gender, race, PAH etiology] 
FAS 
x 
FIGFOREST001 
 
PVR-
COMP 
T 
Summary and change from 
baseline to Week 26 of PVR 
in subjects who took all three 
study medications until Week 
26 
mFAS 
 
SUM001 
 
RHC 
L 
Listing of right-heart 
catheterization results 
SCR 
 
LSTRHC001 
x 
*T = Summary table, L = Listing, **SCR = Screened analysis set, FAS = Full analysis set, mFAS = Modified full 
analysis set, P = Per-protocol analysis set, S = Safety analysis set 
 


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13.6.4 Secondary efficacy analyses 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
MWD-
MAIN 
T 
Analysis of covariance: 
Change from baseline to 
Week 26 in six-minute walk 
distance  
FAS, 
mFAS1, 
P  
x (FAS) 
MAIN001 
 
MWD 
F 
Scatter plot of change from 
baseline in six-minute walk 
distance at Week 26 versus 
baseline 
FAS 
 
FIGSCAT001 
(from standard 
catalog) 
 
MWD-
COMP 
T 
Analysis of covariance: 
Change from baseline to 
Week 26 in six-minute walk 
distance in subjects who took 
all three study medications 
until Week 26 
mFAS 
 
MAIN001 
 
MWD-
MAIN-
IMP2 
T 
Analysis of covariance: 
Change from baseline to 
Week 26 in six-minute walk 
distance (alternative 
imputation) 
FAS  
x  
MAIN001 
 
MWD-
MAIN-
NOADJ 
T 
Analysis of covariance: 
Change from baseline to 
Week 26 in six-minute walk 
distance (without adjustment) 
FAS  
x  
MAIN001 
 
MWD-
MI 
T 
Multiple imputation analysis 
of 6MWD 
FAS 
x  
MI001 
 
MWD-
MAIN-
NOIMP 
T 
Analysis of covariance: 
Change from baseline to 
Week 26 in six-minute walk 
distance (observed cases) 
FAS  
x  
MAIN001 
 


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Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
MWD-
MM 
T 
Repeated measures model: 
Change from baseline in six-
minute walk distance to 
Week 26 
FAS  
x  
MMRM001 
 
MWD-
MAIN-
IMP3 
T 
Analysis of covariance: 
Change from baseline to 
Week 26 in six-minute walk 
distance (alternative 
imputation 2) 
FAS  
x  
MAIN001 
 
MWD-
SUB 
T 
Summary and change from 
baseline of six-minute walk 
distance by visit and 
subgroups [region, WHO FC, 
age, gender, PAH etiology], 
one page per subgroup] 
FAS  
 
SUM001 
 
MWD-
MAIN-
SUB 
T 
Analysis of covariance: 
Change from baseline to 
Week 26 in six-minute walk 
distance by subgroups 
[region, WHO FC, age, 
gender, PAH etiology], one 
page per subgroup 
FAS  
 
MAIN001 
 
MWD-
MAIN-
SUB 
F 
Forest plot of Analysis of 
covariance: Change from 
baseline to Week 26 in six-
minute walk distance by 
subgroups 
[region, WHO FC, age, 
gender, race, PAH etiology] 
FAS 
x 
FIGFOREST001 
 
MWD-
SUMC 
T 
Summary and change from 
baseline of six-minute walk 
distance by visit in subjects 
who took all three study 
medications until Week 26 
mFAS 
 
SUM001 
 


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Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
MWD 
L 
Listing of six-minute walk 
test results 
SCR 
 
LSTMWD001 
x 
BNP-
MAIN 
T 
Analysis of covariance: NT-
proBNP ratio of Week 26 to 
baseline 
FAS, 
mFAS1, 
P  
x (FAS) 
MAIN001 
 
BNP-
COMP 
T 
Analysis of covariance: NT-
proBNP ratio of Week 26 to 
baseline in subjects who took 
all three study medications 
until Week 26 
mFAS 
 
MAIN001 
 
BNP-
MM 
T 
Repeated measures model: 
Ratio to baseline in NT-
proBNP up to Week 26 
FAS  
 
MMRM001 
 
BNP-
MAIN-
IMP2 
T 
Analysis of covariance: NT-
proBNP ratio of Week 26 to 
baseline (alternative 
imputation) 
FAS 
 
MAIN001 
 
BNP-
MAIN-
NOIMP 
T 
Analysis of covariance: NT-
proBNP ratio of Week 26 to 
baseline (observed cases) 
FAS 
 
MAIN001 
 
BNP-
SUMC 
T 
Summary and change from 
baseline of NT-proBNP by 
visit in subjects who took all 
three study medications until 
Week 26 
mFAS 
 
SUM001 
 
BNP 
L 
Listing of NT-proBNP 
SCR 
 
LSTLB001 
x 
ABW 
T 
Logistic regression: Absence 
of worsening from baseline to 
Week 26 in WHO functional 
class 
FAS, 
mFAS1, 
P  
x 
(FAS***) 
BIN001 
 


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Confidential  
Statistical Analysis Plan 
Doc No D-19.253 
 
 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
ABW-
IMP2 
T 
Logistic regression: Absence 
of worsening from baseline to 
Week 26 in WHO functional 
class (alternative imputation) 
FAS  
 
BIN001 
 
ABW-
NOIMP 
T 
Logistic regression: Absence 
of worsening from baseline to 
Week 26 in WHO functional 
class (observed cases) 
FAS  
 
BIN001 
 
ABW-
COMP 
T 
Logistic regression: Absence 
of worsening from baseline to 
Week 26 in WHO functional 
class in subjects who took all 
three study medications until 
Week 26 
mFAS 
 
BIN001 
 
WHO-
SHF 
T 
Shift table of WHO 
functional class from baseline 
to Week 26 
FAS 
x 
BIN004 
 
WHO 
L 
Listing of WHO functional 
class 
SCR 
 
LSTWHO001 
x 
RHC-
MAIN 
T 
Analysis of covariance: 
Change from baseline to 
Week 26 in hemodynamic 
parameters other than PVR  
[Summarize mPAP, CI, TPR, 
mRAP, Venous oxygen 
saturation] 
FAS, 
mFAS1, 
P  
x (FAS) 
MAIN001 
 


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Confidential  
Statistical Analysis Plan 
Doc No D-19.253 
 
 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
RHC-
COMP 
T 
Analysis of covariance: 
Change from baseline to 
Week 26 in hemodynamic 
parameters other than PVR in 
subjects who took all three 
study medications until Week 
26 
[Summarize mPAP, CI, TPR, 
mRAP, Venous oxygen 
saturation] 
mFAS 
 
MAIN001 
 
RHC-
NOIMP 
T 
Analysis of covariance: 
Change from baseline to 
Week 26 in hemodynamic 
parameters other than PVR 
(observed cases) 
[Summarize mPAP, CI, TPR, 
mRAP, Venous oxygen 
saturation] 
FAS 
 
MAIN001 
 
RHC-
SUM 
T 
Summary and change from 
baseline of hemodynamic 
parameters other than PVR 
FAS, 
mFAS1, 
P  
*** 
SUM001 
 
RHC-
SUMC 
T 
Summary and change from 
baseline of hemodynamic 
parameters other than PVR in 
subjects who took all three 
study medications until 
Week 26 
mFAS 
 
SUM001 
 
TTP 
T 
Time to first disease 
progression event (up to 
EOMOP + 7 days) 
FAS, 
mFAS1, 
P  
x 
(FAS***) 
TTE001 
 
TTP 
F 
Time to first disease 
progression event (up to 
EOMOP + 7 days) 
FAS, 
mFAS1, 
P  
x 
(FAS***) 
FIGLINE002 
(from standard 
catalog) 
 


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Confidential  
Statistical Analysis Plan 
Doc No D-19.253 
 
 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
PROG 
T 
Reason for disease 
progression (up to EOMOP + 
7 days) 
FAS, 
mFAS1, 
P  
x 
(FAS***) 
TTE002 
 
PROG 
L 
Listing of disease progression 
events as adjudicated by the 
clinical events committee 
SCR 
 
LSTPROG001 
x 
TTP-
COMP 
T 
Time to first disease 
progression event (up to 
EOMOP + 7 days) in subjects 
who took all three study 
medications until Week 26 
mFAS 
 
TTE001 
 
TTP-
COMP 
F 
Time to first disease 
progression event (up to 
EOMOP + 7 days) in subjects 
who took all three study 
medications until Week 26 
mFAS 
 
FIGLINE002 
(from standard 
catalog) 
 
PROG-
COMP 
T 
Reason for disease 
progression (up to EOMOP + 
7 days) in subjects who took 
all three study medications 
until Week 26 
mFAS 
 
TTE002 
 
TTP-
XC 
T 
Time to first disease 
progression event (up to at 
EOMOP + 7 days or day of 
last drug intake of any of the 
three study medications + 7 
days, whichever is the 
earliest) 
FAS 
  
TTE001 
 


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Confidential  
Statistical Analysis Plan 
Doc No D-19.253 
 
 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
TTP-
XC 
F 
Time to first disease 
progression event (up to at 
EOMOP + 7 days or day of 
last drug intake of any of the 
three study medications + 7 
days, whichever is the 
earliest) 
FAS 
 
FIGLINE002 
(from standard 
catalog) 
 
PROG-
XC 
T 
Reason for disease 
progression (up to at EOMOP 
+ 7 days or day of last drug 
intake of any of the three 
study medications + 7 days, 
whichever is the earliest) 
FAS 
 
TTE002 
 
TTP-
XC2 
T 
Time to first disease 
progression event (up to 
EOMOP + 7 days or end of 
double-blind study treatment 
+ 7 days, whichever is the 
earliest) in patients in FAS 
who received at least one 
dose of double-blind study 
treatment 
FAS 
 
TTE001 
 
TTP-
XC2 
F 
Time to first disease 
progression event (up to 
EOMOP + 7 days or end of 
double-blind study treatment 
+ 7 days, whichever is the 
earliest) in patients in FAS 
who received at least one 
dose of double-blind study 
treatment 
FAS 
 
FIGLINE002 
(from standard 
catalog) 
 


Selexipag (ACT-293987) 
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Confidential  
Statistical Analysis Plan 
Doc No D-19.253 
 
 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
PROG-
XC2 
T 
Reason for disease 
progression (up to EOMOP + 
7 days or end of double-blind 
study treatment + 7 days, 
whichever is the earliest) in 
patients in FAS who received 
at least one dose of double-
blind study treatment 
FAS 
 
TTE002 
 
TTP-
XC3 
T 
Time to first disease 
progression event (up to 
EOS) 
FAS 
 
TTE001 
Only 
after 
EOS 
TTP-
XC3 
F 
Time to first disease 
progression event (up to 
EOS) 
FAS 
 
FIGLINE002 
(from standard 
catalog) 
Only 
after 
EOS 
PROG-
XC3 
T 
Reason for disease 
progression (up to EOS) 
FAS 
 
TTE002 
Only 
after 
EOS 
*T = Summary table, L = Listing, F = Figure, **SCR = Screened analysis set, FAS = Full analysis set, mFAS = 
Modified full analysis set, P = Per-protocol analysis set, 1 only if mFAS is ≥5% different from FAS, ***Created on 
blinded combined groups for IDMC open sessions 
13.7 Other efficacy analyses 
Output name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
MWD-SUM 
T 
Summary and change 
from baseline of six-
minute walk distance by 
visit up to EOMOP 
FAS 
***  
SUM001 
 
BNP-SUM 
T 
Summary and change 
from baseline of NT-
proBNP by visit up to 
EOMOP 
FAS 
(FAS***) 
SUM001 
 


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Confidential  
Statistical Analysis Plan 
Doc No D-19.253 
 
 
Output name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
ABW-SUM 
T 
Summary of absence of 
worsening from baseline 
to all visits in WHO 
functional class up to 
EOMOP 
FAS  
*** 
BIN002 
 
UNS-SUM 
T 
Summary of 
unsatisfactory clinical 
response up to EOMOP 
FAS  
*** 
BIN003 
 
UNS 
L 
Listing of unsatisfactory 
response criteria  
SCR 
 
LSTUNS001 
x 
GOL-SUM 
T 
Number of treatment 
goals met at Week 26  
FAS  
*** 
SUM002 
 
GOLS 
T 
Treatment goals shift 
table from baseline to 
Week 26 
FAS 
 
BIN005 
 
GOL 
L 
Listing of treatment goals 
met  
SCR 
 
LSTGOL001 
x 
IMP 
T 
Logistic regression: 
Improvement from 
baseline to Week 26 in 
WHO functional class  
FAS  
 
BIN005 
 
TTP_FHO 
T 
Time to first 
hospitalization (all 
causes) up to EOMOP 
FAS 
 
TTE001 
 
TTP_FHO 
F 
Time to first 
hospitalization (all 
causes) up to EOMOP 
FAS 
 
FIGLINE002 
(from 
standard 
catalog) 
 
TTP_FHOPAH 
T 
Time to first 
hospitalization for 
worsening PAH up to 
EOMOP 
FAS 
 
TTE001 
 


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Confidential  
Statistical Analysis Plan 
Doc No D-19.253 
 
 
Output name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
TTP_FHOPAH 
F 
Time to first 
hospitalization for 
worsening PAH up to 
EOMOP 
FAS 
 
FIGLINE002 
(from 
standard 
catalog) 
 
HO_POI 
T 
Annualized rate of 
hospitalizations (all 
causes) up to EOMOP 
FAS 
 
HOSP001 
 
HOPAH_POI 
T 
Annualized rate of 
hospitalizations for 
worsening PAH up to 
EOMOP 
FAS 
 
HOSP001 
 
HO_DUR 
T 
Annualized rate of days 
spent in hospital (all 
causes) up to EOMOP 
FAS 
 
HOSP002 
 
HOPAH_DUR 
T 
Annualized rate of days 
spent in hospital for 
worsening PAH up to 
EOMOP 
FAS 
 
HOSP002 
 
SAE_HOS 
L 
Listing of serious adverse 
events leading to 
hospitalization  
SCR 
 
LSTHOS001 
x 
*T = Summary table, L = Listing, F=Figure, **SCR = Screened analysis set, FAS = Full analysis set, ***Created on 
blinded combined groups for IDMC open sessions 
 


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Statistical Analysis Plan 
Doc No D-19.253 
 
 
13.8 Safety analyses 
13.8.1 Adverse events 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock 
layout 
Rerun 
after 
EOS 
TEAE-
SOC 
T 
Incidence of treatment-emergent 
adverse events up to EOMOP by 
primary system organ class and 
preferred term 
S 
x*** 
LAYAE001 
(from 
standard 
catalog) 
x# 
TEAE-PT 
T 
Incidence of treatment-emergent 
adverse events up to EOMOP by 
preferred term 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
x# 
TEAE-
SOC-M 
T 
Incidence of treatment-emergent 
adverse events related to 
macitentan up to EOMOP by 
primary system organ class and 
preferred term 
S 
*** 
LAYAE001 
(from 
standard 
catalog) 
x# 
TEAE-PT-
M 
T 
Incidence of treatment-emergent 
adverse events related to 
macitentan up to EOMOP by 
preferred term 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
x# 
TEAE-
SOC-T 
T 
Incidence of treatment-emergent 
adverse events related to tadalafil 
up to EOMOP by primary system 
organ class and preferred term 
S 
*** 
LAYAE001 
(from 
standard 
catalog) 
x# 
TEAE-PT-
T 
T 
Incidence of treatment-emergent 
adverse events related to tadalafil 
up to EOMOP by preferred term 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
x# 
TEAE-
SOC-S 
T 
Incidence of treatment-emergent 
adverse events related to 
selexipag/placebo up to EOMOP 
by primary system organ class 
and preferred term 
S 
*** 
LAYAE001 
(from 
standard 
catalog) 
x# 


Selexipag (ACT-293987) 
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20 August 2019, page 94/117 
Confidential  
Statistical Analysis Plan 
Doc No D-19.253 
 
 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock 
layout 
Rerun 
after 
EOS 
TEAE-PT-
S 
T 
Incidence of treatment-emergent 
adverse events related to 
selexipag/placebo up to EOMOP 
by preferred term 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
x# 
TEAE-
INT-PT 
T 
Incidence of treatment-emergent 
adverse events up to EOMOP by 
maximum intensity and preferred 
term 
S 
*** 
LAYAE003 
(from 
standard 
catalog) 
 
TEAE-
FREQ 
T 
Incidence of the most frequent (at 
least 5% in any treatment group) 
treatment-emergent adverse 
events up to EOMOP, by 
preferred term 
S 
x*** 
LAYAE002 
(from 
standard 
catalog) 
 
SCR-AE-
SOC 
T 
Incidence of AEs from informed 
consent signature till initiation of 
first study drug −1 day by primary 
system organ class and preferred 
term 
S 
*** 
LAYAE001 
(from 
standard 
catalog) 
 
SCR-AE-
PT 
T 
Incidence of AEs from informed 
consent signature till initiation of 
first study drug −1 day by 
preferred term 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
 
AE-
1EOMOP-
SOC 
T 
Incidence of adverse events with 
onset between Day 1 and end of 
main observation period, by 
primary system organ class and 
preferred term 
S 
 
LAYAE001 
(from 
standard 
catalog) 
 
AE-
1EOMOP-
PT 
T 
Incidence of adverse events with 
onset between Day 1 and end of 
main observation period, by 
preferred term 
S 
 
LAYAE002 
(from 
standard 
catalog) 
 


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20 August 2019, page 95/117 
Confidential  
Statistical Analysis Plan 
Doc No D-19.253 
 
 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock 
layout 
Rerun 
after 
EOS 
AE-1DB-
SOC 
T 
Incidence of adverse events with 
onset between Day 1 and start of 
double-blind treatment, by 
primary system organ class and 
preferred term 
S 
*** 
LAYAE001 
(from 
standard 
catalog) 
 
AE-1DB-
PT 
T 
Incidence of adverse events with 
onset between Day 1 and start of 
double-blind treatment, by 
preferred term 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
 
AE-M-
SOC 
T 
Incidence of adverse events with 
onset between Day 1 and 30 days 
after macitentan treatment or 
EOMOP, whichever is earlier, by 
primary system organ class and 
preferred term 
S 
*** 
LAYAE001 
(from 
standard 
catalog) 
 
AE-M-PT 
T 
Incidence of adverse events with 
onset between Day 1 and 30 days 
after macitentan treatment or 
EOMOP, whichever is earlier, by 
preferred term 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
 
AE-T-
SOC 
T 
Incidence of adverse events with 
onset between Day 1 and 30 days 
after tadalafil treatment or 
EOMOP, whichever is earlier, by 
primary system organ class and 
preferred term 
S 
*** 
LAYAE001 
(from 
standard 
catalog) 
 
AE-T-PT 
T 
Incidence of adverse events with 
onset between Day 1 and 30 days 
after tadalafil treatment or 
EOMOP, whichever is earlier, by 
preferred term 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
 


Selexipag (ACT-293987) 
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20 August 2019, page 96/117 
Confidential  
Statistical Analysis Plan 
Doc No D-19.253 
 
 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock 
layout 
Rerun 
after 
EOS 
AE-S-
SOC 
T 
Incidence of adverse events with 
onset between Day 1 and 30 days 
after selexipag/placebo treatment 
or EOMOP, whichever is earlier, 
by primary system organ class 
and preferred term 
S 
*** 
LAYAE001 
(from 
standard 
catalog) 
 
AE-S-PT 
T 
Incidence of adverse events with 
onset between Day 1 and 30 days 
after selexipag/placebo treatment 
or EOMOP, whichever is earlier, 
by preferred term 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
 
AE-
EOMEOT-
SOC 
T 
Incidence of adverse events with 
onset between EOMOP and 30 
days after EOT by primary system 
organ class and preferred term in 
patients with ongoing treatment at 
EOMOP visit 
S 
 
LAYAE001 
(from 
standard 
catalog) 
Only 
after 
EOS 
AE-
EOMEOT-
PT 
T 
Incidence of adverse events with 
onset between EOMOP and 30 
days after EOT by preferred term 
in patients with ongoing treatment 
at EOMOP visit 
S 
 
LAYAE002 
(from 
standard 
catalog) 
Only 
after 
EOS 
AE-
EOTEOS-
SOC 
T 
Incidence of adverse events with 
onset during follow up after EOT 
by primary system organ class 
and preferred term 
S 
*** 
LAYAE001 
(from 
standard 
catalog) 
Only 
after 
EOS 
AE-
EOTEOS-
PT 
T 
Incidence of adverse events with 
onset during follow up after EOT 
by preferred term 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
Only 
after 
EOS 
AE-S-
PERI-PT 
T 
Incidence of adverse events with 
onset during selexipag/placebo 
titration and maintenance periods 
up to EOMOP by preferred term 
S 
 
AETM002 
 


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Confidential  
Statistical Analysis Plan 
Doc No D-19.253 
 
 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock 
layout 
Rerun 
after 
EOS 
AE-S-
PERI-SOC 
T 
Incidence of adverse events with 
onset during selexipag/placebo 
titration and maintenance periods 
up to EOMOP by primary system 
organ class and preferred term 
S 
 
AETM001 
 
TEAE2-S-
SOC 
T 
Incidence of adverse events with 
onset between start of 
selexipag/placebo treatment and 3 
days after end of 
selexipag/placebo treatment or 
EOMOP, whichever is earlier, by 
primary system organ class and 
preferred term 
S 
 
LAYAE001 
(from 
standard 
catalog) 
 
TEAE2-S-
PT 
T 
Incidence of adverse events with 
onset between start of 
selexipag/placebo treatment and 3 
days after end of 
selexipag/placebo treatment or 
EOMOP, whichever is earlier, by 
preferred term 
S 
 
LAYAE002 
(from 
standard 
catalog) 
 
AE 
L 
Listing of adverse events 
SCR 
 
LSTAE001 
x 
*T = Summary table, L = Listing, **SCR = Screened analysis set, S = Safety analysis set, ***Created on blinded 
combined groups for IDMC open sessions, # without ‘up to EOMOP’ in the title 
13.9 Deaths and serious adverse events 
13.9.1 Deaths 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
DTH-
SOC 
T 
Study deaths up to EOMOP by 
primary system organ class and 
preferred term 
S 
x*** 
LAYAE001 
(from 
standard 
catalog) 
x# 


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20 August 2019, page 98/117 
Confidential  
Statistical Analysis Plan 
Doc No D-19.253 
 
 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
Rerun 
after 
EOS 
DTH 
L 
Listing of study deaths  
SCR 
*** 
LSTCSR072 
(from 
standard 
catalog) 
x 
AEDTH 
L 
Listing of all adverse events 
leading to death 
SCR 
 
LSTAE001 
x 
*T = Summary table, L = Listing, **SCR = Screened analysis set, S = Safety analysis set, ***Created on blinded 
combined groups for IDMC open sessions, # without ‘up to EOMOP’ in the title 
13.9.2 Serious adverse events 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock 
layout 
Rerun 
after 
EOS 
TESAE-
SOC 
T 
Incidence of treatment-emergent 
serious adverse events up to 
EOMOP by primary system organ 
class and preferred term 
S 
x*** 
LAYAE001 
(from 
standard 
catalog) 
x# 
TESAE-
PT 
T 
Incidence of treatment-emergent 
serious adverse events up to 
EOMOP by preferred term 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
x# 
TESAE-
SOC-M 
T 
Incidence of treatment-emergent 
serious adverse events related to 
macitentan up to EOMOP by 
primary system organ class and 
preferred term 
S 
*** 
LAYAE001 
(from 
standard 
catalog) 
 
TESAE-
PT-M 
T 
Incidence of treatment-emergent 
serious adverse events related to 
macitentan up to EOMOP by 
preferred term 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
 


Selexipag (ACT-293987) 
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20 August 2019, page 99/117 
Confidential  
Statistical Analysis Plan 
Doc No D-19.253 
 
 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock 
layout 
Rerun 
after 
EOS 
TESAE-
SOC-T 
T 
Incidence of treatment-emergent 
serious adverse events related to 
tadalafil up to EOMOP by primary 
system organ class and preferred 
term 
S 
*** 
LAYAE001 
(from 
standard 
catalog) 
 
TESAE-
PT-T 
T 
Incidence of treatment-emergent 
serious adverse events related to 
tadalafil up to EOMOP by 
preferred term 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
 
TESAE-
SOC-S 
T 
Incidence of treatment-emergent 
serious adverse events related to 
selexipag/placebo up to EOMOP 
by primary system organ class and 
preferred term 
S 
*** 
LAYAE001 
(from 
standard 
catalog) 
 
TESAE-
PT-S 
T 
Incidence of treatment-emergent 
serious adverse events related to 
selexipag/placebo up to EOMOP 
by preferred term 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
 
TESAE-
SOC-DB 
T 
Incidence of treatment-emergent 
serious adverse events up to 
EOMOP by primary system organ 
class and preferred term in 
patients who received at least one 
dose of double-blind study 
medication 
S 
*** 
LAYAE001 
(from 
standard 
catalog) 
 
TESAE-
PT-DB 
T 
Incidence of treatment-emergent 
serious adverse events up to 
EOMOP by preferred term in 
patients who received at least one 
dose of double-blind study 
medication 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
 
SAE-
ALL 
L 
Listing of serious adverse events  
SCR 
*** 
LSTAE001 
x 


Selexipag (ACT-293987) 
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20 August 2019, page 100/117 
Confidential  
Statistical Analysis Plan 
Doc No D-19.253 
 
 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock 
layout 
Rerun 
after 
EOS 
SAE-PRI 
L 
Listing of serious adverse events 
occurring prior to first intake of 
study medication 
SCR 
*** 
LSTAE001 
 
SAE-
POST 
L 
Listing of serious adverse events 
occurring more than 30 days after 
last dose of study medication 
SCR 
*** 
LSTAE001 
x 
SAEPAH 
L 
Listing of serious adverse events 
occurring after the start of a new 
PAH therapy 
SCR 
 
LSTAE001 
x 
*T = Summary table, L = Listing, **SCR = Screened analysis set, S = Safety analysis set, ***Created on blinded 
combined groups for IDMC open sessions, # without ‘up to EOMOP’ in the title 
13.9.3 Adverse events leading to treatment discontinuation 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock 
layout 
Rerun 
after 
EOS 
TEAE-
DC-SOC-
M 
T 
Incidence of treatment-emergent 
adverse events leading to 
discontinuation of macitentan up 
to EOMOP, by primary system 
organ class and preferred term 
S 
x*** 
LAYAE001 
(from 
standard 
catalog) 
x# 
TEAE-
DC-PT-
M 
T 
Incidence of treatment-emergent 
adverse events leading to 
discontinuation of macitentan up 
to EOMOP, by preferred term 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
x# 
TEAE-
DC-SOC-
T 
T 
Incidence of treatment-emergent 
adverse events leading to 
discontinuation of tadalafil up to 
EOMOP, by primary system organ 
class and preferred term 
S 
x*** 
LAYAE001 
(from 
standard 
catalog) 
x# 
TEAE-
DC-PT-T 
T 
Incidence of treatment-emergent 
adverse events leading to 
discontinuation of tadalafil up to 
EOMOP, by preferred term 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
x# 


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Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock 
layout 
Rerun 
after 
EOS 
TEAE-
DC-SOC-
S 
T 
Incidence of treatment-emergent 
adverse events leading to 
discontinuation of 
selexipag/placebo up to EOMOP, 
by primary system organ class and 
preferred term 
S 
x*** 
LAYAE001 
(from 
standard 
catalog) 
x# 
TEAE-
DC-PT-S 
T 
Incidence of treatment-emergent 
adverse events leading to 
discontinuation of 
selexipag/placebo up to EOMOP, 
by preferred term 
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
x# 
*T = Summary table, ** S = Safety analysis set, ***Created on blinded combined groups for IDMC open sessions, 
# without ‘up to EOMOP’ in the title 
13.9.4 Other significant adverse events 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
SEL-
TEAE-
RSK 
T 
Incidence of selexipag 
treatment-emergent adverse events up 
to EOMOP by important identified or 
potential risk and preferred term 
[Only AEs with onset between first 
and last intake of selexipag/placebo + 
30 days will be shown].  
S 
x*** 
AERSK001 
TEAE-
HYPO-
RSK 
T 
Incidence of treatment-emergent 
symptomatic hypotension adverse 
events up to EOMOP, by preferred 
term 
S 
x*** 
LAYAE002 
(from 
standard 
catalog) 
SEL-AE-
SOC 
T 
Incidence of adverse events during 
selexipag/placebo exposure up to 
EOMOP, by primary system organ 
class and preferred term 
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown].  
S 
*** 
LAYAE001 
(from 
standard 
catalog) 


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Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
SEL-AE-
PT 
T 
Incidence of adverse events during 
selexipag/placebo exposure up to 
EOMOP, by preferred term 
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown].  
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
SEL-SAE-
SOC 
T 
Incidence of serious adverse events 
during selexipag/placebo exposure up 
to EOMOP, by primary system organ 
class and preferred term 
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown].  
S 
*** 
LAYAE001 
(from 
standard 
catalog) 
SEL-SAE-
PT 
T 
Incidence of serious adverse events 
during selexipag/placebo exposure up 
to EOMOP, by preferred term 
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown].  
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
SEL-AE-
R-SOC 
T 
Incidence of adverse events during 
selexipag/placebo exposure up to 
EOMOP, related to selexipag/placebo, 
by primary system organ class and 
preferred term 
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown].  
S 
*** 
LAYAE001 
(from 
standard 
catalog) 
SEL-AE-
R-PT 
T 
Incidence of adverse events during 
selexipag/placebo exposure up to 
EOMOP, related to selexipag/placebo, 
by preferred term 
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown].  
S 
*** 
LAYAE002 
(from 
standard 
catalog) 


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Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
SEL-AE-
DC-SOC 
T 
Incidence of adverse events during 
selexipag/placebo exposure leading to 
discontinuation of selexipag/placebo 
up to EOMOP, by primary system 
organ class and preferred term 
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown].  
S 
*** 
LAYAE001 
(from 
standard 
catalog) 
SEL-AE-
DC-PT 
T 
Incidence of adverse events during 
selexipag/placebo exposure leading to 
discontinuation of selexipag/placebo 
up to EOMOP, by preferred term 
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown].  
S 
*** 
LAYAE002 
(from 
standard 
catalog) 
SEL-AE-
DTH-SOC 
T 
Incidence of adverse events during 
selexipag/placebo exposure leading to 
death up to EOMOP, by primary 
system organ class and preferred term 
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown].  
S 
*** 
LAYAE001 
(from 
standard 
catalog) 
TEAE-
SOC-SUB 
T 
Incidence of treatment-emergent 
adverse events up to EOMOP by 
primary system organ class, preferred 
term, age, group gender and race 
S 
 
LAYAE001 
(from 
standard 
catalog) 
TEAE2-S-
PROST-
SOC 
T 
Incidence of adverse events typical of 
prostanoid treatments with onset 
between start date of 
selexipag/placebo treatment and 3 
days after end of selexipag/placebo 
treatment or EOMOP whichever is 
earlier.  
S 
 
LAYAE001 
(from 
standard 
catalog) 
*T = Summary table, **S=Safety analysis set, ***Created on blinded combined groups for IDMC open sessions 


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13.10 
Summaries of adverse events for disclosure (EudraCT and 
ClinicalTrials.gov) 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
TESAE-
DTH-SOC 
T 
Incidence of treatment-emergent 
serious adverse events with fatal 
outcome up to EOMOP by primary 
system organ class and preferred term  
S 
 
LAYAE001 
(from 
standard 
catalog) 
TESAE-
DTH-SOC-
T 
T 
Incidence of treatment-emergent 
serious adverse events with fatal 
outcome related to tadalafil up to 
EOMOP by primary system organ 
class and preferred term  
S 
 
LAYAE001 
(from 
standard 
catalog) 
TESAE-
DTH-SOC-
M 
T 
Incidence of treatment-emergent 
serious adverse events with fatal 
outcome related to macitentan up to 
EOMOP by primary system organ 
class and preferred term 
S 
 
LAYAE001 
(from 
standard 
catalog) 
TESAE-
DTH-SOC-
S 
T 
Incidence of treatment-emergent 
serious adverse events with fatal 
outcome related to selexipag/placebo 
up to EOMOP by primary system 
organ class and preferred term 
S 
 
LAYAE001 
(from 
standard 
catalog) 
TENSAE-
5PCT-COS 
T 
Incidence of treatment-emergent non-
serious adverse events with an 
incidence of 5% or higher in any 
treatment group up to EOMOP by 
primary system organ class and 
preferred term 
S 
 
LAYAE001 
(from 
standard 
catalog) 
*T = Summary table, **S = Safety analysis set 


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13.11 Laboratory tests 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
LB-SUM 
T 
Summary and change from baseline 
of quantitative laboratory values up to 
EOMOP 
S 
*** 
SUM001 
LB-ABN 
T 
Incidence of treatment-emergent 
marked laboratory values up to 
EOMOP 
S 
x*** 
LAB001 
LB-ABN-
SPEC 
T 
Incidence of treatment-emergent 
treatment notable laboratory values 
for hepatic safety up to EOMOP 
S 
x*** 
LAB002 
LB-DISH 
F 
Scatter plot of maximum ALT versus 
concomitant bilirubin (eDISH plot) up 
to EOMOP 
S 
*** 
FIGSCAT001 
(from 
standard 
catalog) 
LB-ABN 
L 
Listing of all parameters with marked 
laboratory values 
[List all values of the laboratory 
parameter where a marked abnormal 
value occurred]  
SCR 
*** 
LSTLB001 
LB 
L 
Listing of all laboratory values 
SCR 
 
LSTLB001 
PREG 
L 
Listing of pregnancy test results [Do 
not display columns for reference 
range and changes from baseline] 
SCR 
 
LSTLB001 
*T = Summary table, L = Listing, **SCR = Screened analysis set, S = Safety analysis set, ***Created on blinded 
combined groups for IDMC open sessions 


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13.12 Vital signs and body weight 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s)** 
Key 
output 
Mock layout 
VS-SUM 
T 
Summary and change from baseline 
of vital signs up to EOMOP 
S 
*** 
SUM001 
VS-ABN 
T 
Incidence of notable 
treatment-emergent blood pressure 
values up to EOMOP 
S 
*** 
VS001 
VS-ABN 
L 
List of notable treatment-emergent 
blood pressure values  
[List all values of the parameter 
where a marked abnormal value 
occurred]  
SCR 
 
LSTCSR091 
(from 
standard 
catalog) 
VS 
L 
Listing of vital signs 
SCR 
 
LSTCSR091 
(from 
standard 
catalog) 
*T = Summary table, L = Listing, **SCR = Screened analysis set, S = Safety analysis set, ***Created on blinded 
combined groups for IDMC open sessions 
14 REFERENCES 
[D-18.392] 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. Actelion Pharmaceuticals Ltd; clinical study protocol, 4 December 2018. 
 
 


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15 APPENDICES 
Appendix 1 
 
Protocol Synopsis 
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.  
 


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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. 
• Forced expiratory volume in one second (FEV1) < 60% of 
predicted. 


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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).  
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. 


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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. 
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. 


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• 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.  
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. 


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• 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 
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.  


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20 August 2019, page 115/117 
Confidential  
Statistical Analysis Plan 
Doc No D-19.253 
 
 
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: 
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.  


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20 August 2019, page 116/117 
Confidential  
Statistical Analysis Plan 
Doc No D-19.253 
 
 
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 
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.  
 


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20 August 2019, page 117/117 
Confidential  
Statistical Analysis Plan 
Doc No D-19.253 
 
 
Appendix 2 
 
Document history 
Version 
Effective Date 
Reason 
1.0 
28-Jun-2016 
Final Version 1.0 
Amendment 
1.0 
8-Feb-2018 
Included substantial changes in testing strategy 
and sample size from global protocol 
amendment 3; corrections of minor errors; 
clarifications for sample SAS code in Section 9; 
inclusion of estimand tables for primary and first 
secondary efficacy endpoint; addition of 
sensitivity analyses for primary and secondary 
efficacy endpoints. 
Version 3.0 
(Amendment 
2) 
20-Aug-2019 
Some small changes are done following dry run 
1. In addition, the following was added:  
- individual maximum tolerated dose definition  
- sensitivity analysis related to use of 
prostanoids PH therapy  
- additional definition of treatment goal (Galiè) 
- analysis of improvement in WHO FC  
- exploratory analyses of hospitalization. 
- additional summaries of adverse events  
 


STATISTICAL ANALYSIS PLAN 
FOR EOS CSR
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 (TRITON)
Purpose of Analysis
Clinical Study Report (analyses up to EOS) / 
final CSR
Investigational Drug
Selexipag / ACT-293987
Protocol Number
AC-065A308/TRITON
Actelion Document Number
D-20.063
Document Status/Version Number
Final
Date
26 February 2020
Author(s)
 CRO Trial Statistician
, Actelion Trial Statistician
, Statistician
Reviewer
, Head of Global Post Approval 
Studies
Reviewer
, Global Medical Affairs 
Director
Reviewer
 Clinical Trial Scientist
Reviewer
, Senior Drug Safety 
Physician
Confidential
Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or 
otherwise disclosed without the consent of Actelion Pharmaceuticals Ltd.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
NCT02558231


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Statistical Analysis Plan for 
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND ACRONYMS.................................................3
1
INTRODUCTION ...........................................................................................4
2
LIST OF SUMMARY TABLES, LISTINGS AND FIGURES.........................4
2.1
Subject disposition.............................................................................4
2.2
Protocol deviations.............................................................................5
2.3
Subject characteristics........................................................................5
2.3.1
Previous and concomitant therapies ........................................5
2.4
Study treatment exposure ...................................................................5
2.4.1
Exposure.................................................................................5
2.4.2
Study treatment discontinuation..............................................7
2.5
Study withdrawal ...............................................................................7
2.6
Primary efficacy analyses...................................................................7
2.6.1
Primary efficacy analyses .......................................................7
2.6.2
Secondary efficacy analyses....................................................7
2.7
Other efficacy analyses ......................................................................8
2.8
Safety analyses...................................................................................8
2.8.1
Adverse events .......................................................................8
2.9
Deaths and serious adverse events....................................................12
2.9.1
Deaths ..................................................................................12
2.9.2
Serious adverse events..........................................................12
2.9.3
Adverse events leading to treatment discontinuation.............14
2.9.4
Other significant adverse events............................................15
2.10
Summaries of adverse events for disclosure (EudraCT and 
ClinicalTrials.gov) ...........................................................................18
2.11
Laboratory tests................................................................................19
2.12
Vital signs and body weight .............................................................20
3
REFERENCES ..............................................................................................21
4
APPENDICES ...............................................................................................21
LIST OF APPENDICES
Appendix 1 Document history.......................................................................................21


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LIST OF ABBREVIATIONS AND ACRONYMS
ADaM
Analysis data model
CSR
Clinical study report
EOS
End-of-study
EOMOP
End of main observation period
EOT
End-of-treatment
EudraCT
European Union Drug Regulating Authorities Clinical Trials
SAP
Statistical analysis plan


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Statistical Analysis Plan for 
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Doc No D-20.063
1
INTRODUCTION
The statistical analysis plan (SAP) for the clinical study report (CSR) of study 
AC-065A308 (TRITON) was finalized on 20 August 2019 (version 3) [D-19.253] prior to 
data unblinding, which occurred on 17 October 2019. Analyses performed following 
unblinding covered locked data up to the end of the main observation period (EOMOP)
and are considered as the main analyses for efficacy and the interim analyses for safety. 
After the EOMOP, subjects remained on treatment up to their end-of-treatment (EOT) visit 
and remained in the study up to their end-of-study (EOS) visit. In the SAP [D-19.253] only 
specific analyses were planned to be performed after final database lock following EOS 
visit of all subjects. In the final CSR, safety will be fully described for the full treatment 
period, ie, including all data up to EOS. In addition, specific post hoc efficacy analyses 
performed up to EOMOP will be reproduced including all data up to EOS. 
All definitions and analyses specifications are described in the main CSR SAP [D-19.253]
and in the post hoc SAP for CSR [D-20.062].
Analyses described in this SAP are to be performed after the full database lock of the study. 
All data are converted into study data tabulation model datasets and are provided by data 
management. Technical procedures and steps for processing these data and for 
implementing the definitions of variables for the purpose of the statistical analysis in 
analysis data model (ADaM) datasets are covered in the analysis datasets specifications 
document.
2
LIST OF SUMMARY TABLES, LISTINGS AND FIGURES
This section lists all outputs (ie, listings, tables and figures) produced to display the results 
of the analyses to be re-run with the full data package up to EOS. 
The table, listing and figure naming conventions have 3 components: Type (T, L, F), Name
(free text, not longer than ten characters), Suffix (for example, for analysis sets, or 
subgroups, not longer than four characters). Multiple suffixes can be added; 
components/suffixes are separated by ‘_’.
Mock layouts refer to specifications in the AC-065A308 ‘Layouts for TLFs’ document.
2.1
Subject disposition
Output
name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
DISP
T
Subject disposition up to EOS
SCR
DISP001
PWDS
T
Reasons for premature discontinuation of 
study up to EOS
FAS
DISP004


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Statistical Analysis Plan for 
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Doc No D-20.063
Output
name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
VIS
L
Listing of study visits
SCR
LSTVIS001
*T = Summary table, L = Listing, **SCR = Screened analysis set, FAS = Full analysis set.
EOS = end-of-study
2.2
Protocol deviations
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock 
layout
PDALL
L
Listing of all protocol deviations 
SCR
LSTPD001
*T = Summary table, L = Listing, **SCR = Screened analysis set, FAS = Full analysis set
2.3
Subject characteristics
2.3.1
Previous and concomitant therapies
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
CM-SOC
T
Summary of therapies concomitant to study 
treatment up to EOS
by Anatomical 
Therapeutic Chemistry (ATC) Class and 
Preferred Term 
FAS, 
mFAS
LAYCMED001
(from standard 
catalog)
CM-PT
T
Summary of therapies concomitant to study 
treatment up to EOS by Preferred Term 
FAS, 
mFAS
LAYCMED002
CM
L
Listing of subjects with previous and 
concomitant therapies
SCR
LSTCSR044
(with 
relative 
study day)
*T = Summary table, L = Listing, **SCR = Screened analysis set, FAS = Full analysis set, mFAS = Modified full 
analysis set
EOS = end-of-study
2.4
Study treatment exposure 
2.4.1
Exposure
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
EXP-M
T
Exposure to macitentan up to EOS
S
EXP001


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Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
EXP-M
F
Exposure to macitentan up to EOS
S
FIGLINE001
(from standard 
catalog)
EXP-T
T
Exposure to tadalafil up to EOS
S
EXP001
EXP-T
F
Exposure to tadalafil up to EOS
S
FIGLINE001
(from standard 
catalog)
EXP-S
T
Exposure 
to 
double-blind 
study 
treatment (selexipag/placebo) up to EOS
S
EXP0001
EXP-S
F
Exposure 
to 
double-blind 
study 
treatment (selexipag/placebo) up to EOS
S
FIGLINE001
(from standard 
catalog)
EXP-MT
T
Exposure to concomitant macitentan and 
tadalafil up to EOS
S
EXP0001
EXP-MT
F
Exposure to concomitant macitentan and 
tadalafil up to EOS
S
FIGLINE001
(from standard 
catalog)
EXP-MTS
T
Exposure to concomitant macitentan and 
tadalafil and selexipag/placebo up to 
EOS
S
EXP0001
EXP-MTS
F
Exposure to concomitant macitentan and 
tadalafil and selexipag/placebo up to 
EOS
S
FIGLINE001
(from standard 
catalog)
DOS-S
T
Maximum and weighted-average double-
blind treatment daily dose up to EOS
S
EXP004
DOS-TM
T
Individual 
maintenance 
dose 
and 
maximum tolerated dose of double-blind 
study treatment up to EOS
S
EXP005
DOS
L
Study medication dosing records
S
LSTDOS001
*T = Summary table, L = Listing, F=Figure, **S = Safety analysis set
EOS = end-of-study


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Doc No D-20.063
2.4.2
Study treatment discontinuation
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
PWDT
T
Reasons for premature discontinuation of 
study treatment up to EOS
S
DISP003
PWDT
L
Listing of reasons for premature 
discontinuation of study and study 
treatment
S
LSTDSP001
*T = Summary table, L = Listing, ** S = Safety analysis set
EOS = end-of-study
2.5
Study withdrawal
See Section 2.1.
2.6
Primary efficacy analyses
2.6.1
Primary efficacy analyses
Output 
name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
RHC
L
Listing of right-heart catheterization 
results
SCR
LSTRHC001
*T = Summary table, L = Listing, **SCR = Screened analysis set
2.6.2
Secondary efficacy analyses
Output 
name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
MWD
L
Listing of six-minute walk test 
results
SCR
LSTMWD001
BNP
L
Listing of NT-proBNP
SCR
LSTLB001
WHO
L
Listing of WHO functional class
SCR
LSTWHO001
PROG
L
Listing of disease progression 
events as adjudicated by the 
clinical events committee
SCR
LSTPROG001


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Doc No D-20.063
Output 
name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
TTP-XC3
T
Time to first disease progression 
event (up to EOS)
FAS
TTE001
TTP-XC3
F
Time to first disease progression 
event (up to EOS)
FAS
FIGLINE002
(from standard catalog)
PROG-
XC3
T
Reason for disease progression 
(up to EOS)
FAS
TTE002
*T = Summary table, L = Listing, F = Figure, **SCR = Screened analysis set, FAS = Full analysis set
EOS = end-of-study; NT-proBNP = N-terminal pro B-type natriuretic peptide; WHO = World Health Organization
2.7
Other efficacy analyses
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
SAE_HOS
L
Listing of serious adverse events 
leading to hospitalization 
SCR
LSTHOS001
TTP-DTHEOS
F
Time to death up to EOS
FAS
FIGLINE002
TTP-DTHEOS
T
Time to death up to EOS
FAS
TTE001
RECEVENT-
FREQEOS
T
Summary of  (potentially) recurrent 
disease progression events up to EOS
FAS
RECEVENT01 
RECEVENT-
MODEOS
T
Negative binomial and Andersen-Gill 
models for (potentially) recurrent 
disease progression events up to EOS
FAS
RECEVENT02 
*T = Summary table, L = Listing, F=Figure, **SCR = Screened analysis set, FAS= Full analysis set
EOS = end-of-study
2.8
Safety analyses
2.8.1
Adverse events
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
TEAE-SOC
T
Incidence of treatment-emergent adverse 
events up to EOS by primary system 
organ class and preferred term
S
LAYAE001
(from 
standard 
catalog)


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Statistical Analysis Plan for 
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Doc No D-20.063
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
TEAE-PT
T
Incidence of treatment-emergent adverse 
events up to EOS by preferred term
S
LAYAE002
(from 
standard 
catalog)
TEAE-SOC-M
T
Incidence of treatment-emergent adverse 
events related to macitentan up to EOS
by primary system organ class and 
preferred term
S
LAYAE001
(from 
standard 
catalog)
TEAE-PT-M
T
Incidence of treatment-emergent adverse 
events related to macitentan up to EOS
by preferred term
S
LAYAE002
(from 
standard 
catalog)
TEAE-SOC-T
T
Incidence of treatment-emergent adverse 
events related to tadalafil up to EOS by 
primary system organ class and preferred 
term
S
LAYAE001
(from 
standard 
catalog)
TEAE-PT-T
T
Incidence of treatment-emergent adverse 
events related to tadalafil up to EOS by 
preferred term
S
LAYAE002
(from 
standard 
catalog)
TEAE-SOC-S
T
Incidence of treatment-emergent adverse 
events related to selexipag/placebo up to 
EOS by primary system organ class and 
preferred term
S
LAYAE001
(from 
standard 
catalog)
TEAE-PT-S
T
Incidence of treatment-emergent adverse 
events related to selexipag/placebo up to 
EOS by preferred term
S
LAYAE002
(from 
standard 
catalog)
TEAE-INT-PT
T
Incidence of treatment-emergent adverse 
events up to EOS by maximum intensity 
and preferred term
S
LAYAE003
(from 
standard 
catalog)


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Statistical Analysis Plan for 
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Doc No D-20.063
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
TEAE-FREQ
T
Incidence of the most frequent (at least 
5% in any treatment group) 
treatment-emergent adverse events up to 
EOS, by preferred term
S
LAYAE002
(from 
standard 
catalog)
AE-M-SOC
T
Incidence of adverse events with onset 
between Day 1 and 30 days after 
macitentan treatment or EOS, whichever 
is earlier, by primary system organ class 
and preferred term
S
LAYAE001
(from 
standard 
catalog)
AE-M-PT
T
Incidence of adverse events with onset 
between Day 1 and 30 days after 
macitentan treatment or EOS, whichever 
is earlier, by preferred term
S
LAYAE002
(from 
standard 
catalog)
AE-T-SOC
T
Incidence of adverse events with onset 
between Day 1 and 30 days after tadalafil 
treatment or EOS, whichever is earlier, 
by primary system organ class and 
preferred term
S
LAYAE001
(from 
standard 
catalog)
AE-T-PT
T
Incidence of adverse events with onset 
between Day 1 and 30 days after tadalafil 
treatment or EOS, whichever is earlier, 
by preferred term
S
LAYAE002
(from 
standard 
catalog)
AE-S-SOC
T
Incidence of adverse events with onset 
between Day 1 and 30 days after 
selexipag/placebo treatment or EOS, 
whichever is earlier, by primary system 
organ class and preferred term
S
LAYAE001
(from 
standard 
catalog)
AE-S-PT
T
Incidence of adverse events with onset 
between Day 1 and 30 days after 
selexipag/placebo treatment or EOS, 
whichever is earlier, by preferred term
S
LAYAE002
(from 
standard 
catalog)


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Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
AE-EOMEOT-
SOC
T
Incidence of adverse events with onset 
between EOMOP and 30 days after last 
dose of study treatment by primary 
system organ class and preferred term in 
patients with ongoing treatment at 
EOMOP visit
S
LAYAE001
(from 
standard 
catalog)
AE-EOMEOT-
PT
T
Incidence of adverse events with onset 
between EOMOP and 30 days after last 
dose of study treatment by preferred term 
in patients with ongoing treatment at 
EOMOP visit
S
LAYAE002
(from 
standard 
catalog)
AE-EOTEOS-
SOC
T
Incidence of adverse events with onset 
during follow up after last dose of study 
treatment by primary system organ class 
and preferred term
S
LAYAE001
(from 
standard 
catalog)
AE-EOTEOS-
PT
T
Incidence of adverse events with onset 
during follow up after last dose of study 
treatment by preferred term
S
LAYAE002
(from 
standard 
catalog)
AE-S-PERI-
PT
T
Incidence of adverse events with onset 
during selexipag/placebo titration and 
maintenance periods up to EOS by 
preferred term
S
AETM002
AE-S-PERI-
SOC
T
Incidence of adverse events with onset 
during selexipag/placebo titration and 
maintenance periods up to EOS by 
primary system organ class and preferred 
term
S
AETM001
TEAE2-S-
SOC
T
Incidence of adverse events with onset 
between start of selexipag/placebo 
treatment and 3 days after end of
selexipag/placebo treatment or EOS, 
whichever is earlier, by primary system 
organ class and preferred term
S
LAYAE001
(from 
standard 
catalog)


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Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
TEAE2-S-PT
T
Incidence of adverse events with onset 
between start of selexipag/placebo 
treatment and 3 days after end of 
selexipag/placebo treatment or EOS, 
whichever is earlier, by preferred term
S
LAYAE002
(from 
standard 
catalog)
AE
L
Listing of adverse events
SCR
LSTAE001
*T = Summary table, L = Listing, **SCR = Screened analysis set, S = Safety analysis set
EOMOP = end of main observation period; EOS = end-of-study
2.9
Deaths and serious adverse events
2.9.1
Deaths
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
DTH-SOC
T
Study deaths up to EOS by primary system 
organ class and preferred term
S
LAYAE001
(from standard 
catalog)
DTH
L
Listing of study deaths 
SCR
LSTCSR072
(with relative 
study day and 
day off 
treatment)
AEDTH
L
Listing of all adverse events leading to 
death
SCR
LSTAE001
*T = Summary table, L = Listing, **SCR = Screened analysis set, S = Safety analysis set
EOS = end-of-study
2.9.2
Serious adverse events
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
TESAE-SOC
T
Incidence of treatment-emergent 
serious adverse events up to EOS by 
primary system organ class and 
preferred term
S
LAYAE001
(from standard 
catalog)


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Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
TESAE-PT
T
Incidence of treatment-emergent 
serious adverse events up to EOS by 
preferred term
S
LAYAE002
(from standard 
catalog)
TESAE-SOC-
M
T
Incidence of treatment-emergent 
serious adverse events related to 
macitentan up to EOS by primary 
system organ class and preferred term
S
LAYAE001
(from standard 
catalog)
TESAE-PT-M
T
Incidence of treatment-emergent 
serious adverse events related to 
macitentan up to EOS by preferred 
term
S
LAYAE002
(from standard 
catalog)
TESAE-SOC-
T
T
Incidence of treatment-emergent 
serious adverse events related to 
tadalafil up to EOS by primary 
system organ class and preferred term
S
LAYAE001
(from standard 
catalog)
TESAE-PT-T
T
Incidence of treatment-emergent 
serious adverse events related to 
tadalafil up to EOS by preferred term
S
LAYAE002
(from standard 
catalog)
TESAE-SOC-
S
T
Incidence of treatment-emergent 
serious adverse events related to 
selexipag/placebo up to EOS by 
primary system organ class and 
preferred term
S
LAYAE001
(from standard 
catalog)
TESAE-PT-S
T
Incidence of treatment-emergent 
serious adverse events related to 
selexipag/placebo up to EOS by 
preferred term
S
LAYAE002
(from standard 
catalog)
TESAE-SOC-
DB
T
Incidence of treatment-emergent 
serious adverse events up to EOS by 
primary system organ class and 
preferred term in patients who 
received at least one dose of double-
blind study medication
S
LAYAE001
(from standard 
catalog)


Selexipag (ACT-293987)
Study AC-065A308 (TRITON)
26 February 2020, page 14/21
Confidential 
Statistical Analysis Plan for 
EOS CSR
Doc No D-20.063
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
TESAE-PT-
DB
T
Incidence of treatment-emergent 
serious adverse events up to EOS by 
preferred term in patients who 
received at least one dose of double-
blind study medication
S
LAYAE002
(from standard 
catalog)
SAE-ALL
L
Listing of serious adverse events 
SCR
LSTAE001
SAE-POST
L
Listing of serious adverse events 
occurring more than 30 days after last 
dose of study medication
SCR
LSTAE001
SAEPAH
L
Listing of serious adverse events 
occurring after the start of a new 
PAH therapy
SCR
LSTAE001
*T = Summary table, L = Listing, **SCR = Screened analysis set, S = Safety analysis set
EOS = end-of-study; PAH = pulmonary arterial hypertension
2.9.3
Adverse events leading to treatment discontinuation
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock 
layout
TEAE-DC-SOC-
M
T
Incidence of treatment-emergent adverse 
events leading to discontinuation of 
macitentan up to EOS, by primary system 
organ class and preferred term
S
LAYAE001
(from 
standard 
catalog)
TEAE-DC-PT-M
T
Incidence of treatment-emergent adverse 
events leading to discontinuation of 
macitentan up to EOS, by preferred term
S
LAYAE002
(from 
standard 
catalog)
TEAE-DC-SOC-
T
T
Incidence of treatment-emergent adverse 
events leading to discontinuation of 
tadalafil up to EOS, by primary system 
organ class and preferred term
S
LAYAE001
(from 
standard 
catalog)
TEAE-DC-PT-T
T
Incidence of treatment-emergent adverse 
events leading to discontinuation of 
tadalafil up to EOS, by preferred term
S
LAYAE002
(from 
standard 
catalog)


Selexipag (ACT-293987)
Study AC-065A308 (TRITON)
26 February 2020, page 15/21
Confidential 
Statistical Analysis Plan for 
EOS CSR
Doc No D-20.063
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock 
layout
TEAE-DC-SOC-S
T
Incidence of treatment-emergent adverse 
events leading to discontinuation of 
selexipag/placebo up to EOS, by primary 
system organ class and preferred term
S
LAYAE001
(from 
standard 
catalog)
TEAE-DC-PT-S
T
Incidence of treatment-emergent adverse 
events leading to discontinuation of 
selexipag/placebo up to EOS, by preferred 
term
S
LAYAE002
(from 
standard 
catalog)
L
Listing of adverse events leading to 
discontinuation of any study treatment 
SCR
LSTAE001
*T = Summary table, ** S = Safety analysis set
EOS = end-of-study
2.9.4
Other significant adverse events
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
SEL-TEAE-RSK
T
Incidence of selexipag 
treatment-emergent adverse events up 
to EOS by important identified or 
potential risk and preferred term
[Only AEs with onset between first 
and last intake of selexipag/placebo + 
30 days will be shown]. 
S
AERSK001
TEAE-HYPO-RSK
T
Incidence of treatment-emergent 
symptomatic hypotension adverse 
events up to EOS, by preferred term
S
LAYAE002
(from 
standard 
catalog)
SEL-AE-SOC
T
Incidence of adverse events during 
selexipag/placebo exposure up to 
EOS, by primary system organ class 
and preferred term
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown]. 
S
LAYAE001
(from 
standard 
catalog)


Selexipag (ACT-293987)
Study AC-065A308 (TRITON)
26 February 2020, page 16/21
Confidential 
Statistical Analysis Plan for 
EOS CSR
Doc No D-20.063
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
SEL-AE-PT
T
Incidence of adverse events during 
selexipag/placebo exposure up to 
EOS, by preferred term
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown]. 
S
LAYAE002
(from 
standard 
catalog)
SEL-SAE-SOC
T
Incidence of serious adverse events 
during selexipag/placebo exposure up 
to EOS, by primary system organ 
class and preferred term
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown]. 
S
LAYAE001
(from 
standard 
catalog)
SEL-SAE-PT
T
Incidence of serious adverse events 
during selexipag/placebo exposure up 
to EOS, by preferred term
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown]. 
S
LAYAE002
(from 
standard 
catalog)
T
Incidence of serious adverse events 
with onset between start of 
selexipag/placebo treatment and 3 
days after end of selexipag/placebo 
treatment up to EOS, by preferred 
term  
S
LAYAE002
(from 
standard 
catalog)
T
Incidence of serious adverse events 
with onset between start of 
selexipag/placebo treatment and 3 
days after end of selexipag/placebo 
treatment up to EOS, by primary 
system organ class and preferred term  
S
LAYAE002
(from 
standard 
catalog)


Selexipag (ACT-293987)
Study AC-065A308 (TRITON)
26 February 2020, page 17/21
Confidential 
Statistical Analysis Plan for 
EOS CSR
Doc No D-20.063
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
SEL-AE-R-SOC
T
Incidence of adverse events during 
selexipag/placebo exposure up to 
EOS, related to selexipag/placebo, by 
primary system organ class and 
preferred term
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown]. 
S
LAYAE001
(from 
standard 
catalog)
SEL-AE-R-PT
T
Incidence of adverse events during 
selexipag/placebo exposure up to 
EOS, related to selexipag/placebo, by 
preferred term
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown]. 
S
LAYAE002
(from 
standard 
catalog)
SEL-AE-DC-SOC
T
Incidence of adverse events during 
selexipag/placebo exposure leading to 
discontinuation of selexipag/placebo 
up to EOS, by primary system organ 
class and preferred term
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown]. 
S
LAYAE001
(from 
standard 
catalog)
SEL-AE-DC-PT
T
Incidence of adverse events during 
selexipag/placebo exposure leading to 
discontinuation of selexipag/placebo 
up to EOS, by preferred term
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown]. 
S
LAYAE002
(from 
standard 
catalog)
SEL-AE-DTH-SOC
T
Incidence of adverse events during 
selexipag/placebo exposure leading to 
death up to EOS, by primary system 
organ class and preferred term
[Only AEs with onset between first 
and last intake of selexipag/placebo 
will be shown]. 
S
LAYAE001
(from 
standard 
catalog)


Selexipag (ACT-293987)
Study AC-065A308 (TRITON)
26 February 2020, page 18/21
Confidential 
Statistical Analysis Plan for 
EOS CSR
Doc No D-20.063
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
TEAE-SOC-SUB
T
Incidence of treatment-emergent 
adverse events up to EOS by primary 
system organ class, preferred term, 
age, group gender and race
S
LAYAE001
(from 
standard 
catalog)
TEAE2-S-PROST-
SOC
T
Incidence of adverse events typical of 
prostanoid treatments with onset 
between start date of 
selexipag/placebo treatment and 3 
days after end of selexipag/placebo 
treatment up to EOS. 
S
LAYAE001
(from 
standard 
catalog)
T
Incidence of adverse events typical of 
prostanoid treatments with onset 
during selexipag/placebo titration and 
maintenance periods between start 
date of selexipag/placebo treatment 
and 3 days after end of 
selexipag/placebo treatment up to 
EOS
S
AETM002
*T = Summary table, **S=Safety analysis set
AE = adverse event; EOS = end-of-study
2.10
Summaries of adverse events for disclosure (EudraCT and 
ClinicalTrials.gov)
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
TESAE-DTH-
SOC
T
Incidence of treatment-emergent serious 
adverse events with fatal outcome up to EOS
by primary system organ class and preferred 
term 
S
LAYAE001
(from 
standard 
catalog)
TESAE-DTH-
SOC-T
T
Incidence of treatment-emergent serious 
adverse events with fatal outcome related to 
tadalafil up to EOS by primary system organ 
class and preferred term 
S
LAYAE001
(from 
standard 
catalog)


Selexipag (ACT-293987)
Study AC-065A308 (TRITON)
26 February 2020, page 19/21
Confidential 
Statistical Analysis Plan for 
EOS CSR
Doc No D-20.063
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
TESAE-DTH-
SOC-M
T
Incidence of treatment-emergent serious 
adverse events with fatal outcome related to 
macitentan up to EOS by primary system 
organ class and preferred term
S
LAYAE001
(from 
standard 
catalog)
TESAE-DTH-
SOC-S
T
Incidence of treatment-emergent serious 
adverse events with fatal outcome related to 
selexipag/placebo up to EOS by primary 
system organ class and preferred term
S
LAYAE001
(from 
standard 
catalog)
TENSAE-
5PCT-COS
T
Incidence of treatment-emergent non-serious 
adverse events with an incidence of 5% or 
higher in any treatment group up to EOS by 
primary system organ class and preferred 
term
S
LAYAE001
(from 
standard 
catalog)
*T = Summary table, **S = Safety analysis set
EOS = end-of-study
2.11 Laboratory tests
Output 
name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
LB-SUM
T
Summary and change from baseline of 
quantitative laboratory values up to EOS
S
SUM001
LB-ABN
T
Incidence of treatment-emergent marked 
laboratory values up to EOS
S
LAB001
t-lb-abn-sel-
s
T
Incidence of treatment-emergent marked 
laboratory values with onset date between start 
of selexipag/placebo treatment and 3 days after 
end of selexipag/placebo treatment up to EOS. 
S
LAB001
LB-ABN-
SPEC
T
Incidence of treatment-emergent treatment 
notable laboratory values for hepatic safety up 
to EOS
S
LAB002


Selexipag (ACT-293987)
Study AC-065A308 (TRITON)
26 February 2020, page 20/21
Confidential 
Statistical Analysis Plan for 
EOS CSR
Doc No D-20.063
Output 
name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
LB-DISH
F
Scatter plot of maximum ALT versus 
concomitant bilirubin (eDISH plot) up to EOS
S
FIGSCAT001
(from 
standard 
catalog)
LB-ABN
L
Listing of all parameters with marked 
laboratory values
[List all values of the laboratory parameter 
where a marked abnormal value occurred]
SCR
LSTLB001
LB
L
Listing of all laboratory values
SCR
LSTLB001
PREG
L
Listing of pregnancy test results [Do not 
display columns for reference range and 
changes from baseline]
SCR
LSTLB001
*T = Summary table, L = Listing, **SCR = Screened analysis set, S = Safety analysis set
ALT = alanine aminotransferase; EOS = end-of-study
2.12 Vital signs and body weight
Output name
Display*
Title (Description)
Analysis 
set(s)**
Mock layout
VS-SUM
T
Summary and change from baseline of vital 
signs up to EOS
S
SUM001
VS-ABN
T
Incidence of notable treatment-emergent blood 
pressure values up to EOS
S
VS001
VS-ABN
L
List of notable treatment-emergent blood 
pressure values 
[List all values of the parameter where a 
marked abnormal value occurred] 
SCR
LSTCSR091
(from 
standard 
catalog)
VS
L
Listing of vital signs
SCR
LSTCSR091
(from 
standard 
catalog)
*T = Summary table, L = Listing, **SCR = Screened analysis set, S = Safety analysis set
EOS = end-of-study


Selexipag (ACT-293987)
Study AC-065A308 (TRITON)
26 February 2020, page 21/21
Confidential 
Statistical Analysis Plan for 
EOS CSR
Doc No D-20.063
3
REFERENCES
[D-19.253] Statistical analysis plan for clinical study report 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. Actelion Pharmaceuticals Ltd; 
statistical analysis plan, 20 August 2019.
[D-20.062] Post-hoc Statistical analysis plan for interim clinical study report 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. Actelion Pharmaceuticals 
Ltd; post-hoc statistical analysis plan, 21 February 2020.
4
APPENDICES
Appendix 1
Document history
Version
Effective Date
Reason
1.0
26-Feb-2020
Final Version 1.0

Prot_000.pdf: 
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 
NCT02558231


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 
NCT02558231


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 
NCT02558231


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. 
NCT02558231


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.  
NCT02558231


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: 
NCT02558231


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 
NCT02558231


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].  
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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.  
NCT02558231


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.  
NCT02558231


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 
NCT02558231


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. 
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• 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.  
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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 
14 REFERENCES 
[Adcirca SmPC] Adcirca Summary of Product Characteristics. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/001021/WC500032789.pdf.  
[Adcirca USPI] Adcirca Prescribing Information. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022332s009lbl.pdf.  
[ATS Statement 2002] Guidelines for the Six-Minutes Walk Test. Am J Respir Crit Care 
Med. 2002;166:111-7.  
[Benza 2010] Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, 
Coffey CS. Predicting survival in pulmonary arterial hypertension insights from the 
registry to evaluate early and long-term pulmonary arterial hypertension disease 
management (REVEAL). Circulation. 2010;122:164-172.  
[Chadha 2009] Chadha C, Pritzker M, Mariash CN. Effect of epoprostenol on the thyroid 
gland: enlargement and secretion of thyroid hormone. Endocr Pract. 2009;15: 
116-21.  
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[ESC Guidelines] ESC Guidelines on the management of cardiovascular diseases during 
pregnancy. Eur Heart J. 2011;32:3147-3191. 
[Galiè 2013] Galiè N, Corris PA, Frost A, Girgis RE, Granton J, Jing ZC. Updated 
Treatment Algorithm of Pulmonary Arterial Hypertension. J Am Coll Cardiol. 
2013;62:D60-72.  
[Galiè 2015a] Galiè N, Albert Barbera J, Frost A, Ardeschir Ghofrani H, Hoeper M, 
Mclaughlin V, et al. AMBITION: Initial use of ambrisentan plus tadalafil in 
pulmonary arterial hypertension. N Engl J Med. 2015;373:834-44.  
[Galiè 2015b] Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. 2015 
ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur 
Heart J 2015 doi:10.1093/eurheartj/ehv317.  
[Gomez-Arroyo 2015] Gomez-Arroyo J, Sakagami M, Syed AA, Farkas L, Van Tassell B, 
Kraskauskas D, et al. Iloprost reverses established fibrosis in experimental right 
ventricular failure. Eur Respir J. 2015;45(2):449-62.  
[Hoeper 2013] Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M. 
Definitions and Diagnosis of Pulmonary Hypertension. J Am Coll Cardiol. 
2013;62:D42-50.  
[Humbert 2004] Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial 
hypertension. New Engl J Med. 2004;351:142-136.  
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