Clinical trial NCT03078907
Conditions: Pulmonary Arterial Hypertension
Keywords: daily life physical activity actigraphy PAH-SYMPACT
Sponsor: Actelion
Start date: 2017-11-08; Completion date: 2020-02-10
Enrollment: 108 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the effect of selexipag on the physical activity of patients with pulmonary arterial hypertension (PAH) in their daily life, by using a wearable wrist device (actigraph). The actigraph will collect data on daily life physical activity in the patient's real environment. In addition, the PAH symptoms and their impacts will be assessed by using an electronic patient reported outcome measure in the patient's real environment. Patients will be assigned randomly to either selexipag or placebo.

Detailed description:
This study is designed as exploratory with the purpose to generate hypotheses on new endpoints

Arms: arm 1: Selexipag is up-titrated from Day 1 to Week 12 to the individualized highest tolerated dose (HTD), which can range from 200 mcg b.i.d. to 1600 mcg b.i.d., in 200 mcg steps starting with 200 mcg b.i.d. Then, the dose is increased in increments of 200 mcg b.i.d., usually at weekly intervals, depending on the dose tolerability. Up-titration is followed by a stable maintenance treatment period at the highest tolerated dose, from Week 13 to Week 24. arm 2: Regimen and titration scheme similar to those in the selexipag group
Interventions: intervention 1: Selexipag intervention 2: Placebo
Intervention descriptions: intervention 1: Film-coated tablets for oral use; one tablet (200 mcg) to eight tablets (1600 mcg) are administered depending on the individual tolerability. intervention 2: Matching film coated tablets

Protocol documents:
Prot_000.pdf: 
 
 
TPL-000052_v11 
Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A404 
 
TRACE  
A multi-center, double-blind, placebo-controlled, Phase 4 study in patients with 
pulmonary arterial hypertension to assess the effect of selexipag on daily life 
physical activity and patient’s self-reported symptoms and their impacts 
 
Study Phase: 
4 
EudraCT Number: 
2017-000216-42  
Status and version: 
Final Version 2 
Date: 
5 December 2018 
Document type 
Global protocol 
Actelion document number (Doc No.): 
D-18.398 
 
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The information contained in this document, especially unpublished data, is the property of the sponsor of 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 personnel, and an independent 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. 
 
 
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Pulmonary arterial hypertension 
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SPONSOR CONTACT DETAILS 
Sponsor 
 
Actelion Pharmaceuticals Ltd 
Gewerbestrasse 16 
CH-4123 Allschwil 
Switzerland 
 
+41 61 565 65 65 
Clinical Trial Physician  
Contact details of the Clinical Trial Physician can 
be found in the Investigator Site File 
Medical Emergency Hotline 
Toll phone number: [number] 
Site-specific toll telephone numbers and toll-free 
numbers for the Medical Emergency Hotline can be 
found in the Investigator Site File 
 
 
ACTELION CONTRIBUTORS TO THE PROTOCOL 
Clinical Trial Scientist 
 PhD 
 
Clinical Trial Statistician 
Yoko Shiraga, MSc 
 
Clinical Trial Physician 
Maziar Assadi Gehr, MD 
 
Drug Safety Physician 
 MD 
 
 
COORDINATING INVESTIGATOR 
Name / Title 
Address 
Ioana Preston, MD 
Tufts Medical Center, 
 US 
 
 
PPD
PPD
PPD
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Pulmonary arterial hypertension 
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CONTRACT RESEARCH ORGANIZATIONS INFORMATION 
 
CENTRAL LABORATORY 
 
  
 USA 
CENTRAL RANDOMIZATION 
 
, USA 
CRO (study conduct) 
Chiltern International Ltd,  
171 Bath Road,  
Slough, Berkshire SL1 4AA, UK 
CRO (ePRO and actigraphy) 
Exco InTouch Limited, 
Unit 6, Wheatcroft Business Park,  
Landmere Lane,  
Nottingham, NG12 4DG, UK 
Biostatistics 
 
 Germany 
A list of site-specific contact details for Contract Research Organizations (CROs) can be 
found in the Investigator Site File. 
 
 
PPD
PPD
PPD
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Pulmonary arterial hypertension 
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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-065A404, TRACE: A multi-center, double-blind, placebo-controlled, Phase 4 study 
in patients with pulmonary arterial hypertension to assess the effect of selexipag on daily 
life physical activity and patient’s self-reported symptoms and their impacts. 
I approve the design of this study. 
 
PPD
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Pulmonary arterial hypertension 
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INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
Selexipag / ACT-293987 
Indication 
Pulmonary arterial hypertension 
Protocol number, study acronym, study title 
AC-065A404, TRACE: A multi-center, double-blind, placebo-controlled, Phase 4 study 
in patients with pulmonary arterial hypertension to assess the effect of selexipag on daily 
life physical activity and patient’s self-reported symptoms and their impacts. 
I agree to the terms and conditions relating to this study as defined in this protocol, the 
Case Report Form (CRF), and any other protocol-related documents. I fully understand 
that any changes instituted by the investigator(s) without previous agreement with the 
sponsor would constitute a protocol deviation, including any ancillary studies or 
procedures performed on study patients (other than those procedures necessary for the 
wellbeing of the patients). 
I agree to conduct this study in accordance with the latest versions, respectively, of the 
Declaration of Helsinki principles (currently 2013 version), International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, and applicable 
regulations and laws. I will obtain approval by an independent ethics committee or 
institutional review board (IEC/IRB) prior to study start and signed informed consent 
from all patients included in this study. If an amendment to the protocol is necessary, I 
will obtain approval by an IEC/IRB and ensure approval by regulatory authorities has 
been obtained before the implementation of changes described in the amendment, and I 
will re-consent the patients (if applicable). I will allow direct access to source documents 
and study facilities to sponsor representative(s), particularly Clinical Research 
Associate(s) (CRA[s]) and auditor(s), and agree to inspection by regulatory authorities or 
IEC/IRB representative(s). I will ensure that the study treatment(s) supplied by the 
sponsor is/are being used only as described in this protocol. I will ensure that all patients 
or legally designated representatives have understood the nature, objectives, benefits, 
implications, risks and inconveniences for participating in this study. During the conduct 
of the study, I will constantly monitor the risk/benefit balance for an individual patient. I 
confirm herewith that the sponsor is allowed to enter and utilize my professional contact 
details and function in an electronic database for internal purposes and for submission to 
health authorities worldwide. 
 
Country 
Site 
number 
Town 
Date 
 
Signature 
Principal 
Investigator 
 
 
 
 
 
 
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TABLE OF CONTENTS 
SPONSOR CONTACT DETAILS ......................................................................................2 
ACTELION CONTRIBUTORS TO THE PROTOCOL .....................................................2 
COORDINATING INVESTIGATOR.................................................................................2 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION ...................................3 
TABLE OF CONTENTS .....................................................................................................6 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................12 
PROTOCOL SYNOPSIS AC-065A404 ............................................................................17 
PROTOCOL ......................................................................................................................31 
1 
BACKGROUND .........................................................................................................31 
1.1 
Indication ......................................................................................................31 
1.2 
Study treatment .............................................................................................31 
1.2.1 
Nonclinical results ............................................................................31 
1.2.2 
Clinical pharmacology ......................................................................32 
1.2.3 
Clinical efficacy ................................................................................32 
1.2.4 
Summary of safety profile ................................................................32 
1.3 
Purpose and rationale of the study ................................................................33 
1.4 
Summary of known and potential risks and benefits ....................................34 
2 
STUDY OBJECTIVES ...............................................................................................34 
2.1 
Primary objective ..........................................................................................34 
2.2 
Secondary objectives ....................................................................................34 
2.3 
Other objectives ............................................................................................35 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................35 
3.1 
Study design .................................................................................................35 
3.1.1 
Study periods ....................................................................................35 
3.1.2 
Study duration ...................................................................................37 
3.2 
Study design rationale ..................................................................................37 
3.3 
Study committees .........................................................................................38 
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4 
PATIENT POPULATION ..........................................................................................38 
4.1 
Patient population description ......................................................................38 
4.2 
Rationale for the selection of the study population ......................................38 
4.3 
Inclusion criteria ...........................................................................................39 
4.4 
Exclusion criteria ..........................................................................................40 
4.5 
Criteria for women of childbearing potential ...............................................42 
4.5.1 
Definition of childbearing potential ..................................................42 
4.5.2 
Acceptable methods of contraception ...............................................42 
5 
TREATMENTS ..........................................................................................................43 
5.1 
Study treatment .............................................................................................43 
5.1.1 
Investigational treatment: Description and rationale ........................43 
5.1.2 
Matching placebo: Description and rationale ...................................44 
5.1.3 
Study treatment administration .........................................................44 
5.1.3.1 
Individualized dose titration (Weeks 1 to 12) .........................44 
5.1.3.2 
Individualized maintenance dose (Weeks 13 to 24) ................45 
5.1.4 
Treatment assignment .......................................................................46 
5.1.5 
Blinding ............................................................................................46 
5.1.6 
Unblinding ........................................................................................47 
5.1.6.1 
Unblinding for final analyses ..................................................47 
5.1.6.2 
Unblinding for interim analyses ..............................................47 
5.1.6.3 
Unblinding for suspected unexpected serious adverse 
reactions ...................................................................................47 
5.1.6.4 
Emergency procedure for unblinding ......................................47 
5.1.7 
Study treatment supply .....................................................................47 
5.1.7.1 
Study treatment packaging and labeling .................................48 
5.1.7.2 
Study treatment distribution and storage .................................48 
5.1.7.3 
Study treatment dispensing .....................................................48 
5.1.7.4 
Study treatment return and destruction ...................................48 
5.1.8 
Study treatment accountability and compliance with study 
treatment ...........................................................................................49 
5.1.8.1 
Study treatment accountability ................................................49 
5.1.8.2 
Study treatment compliance ....................................................49 
5.1.9 
Study treatment dose adjustments and interruptions ........................50 
5.1.10 
Premature discontinuation of study treatment ..................................50 
5.1.11 
Study-specific criteria for interruption / permanent 
discontinuation of study treatment ....................................................51 
5.1.11.1 
Hemoglobin abnormalities ......................................................51 
5.1.11.2 
Severe hepatic impairment ......................................................52 
5.1.11.3 
Start of a CYP2C8 inhibitor ....................................................52 
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5.1.11.4 
Pregnancy ................................................................................52 
5.1.11.5 
Hyperthyroidism ......................................................................52 
5.2 
Previous and concomitant therapy ................................................................52 
5.2.1 
Definitions ........................................................................................52 
5.2.2 
Recording of previous/concomitant therapy .....................................52 
5.2.3 
Allowed concomitant therapy ...........................................................53 
5.2.4 
Forbidden concomitant therapy ........................................................53 
5.2.5 
Rescue therapy ..................................................................................53 
6 
STUDY ENDPOINTS ................................................................................................53 
6.1 
Efficacy endpoints ........................................................................................53 
6.1.1 
Primary efficacy endpoint(s) ............................................................53 
6.1.2 
Secondary efficacy endpoints ...........................................................54 
6.1.3 
Other efficacy endpoints ...................................................................54 
6.2 
Safety endpoints ...........................................................................................54 
6.3 
Biomarkers ....................................................................................................55 
7 
STUDY ASSESSMENTS ...........................................................................................55 
7.1 
Patient characteristics ...................................................................................55 
7.1.1 
Informed consent signature (Visit 1) ................................................55 
7.1.2 
Demographics (Visit 1) .....................................................................55 
7.1.3 
Documentation of PAH disease (Visit 1) .........................................56 
7.1.4 
Medical history (Visit 1) ...................................................................56 
7.1.5 
Previous and concomitant therapies .................................................56 
7.1.6 
Eligibility, randomization (Visit 1 and Visit 2) ................................56 
7.2 
Efficacy assessments ....................................................................................56 
7.2.1 
6MWT and Borg dyspnea index .......................................................56 
7.2.2 
WHO FC ...........................................................................................57 
7.2.3 
Daily life physical activity ................................................................57 
7.3 
Safety assessments ........................................................................................57 
7.3.1 
Vital signs .........................................................................................57 
7.3.2 
AEs and SAEs ...................................................................................58 
7.4 
Laboratory assessments ................................................................................58 
7.4.1 
Type of laboratory ............................................................................58 
7.4.2 
Laboratory tests .................................................................................59 
7.5 
Patient reported outcome PAH-SYMPACT® ...............................................60 
7.6 
Additional assessments for women ..............................................................60 
7.6.1 
Childbearing potential .......................................................................60 
7.6.2 
Contraception check (women of childbearing potential only) ..........61 
7.6.3 
Pregnancy tests (women of childbearing potential only) ..................61 
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8 
VISIT SCHEDULE .....................................................................................................61 
8.1 
Site visits .......................................................................................................61 
8.1.1 
Visit 1: Screening/re-screening .........................................................61 
8.1.2 
Visit 2: Randomization .....................................................................63 
8.1.3 
Visit 3: Intermediate Visit .................................................................63 
8.1.4 
Visit 4: End of treatment visit ...........................................................64 
8.1.5 
Unscheduled visits ............................................................................64 
8.2 
Telephone calls .............................................................................................65 
8.2.1 
Weekly telephone calls up to Week 12 .............................................65 
8.2.2 
Telephone calls from Week 13 to Week 24 ......................................65 
8.2.3 
Post-Treatment Safety Follow-up telephone call ..............................66 
8.2.4 
Unscheduled telephone calls .............................................................66 
9 
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL 
CARE ..........................................................................................................................66 
9.1 
Study completion as per protocol .................................................................66 
9.2 
Premature withdrawal from study ................................................................66 
9.3 
Premature termination or suspension of the study ........................................67 
9.4 
Medical care of patients after study completion / withdrawal from 
study ..............................................................................................................68 
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................68 
10.1 
Adverse events ..............................................................................................68 
10.1.1 
Definition of adverse events .............................................................68 
10.1.2 
Intensity of adverse events ................................................................69 
10.1.3 
Relationship to study treatment ........................................................70 
10.1.4 
Recording of adverse events .............................................................70 
10.1.5 
Follow-up of adverse events .............................................................70 
10.2 
Serious adverse events ..................................................................................70 
10.2.1 
Definitions of serious adverse events ...............................................70 
10.2.2 
Reporting of serious adverse events .................................................71 
10.2.3 
Follow-up of serious adverse events .................................................71 
10.2.4 
After the [30-day] follow-up period .................................................71 
10.2.5 
Reporting procedures ........................................................................71 
10.3 
Pregnancy .....................................................................................................72 
10.3.1 
Reporting of pregnancy ....................................................................72 
10.3.2 
Follow-up of pregnancy ....................................................................73 
10.4 
Study safety monitoring ................................................................................73 
11 STATISTICAL METHODS .......................................................................................73 
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11.1 
Analysis sets .................................................................................................73 
11.1.1 
Screened Analysis Set .......................................................................73 
11.1.2 
Full Analysis Set ...............................................................................73 
11.1.3 
Per-protocol Analysis Set .................................................................73 
11.1.4 
Safety Set ..........................................................................................74 
11.1.5 
Usage of the analysis sets .................................................................74 
11.2 
Variables .......................................................................................................74 
11.2.1 
Primary efficacy variables ................................................................74 
11.2.2 
Secondary efficacy variables ............................................................74 
11.2.3 
Other efficacy variables ....................................................................75 
11.2.4 
Safety variables .................................................................................75 
11.3 
Description of statistical analyses .................................................................75 
11.3.1 
Overall testing strategy .....................................................................75 
11.3.2 
Analysis of the primary efficacy variables .......................................75 
11.3.2.1 
Hypotheses and statistical model ............................................76 
11.3.2.2 
Handling of missing data .........................................................76 
11.3.2.3 
Main analysis ...........................................................................76 
11.3.2.4 
Supportive/sensitivity analyses ...............................................76 
11.3.2.5 
Sub-group analyses ..................................................................76 
11.3.3 
Analysis of secondary efficacy variables ..........................................77 
11.3.3.1 
PAH-SYMPACT® ...................................................................77 
11.3.3.2 
Others PAH related clinical outcomes ....................................77 
11.3.3.3 
Association between actigraphy and others efficacy 
endpoints .................................................................................77 
11.3.4 
Analysis of the safety variables ........................................................77 
11.3.4.1 
Adverse events ........................................................................78 
11.3.4.2 
Laboratory variables ................................................................78 
11.3.4.3 
Vital signs and body weight ....................................................79 
11.3.5 
Exposure to study drug .....................................................................79 
11.3.6 
Baseline characteristics and concomitant medications .....................79 
11.4 
Interim analyses ............................................................................................79 
11.5 
Sample size ...................................................................................................79 
12 DATA HANDLING ....................................................................................................80 
12.1 
Data collection ..............................................................................................80 
12.2 
Maintenance of data confidentiality .............................................................81 
12.3 
Database management and quality control ...................................................81 
13 PROCEDURES AND GOOD CLINICAL PRACTICE .............................................82 
13.1 
Ethics and Good Clinical Practice ................................................................82 
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13.2 
Independent Ethics Committee / Institutional Review Board ......................82 
13.3 
Informed consent ..........................................................................................83 
13.4 
Compensation to patients and investigators .................................................84 
13.5 
Protocol adherence/compliance ....................................................................84 
13.6 
Protocol amendments ...................................................................................84 
13.7 
Essential documents and retention of documents .........................................85 
13.8 
Monitoring ....................................................................................................86 
13.9 
Investigator Site File .....................................................................................87 
13.10 
Audit .............................................................................................................87 
13.11 
Inspections ....................................................................................................87 
13.12 
Reporting of study results and publication ...................................................88 
14 REFERENCES ............................................................................................................89 
15 APPENDICES .............................................................................................................92 
 
LIST OF TABLES 
 
Table 1 
Study periods, visits at study site and assessments ....................................28 
Table 2 
Telephone calls from the study site to the patient, and assessments ..........30 
Table 3 
Recommended double-blind up-titration scheme ......................................45 
Table 4 
Confidence interval (2-sided 5%) width assuming different scenarios 
of SD ..........................................................................................................80 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design ...............................................................................................37 
 
LIST OF APPENDICES 
 
Appendix 1 
Actelion guidelines for 6-minute walk test ................................................92 
Appendix 2 
Borg dyspnea index ....................................................................................97 
Appendix 3 
WHO Functional Classification of pulmonary hypertension .....................98 
Appendix 4 
PAH-SYMPACT® Questionnaire ..............................................................99 
 
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LIST OF ABBREVIATIONS AND ACRONYMS 
6MWD  
6-Minute walk distance 
6MWT  
6-Minute walk test 
AE  
Adverse event 
ANCOVA  
Analysis Of Covariance 
ATS  
American Thoracic Society 
b.i.d.  
Twice daily 
BMI  
Body mass index 
BP  
Blood pressure 
CFR  
Code of Federal Regulations 
CI  
Confidence interval  
CRA  
Clinical Research Associate 
CRO  
Contract Research Organization 
CSR  
Clinical Study Report 
CTT  
Clinical Trial Team 
CYP  
Cytochrome P450 
DBP  
Diastolic blood pressure 
DLPA  
Daily life physical activity 
ECG  
Electrocardiogram 
eCRF  
electronic Case Report Form  
EOS  
End-of-study 
EOT  
End-of-treatment 
ePRO  
Electronic Patient-Reported Outcome 
ERA  
Endothelin receptor antagonist 
FAS  
Full Analysis Set 
FC  
Functional class 
FDA  
Food and Drug Administration 
GCP  
Good Clinical Practice 
HIV  
Human immunodeficiency virus 
HR  
Heart rate 
HTD  
Highest tolerated dose 
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IB  
Investigator’s Brochure 
ICF  
Informed Consent Form 
ICH  
International Council for Harmonisation 
IEC  
Independent Ethics Committee 
IMD  
Individualized maintenance dose  
INN  
International nonproprietary name 
IRB  
Institutional Review Board 
IRT  
Interactive Response Technology 
ISF  
Investigator Site File 
LVEDP  
Left ventricular end diastolic pressure 
mPAP  
Mean pulmonary arterial pressure  
MedDRA  
Medical Dictionary for Regulatory Activities 
NT-proBNP  
N-terminal pro b-type natriuretic peptide  
PAH  
Pulmonary arterial hypertension 
PAH-SYMPACT®  
Pulmonary Arterial Hypertension Symptoms and Impact  
PAP  
Pulmonary artery pressure 
PAWP  
Pulmonary artery wedge pressure 
PDE-5  
Phosphodiesterase-5  
PH  
Pulmonary hypertension 
PI  
Principal Investigator 
p.o.  
Oral 
PPS  
Per-protocol Analysis Set 
PRO  
Patient-reported outcome 
PVR  
Pulmonary vascular resistance 
QoL  
Quality of Life 
QS  
Quality System 
RHC  
Right heart catheterization 
RSI  
Reference safety information  
SAE  
Serious adverse event 
SAP  
Statistical Analysis Plan 
SBP  
Systolic blood pressure 
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SD  
Standard deviation 
sGC  
Soluble guanylate cyclase 
SIV  
Site initiation visit 
SmPC  
Summary of Product Characteristics 
SUSAR  
Suspected unexpected serious adverse reaction 
TST  
Total sleep time 
USPI  
United States Product Information 
WASO  
Wake after sleep onset 
WHO  
World Health Organization 
WU  
Wood Units 
 
 
 
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SUBSTANTIAL GLOBAL AMENDMENT 1 
Amendment rationale 
This amendment applies to global protocol AC-065A404, Version 1, dated 23 February 
2017. The resulting amended global protocol is Version 2, dated 5 December 2018. 
The reasons for this amendment are as follows: 
Update of the dosing instructions for selexipag/placebo study drug, based on a recent 
drug-drug interaction study with a moderate CYP2C8 inhibitor, clopidogrel, as described 
in the Investigator Brochure version 13 of September 2018. 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 
and reverted to twice a day when co-administration of moderate CYP2C8 inhibitor is 
stopped. 
Exclusion Criterion 12 of the TRACE protocol sets low-end thresholds for the values 
obtained from the pulmonary function test after the use of bronchodilator. If the values 
obtained without bronchodilator are above the threshold, they would not fall below the 
threshold in the presence of the bronchodilator. Therefore, the pulmonary function test 
can be performed in the presence or absence of bronchodilation whereby the eligible 
patient population remains unchanged.  
The list of assessments has been modified without affecting endpoint variables. The 
sampling for blood biomarkers is not repeated at re-screening if the sampling has been 
performed at the initial screening, and there is no interaction with the Interactive 
Response Technology system at end of study.  
Reference to the current Investigator Brochure Version 13, dated September 2018, is 
made as applicable. 
Changes to the protocol 
Two versions of the amended protocol will be prepared: 1) a clean version and 2) a Word 
comparison document, showing deletions and insertions in comparison to the previous 
protocol version. 
Amended protocol sections 
The main sections of the protocol affected by this amendment are listed below. Where 
applicable, the same changes have also been made to the corresponding sections of the 
protocol synopsis: 
Table 1 
Study periods, visits at study site and assessments 
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4.4 
Exclusion criteria 
5.1.1 
Investigational treatment: Description and rationale 
5.1.2 
Matching placebo: Description and rationale 
5.1.3.1 
Individualized dose titration (Weeks 1 to 12) 
Table 3 
Recommended double-blind up-titration scheme 
5.1.11.3  
Start of a CYP2C8 inhibitor 
8.1.1 
Visit 1: Screening/re-screening 
14 
REFERENCES 
NCT03078907


Selexipag (ACT-293987) 
Pulmonary arterial hypertension 
Protocol AC-065A404 
Version 2 
5 December 2018, page 17/105 
Confidential 
EudraCT 2017­000216­42 
Doc No D-18.398 
 
PROTOCOL SYNOPSIS AC-065A404 
TITLE 
A multi-center, double-blind, placebo-controlled, Phase 4 study 
in patients with pulmonary arterial hypertension to assess the 
effect of selexipag on daily life physical activity and patient’s 
self-reported symptoms and their impacts 
ACRONYM 
TRACE: EffecT of selexipag on daily life physical activity 
assessed by a weaRAble deviCE 
OBJECTIVES 
Primary objective 
• Evaluate the effect of selexipag on daily life physical 
activity (DLPA) of patients with pulmonary arterial 
hypertension (PAH). 
Secondary objectives 
• Evaluate the effect of selexipag on PAH symptoms and 
their impacts in patients’ daily life. 
• Evaluate the effect of selexipag on exercise capacity, and 
disease severity in patients with PAH. 
• Evaluate the safety and tolerability of selexipag in patients 
with PAH. 
Other objectives 
• Explore potential association between traditional efficacy 
outcomes and DLPA.  
• Explore the levels and level changes of biomarkers 
potentially associated with PAH. 
DESIGN 
A 
prospective, 
multi-center, 
double-blind, 
randomized, 
placebo-controlled, parallel-group, exploratory Phase 4 study. 
PERIODS 
Screening period (duration up to 14 days): The period 
includes the informed consent process and assessments 
determining patient eligibility at Visit 1. Some of the 
assessments provide baseline data. At Visit 1 the devices for 
the assessment of DLPA and PAH-SYMPACT® are given to 
the patient for outpatient use. Visit 2 defined as Day 1 is being 
scheduled. 
Baseline period (duration 14–28 days): The period starts at 
the end of Visit 1 and ends with randomization at Visit 2 on 
Day 1. The actigraphy device is worn for the entire period, 
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Pulmonary arterial hypertension 
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Version 2 
5 December 2018, page 18/105 
Confidential 
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Doc No D-18.398 
 
24 hours per day (except during charging) for the collection of 
baseline DLPA. The recording of DLPA starts on the day of 
Visit 1. The PAH-SYMPACT® is assessed daily over a period 
of 7 days starting on Day −14. The start of the 
PAH-SYMPACT® can be delayed until Day −11, if the start on 
Day −14 has been missed. Valid baseline data for DLPA and 
PAH-SYMPACT® are required for eligibility.  
Treatment period (duration 24 weeks): For eligible patients 
with valid baseline data for DLPA and PAH-SYMPACT®, the 
period starts on Day 1 (Visit 2) with confirmation of eligibility 
and randomization to one of the two double-blind treatment 
arms. Patients will receive the first dose of study treatment on 
Day 1. From Day 1 up to end of Week 12 (Day 85) study 
treatment will be titrated to the highest individually tolerated 
dose. Patients will be called weekly by the site staff to guide 
the titration process, assess safety/tolerability, and support 
compliance with the actigraphy device. From Week 13 to 
Week 24 the individualized highest tolerated dose (HTD) is 
intended to be maintained (individualized maintenance dose 
[IMD]). Change of study treatment dose is allowed if needed 
for efficacy or tolerability reasons.  
Patients will continue to wear the actigraphy device during the 
whole 24-week period. At Week 15 and Week 23, 
PAH-SYMPACT® is assessed by the patient at their actual 
location (home, vacation, etc.). Patients will be called by the 
site staff on the first day of each PAH-SYMPACT® assessment 
period (Week 15 and Week 23) and at Week 20, to assess 
safety/tolerability, and to support compliance with the 
actigraphy device and the PAH-SYMPACT®. Visits at the 
study site are scheduled on Day 1 (Visit 2), Week 16/Day 113 
(Visit 3), and Week 24/Day 169 (Visit 4). An unscheduled visit 
is required for study treatment dispensing if dose is increased 
after Visit 3. At Visit 4, study treatment is terminated (end-of-
treatment, EOT). Upon premature discontinuation of study 
treatment prior to Week 24, the Visit 4 assessments should be 
performed within 10 days. Patient and investigator remain 
blinded regarding study treatment.  
Post-treatment safety follow-up period (duration 30 days): 
This period starts 1 day after EOT, defined as the last day of 
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Selexipag (ACT-293987) 
Pulmonary arterial hypertension 
Protocol AC-065A404 
Version 2 
5 December 2018, page 19/105 
Confidential 
EudraCT 2017­000216­42 
Doc No D-18.398 
 
intake of study drug. Patients will be followed by telephone 
regarding ongoing and new adverse events (AEs) at 
investigator’s discretion. The period is completed by an end-of-
study (EOS) telephone call 30 days after EOT. This telephone 
call represents the end of the patient’s study participation. 
At any time during the study, unscheduled telephone calls or 
visits at the study site may be conducted if medically indicated 
at the discretion of the investigator. 
PLANNED DURATION 
Approximately 20 months from first patient, first visit to last 
patient, last visit. 
SITE(S) 
/ COUNTRY(IES) 
The study will be conducted at approximately 45 sites in 
approximately 12 countries. 
SUBJECTS / GROUPS 
Approximately 100 patients will be randomized in a 1:1 ratio to 
the two treatment groups (approximately 50 patients per 
group), stratified by region (Europe/rest of the world versus 
North America). 
INCLUSION CRITERIA 
1. Signed informed consent prior to initiation of any study 
mandated procedure. 
2. Male and female patients with symptomatic PAH, aged from 
18 years to 75 years inclusive. A woman of childbearing 
potential [see definition in Section 4.5.1] is eligible only if 
the following applies: 
a) Negative serum pregnancy test at Screening Visit 1 and a 
negative urine 
pregnancy 
test 
at 
randomization, 
AND 
b) Agreement to undertake monthly urine pregnancy tests 
during the study up to 30 days after study treatment 
discontinuation 
AND 
c) Agreement to use an acceptable method of contraception 
[see definition in Section 4.5.2] from screening to 
30 days after study treatment discontinuation. 
3. Diagnosis of PAH belonging to one of the following 
subgroups of Group 1 pulmonary hypertension (PH) 
according 
to 
the 
updated 
clinical 
classification  
[Galiè 2015a]:  
NCT03078907


Selexipag (ACT-293987) 
Pulmonary arterial hypertension 
Protocol AC-065A404 
Version 2 
5 December 2018, page 20/105 
Confidential 
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1.1. Idiopathic (IPAH) 
1.2. Heritable (HPAH) 
1.3. Drugs or toxins induced 
1.4. Associated (APAH) with one of the following: 
1.4.1. Connective tissue disease 
1.4.2. Human immunodeficiency virus (HIV) infection 
1.4.4. Congenital heart disease with simple systemic-
to-pulmonary 
shunt 
(atrial 
septal 
defect, 
ventricular septal defect, patent ductus arteriosus) 
≥ 1 year after surgical repair. 
4. Documented hemodynamic diagnosis of PAH by right heart 
catheterization (RHC). Prior to randomization the most 
recently performed RHC at rest showing: 
a) Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg; 
and 
b) Resting 
pulmonary 
vascular 
resistance 
(PVR) 
≥ 240 dyn•s•cm-5 or 3 Wood Units; and 
c) Pulmonary artery wedge pressure (PAWP) or left 
ventricular 
end 
diastolic 
pressure 
(LVEDP) 
≤ 15 mmHg. 
5. Treatment with an endothelin receptor antagonist (ERA) for 
at least 90 days and on a stable dose for 30 days prior to 
randomization.  
6. Possible treatment with a phosphodiesterase-5 (PDE-5) 
inhibitor or soluble guanylate cyclase (sGC) stimulator must 
be ongoing for at least 90 days and on a stable dose for 
30 days prior to randomization. 
7. WHO functional class (FC) II or III at randomization. 
8. 6-minute walk distance (6MWD) ≥ 100 m at Visit 1. 
9. Ability to walk without a walking aid. 
10. Valid 
baseline 
data 
at 
Visit 
2 
for 
DLPA 
and 
PAH-SYMPACT® defined as: 
a) DLPA: Within the last 14 days (excluding Day 1), at 
least 9 days each with a minimum of 14 hours wear 
time; 
b) PAH-SYMPACT®: Of the 7-day PAH-SYMPACT® 
NCT03078907


Selexipag (ACT-293987) 
Pulmonary arterial hypertension 
Protocol AC-065A404 
Version 2 
5 December 2018, page 21/105 
Confidential 
EudraCT 2017­000216­42 
Doc No D-18.398 
 
assessment period, 5 days with complete data of the 
symptom part and 1 day with complete data of the 
impact part. 
EXCLUSION CRITERIA 
1. PH Groups 2–5 according to the updated clinical 
classification [Galiè 2015a], and PAH Group 1 subgroups 
that are not covered by the inclusion criterion 3. 
2. Patients on a PAH-specific monotherapy targeting the 
nitric oxide pathway (i.e., PDE-5 inhibitor or sGC 
stimulator). 
3. Patients treated with prostacyclin, prostacyclin analog, or 
prostacyclin receptor agonist) at any time prior to Day 1 
(administration for vasoreactivity testing is permitted; 
previous 
prostacyclin 
/ 
prostacyclin 
analogs 
used 
intermittently for the treatment of digital ulcers or 
Raynaud’s 
phenomenon 
are 
permitted 
if 
stopped 
> 6 months prior to Day 1). 
4. Any hospitalization during the last 30 days prior to Visit 1. 
5. Worsening in WHO FC during the last 30 days prior to 
Visit 1. 
6. Severe coronary heart disease or unstable angina. 
7. Myocardial infarction within the last 6 months. 
8. Decompensated cardiac failure. 
9. Ongoing severe arrhythmias. 
10. Cerebrovascular events (e.g., transient ischemic attack, 
stroke) within the last 3 months. 
11. Congenital or acquired valvular defects with clinically 
relevant myocardial function disorders not related to PH.  
12. Presence of one or more of the following signs of relevant 
lung disease at the last examination any time up to Visit 1: 
a) Diffusing capacity of the lung for carbon monoxide 
< 40% of predicted UNLESS computed tomography 
NCT03078907


Selexipag (ACT-293987) 
Pulmonary arterial hypertension 
Protocol AC-065A404 
Version 2 
5 December 2018, page 22/105 
Confidential 
EudraCT 2017­000216­42 
Doc No D-18.398 
 
reveals no or mild parenchymal lung disease; OR 
b) Forced vital capacity < 60% of predicted1; OR 
c) Forced expiratory volume in one second < 60% of 
predicted1. 
13. Documented severe hepatic impairment (with or without 
cirrhosis) at Visit 1, defined as Child-Pugh Class C. 
14. Documented severe renal insufficiency at Visit 1, defined as 
estimated creatinine clearance < 30 mL/min, or serum 
creatinine > 2.5 mg/dL. 
15. Hemoglobin < 80 g/L (< 4.96 mmol/L) at Visit 1. 
16. Known or suspected uncontrolled hyperthyroidism. 
17. Known or suspected pulmonary veno-occlusive disease. 
18. Ongoing or planned dialysis. 
19. Body mass index above 40 kg/m2 at Visit 1. 
20. Sitting systolic blood pressure below 90 mmHg at Visit 1. 
21. Treatment 
with 
a 
strong 
inhibitor 
of 
CYP2C8 
(e.g., gemfibrozil). 
22. Receiving or having received any investigational drugs 
within 90 days prior to Visit 1. 
23. Participation in a cardio-pulmonary rehabilitation program 
based on exercise training within 8 weeks prior to Visit 1. 
Such program must not be started during the course of the 
study. 
24. Concomitant life-threatening disease with a life expectancy 
of less than 12 months. 
25. Known hypersensitivity to any of the excipients of the study 
treatment formulation. 
26. Pregnancy, breastfeeding, or intention to become pregnant 
during the study. 
27. Any factor or condition likely to impair adherence to 
                                                 
1 Pulmonary function tests may be performed either with or without the use of bronchodilators, as per local clinical 
practice. 
NCT03078907


Selexipag (ACT-293987) 
Pulmonary arterial hypertension 
Protocol AC-065A404 
Version 2 
5 December 2018, page 23/105 
Confidential 
EudraCT 2017­000216­42 
Doc No D-18.398 
 
protocol 
mandated 
procedures, 
as 
judged 
by 
the 
investigator. 
STUDY TREATMENTS 
Investigational treatment 
Selexipag (ACT-293987) 200 mcg oral tablet twice daily 
(b.i.d.). 
Comparative treatment 
Matching placebo 200 mcg oral tablet b.i.d. 
Study treatments will be provided as film-coated tablets in 
childproof bottles of 120 tablets. Store below 25 °C (77 °F). 
Keep the bottle tightly closed in order to protect from moisture. 
Individualized dose titration (Weeks 1 to 12) 
Each patient should be titrated to the individualized HTD, 
which can range from 200 mcg b.i.d. to 1600 mcg b.i.d. 
The starting dose is 200 mcg b.i.d., approximately 12 hours 
apart. The dose is increased in increments of 200 mcg b.i.d., 
usually at weekly intervals. At the beginning of treatment and 
at each up-titration step it is recommended to take the first dose 
in the evening. During dose titration some adverse reactions, 
reflecting the mode of action of the study treatment (such as 
headache, diarrhea, nausea and vomiting, jaw pain, myalgia, 
pain in extremity, arthralgia, and flushing), may occur. They 
are usually transient or manageable with symptomatic 
treatment. However, if a patient reaches a dose that cannot be 
tolerated or managed, the dose should be reduced to the 
previous dose level. In patients in whom up-titration was 
limited by reasons other than adverse reactions reflecting the 
mode of action of study treatment, a second attempt to continue 
up-titration to the HTD up to a maximum dose of 1600 mcg 
b.i.d. may be considered until Week 12. 
Individualized maintenance dose (Weeks 13 to 24) 
The individualized maintenance dose is the HTD reached 
during individualized dose titration and should be maintained 
from Week 13 to Week 24. Change of study treatment dose is 
allowed if needed for efficacy or safety/tolerability reasons. If 
the therapy over time is less tolerated at a given dose, 
symptomatic treatment and/or a dose reduction to the next 
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Selexipag (ACT-293987) 
Pulmonary arterial hypertension 
Protocol AC-065A404 
Version 2 
5 December 2018, page 24/105 
Confidential 
EudraCT 2017­000216­42 
Doc No D-18.398 
 
lower dose should be considered. The dose may be increased 
(to a maximum dose of 1600 mcg b.i.d.) if the patient may 
benefit from a higher dose, as judged by the investigator.  
ENDPOINTS 
Primary endpoints 
• Change from baseline to Week 24/EOT in actigraphy-
assessed DLPA as measured by: 
o Daily time spent (minutes) in non-sedentary activity  
(> 100 activity counts per minute)  
o Percentage of daily time spent in non-sedentary activity 
(> 100 activity counts per minute)  
o Total DLPA in counts/min 
o Sleep: Total sleep time; minutes, wake after sleep onset; 
minutes, number of awakenings, efficiency (percentage)  
The study is designed as exploratory, and therefore all 
actigraphy variables are listed under primary endpoints. 
Secondary endpoints 
• Change from baseline to Week 24/EOT for following 
PAH-SYMPACT® domain scores: 
o Cardiovascular symptom domain score 
o Cardiopulmonary symptom domain score 
o Physical impact domain score 
o Cognitive/emotional impact domain score 
• Change from baseline to Week 24/EOT for following 
variables: 
o WHO FC 
o 6MWD 
o Borg dyspnea index at 6MWT 
o N-terminal pro b-type natriuretic peptide (NT-proBNP) 
Other endpoints 
• Change from baseline to Week 24/EOT for blood 
biomarkers associated with, e.g., PAH worsening, right/left 
ventricle function, inflammation. 
• Association between actigraphy variables and other efficacy 
endpoints (PAH-SYMPACT®, 6MWD, etc.) 
Safety endpoints 
• Treatment-emergent AEs and serious AEs up to 30 days 
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Pulmonary arterial hypertension 
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Version 2 
5 December 2018, page 25/105 
Confidential 
EudraCT 2017­000216­42 
Doc No D-18.398 
 
after study treatment discontinuation. 
• AEs leading to discontinuation of study treatment. 
• Change from baseline in vital signs (systolic and diastolic 
arterial blood pressure and pulse rate) and body weight from 
baseline to all assessed time points during the study. 
• Treatment-emergent marked laboratory abnormalities up to 
30 days after study treatment discontinuation. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 1. 
STATISTICAL 
METHODOLOGY 
All statistical analyses will be conducted by Actelion or by 
designated CRO supervised by Actelion. A Statistical Analysis 
Plan (SAP) will provide full details of the analyses, data 
displays, and algorithms to be used for data derivations. 
Analysis sets: 
The Screened Analysis Set includes all patients who are 
screened and have a patient identification number. 
The Full Analysis Set (FAS) includes all patients randomly 
assigned to a study treatment. In order to adhere to the 
intention-to-treat principle as much as possible:  
• Patients are evaluated according to the study treatment they 
have been assigned to (which may be different from the 
study treatment they have received), 
• All available data are included. 
The Per-protocol Analysis Set comprises all patients who 
received study treatment and who complied with the protocol 
sufficiently to allow assessment of the treatment effects. 
Criteria for sufficient compliance include exposure to 
treatment, availability of measurements and absence of major 
protocol deviations that have an impact on the treatment effect. 
The full list of criteria will be detailed in the SAP before 
making the full randomization information available. 
The Safety Set includes all patients who received at least one 
dose of study treatment, and the analysis will be based on the 
actual treatment received. 
Primary analysis: 
This study is designed as exploratory with the purpose to 
generate hypotheses on new endpoints. All analyses performed 
will be descriptive in nature with summary statistics and 
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Pulmonary arterial hypertension 
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Version 2 
5 December 2018, page 26/105 
Confidential 
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Doc No D-18.398 
 
associated 95% confidence intervals (CI) provided when 
applicable. Any p-value provided as result of a statistical model 
is to be considered as exploratory only.  
No adjustment for multiplicity will be performed. There will be 
no interim analysis.  
All actigraphy variables will be summarized by period of 
14 days: Baseline (last 14 days before first dose), Week 2 
(Day 1–14), Week 4 (Day 15–28), and so on until Week 24 
(Day 155–168) or EOT (last 14 days period on study treatment) 
in case of premature discontinuation. Any actigraphy data 
recorded after Day 168/EOT will not be considered in summary 
statistics and will be listed only. 
For all actigraphy variables (continuous), change from baseline 
to Week 24/EOT will be analyzed (on the FAS) using an 
analysis of covariance including terms for treatment and region, 
and baseline values as covariates. The differences in least 
square means between treatment and placebo, corresponding 2-
sided 95% CI and p-value will be provided. 
All actigraphy variables will be also reported overtime with 
actual values, absolute change and percentage change from 
baseline at each time point (14 days periods).  
Daily time spent and percentage of daily time spent will be also 
displayed according to activity categories “sedentary”, “light”, 
“moderate”, “vigorous” and “very vigorous” based on the 
Freedson Adult algorithm [Freedson 1998]. 
Secondary/exploratory analyses: 
PAH-SYMPACT® domain scores and others PAH-related 
variables (6MWD, Borg dyspnea index, NT-proBNP) will be 
analyzed similarly as actigraphy variables (as continuous). 
WHO FCs will be described by shift tables from baseline to 
each time point. The association between actigraphy variables 
and others efficacy endpoints (PAH-SYMPACT® domain 
scores, 6MWD, NT-proBNP) will be described using 
correlations, scatter plots and regressions. Details will be 
provided in the SAP.  
Safety analysis: 
All safety analyses will be performed on the Safety Set using 
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Pulmonary arterial hypertension 
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descriptive statistics. 
Sample size: 
There are no longitudinal data available for actigraphy 
variables in PAH patients. Therefore, the study is designed as 
exploratory and sample size is based on enrolment capabilities: 
100 patients will be randomized in total (50 in placebo group 
and 50 in selexipag group).  
STUDY COMMITTEES 
A Steering Committee has been appointed by Actelion to 
contribute to the design of the protocol, the oversight of study 
conduct, the evaluation of results, and the support in 
publication. The committee is governed by a Steering 
Committee charter. 
 
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Pulmonary arterial hypertension 
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Version 2 
5 December 2018, page 28/105 
Confidential 
EudraCT 2017­000216­42 
Doc No D-18.398 
 
Table 1 
Study periods, visits at study site and assessments 
Telephone calls from the study site to the patient and assessments during telephone calls are shown in Table 2. 
PERIOD 
(DURATION) 
SCREENING  
(up to 14 days) 
BASELINE  
(at least 14 
days) 
TREATMENT 
(24 weeks) 
FOLLOW-UP 
(30 days) 
VISIT 
Number 
1 
 
2 
 
3 
 
4 
U1, U2, … 
P16 
 
Name 
Screening 
Actigraphy, 
ePRO period 
Randomization1 
ePRO period 
Intermediate visit 
ePRO period 
End-of-
treatment 
Unscheduled 
visits3 
End-of-study 
telephone call 
 
Time  
(Time window) 
Days 
−28 to −15 
Days 
−14 to −1 
Day  
1 
Week 15 
Days 99 to 105 
(+3 days) 
Week 16  
Day 113 
(−4 to +7 days) 
Week 23 
Days 155 to 161  
(+3 days) 
Week 242 
Day 169 
(−4 to +14 days) 
Any day between 
Day 1 and 
EOT+30 days 
End-of-Treatment 
+30 days 
(+10 days) 
Informed consent4 
X 
 
 
 
 
 
 
 
 
IRT interaction 
X 
 
X 
 
X 
 
X 
X11 
 
Eligibility 
X 
 
X 
 
 
 
 
 
 
Demographics, PAH 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Prev./conc. therapies 
X 
 
X5 
 
X5 
 
X5 
X5 
X5 
Vital signs (BP, HR, body weight, 
height6) 
X 
 
X 
 
X 
 
X 
X 
 
WHO FC 
X 
 
X 
 
X 
 
X 
X 
 
6MWT/Borg index 
X 
 
 
 
X 
 
X 
X 
 
NT-proBNP, biomarkers 
X13 
 
 
 
X 
 
X 
X 
 
Hematology, chemistry 
X 
 
 
 
 
 
X 
X 
 
Contraceptive methods used, 
pregnancy test7, 8 
X 
 
X 
 
X 
 
X 
X 
X 
Actigraphy9 
 
E v e r y  d a y ,  2 4  h o u r s  p e r  d a y  
 
 
PAH-SYMPACT®10  
 
X 
 
X 
 
X 
 
 
 
Study treatment dose 
 
 
X 
 
X5 
 
X5 
X5, 11 
 
Study treatment dispensing/return 
 
 
X 
 
X 
 
X 
X11 
 
AE and SAE12 
X 
 
X 
 
X 
 
X 
X 
X 
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Pulmonary arterial hypertension 
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1) All assessments are to be done prior to first intake of study drug. 
2) In case of premature study treatment discontinuation, this visit with all assessments should be performed within 10 days after 
end-of-treatment, if possible. 
3) Unscheduled visits may be performed at any time during the study and may include all, some or additional assessments, based 
on the judgment of the investigator. Study assessments must be entered in the eCRF. 
4) Prior to any study mandated assessments. 
5) Only the changes are recorded. 
6) Height is measured at Visit 1 only. 
7) Serum pregnancy tests performed by central laboratory at Visit 1, Visit 3 (Week 16) and Visit 4 (Week 24).  
8) Urine pregnancy tests performed at study site during Visit 2 and by patient at home within 3 days prior to the telephone call at 
EOT + 30 days. 
9) Actigraphy data are collected starting at Visit 1, uploaded by patients daily, AND by the site at all site visits. 
10) The PAH-SYMPACT® questionnaire is being completed daily during each of the 3 7-day ePRO periods starting on Day −14, 
Day 99 (Week 15), and Day 155 (Week 23). 
11) An unscheduled visit is required for study treatment dispensing if dose is increased after Visit 3.  
12) All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after EOT must be recorded in the 
eCRF. SAEs must be reported to Actelion drug safety on an SAE form. 
13) No sampling for blood biomarkers at re-screening, if collected at initial screening. 
 
6MWT, 6-minute walk test; AE, adverse event; BP, blood pressure; eCRF, electronic Case Report Form; EOT, end-of-treatment; 
ePRO, electronic patient-reported outcome; HR, heart rate; IRT, interactive response technology; NT-proBNP, N-terminal pro b-
type natriuretic peptide; PAH, pulmonary arterial hypertension; PAH-SYMPACT®, Pulmonary Arterial Hypertension Symptoms 
and Impact questionnaire; SAE, serious adverse event; WHO FC, World Health Organization functional class.  
 
 
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Pulmonary arterial hypertension 
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Confidential 
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Table 2 
Telephone calls from the study site to the patient, and assessments 
PERIODS (DURATION) 
TREATMENT (24 weeks) 
FOLLOW-UP 
(30 days) 
Weeks 1 to 12 
Weeks 13 to 24 
Any time 
Telephone call Number 
P1 to P12 
P13 
P14 
P15 
UP1, UP2, … 
P16 
 
Name 
Weekly telephone calls 
Week 15 
Week 20 
Week 23 
Unscheduled telephone call2 
End-of-study telephone call 
 
Time  
(Time window) 
Days 8, 15, 22, 29, 36, 43, 50, 57, 
64, 71, 78, 85 
(±3 days) 
99 
(+3 days) 
141 
(±3 days) 
155 
(+3 days)  
Any day between Day 1 and 
EOT+30 days 
End-of-treatment +30 days 
(+10 days) 
Conc. therapies3 
X 
X 
X 
X 
X 
X 
Contraceptive methods used3, 
urine pregnancy test4 
Days 29, 57, 85 
 
X 
 
 
X 
PAH-SYMPACT®1 
 
X 
 
X 
 
 
Study treatment dose3 
X 
X 
X 
X 
X 
 
AE and SAE5 
X 
X 
X 
X 
X 
X 
 
1) PAH-SYMPACT® refers to reminding the patient of the start of the PAH-SYMPACT® assessment period. The call cannot be 
made earlier than the day indicated but can be postponed by a maximum of 3 days. 
2) Unscheduled telephone calls may be performed at any time during the study and may include all, some or additional 
assessments, based on the judgment of the investigator. Study assessments must be entered in the eCRF. 
3) Only the changes are recorded. 
4) Urine pregnancy tests are performed by patient at home within 3 days prior to the telephone calls. 
5) All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after EOT must be recorded in the 
eCRF. SAEs must be reported to Actelion drug safety on an SAE form. 
 
AE, adverse event; eCRF, electronic Case Report Form; EOT, end-of-treatment; PAH-SYMPACT®, Pulmonary Arterial 
Hypertension Symptoms and Impact Questionnaire; SAE, serious adverse event.  
 
NCT03078907


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Pulmonary arterial hypertension 
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Version 2 
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Doc No D-18.398 
 
 
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) [Galiè 2015a] 
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 treatment 
Uptravi® (Selexipag) has been approved in the US and Europe for the indication of 
long-term treatment of PAH. More detailed information on selexipag can be found in the 
Investigator’s Brochure (IB) [Selexipag IB] 
1.2.1 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.  
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1.2.2 Clinical pharmacology 
For interactions as well as the pharmacodynamics and pharmacokinetics of selexipag, see 
the IB [Selexipag IB]. 
1.2.3 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) (log-rank P < 0.0001) 
[Sitbon 2015]. 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 functional class 
[FC], and baseline PAH background medication).  
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 
[Sitbon 2015]. 
1.2.4 Summary of safety profile 
In the GRIPHON trial, patients were treated for up to 4.2 years. The most frequently 
reported adverse events (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% 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]. 
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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]. 
1.3 Purpose and rationale of the study 
Patient-centered outcomes are outcomes from medical care that are important to patients. 
Insurance payments are increasingly linked to the provision of patient-centered outcomes. 
New measures are necessary for measuring treatment effect in a real life, day-to-day 
setting. It is also recognized that no single measurement will adequately capture the 
aspects of disease and treatment from the point of view of and relevant to the patient. 
Such patient-centered outcomes may play an important role in patient follow-up and 
treatment reimbursement in the future. 
Actigraphy is a non-invasive method for the collection of information about the physical 
activity of patients in their real-life, day-to-day setting [Godfrey 2008]. The technology 
can be used for capturing objective information on sleep/wake behavior, circadian 
rhythm, and physical activity. Devices validated for the use in clinical trials are available 
and allow for monitoring the adherence to proper wearing and handling. Actigraphy can 
provide insights into the effect of an investigational therapy on the patient’s activity and 
mobility by comparing patient’s baseline activity and sleep behavior to their changes 
after the intervention. This allows assessing whether the treatment has a positive impact 
on the exercise capacity of the patient. In contrast to other methods for assessing the 
exercise capacity of the patient (i.e., 6-minute walk test [6MWT]) actigraphy allows this 
assessment to be performed in the every-day environment of the patient [Mainguy 2011, 
Okumus 2016, Pugh 2012, Ulrich 2012]. 
Patient-reported outcome (PRO) is a method by which the patient’s perceptions and 
experiences are collected by using a questionnaire. The most widely used PRO for 
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evaluating symptoms, functioning and quality of life (QoL) in PAH clinical studies is the 
Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) [McKenna 2006]. 
In addition, other non-PAH specific QoL questionnaires have been used previously in 
PAH studies. However, as these questionnaires were not developed specifically for use in 
PAH, they may not capture the aspects most important to patients with PAH and would 
not meet the FDA guidance requirements for a validated questionnaire [FDA 2009]. 
PAH-SYMPACT® is a PAH specific PRO tool developed according to the FDA 
guidelines that allows the assessment of PAH-specific SYMptoms and their physical and 
cognitive/emotional impact [McCollister 2016]. 
The assessments of daily life physical activity (DLPA) and PAH-SYMPACT® in a Phase 
4 clinical study with selexipag will provide patient-centered, real-world, and 
PAH-specific information about the effects of selexipag on the daily life of patients with 
PAH. The additional assessment of objective clinical variables (i.e., WHO FC, 6-minute 
walk distance [6MWD]) may reveal their potential correlation with the patient’s daily life 
experience and shed new light on disease mechanism. 
1.4 Summary of known and potential risks and benefits 
The study mandated procedures at site visits (i.e., blood draw, 6MWT) and wearing the 
actigraphy device during the participation in the study do not pose a risk to the study 
participants. Given the extensive and long-term controlled efficacy and safety data 
available with selexipag [see Section 1.2] and the careful follow-up of patients mandated 
by this protocol (i.e., clinical examination, laboratory checks, weekly telephone calls 
during the titration phase of study treatment), the benefit/risk assessment supports the 
treatment of the patients with selexipag for the purpose of the current study. 
It is the investigator’s responsibility to monitor the risk-benefit ratio of study treatment 
administration, as well as the degree of distress caused by study procedures on an 
individual patient level, and to discontinue study treatment or the study if, on balance, 
he/she believes that continuation would be detrimental to the patients’ well-being. 
2 
STUDY OBJECTIVES 
2.1 Primary objective 
To evaluate the effect of selexipag on DLPA of patients with PAH. 
2.2 Secondary objectives 
• To evaluate the effect of selexipag on PAH symptoms and the impact on patients’ 
daily life. 
• To evaluate the effect of selexipag on exercise capacity and disease severity in 
patients with PAH. 
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• To evaluate the safety and tolerability of selexipag in patients with PAH. 
2.3 Other objectives 
• Explore potential association between traditional efficacy outcomes and DLPA. 
• Explore the levels and level changes of biomarkers potentially associated with PAH. 
3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
This is a prospective, multi-center, double-blind, randomized, placebo-controlled, 
parallel-group, exploratory Phase 4 study. 
Approximately 100 patients will be randomized in a 1:1 ratio to either selexipag or 
placebo. Treatment allocation will be stratified by region, i.e., Europe/rest of the world vs 
North America. 
The study will be conducted in approximately 45 sites in approximately 12 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. 
3.1.1 Study periods 
The study comprises the following consecutive periods: 
Screening period (duration up to 14 days): The period includes the informed consent 
process and assessments determining patient eligibility at Visit 1. Some of the 
assessments provide baseline data. At Visit 1 the devices for the assessment of DLPA and 
PAH-SYMPACT® are given to the patient for outpatient use. Visit 2 defined as Day 1 is 
being scheduled. 
Baseline period (duration at least 14 days, at most 28 days): The period starts at the 
end of Visit 1 and ends with randomization at Visit 2 on Day 1. The actigraphy device is 
worn for the entire period, 24 hours per day (except during charging) for the collection of 
baseline DLPA. The recording of DLPA starts on the day of Visit 1. The PAH-
SYMPACT® is assessed daily over a period of 7 days starting on Day −14. The start of 
the PAH-SYMPACT® can be delayed until Day −11, if the start on Day −14 has been 
missed. Valid baseline data for DLPA and PAH-SYMPACT® are required for eligibility. 
Treatment period (duration 24 weeks): For eligible patients with valid baseline data for 
DLPA and PAH-SYMPACT®, the period starts on Day 1 (Visit 2) with confirmation of 
eligibility and randomization to one of the two double-blind treatment arms. Patients will 
receive the first dose of study treatment on Day 1. From Day 1 up to end of Week 12 
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(Day 85) study treatment will be titrated to the highest individually tolerated dose. 
Patients will be called weekly by the site staff to guide the titration process, assess 
safety/tolerability, and support compliance with the actigraphy device. From Week 13 to 
Week 24 the individualized highest tolerated dose (HTD) is intended to be maintained 
(individualized maintenance dose [IMD]). Change of study treatment dose is allowed if 
needed for efficacy or tolerability reasons. An unscheduled visit is required for study 
treatment dispensing if dose is increased after Visit 3 (Week 16).  
Patients will continue to wear the actigraphy device during the whole 24-week period. At 
Week 15 and Week 23, PAH-SYMPACT® is assessed by the patient at their actual 
location (home, vacation, etc.). Patients will be called by the site staff on the first day of 
each PAH-SYMPACT® assessment period (Day 99 for Week 15 and Day 155 for Week 
23) and at Week 20, to assess safety/tolerability, and to support compliance with the 
actigraphy device and the PAH-SYMPACT®. Visits at the study site are scheduled on 
Day 1 (Visit 2), Week 16/Day 113 (Visit 3), and Week 24/Day 169 (Visit 4). At Visit 4, 
study treatment is terminated (EOT). Upon premature discontinuation of study treatment 
prior to Week 24, the Visit 4 assessments should be performed within 10 days. Patient 
and investigator remain blinded regarding study treatment. 
Post-treatment safety follow-up period (duration 30 days): This period starts 1 day 
after EOT, defined as the last day of intake of study drug. Patients will be followed up by 
telephone regarding ongoing and new AEs at investigator’s discretion. The period is 
completed by an end-of-study (EOS) telephone call 30 days after EOT. This telephone 
call represents the end of the patient’s study participation. 
At any time during the study, unscheduled telephone calls or visits at the study site may 
be conducted if medically indicated at the discretion of the investigator. 
The visit schedule and protocol-mandated assessments are displayed in Table 1 and  
Table 2 and described in Sections 7 and 8. 
The overall study design is depicted in [Figure 1]. 
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Figure 1 
Study design  
 
3.1.2 Study duration 
The study starts with the first act of recruitment (i.e., first Informed Consent Form [ICF] 
signed) and ends with the last visit of the last patient. Patients will be treated for 
24 weeks or less in case of premature discontinuation of the study treatment.  
Patients enter a post-treatment observation period which lasts until 30 days after EOT to 
collect safety information. For an individual patient, the EOS is marked with a telephone 
call from the site at the end of the 30-day safety follow-up. The duration of study 
participation of a patient is about 7.5 months from ICF signed to EOS. 
3.2 Study design rationale 
The primary objective of this study is to evaluate the effect of selexipag on patient’s 
DLPA. A placebo-controlled study design was chosen since several medication-
independent factors may have an influence on DLPA, such as changes in duration of day 
light, weather conditions, season, and motivational effect by the use of an actigraphy 
device during the course of the study. The placebo control will thus allow for the 
non-confounded evaluation of the treatment effect of selexipag on DLPA, but also on the 
patient reported PAH symptoms and their impacts on daily life.  
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The use of placebo is considered safe and ethically justified because patients are required 
to be on background PAH therapy proven to be effective (Section 4.2).  
Selexipag is titrated to the patient’s individualized HTD during 12 weeks as per the 
pivotal Phase 3 trial GRIPHON. Titration includes time periods during which the patient 
does not receive the effective dose and/or experiences transient side effects. Both may 
affect DLPA adversely. Therefore, a subsequent time period of additional 12 weeks 
during which the patient receives the individual optimal dose is considered appropriate to 
assess DLPA and PAH-SYMPACT® under conditions reflecting maintenance therapy. 
3.3 Study committees 
A Steering Committee has been appointed by Actelion to contribute to the design of the 
protocol, the oversight of study conduct, the evaluation of results, and the support in 
publication. The committee is governed by a Steering Committee charter. 
4 
PATIENT POPULATION 
4.1 Patient population description  
This study will enroll adult male and female patients aged 18 to 75 with Group I PH 
[Galiè 2015a], except subgroups 1.4.3 (Portal hypertension) and 1.4.5 (Schistosomiasis), 
and except patients of subgroup 1.4.4 (Congenital heart disease) with other than corrected 
simple congenital heart defects.  
Patients must be in WHO FC II and III, stably treated with an endothelin receptor 
antagonist (ERA), and must have no significant pulmonary or cardiac concomitant 
diseases as detailed in Sections 4.3 and 4.4. 
Eligible patients must be able and willing to give informed consent for participation in 
the clinical study. 
4.2 Rationale for the selection of the study population 
The study population was selected based on the United States Product Information 
(USPI) and the EU Summary of Product Characteristics (SmPC) indication for Uptravi®. 
Patients with significant cardiovascular, pulmonary, immunological, hepatic, or 
ophthalmological medical conditions or therapies are excluded since they could 
potentially be at greater risk of experiencing side effects, and/or their conditions could 
interfere with evaluation of the treatment effect, study assessment and interpretation of 
study results.  
To ensure an appropriate treatment for patients assigned to placebo, all eligible patients 
are required to be on background PAH therapy with either an ERA or an ERA in 
combination with a drug targeting the nitric oxide pathway for at least 90 days and on a 
stable dose for 30 days prior to initiation of study drug. Two clinical trials have 
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demonstrated that an ERA either alone or in combination with a phosphodiesterase-5 
(PDE-5) inhibitor significantly reduces morbidity events in patients with PAH 
[Pulido 2013, Galiè 2015b]. This evidence is not available for PDE-5 inhibitors and 
soluble guanylate cyclase (sGC) stimulators if administered as the only PAH specific 
therapy. Therefore, PDE-5 inhibitors and sGC stimulators are allowed only if 
administered concomitantly with an ERA for at least 3 months and on a stable dose for 30 
days prior to initiation of study drug.  
The safety and efficacy of selexipag in a pediatric population (< 18 years of age) have not 
been established. Patients above 75 years of age are excluded from the study due to 
potential age-related comorbidities that may interfere with PAH disease stability.  
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 patient: 
1. Signed informed consent prior to initiation of any study mandated procedure. 
2. Male and female patients with symptomatic PAH, aged from 18 years to 75 years 
inclusive. 
 
A woman of childbearing potential [see definition in Section 4.5.1] is eligible only if 
the following applies: 
a) Negative serum pregnancy test at Screening Visit 1 and a negative urine 
pregnancy test at randomization,  
AND  
b) Agreement to undertake monthly urine pregnancy tests during the study up to 
30 days after study treatment discontinuation,  
AND 
c) Agreement to use an acceptable method of contraception [see definition in 
Section 4.5.2] from screening to 30 days after study treatment discontinuation. 
3. Diagnosis of PAH belonging to one of the following subgroups of Group 1 PH 
according to the updated clinical classification [Galiè 2015a]:  
1.1. Idiopathic (IPAH) 
1.2. Heritable (HPAH) 
1.3. Drugs or toxins induced 
1.4. Associated (APAH) with one of the following: 
1.4.1. Connective tissue disease 
1.4.2. Human immunodeficiency virus (HIV) infection 
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1.4.4. Congenital heart disease with simple systemic-to-pulmonary shunt (atrial 
septal defect, ventricular septal defect, patent ductus arteriosus) ≥ 1 year 
after surgical repair. 
4. Documented hemodynamic diagnosis of PAH by right heart catheterization (RHC). 
Prior to randomization the most recently performed RHC at rest showing: 
a) mPAP ≥ 25 mmHg; and 
b) Resting PVR ≥ 240 dyn•s•cm-5 or 3 WUs; and 
c) PAWP or LVEDP ≤ 15 mmHg. 
5. Treatment with an ERA for at least 90 days and on a stable dose for 30 days prior to 
randomization.  
6. Possible treatment with a PDE-5 inhibitor or sGC stimulator must be ongoing for at 
least 90 days and on a stable dose for 30 days prior to randomization. 
7. WHO FC II or III at randomization. 
8. 6MWD ≥ 100 m at Visit 1. 
9. Ability to walk without a walking aid. 
10. Valid baseline data at Visit 2 for DLPA and PAH-SYMPACT® defined as: 
a. 
DLPA: Within the last 14 days (excluding Day 1), at least 9 days each with a 
minimum of 14 hours wear time; 
AND  
b. PAH-SYMPACT®: Of the 7-day PAH-SYMPACT® assessment period, 5 days 
with complete data of the symptom part and 1 day with complete data of the 
impact part. 
4.4 Exclusion criteria 
Patients must not fulfill any of the following exclusion criteria. It is not permitted to 
waive any of the criteria for any patient: 
1. PH Groups 2–5 according to the updated clinical classification [Galiè 2015a], and 
PAH Group 1 subgroups that are not covered by the inclusion criterion 3. 
2. Patients on a PAH-specific monotherapy targeting the nitric oxide pathway 
(i.e., PDE-5 inhibitor or sGC stimulator). 
3. Patients treated with prostacyclin, prostacyclin analog, or prostacyclin receptor 
agonist) at any time prior to Day 1 (administration for vasoreactivity testing is 
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permitted; previous prostacyclin / prostacyclin analogs used intermittently for the 
treatment of digital ulcers or Raynaud’s phenomenon are permitted if stopped  
> 6 months prior to Day 1). 
4. Any hospitalization during the last 30 days prior to Visit 1. 
5. Worsening in WHO FC during the last 30 days prior to Visit 1. 
6. Severe coronary heart disease or unstable angina. 
7. Myocardial infarction within the last 6 months. 
8. Decompensated cardiac failure. 
9. Ongoing severe arrhythmias. 
10. Cerebrovascular events (e.g., transient ischemic attack, stroke) within the last 
3 months. 
11. Congenital or acquired valvular defects with clinically relevant myocardial function 
disorders not related to PH.  
12. Presence of one or more of the following signs of relevant lung disease at the last 
examination any time up to Visit 1: 
a) Diffusing capacity of the lung for carbon monoxide < 40% of predicted 
UNLESS computed tomography reveals no or mild parenchymal lung disease;  
OR 
b) Forced vital capacity < 60% of predicted2;  
OR 
c) Forced expiratory volume in one second < 60% of predicted2. 
13. Documented severe hepatic impairment (with or without cirrhosis) at Visit 1, defined 
as Child-Pugh Class C. 
14. Documented severe renal insufficiency at Visit 1, defined as estimated creatinine 
clearance < 30 mL/min, or serum creatinine > 2.5 mg/dL. 
15. Hemoglobin < 80 g/L (< 4.96 mmol/L) at Visit 1. 
16. Known or suspected uncontrolled hyperthyroidism. 
                                                 
2 Pulmonary function tests may be performed either with or without the use of bronchodilators, as per local clinical 
practice. 
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17. Known or suspected pulmonary veno-occlusive disease. 
18. Ongoing or planned dialysis. 
19. Body mass index (BMI) above 40 kg/m2 at Visit 1. 
20. Sitting SBP below 90 mmHg at Visit 1. 
21. Treatment with a strong inhibitor of CYP2C8 (e.g., gemfibrozil). 
22. Receiving or having received any investigational drugs within 90 days prior to 
Visit 1. 
23. Participation in a cardio-pulmonary rehabilitation program based on exercise training 
within 8 weeks prior to Visit 1. Such program must not be started during the course 
of the study. 
24. Concomitant life-threatening disease with a life expectancy of less than 12 months. 
25. Known hypersensitivity to any of the excipients of the study treatment formulation. 
26. Pregnancy, breastfeeding, or intention to become pregnant during the study. 
27. Any factor or condition likely to impair adherence to protocol mandated procedures, 
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. 
• Postmenopausal (defined as 12 consecutive months with no menses without an 
alternative medical cause [ICH M3]). 
• Premature ovarian failure (confirmed by a specialist), XY genotype, Turner 
syndrome, uterine agenesis. 
The reason for not being of childbearing potential will be recorded in the electronic Case 
Report Form (eCRF). 
4.5.2 Acceptable methods of contraception 
Women of childbearing potential as defined in Section 4.5.1 must use reliable 
contraception from screening up to 1 month following discontinuation of the last study 
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treatment. Reliable contraception must be started from screening. The methods of 
contraception used (including non-pharmacological methods) must be recorded in the 
eCRF every 4 weeks.  
The use of at least one of the following methods is accepted as reliable contraception:  
1. Oral, implantable, transdermal, or injectable hormonal contraceptives or intrauterine 
devices with hormones;  
OR 
2. True abstinence from intercourse with a male partner only when this is in line with the 
preferred lifestyle of the patient; 
OR 
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.  
5 
TREATMENTS 
5.1 Study treatment 
Study treatments are selexipag or placebo. Details and references are provided in Section 
1.2. 
5.1.1 Investigational treatment: Description and rationale 
• INN: Selexipag.  
• Formulation, strengths: Tablets of 200 micrograms (mcg). 
• Route of administration: Oral (p.o.). 
• Dose: 200 mcg to 1600 mcg. Titration to the patient’s individual HTD. 
• Regimen: One to 8 tablets twice daily (b.i.d.) (in the morning and in the evening). 
Exceptions from the twice daily dosing regimen are described in Section 5.1.3.1. 
Dose, regimen, and titration scheme are in accordance with the IB for selexipag 
[Selexipag IB]. 
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5.1.2 Matching placebo: Description and rationale 
• INN: Not applicable. 
• Formulation, strengths: Tablets of 200 mcg (matching appearance). 
• Route of administration: p.o. 
• Dose: 200 mcg to 1600 mcg. Titration to the patient’s individual HTD. 
• Regimen: One to 8 tablets b.i.d. (in the morning and in the evening). Exceptions from 
the twice daily dosing regimen are described in Section 5.1.3.1.  
Dose, regimen, and titration scheme are in accordance with the IB for selexipag 
[Selexipag IB]. 
5.1.3 Study treatment administration  
The film-coated tablets are to be taken orally in the morning and in the evening. To 
improve tolerability, it is recommended to take Uptravi with food and, at the beginning of 
each up-titration phase, to take the first increased dose in the evening. 
The tablets should not be split, crushed or chewed, and are to be swallowed with water. 
5.1.3.1 Individualized dose titration (Weeks 1 to 12) 
Each patient should be up-titrated to the individually HTD, which can range from 
200 micrograms given b.i.d. to 1600 micrograms given b.i.d. (individualized maintenance 
dose [IMD]).  
The starting dose is 200 mcg given b.i.d., approximately 12 hours apart. The dose is 
increased in increments of 200 mcg b.i.d., usually at weekly intervals. At the beginning 
of treatment and at each up-titration step it is recommended to take the first dose in the 
evening. During dose titration some adverse reactions, reflecting the mode of action of 
the study treatment (such as headache, diarrhea, nausea and vomiting, jaw pain, myalgia, 
pain in extremity, arthralgia, and flushing), may occur. They are usually transient or 
manageable with symptomatic treatment. However, if a patient reaches a dose that cannot 
be tolerated, the dose should be reduced to the previous dose level.  
In patients in whom up-titration was limited by reasons other than adverse reactions 
reflecting the mode of action of study treatment, a second attempt to continue up-titration 
to the HTD up to a maximum dose of 1600 mcg b.i.d. may be considered until Week 12.  
For every dose change, the end date of the previous dose and the start date of the new 
dose are recorded on a dedicated page in the eCRF.  
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A once-daily regimen (1 to 8 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. Specifically, rifampicin did not lead to a relevant change in 
exposure to selexipag, whereas exposure to the active metabolite decreased by half 
[Selexipag IB]. 
Table 3 
Recommended double-blind up-titration scheme 
Duration (Study Days)1 
Dose regimen2, 3, 4 
Day 1 to Day 7 
200 mcg twice daily 
(1 tablet twice daily) 
Day 8 to Day 14 
400 mcg twice daily 
(2 tablets twice daily) 
Day 15 to Day 21 
600 mcg twice daily 
(3 tablets twice daily) 
Day 22 to Day 28 
800 mcg twice daily 
(4 tablets twice daily) 
Day 29 to Day 35 
1000 mcg twice daily 
(5 tablets twice daily) 
Day 36 to Day 42 
1200 mcg twice daily 
(6 tablets twice daily) 
Day 43 to Day 49 
1400 mcg twice daily 
(7 tablets twice daily) 
Day 50 to Day 56 
1600 mcg twice daily 
(8 tablets twice daily) 
1 Duration is indicated to guide the recommended weekly up-titration. Intervals may be prolonged based on 
tolerability considerations. The individualized dose titration should be completed no later than Day 85 
(Week 12). 
2 Or highest tolerated dose. The indicated doses are target doses if previous dose level was tolerated or if 
tolerability issues were addressed by down-titration.  
3 The first dose within a period may be taken in the evening only, i.e., once a day.  
4 Exceptions from the twice daily dosing regimen are described in Section 5.1.3.1. 
5.1.3.2 Individualized maintenance dose (Weeks 13 to 24) 
The IMD is the HTD reached during individualized dose titration and should be 
maintained from Week 13 to Week 24. Change of study treatment dose is allowed if 
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needed for efficacy or safety/tolerability reasons. If the therapy over time is less tolerated 
at a given dose, symptomatic treatment and/or a dose reduction to the next lower dose 
should be considered. The dose may be increased (to a maximum dose of 1600 mcg 
b.i.d.) if the patient may benefit from a higher dose, as judged by the investigator. For 
every dose change, the end date of the previous dose and the start date of the new dose 
are recorded on a dedicated page in the eCRF. 
5.1.4 Treatment assignment 
At Screening (Visit 1), patients will be assigned a study-specific subject number by the 
Interactive Response Technology (IRT) system. This number consists of 4 digits 
identifying the site and 3 digits identifying the patient and is kept throughout the study 
and is the main subject identifier. In case of re-screening, the original number will also be 
used the second time.  
After having verified that the patient meets all inclusion criteria and none of the exclusion 
criteria, the investigator/delegate contacts the IRT system at Visit 2 to randomize the 
patient. The IRT assigns a randomization number to the patient (in addition to the subject 
number mentioned above) and assigns the treatment kit numbers, which matches the 
treatment arm assigned by the randomization list to the randomization number. The 
randomization list is generated by the independent CRO Almac, using IXRS 3.0. 
Patients will be randomized in a 1:1 ratio to either selexipag or placebo. Treatment 
allocation will be stratified by region, i.e. Europe/rest of the world vs. North America. 
5.1.5 Blinding 
This study will be performed in a double-blind fashion. The investigator and study 
personnel, the patients, the Clinical Research Associates (CRAs), Actelion personnel, and 
CRO personnel involved in the conduct of the study will remain blinded to the study 
treatment until study closure. Actelion personnel responsible for clinical study supply 
distribution will need to be unblinded to ensure adequate supply of study treatment. 
These persons will be clearly identified, their unblinding will be documented in the trial 
master file and they will not take part in any Clinical Trial Team (CTT) meetings after 
study set-up has been completed. 
Until the time of unblinding for final data analysis, the randomization list is kept strictly 
confidential, and accessible only to authorized persons, who are not involved in the 
conduct of the study. 
The investigational treatment and its matching placebo are indistinguishable, and all 
treatment kits will be packaged in the same way. 
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Pulmonary arterial hypertension 
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5.1.6 Unblinding 
5.1.6.1 Unblinding for final analyses 
Full randomization information will be made available for data analysis only after 
database closure, in accordance with Actelion Quality System (QS) documents. 
5.1.6.2 Unblinding for interim analyses 
Not applicable. 
5.1.6.3 Unblinding for suspected unexpected serious adverse reactions 
If a suspected unexpected serious adverse reaction (SUSAR) occurs for a patient 
participating in the study, Actelion Global Drug Safety will request the unblinding of the 
treatment assignment. The treatment assignment will not be communicated to site 
personnel or to the Actelion CTT. Unblinded SUSAR information will be provided to 
respective health authorities and independent ethics committees (IECs) or institutional 
review board (IRBs) only. SUSARs will be reported to investigators in a blinded fashion. 
5.1.6.4 Emergency procedure for unblinding 
The investigator, study personnel and Actelion personnel must remain blinded to the 
patient’s treatment assignment. The identity of the study treatment may be revealed only 
if the patient experiences a medical event, the management of which would require 
knowledge of the blinded treatment assignment. In this case, the investigator can receive 
the unblinded treatment assignment through the IRT. In these situations, the decision to 
unblind resides solely with the investigator. Whenever it is possible, and if it does not 
interfere with or delay any decision in the best interest of the patient, the investigator is 
invited to discuss the intended unblinding with Actelion personnel. 
The occurrence of any unblinding during the study must be clearly justified and 
explained by the investigator. In all cases, Actelion personnel must be informed as soon 
as possible before or after the unblinding. 
The circumstances leading to unblinding must be documented in the Investigator Site File 
(ISF) and eCRF. 
5.1.7 Study treatment supply 
Manufacture, labeling, packaging, and supply of study treatment will be conducted 
according to Good Manufacturing Practice, Good Distribution Practice, Good Clinical 
Practice (GCP), and any local or national regulatory requirements. 
All study treatment supplies are to be used only in accordance with this protocol, and not 
for any other purpose. 
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5.1.7.1 Study treatment packaging and labeling 
Study treatment is provided as tablets and supplied in childproof bottles of 120 tablets. 
Study treatment is labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located. 
5.1.7.2 Study treatment distribution and storage 
Study treatment supplies must be kept in an appropriate, secure area and stored according 
to the conditions specified on the label. 
5.1.7.3 Study treatment dispensing 
The patients will receive sufficient study treatment to cover the period up to the next 
scheduled visit. Patients are asked to return all used, partially used, and unused study 
treatment bottles at each visit. The protocol-mandated study-treatment dispensing 
procedures may not be altered without prior written approval from Actelion. 
Once treatment is assigned to the patient as described in Section 5.1.4, the IRT system 
allocates the treatment kit numbers matching the treatment arm assigned by the 
randomization list, for the titration period and start of maintenance period until Week 16.  
Likewise at Visit 3 (Week 16), the investigator/delegate contacts the IRT system which 
assigns the treatment kit numbers based on the patient’s HTD for the maintenance period 
until Visit 4 (Week 24). 
The same process will be performed in IRT at unscheduled visits in the specific dedicated 
module, for additional kit number assignment when applicable. 
An accurate record of the date and amount of study treatment dispensed to each patient 
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 CRA will collect used and 
unused treatment kits, which will be sent to the warehouse, where Actelion personnel or a 
deputy will check treatment reconciliation. In certain circumstances, used and unused 
study treatment containers may be destroyed at the site once study treatment 
accountability is finalized and has been checked by Actelion personnel or the deputy, and 
written permission for destruction has been obtained from Actelion. The 
protocol-mandated study treatment return procedures may not be altered without prior 
written approval from Actelion. 
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5.1.8 Study treatment accountability and compliance with study treatment 
5.1.8.1 Study treatment accountability 
The inventory of study treatment dispensed to and returned by the patient 
(i.e., study-treatment accountability) must be performed by site personnel on the day of 
the visit and before dispensing further study treatment. It is to be recorded by site 
personnel on the study-treatment dispensing and accountability log and in the eCRF, and 
checked by the CRA during site visits and at the end of the study. The study treatment 
accountability log in the eCRF will include at least the following information for each 
study treatment unit (i.e., bottle) dispensed to the patient: 
• Dispensed bottle number 
• Date dispensed, and number of tablets dispensed (prepopulated in eCRF) 
• Date returned, and number of tablets returned 
Each medication bottle will have a label with a tear-off part specifying the study protocol 
number and the batch number. When the medication is issued to the patient, the 
investigator or pharmacist must remove the tear-off part and affix it to the Drug 
Dispensing Log. 
All study treatment supplies, including partially used or empty bottles must be retained at 
the site for review by the CRA. 
If the patient forgets to bring the remaining study treatment to a study visit, he/she must 
be instructed to not take any tablets from the remaining study treatment bottle and to 
return it at the next visit. 
5.1.8.2 Study treatment compliance 
Study treatment compliance is based on study treatment accountability. Study treatment 
compliance will be calculated at Visit 4/EOT for the period between Visit 3 and Visit 4 
using the below formula: 
Compliance = [(number of tablets dispensed at Visit 3 − number of tablets returned at 
Visit 4) / Total number of tablets that should have been taken during the period] × 100. 
The number of tablets that should have been taken is derived from the HTD. 
Compliance is expected to be between 80% and 120%. Compliance values outside of this 
range will be considered as a protocol deviation.  
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5.1.9 Study treatment dose adjustments and interruptions 
Dose adjustments are allowed if needed for efficacy or tolerability reasons at the 
discretion of the investigator. The end date of the previous dose and the start date of the 
new dose are recorded for every dose adjustment on a dedicated page in the eCRF.  
If a dose of medication is missed, it should be taken as soon as possible. The missed dose 
should not be taken if it is almost time for the next scheduled dose (within approximately 
6 hours).  
Study treatment may be temporarily interrupted in response to an AE, a diagnostic or 
therapeutic procedure, a laboratory abnormality, or for administrative reasons. If study 
treatment is missed or interrupted for 3 days or more, study treatment should be re-started 
at a lower dose at the discretion of the investigator, and then titrated to HTD [Section 
5.1.3.1].  
If the dose is adjusted or study treatment intake is interrupted for more than 1 day by the 
patient for any reason, she/he must immediately inform the investigator. 
Study treatment interruptions greater than 1 day must be recorded in the eCRF. 
Study treatment interruptions exceeding 2 consecutive weeks must lead to permanent 
discontinuation of study treatment. 
5.1.10 Premature discontinuation of study treatment 
The decision to prematurely discontinue study treatment may be made by the patient, the 
investigator, or Actelion personnel. The main reason and whether discontinuation of 
study treatment is the decision of the patient (e.g., tolerability- or efficacy-related), the 
investigator (e.g., due to pre-specified study treatment discontinuation criteria, an AE or 
lack of efficacy), or Actelion (e.g., study terminated) must be documented in the eCRF. 
A patient has the right to discontinue study treatment at any time, without any 
justification, by withdrawal from study treatment only or by withdrawal from any further 
participation in the study (i.e., premature withdrawal from the study [see Section 9.2]). 
Although a patient is not obliged to give his/her reason for withdrawing from the 
treatment or the study, it is recommended that the investigator makes a reasonable effort 
to ascertain the reason(s), while fully respecting the patient’s rights. 
The investigator must discontinue study treatment for a given patient if, on balance, 
he/she believes that continued administration would be contrary to the best interests of 
the patient. 
Study-specific criteria for discontinuation of study treatment are described in 
Section 5.1.11. 
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A patient who prematurely discontinues study treatment is NOT considered as withdrawn 
from the study. The patient will be asked to return for the EOT visit within 10 days of last 
intake of study treatment and to have a 30-day safety follow-up period after EOT. The 
period is completed by the EOS telephone call. This telephone call represents the end of 
the patient’s study participation. 
A patient who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered as withdrawn from the study. 
Withdrawal of consent must lead to permanent discontinuation of study treatment. 
Patients 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 patients withdrawn from the 
study is described in Sections 9.2 and 9.4, respectively. 
5.1.11 Study-specific criteria for interruption / permanent discontinuation of study 
treatment 
Study treatment interruptions exceeding 2 consecutive weeks must lead to permanent 
discontinuation of study treatment. 
5.1.11.1  Hemoglobin abnormalities 
If there is a decrease in hemoglobin from baseline3 of > 20 g/L during the treatment 
period, a re-test must be performed within 10 days, with additional laboratory evaluations 
that may include, but are not limited to, any of the following: 
• Red blood cell cellular indices (mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration), peripheral blood smear, 
reticulocyte count, iron status (iron level, serum ferritin, total iron binding capacity, 
transferrin saturation), lactate dehydrogenase, indirect bilirubin. 
Study treatment must be temporarily interrupted if clinically mandated based on the 
investigator’s judgment, or in any of the following situations: 
• A decrease in hemoglobin to < 80 g/L (< 4.96 mmol/L), 
• A decrease in hemoglobin from baseline of > 50 g/L (> 3.10 mmol/L), 
• The need for transfusion. 
Re-introduction of study treatment may be considered by the investigator if hemoglobin 
recovery, defined as a return of hemoglobin above the lower limit of the normal range or 
to baseline, is achieved. 
                                                 
3 Baseline hemoglobin refers to the last hemoglobin value obtained prior to first intake of study treatment. 
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5.1.11.2 Severe hepatic impairment 
If liver impairment is suspected, a clinical assessment of severity (e.g., Child-Pugh score) 
should be performed. If a severe hepatic impairment (e.g., Child-Pugh C) is diagnosed, 
the study treatment must be discontinued.  
5.1.11.3 Start of a CYP2C8 inhibitor 
Study 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]. 
5.1.11.4 Pregnancy 
If a female patient becomes pregnant while on study treatment, study treatment must be 
discontinued immediately, and a Pregnancy Form must be completed along with 
documentation on AE page in the eCRF [see Section 10.3]. 
5.1.11.5 Hyperthyroidism 
In the event of clinical suspicion or manifestation of hyperthyroidism, 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 signing of informed 
consent. 
A therapy that is study-concomitant is any treatment that is ongoing at or initiated after 
signing of informed consent or initiated up to 30 days after EOT. 
A therapy that is study treatment-concomitant is any treatment that is either ongoing at 
the start of study treatment or is initiated during the treatment period. 
5.2.2 Recording of previous/concomitant therapy 
The use of all study-concomitant therapy (including contraceptives and traditional and 
alternative medicines, e.g., plant-, animal-, or mineral-based medicines) will be recorded 
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in the eCRF. Previous therapy must be recorded in the eCRF if discontinued less than 
3 months prior to signing of the informed consent. The generic name, start/end dates of 
administration (as well as whether it was ongoing at start of treatment and/or EOS), route, 
dose, and indication will be recorded in the eCRF. 
5.2.3 Allowed concomitant therapy 
Single-dose administration of a drug for vasoreactivity testing during RHC is allowed.  
Cardio pulmonary rehabilitation programs based on exercise starting after Visit 4 
(Week 24) are allowed. 
5.2.4 Forbidden concomitant therapy 
Gemfibrozil, a strong CYP2C8 inhibitor, has been shown to increase the exposure of 
selexipag and its active metabolite significantly. Hence, concomitant administration of 
selexipag and strong inhibitors of CYP2C8 (e.g., gemfibrozil) is forbidden. 
Cardio pulmonary rehabilitation programs based on exercise ongoing or initiated at any 
time from 8 weeks prior to Visit 1 until Visit 4 (Week 24) are forbidden.  
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. Patients starting rescue therapy remain in the 
study until EOS, i.e., Week 24/EOT +30 days. 
6 
STUDY ENDPOINTS 
6.1 Efficacy endpoints 
6.1.1 Primary efficacy endpoint(s) 
The primary efficacy variables are: 
• 
Change from baseline to Week 24/EOT in actigraphy-assessed DLPA as measured 
by: 
– Daily time spent (minutes) in non-sedentary activity (> 100 activity counts per 
minute) 
– Percentage of daily time spent in non-sedentary activity (> 100 activity counts per 
minute) 
– Total DLPA in counts/min 
– Sleep: Total sleep time (TST; minutes), wake after sleep onset (WASO; minutes), 
number of awakenings, sleep efficiency (percentage) 
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The study is designed as exploratory, and therefore all actigraphy variables are listed 
under primary endpoints. 
6.1.2 Secondary efficacy endpoints 
The secondary efficacy variables are: 
• 
Change from baseline to Week 24/EOT for following PAH-SYMPACT® domain 
scores: 
– Cardiovascular symptom domain score 
– Cardiopulmonary symptom domain score 
– Physical impact domain score 
– Cognitive/emotional impact domain score 
• 
Change from baseline to Week 24/EOT for following variables: 
− WHO FC 
− 6MWD 
− Borg dyspnea index at 6MWT 
− N-terminal pro b-type natriuretic peptide (NT-proBNP) 
6.1.3 Other efficacy endpoints 
The other efficacy variables are: 
• 
Change from baseline to Week 24/EOT for blood biomarkers associated with, 
e.g., PAH worsening, right/left ventricle function, and inflammation. 
• 
Association 
between 
actigraphy 
variables 
and 
other 
efficacy 
endpoints  
(PAH-SYMPACT®, 6MWD, etc.). 
6.2 Safety endpoints 
The safety and tolerability endpoints are: 
• 
Treatment-emergent AE4 and SAEs up to 30 days after study treatment 
discontinuation. 
• 
AEs leading to discontinuation of study treatment. 
• 
Change from baseline in vital signs (systolic and diastolic arterial blood pressure and 
pulse rate) and body weight from baseline to all assessed time points during the 
study. 
                                                 
4 A treatment-emergent AE is any AE temporally associated with the use of study treatment (from study treatment start 
until 30 days after study treatment discontinuation) whether or not considered by the investigator as related to 
study treatment. 
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• 
Treatment-emergent marked laboratory abnormalities up to 30 days after study 
treatment discontinuation. 
6.3 Biomarkers  
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 24 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. 
7 
STUDY ASSESSMENTS 
All study assessments will be performed by a qualified study staff member: medical, 
nursing, or specialist technical staff, and recorded in the eCRF, unless otherwise 
specified. Study assessments performed during unscheduled visits will also be recorded 
in the eCRF. Assessments will be performed at the appropriate visits or via telephone 
calls as indicated in the visit and assessment schedules in Table 1 and Table 2. If the 
principal investigator (PI) delegates any study procedure/assessment for a patient 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 patient at the site. 
7.1 Patient characteristics 
During Visit 1, the following assessments are to be obtained and recorded in the eCRF.  
7.1.1 Informed consent signature (Visit 1) 
• Prior to any study-mandated procedures. 
• Original ICF to be kept in the site file. 
• Date and time of informed consent signature to be entered in the eCRF. 
7.1.2 Demographics (Visit 1) 
• Age (in years). 
• Race (if allowed by local regulations) and Ethnicity. 
• Sex.  
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7.1.3 Documentation of PAH disease (Visit 1) 
• Date of diagnosis. 
• Etiology of PAH. 
• Most recent RHC: Date, mPAP (mmHg), PAWP (mmHg) or LVEDP (mmHg) if 
PAWP not available, PVR (WU). 
7.1.4 Medical history (Visit 1) 
• Chronic and acute medical conditions. 
• All previous medically important conditions. 
7.1.5 Previous and concomitant therapies  
Previous therapy (last dose, date of discontinuation) must be recorded in the eCRF if 
discontinued less than 90 days prior to informed consent signature. 
• Concomitant medication start date, dose, route of administration, indication for which 
the medication is taken are to be recorded at Visit 1. 
• Changes to be recorded at site visits and telephone calls. 
7.1.6 Eligibility, randomization (Visit 1 and Visit 2) 
Determination of eligibility: Eligibility criteria [see Section 4] are reviewed based on 
patient medical records, the assessments performed at Visit 1 and Visit 2, and valid 
baseline assessments for DLPA and PAH-SYMPACT®.  
For patients who fail screening, the following assessments must be performed if possible 
and recorded in the eCRF at Visit 1 and/or Visit 2: 
− Informed consent signature. 
− Demographics. 
− Reason for Screen failure. 
An eligible patient is considered randomized if he/she is supplied with study treatment.  
7.2 Efficacy assessments 
7.2.1 6MWT and Borg dyspnea index 
The 6MWT is a non-encouraged test, which measures the distance covered by the patient 
during a 6-minute walk [Appendix 1].  
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At Visits 3 and 4, the 6MWT is performed at trough levels of study treatment. Trough 
level of study treatment is defined as: the last dose has been taken not less than 8 hours 
prior to the 6MWT. 
Borg dyspnea index is assessed immediately after the 6MWT. Dyspnea is rated by the 
patient according to the maximal shortness of breath experienced during the 6MWT 
[Appendix 2]. 
7.2.2 WHO FC 
WHO FC will be assessed according to Appendix 3.  
7.2.3 Daily life physical activity  
The DLPA of the patient is assessed via the actigraphy device ActiGraph GT9X Link. 
The device is given to the patient at Visit 1 (Screening Visit), and the patient is instructed 
to wear the actigraphy device at the wrist of the non-dominant hand (ambidextrous 
patients may wear it at either wrist) during the entire study up to Week 24. Patient is 
instructed to upload data, i.e., epoch data, daily via the hand-held mobile device (same 
device as used for the PAH-SYMPACT®) to the vendor’s server via a cellular 
connection. The submitted data will be used to monitor patient’s compliance with device 
use and handling. Patients will be provided with a paper manual.  
To ensure DLPA data quality, the epoch data received will be checked by the vendor. 
Should corrective actions be necessary, patients may be contacted either from the site 
staff (e.g., telephone call, text message) or via messages onto the hand-held mobile 
device from the vendor. At any time, the site and the CRA will have access to a patient 
report displaying patient’s adherence to DLPA assessment.  
The ActiGraph GT9X Link does not display collected data, i.e., the patients do not have 
access to their activity measurements since this could influence their behavior. At every 
site visit the study site transfers the complete data (raw data) from the ActiGraph GT9X 
Link to the vendor’s server as described in the site manual. The raw data will be 
transferred to Actelion Pharmaceuticals Ltd. at the end of the study. 
Patients must return the ActiGraph GT9X Link to the site at EOT. The devices will be 
returned to the vendor. The patient is provided with a report (on paper) summarizing the 
patient’s individual activity levels during his/her participation in the study. 
7.3 Safety assessments 
7.3.1 Vital signs 
• Sitting SBP and diastolic blood pressure (DBP) (mmHg), measured (always at the 
same arm) after at least 5 minutes of rest in a sitting position. 
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• Pulse rate (beats per minute), measured after at least 5 minutes of rest in a sitting 
position. 
• Body weight (kg, lb). 
• Body height (cm, inch), at Visit 1 only. 
• BMI will be calculated and displayed automatically upon entry of weight and height 
in the eCRF. 
7.3.2 AEs and SAEs  
The patient will be asked at every visit and telephone call whether AEs occurred since the 
previous visit or telephone call. Any AEs or SAEs that occur after signing of the ICF will 
be recorded on AE pages in the eCRF. SAEs must also be reported on SAE forms. The 
definitions, reporting and follow-up of AEs, SAEs and pregnancies are described in 
Section 10. Pregnancies will be considered AEs for the purpose of recording pregnancies 
in the eCRF and must be reported on the Actelion Pregnancy form. 
7.4 Laboratory assessments  
7.4.1 Type of laboratory 
A central laboratory (see central laboratory manual for contact details) will be used for all 
protocol-mandated laboratory tests (excluding urine pregnancy 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 patients 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., patient 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 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. 
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. 
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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. 
All laboratory reports must be reviewed, 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 signing of informed consent must be recorded on the Medical 
History page of the eCRF. Any clinically relevant laboratory abnormalities detected after 
signing 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 abnormality is no longer clinically relevant. 
Details about the collection, sampling, storage, shipment procedures, and reporting of 
results and abnormal findings can be found in the laboratory manual.  
7.4.2 Laboratory tests 
The laboratory tests performed are:  
• Hematology: basic panel. 
• Clinical chemistry: basic panel.  
• NT-proBNP. 
• Circulating biomarkers involved in right ventricular function and structure: Blood 
samples will be collected at the central laboratory, shipped to Actelion at the end of 
the study, and stored at Actelion for up to 2 years after the last patient’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. 
• Pregnancy tests: see Section 7.6. 
• Thyroid function: Hyperthyroidism has been observed with selexipag. Thyroid 
function tests performed locally are recommended as clinically indicated in the 
presence of signs or symptoms of hyperthyroidism. The test result and the normal 
range must be recorded in the eCRF. 
• Other laboratory assessments: Additional laboratory assessments will be done at the 
discretion of the investigator if deemed medically justified. Laboratory assessments 
and the respective normal ranges must be recorded as conventional units in the eCRF. 
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7.5 Patient reported outcome PAH-SYMPACT® 
The PAH-SYMPACT® is a novel PRO developed according to the FDA guidance [FDA 
2009] for PROs specifically for patients with PAH.  
The PAH-SYMPACT® has two main parts: symptoms and impact [Appendix 4]. The 
symptom part is a questionnaire completed daily for 7 consecutive days and contains 
12 items. The patient is asked to rate each of the items for the past 24 hours.  
The impact part has a 7-day recall period and is completed on the seventh day of the 
symptoms questionnaire data collection period. It contains 11 items pertaining to the 
impact of PAH.  
The PAH-SYMPACT® questionnaire should be filled out in the evening, at 
approximately the same time of each day. If the start date of the collection period is 
missed, the PAH-SYMPACT® questionnaire can be started up to 3 days later. The 
questionnaire is administered in local language via an electronic Patient-Reported 
Outcome (ePRO) device (hand-held mobile device) that patients take home. Patients will 
be trained on the ePRO device by the site staff during Visit 1. Patients will receive a 
paper patient guide to take home. Data will be transferred daily to an electronic database 
immediately upon completion of the questionnaire via a cellular connection to the 
vendor. The data received will be checked for completion compliance.  
The site will be informed if the questionnaire has not been completed as per protocol. 
Should corrective actions be necessary, patients may be contacted either from the site 
staff (e.g., telephone call, text message) or via messages onto the mobile device from the 
vendor.  
At any time, the site and the CRA will have access to a web-based patient report 
displaying patient’s compliance based on the specifications listed above for each day and 
summarized for each PAH-SYMPACT® data collection period. All ePRO data will be 
transferred to Actelion Pharmaceuticals Ltd at the end of the study.  
At EOT patients must return the mobile device to the site. The devices will be returned to 
the vendor. 
7.6 Additional assessments for women 
7.6.1 Childbearing potential 
The childbearing potential of a female patient will be assessed at Visit 1 and recorded in 
the eCRF. For definitions see Section 4.5.1. 
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7.6.2 Contraception check (women of childbearing potential only) 
The used method of contraception will be recorded in the eCRF at Visit 1. Changes to the 
used method of contraception will be recorded at each visit and telephone call.  
7.6.3 Pregnancy tests (women of childbearing potential only) 
Serum pregnancy tests for women of childbearing potential must be performed at 
Visits 1, 3, and 4. The test result will be recorded in the eCRF. Urine pregnancy tests will 
be performed at Visit 2 and monthly up to at least 1 month after study drug 
discontinuation. Urine pregnancy tests will either be performed during a scheduled visit 
or at home by the patient within 3 days prior to the scheduled telephone call. The 
performance of urine pregnancy tests will be confirmed in the eCRF. The test result must 
be recorded in the patient’s medical record (source data). A serum pregnancy test is 
mandatory if pregnancy is suspected during the course of the study.  
8 
VISIT SCHEDULE  
For each patient there are 4 scheduled study visits at the study site (Visits 1, 2, 3, and 4; 
see [Table 1]. For all visits, the patients must be seen on the designated day within the 
allowed time window as indicated in Table 1. In case of permanent discontinuation of 
study treatment prior to Week 24, Visit 4, i.e., EOT Visit, must take place as soon as 
possible and no later than 10 days after the last dose of study treatment, if possible.  
During the dose titration phase, i.e., up to Week 12, weekly telephone calls from the 
study site to the patient will be performed. During the dose maintenance phase, telephone 
calls from the study site to the patient are scheduled at Weeks 15, 20, and 23. There will 
be an EOS telephone call from the study site to the patient 30 days after EOT [Table 2]. 
Unscheduled site visits and telephone calls may be performed at any time during the 
study. 
8.1 Site visits 
8.1.1 Visit 1: Screening/re-screening 
Screening starts with the signature of the informed consent. The patient is registered with 
the IRT system. The date on which the first screening assessment is performed 
corresponds to the date of the Screening visit. The visit includes the assessments as 
follows: 
• Informed consent 
• Demographics, PAH etiology 
• Medical history 
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• Previous/concomitant therapies 
• Vital signs (blood pressure [BP], heart rate [HR], body weight, height) 
• WHO FC 
• 6MWT/Borg dyspnea index 
• Central laboratory tests: Hematology, clinical chemistry, NT-proBNP, biomarkers 
• Women only: Assessment of childbearing potential  
• Women of childbearing potential only: Contraceptive methods used, serum pregnancy 
test 
• AE and SAE recording 
• Eligibility 
It is the responsibility of the investigator/delegate to obtain written informed consent 
from each patient participating in this study after adequate face-to-face explanation of the 
objectives, methods, and potential hazards of the study. The patients who agree to 
participate in the study and the investigator/delegate must sign the ICF prior to any 
study-related assessment or procedure. 
Patients who have signed informed consent when the randomization target has been met 
may still be randomized. 
At Visit 1, the patient is being equipped with, and trained on, the actigraphy device 
ActiGraph GT9X Link and the ePRO device (hand-held mobile device). A paper manual 
is handed out to the patient. The patient ID is being registered within the applications for 
the ActiGraph and the mobile device on the vendors’ internet platforms. Valid DLPA and 
PAH-SYMPACT® assessments performed between Visit 1 and Visit 2 are baseline 
assessments.  
It is permitted to re-screen patients once, if the reason for non-eligibility was transient 
(e.g., abnormal laboratory test, invalid DLPA data, invalid PAH-SYMPACT® data). The 
rescreening visit must be performed within 28 days prior to randomization (Visit 2). 
At re-screening, the informed consent process and signature, and all Visit-1 assessments 
need to be repeated, including NT-proBNP, but excluding the sampling for blood 
biomarkers (unless not collected at initial screening). 
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8.1.2 Visit 2: Randomization 
Visit 2 is performed on the day of randomization, i.e., Day 1. Randomization is achieved 
via the IRT system. Actigraphy data are uploaded to the vendor server. At the end of the 
visit, sufficient study treatment is dispensed to the patient. The patient takes the first 
study treatment dose (1 tablet of 200 mcg) at the site. Study treatment is continued the 
following day, b.i.d. (morning and evening, preferably with food). the starting dose 
(200 mcg b.i.d.) of study treatment is recorded in the eCRF. 
The assessments are [see also Table 1]: 
• Concomitant therapies (changes only) 
• Vital signs (BP, HR, body weight) 
• WHO FC 
• Women of childbearing potential: Contraceptive methods used, urine pregnancy test 
• Eligibility (including DLPA and PAH-SYMPACT® validity of baseline assessment) 
• AE and SAE recording 
8.1.3 Visit 3: Intermediate Visit 
Visit 3 is performed at Week 16, Day 113 (−4 to +7 days). Patient adherence to DLPA 
assessment and PAH-SYMPACT® completion are reviewed. Actigraphy data are 
uploaded to the vendor server. The patient should return any used and unused study 
treatment to the site at this visit. Any change in study treatment dose is recorded in the 
eCRF. The IRT system is used to assign study treatment supply to be dispensed to the 
patient. 
The assessments are [see also Table 1]: 
• Concomitant therapies (changes only) 
• Vital signs (BP, HR, body weight) 
• WHO FC 
• 6MWT/Borg dyspnea index 
• Central laboratory tests: NT-proBNP, biomarkers, serum pregnancy test (women of 
childbearing potential) 
• Women of childbearing potential: Contraceptive methods used 
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• Study treatment compliance [see Section 5.1.8.2] 
• AE and SAE recording 
8.1.4 Visit 4: End of treatment visit 
Visit 4 is performed at Week 24, Day 169 (−4 to +14 days). The visit must be scheduled 
at least 1 day after completion of the ePRO period scheduled from Day 155 to Day 161. 
After premature study treatment discontinuation, Visit 4 is performed within 10 days 
after EOT, if possible. Actigraphy data are uploaded to the vendor server. The patient 
should return any used and unused study treatment to the site at this visit. The Actigraph 
GT9X Link and the mobile device are returned to the site. The EOT is indicated in the 
eCRF and entered in the IRT system. The patient is provided with a report (on paper) 
summarizing the patient’s individual activity levels during his/her participation in the 
study. The dose of the last study treatment intake is recorded in the eCRF. 
The assessments are [see also Table 1]: 
• Concomitant therapies (changes only) 
• Vital signs (BP, HR, body weight) 
• WHO FC 
• 6MWT/Borg dyspnea index 
• Central laboratory tests: Hematology, clinical chemistry, NT-proBNP, biomarkers, 
serum pregnancy test (women of childbearing potential). 
• Women of childbearing potential: Contraceptive methods used 
• AE and SAE recording 
The investigator and the patient remain blinded towards the treatment assigned during the 
study (selexipag or placebo). If the patient and investigator decide to transition onto 
commercial selexipag (Uptravi®), every effort will be made to avoid any interruptions in 
the treatment, recognizing that the patients will need to be re-uptitrated and the uptitration 
will be guided by their clinician. 
8.1.5 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.  
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In case of an IMD increase, the IRT system allocates additional treatment kit numbers to 
the patient during this visit. The results of any study procedures performed at an 
unscheduled visit must be recorded in the eCRF. After an unscheduled visit, the regular 
scheduled study visits must continue according to the planned visit and assessment 
schedule. 
8.2 Telephone calls 
The schedule of telephone calls is shown in Table 2. 
8.2.1 Weekly telephone calls up to Week 12 
Weekly (+/−3 days) telephone calls from the study site to the patient will be performed 
starting 7 (+/−3) days after Visit 2. The investigator or delegate reviews the patient’s 
compliance with the actigraphy device and the ePRO, and supports the patient in 
remaining compliant, e.g., reminder to charge the ActiGraph weekly. The investigator (or 
delegate) evaluates the tolerability of study treatment and guides its titration aiming at the 
HTD.  
The assessments are [see also Table 2]: 
• Concomitant therapies (changes only). 
• AE and SAE recording. 
• Study treatment dose changes. 
• Women of childbearing potential only: changes in contraceptive methods used. 
Patient is asked to perform a urine pregnancy test at home at Weeks 4, 8, and 12 
(Days 29, 57, and 85) within 3 days prior to the telephone call. 
8.2.2 Telephone calls from Week 13 to Week 24  
Telephone calls from the study site to the patient will be performed on the first day of 
Week 15 and Week 23 (Days 99 and 155) and at Week 20 (Day 141). The investigator or 
delegate reviews the patient’s compliance with the actigraphy device and the ePRO, and 
supports the patient in remaining compliant, e.g., reminder to charge the ActiGraph 
weekly. The patient is reminded about the PAH-SYMPACT® assessment periods of 
Weeks 15 and 23.  
The assessments are [see also Table 2]: 
• Concomitant therapies (changes only). 
• AE and SAE recording. 
• Study treatment dose changes. 
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• Women of childbearing potential only: Changes in contraceptive methods used. 
Patient is asked to perform a urine pregnancy test at home within 3 days prior to the 
telephone call on Day 141. 
8.2.3 Post-Treatment Safety Follow-up telephone call 
The Post-Treatment Safety Follow-up period starts immediately after EOT defined as the 
last day of intake of study drug, and continues for at least 30 days (EOT +30 days). The 
Post-Treatment Safety Follow-up visit is conducted by telephone 30 days (+10 days 
window) after EOT and represents the EOS for the patient.  
The assessments are [see also Table 1]: 
• Concomitant therapies (changes only).  
• AE and SAE recording. 
• Women of childbearing potential only: changes in contraceptive methods used. 
Patient is asked to perform a urine pregnancy test at home within 3 days prior to the 
telephone call. 
8.2.4 Unscheduled telephone calls 
Unscheduled telephone calls from the site to the patient may be performed at any time 
during the study at the investigators discretion. In addition, unscheduled telephone calls 
may be required to support the patient in adhering to DLPA assessment, 
PAH-SYMPACT® completion, and home urine pregnancy tests. 
9 
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE 
9.1 Study completion as per protocol  
A patient who completes at least 24 weeks of treatment and the 30-day follow-up period 
is considered to have completed the study as per protocol. 
9.2 Premature withdrawal from study  
Patients may voluntarily withdraw from the study without justification for any reason at 
any time. Patients 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 patient withdraws consent, no further data will be collected in the eCRF 
from the date of withdrawal onward. The investigator may withdraw a patient from the 
study (without regard to the patient’s consent) if, on balance, he/she believes that 
continued participation in the study would be contrary to the best interests of the patient. 
Withdrawal from the study may also result from a decision by Actelion for any reason, 
including premature termination or suspension of the study. 
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Patients are considered as lost to follow-up if all reasonable attempts by the investigator 
to communicate with the individual failed. The site must take preventive measures to 
avoid a patient being lost to follow-up (e.g., document different ways of contact such as 
telephone number, home address, email address, person to be contacted in case the 
patient cannot be reached). If the patient cannot be reached, the site must make a 
reasonable effort to contact the patient, document all attempts, and enter the loss of 
follow-up information into the eCRF. The following methods must be used: at least three 
telephone calls must be placed to the last available telephone number and one registered 
letter must be sent by post to the last available home address. Additional methods may be 
acceptable if they are compliant with local rules/regulations (e.g., a visit by site personnel 
to the patient’s home), respecting the patient’s right to privacy. If the patient is still 
unreachable after all contact attempts listed above, he/she will be considered to be lost to 
follow-up. 
If premature withdrawal occurs for any reason, the reason (if known) for premature 
withdrawal from the study, along with who made the decision (patient, investigator, or 
Actelion personnel) must be recorded in the eCRF, if known. 
If for whatever reason (except death or loss-to-follow-up) a patient is withdrawn from the 
study, the investigator should make efforts to schedule a last appointment / telephone call 
to assess the safety and well-being of the patient, collect unused study treatment and 
discuss follow-up medical care. Data obtained during this last appointment / telephone 
call will be recorded in the patients’ medical records but it will not be collected in the 
eCRF. The investigator must provide follow-up medical care for all patients 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 or locally. 
Investigators can terminate the participation of their site in the study at any time. 
If the study is prematurely suspended or terminated, Actelion will promptly inform the 
investigators, the IECs/IRBs, and health authorities, as appropriate, and provide the 
reasons for the suspension or termination. 
If the study is suspended or prematurely terminated for any reason, the investigator – in 
agreement with Actelion – must promptly inform all enrolled patients and ensure their 
appropriate treatment and follow-up, as described in Section 9.4. Actelion may inform 
the investigator of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patients’ interests. 
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In addition, if the investigator suspends or terminates the study without prior agreement 
from Actelion, the investigator must promptly inform Actelion personnel and the 
IEC/IRB, and provide both with a detailed written explanation of the termination or 
suspension. 
If the IEC/IRB suspends or terminates its approval / favorable opinion of the study, the 
investigator must promptly notify Actelion personnel and provide a detailed written 
explanation of the termination or suspension. 
9.4 Medical care of patients after study completion / withdrawal from study 
After the patient’s study completion or premature withdrawal from the study, whichever 
applies, the investigator/delegate will explain to patients what treatment(s) / medical care 
is necessary and available according to local regulations.  
The investigator and the patient remain blinded towards the treatment (selexipag or 
placebo) assigned during the study (selexipag or placebo). If the patient and investigator 
decide to transition onto commercial selexipag (Uptravi®) at the end of study treatment, 
every effort will be made to avoid any interruptions in the treatment, recognizing that the 
patients will need to be re-uptitrated and the uptitration will be guided by their clinician. 
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
10.1 Adverse events 
10.1.1 Definition of adverse events 
An AE is any untoward medical occurrence, i.e., any unfavorable and unintended sign, 
including an abnormal laboratory finding, symptom, or disease that occurs in a patient 
during the course of the study, whether or not considered by the investigator as related to 
study treatment. 
A treatment-emergent AE is any AE temporally associated with the use of study 
treatment (from study treatment initiation until 30 days after study treatment 
discontinuation) whether or not considered by the investigator as related to study 
treatment. 
AEs include: 
• Exacerbation of a pre-existing disease. 
• 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. 
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• Continuous persistent disease or symptoms present at study start that worsen 
following the signing of informed consent. 
• Abnormal assessments, e.g., change on physical examination, ECG findings, if they 
represent a clinically significant finding that was not present at study start or 
worsened during the course of the study. 
• Laboratory test abnormalities if they represent a clinically significant finding, 
symptomatic or not, which was not present at study start or worsened during the 
course of the study or led to dose reduction, interruption or permanent discontinuation 
of study treatment. 
• Overdose, misuse, abuse of the study treatment and study treatment errors. 
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. 
For AEs not ongoing at the start of study treatment, 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 to be 
reported. 
For AEs ongoing at the start of study treatment, if the intensity 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 patient. It does not usually influence daily activities, 
and normally does not require intervention. 
 Moderate 
The event may make the patient 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 patient 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 10.2.1]. These 
terms are used to describe the intensity of a specific event. Medical judgment should be 
used on a case-by-case basis. 
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Seriousness, rather than intensity 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 treatment, and reported as either related or 
unrelated. The determination of the likelihood that the study treatment caused the AE will 
be provided by the investigator. 
10.1.4 Recording of adverse events  
All AEs with an onset date after signing of informed consent and up to 30 days after 
study treatment discontinuation must be recorded on specific AE pages of the eCRF. 
10.1.5 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 or until stabilization. 
The follow-up information obtained after the patient’s EOS visit / telephone call will not 
be collected by Actelion. 
10.2 Serious adverse events  
10.2.1 Definitions of serious adverse events 
An SAE is defined by the ICH guidelines as any AE fulfilling at least one of the 
following criteria: 
• Fatal. 
• Life-threatening: Refers to an event in which the patient was at risk of death at the 
time of the event. It does not refer to an event that hypothetically might have caused 
death had it been more severe. 
• Requiring in-patient hospitalization or prolongation of existing hospitalization. 
• Resulting in persistent or significant disability or incapacity. 
• Congenital anomaly or birth defect. 
• Medically significant: Refers to important medical events that may not immediately 
result in death, be life-threatening, or require hospitalization but may be considered to 
be SAEs when, based upon appropriate medical judgment, they may jeopardize the 
patient, and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definitions above. 
The following reasons for hospitalization are not considered as SAEs: 
• Hospitalization for cosmetic elective surgery, or social and/or convenience reasons. 
• Hospitalization for pre-planned (i.e., planned prior to signing informed consent) 
surgery or standard monitoring of a pre-existing disease or medical condition that did 
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not worsen, e.g., hospitalization for coronary angiography in a patient with stable 
angina pectoris. 
However, complications that occur during hospitalization are AEs or SAEs (e.g., if a 
complication prolongs hospitalization). 
10.2.2 Reporting of serious adverse events 
All SAEs occurring after signing of informed consent up to 30 days after study treatment 
discontinuation must be recorded on AE pages in the eCRF and reported on an SAE form 
to Actelion Global Drug Safety (contact details are provided on the SAE form), 
regardless of the investigator-attributed causal relationship with study treatment or 
study-mandated procedures. 
An SAE is defined as related to protocol-mandated procedures if it appears to have a 
reasonable possibility of a causal relationship to either the study design or to 
protocol-mandated procedures. 
10.2.3 Follow-up of serious adverse events 
SAEs still ongoing more than 30 days after study treatment discontinuation must be 
followed up until resolution or stabilization, or until the event outcome is provided. The 
follow-up information obtained after the patient’s EOS visit / telephone call must be 
reported to Actelion Global Drug Safety, but it is not recorded in the eCRF. 
10.2.4 After the [30-day] follow-up period 
New SAEs occurring after the 30-day follow-up period must be reported to Actelion 
Global Drug Safety within 24 hours of the investigator’s knowledge of the event, only if 
considered by the investigator to be causally related to previous exposure to the study 
treatment. 
10.2.5 Reporting procedures 
All SAEs must be reported by the investigator to Actelion Global Drug Safety 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 patient, and whether or not this event is considered by the investigator to be related 
to study treatment. 
The SAE forms must be sent to Actelion Global Drug Safety (contact details are provided 
on the SAE form). The investigator must complete the SAE form in English, and must 
assess the event’s causal relationship to the study treatment. 
Any relevant information from source documents regarding the SAE, e.g., hospital notes 
or discharge summaries, etc., must be summarized on the SAE form. 
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Follow-up information about a previously reported SAE must also be reported within 
24 hours of receiving it. Actelion Global Drug Safety personnel (or the CRO’s drug 
safety personnel) may contact the investigator to obtain further information. 
If the patient is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE-relevant information and 
documentation. 
The expectedness of an adverse reaction is determined by Actelion in the reference safety 
information (RSI) section provided in the most recent version of the IB and its 
Amendment 1. Any SAE that is assessed as related and unexpected against the RSI is 
known as a SUSAR and must be reported by Actelion to concerned health authorities 
(including the EudraVigilance database if the study is conducted in Europe), IECs/IRBs 
and investigators. 
The following SAEs are commonly seen in patients with underlying PAH disease and are 
therefore anticipated to occur in this patient population. These SAEs (unless fatal) do not 
require expedited reporting to Health Authorities, ECs/IRBs, and investigators: 
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 arterial hypotension, 
and tachycardia. Like all other SAEs, these SAEs must be reported on an SAE form by 
the investigator to the Actelion Global Drug Safety within 24 hours of the investigator’s 
first knowledge of the event, and be reported on the AE form of the eCRF. 
10.3 Pregnancy  
If a woman becomes pregnant while on study treatment, study treatment must be 
discontinued. The investigator must counsel the patient 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 patient, any pregnancy occurring after study 
start (i.e., signing of informed consent) up to 30 days following study treatment 
discontinuation 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 Actelion 
Global Drug Safety (see contact details provided on the Pregnancy form), and on an AE 
page in the eCRF. 
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10.3.2 Follow-up of pregnancy 
Any pregnancies must be followed-up to their conclusion and the outcome must be 
reported to Actelion Global Drug Safety. 
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 10.2.2. 
10.4 Study safety monitoring  
Study safety information (AEs, SAEs, laboratory values, vital signs, and study-specific 
examinations as required) is monitored and reviewed on a continuous basis by the 
Actelion Clinical Team (in charge of ensuring patients’ safety as well as data quality). 
11 STATISTICAL METHODS 
All statistical analyses will be conducted by Actelion or by designated CRO supervised 
by Actelion. 
A Statistical Analysis Plan (SAP) will provide full details of the analyses, data displays, 
and algorithms to be used for data derivations. 
11.1 Analysis sets 
11.1.1 Screened Analysis Set 
The Screened Analysis Set includes all patients who are screened and have a patient 
identification number. 
11.1.2 Full Analysis Set 
The Full Analysis Set (FAS) includes all patients randomly assigned to a study treatment. 
In order to adhere to the intention-to-treat principle as much as possible: 
• Patients are evaluated according to the study treatment they have been assigned to 
(which may be different from the study treatment they have received). 
• All available data are included. 
11.1.3 Per-protocol Analysis Set 
The Per-protocol Analysis Set (PPS) comprises all patients who received study treatment 
and who complied with the protocol sufficiently to allow assessment of the treatment 
effects. Criteria for sufficient compliance include exposure to treatment, availability of 
measurements and absence of major protocol deviations that have an impact on the 
treatment effect. The full list of criteria will be detailed in the SAP before making the full 
randomization information available. 
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11.1.4 Safety Set 
The Safety Set includes all patients who received at least one dose of study treatment, and 
the analysis will be based on the actual treatment received. 
11.1.5 Usage of the analysis sets  
The primary efficacy analysis will be performed on the FAS based on treatment as 
randomized. Secondary and other efficacy analyses will also be performed on the FAS. 
The PPS will be used for sensitivity analyses for primary efficacy variables. 
Safety analyses will be performed on the Safety Set based on treatment as received. 
Patient listings will be based on the FAS, unless otherwise specified. Patient disposition 
will be described for the Screened Analysis Set. 
11.2 Variables 
All variables described thereafter are related to the endpoints defined in Section 6. 
11.2.1 Primary efficacy variables 
The primary efficacy variables are: 
• 
Change from baseline to Week 24/EOT in actigraphy-assessed DLPA as measured 
by: 
– Daily time spent (minutes) in non-sedentary activity (> 100 activity counts per 
minute) 
– Percentage of daily time spent in non-sedentary activity (> 100 activity counts per 
minute) 
– Total DLPA in counts/min 
– Sleep: TST (minutes), WASO (minutes), number of awakenings, efficiency 
(percentage) 
Furthers details on other actigraphy variables will be provided in the SAP. 
11.2.2 Secondary efficacy variables 
The secondary efficacy variables are: 
• 
Change from baseline to Week 24/EOT for following PAH-SYMPACT® domain 
scores: 
– Cardiovascular symptom domain score 
– Cardiopulmonary symptom domain score 
– Physical impact domain score 
– Cognitive/emotional impact domain score 
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• 
Change from baseline to Week 24/EOT for following variables: 
− WHO FC 
− 6MWD 
− Borg dyspnea dyspnea index at 6MWT 
− NT-proBNP 
11.2.3 Other efficacy variables 
The other efficacy variables are: 
• 
Change from baseline to Week 24/EOT for blood biomarkers associated with, 
e.g., PAH worsening, right/left ventricle function, and inflammation. 
• 
Association 
between 
actigraphy 
variables 
and 
other 
efficacy 
endpoints 
(PAH-SYMPACT®, 6MWD, etc.). 
11.2.4 Safety variables  
Safety variables are listed in Section 6.2. 
An AE is defined as any event that is recorded on the AE eCRF module regardless of the 
onset date. Treatment-emergent events are those with onset date/time ≥ start date/time of 
study treatment and up to 30 days after EOT. 
Laboratory analyses are based on data received from the central laboratory. All 
transferred central laboratory data are taken into account regardless of whether they 
correspond to scheduled or unscheduled assessments. 
11.3 Description of statistical analyses 
11.3.1 Overall testing strategy 
This study is designed as exploratory with the purpose to generate hypotheses on new 
endpoints. All analyses performed will be descriptive with summary statistics and 
associated 95% confidence intervals (CI) provided when applicable. Any p-value 
provided as result of a statistical model is to be considered as exploratory only.  
No adjustment for multiplicity will be performed. 
11.3.2 Analysis of the primary efficacy variables 
All actigraphy variables will be summarized by period of 14 days: Baseline (last 14 days 
before first dose), Week 2 (Day 1–14), Week 4 (Day 15–28), and so on until Week 24 
(Day 155–168) or EOT (last 14 days period on study treatment) in case of premature 
discontinuation. Any actigraphy data recorded after Day 168/EOT will not be considered 
in summary statistics and will be listed only. 
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11.3.2.1 Hypotheses and statistical model 
As the study is designed as exploratory, no formal hypothesis will be tested.  
For all actigraphy variables (continuous), change from baseline to Week 24/EOT will be 
analyzed using an analysis of covariance (ANCOVA) including terms for treatment and 
region, and baseline values as covariates. The differences in least square means between 
treatment and placebo, corresponding 2-sided 95% CI, and p-value will be provided. 
All actigraphy variables will be also reported overtime with actual values, absolute 
change and percentage change from baseline at each time point (14 days periods).  
Daily time spent and percentage of daily time spent will be also displayed according to 
activity categories “sedentary”, “light”, “moderate”, “vigorous” and “very vigorous”. The 
different intensity levels (cut points) ranging from sedentary to very vigorous are based 
on the Freedson Adult algorithm [Freedson 1998]: “Sedentary” (0–99 counts/min), 
“Light” (100–1951 counts/min), “Moderate” (1952–5724 counts/min), “Vigorous” 
(5725–9498 counts/min) and “Very Vigorous” (9499 + counts/min). 
11.3.2.2 Handling of missing data  
To be considered evaluable for a given time, actigraphy variables should have been 
measured for at least 7 complete days (consecutive or not) at a specific time period of 
assessment (baseline, Week 2, …, Week 24/EOT). A complete day is defined as a record 
of at least 7 awake hours of data.  
The main analysis will consider the last time period available at Week 24/EOT evaluation 
(last observation carried forward). Further details will be provided in the SAP. 
11.3.2.3 Main analysis 
All actigraphy variables will be analyzed in same way on the FAS population using the 
model and summary statistics described in Section 11.3.2.1. 
11.3.2.4 Supportive/sensitivity analyses  
Supportive analyses based on the PPS will be provided. In addition, repeated measures 
mixed models will be used to evaluate the effect of selexipag relative to placebo over 
time.  
Further supportive analyses will be described in the SAP. 
11.3.2.5 Sub-group analyses 
Subgroup analyses will be performed at least by region (randomization stratification 
factor). Additional subgroups analyses will be described in the SAP.  
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11.3.3 Analysis of secondary efficacy variables 
All secondary analyses will be performed on the FAS. 
11.3.3.1 PAH-SYMPACT® 
All PAH-SYMPACT® domain scores (cardiovascular symptom domain score, 
cardiopulmonary 
symptom 
domain 
score, 
physical 
impact 
domain 
score, 
cognitive/emotional impact domain) will be reported as continuous variables over time 
with actual values, absolute change and percentage change from baseline at each time 
points.  
For change from baseline to Week 24/EOT, the same analysis as for primary variables 
(ANCOVA described in Section 11.3.2.1) will be performed for the 4 PAH-SYMPACT® 
domain scores. 
Further details will be provided in the SAP. 
11.3.3.2 Others PAH related clinical outcomes 
Others PAH related variables (6MWD, Borg dyspnea index) will be reported over time 
with actual values, absolute change and percentage change from baseline at each time 
points.  
For change from baseline to Week 24/EOT, the same analysis as for primary variables 
(ANCOVA described in Section 11.3.2.1) will be performed for 6MWD and Borg 
dyspnea index.  
WHO FCs will be described by shift tables from baseline to each time point. NT-proBNP 
will be described by summary statistics over time. In addition, change from baseline to 
Week 24/EOT in NT-proBNP (log-transformed) will be analyzed using an ANCOVA 
with factors for treatment group, region, and a covariate for baseline NT-proBNP  
(log-transformed).  
11.3.3.3 Association between actigraphy and others efficacy endpoints 
The association between actigraphy variables and others efficacy endpoints  
(PAH-SYMPACT® domain scores, 6MWD, NT-proBNP) will be described using 
correlations, scatter plots and regressions. Details will be provided in the SAP. 
11.3.4 Analysis of the safety variables  
All safety analyses will be performed on the Safety Set using descriptive statistics. All 
safety data will be listed, with flags for quantitative abnormalities. AEs in patients who 
were screened but not randomized will be listed.  
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11.3.4.1 Adverse events 
A treatment-emergent AE is any AE temporally associated with the use of study 
treatment. The number and percentage of patients experiencing treatment emergent AEs 
and SAEs at least once will be tabulated by treatment group and by: 
• Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) 
and individual preferred term within each SOC, in descending order of incidence. 
• Frequency of patients 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.  
AEs leading to premature discontinuation of study treatment 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. 
For AEs occurring more than 30 days after discontinuation of the study treatment, a 
dedicated analysis will be described in the SAP. 
11.3.4.2 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 time point according to the best fitting time window for that assessment.  
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. 
The number and percentage of patients with treatment-emergent laboratory abnormalities 
will be tabulated by treatment group. 
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11.3.4.3 Vital signs and body weight 
Vital signs (BP, pulse rate), and body weight will be summarized at each study visit using 
summary statistics by treatment group for both absolute values and changes from 
baseline. Patients for whom no post-baseline value is available are excluded from the 
analysis of the changes from baseline in the Safety Set. 
11.3.5 Exposure to study drug 
Exposure to study drug will be described in terms of duration, HTD (defined as the dose 
at Week 12) and IMD (defined as the dose to which a patient was exposed for the longest 
duration during the maintenance period).  
The duration of exposure is defined as the time elapsing between the study drug initiation 
and discontinuation, inclusive. The exposure time will be tabulated by treatment group 
using mean, median, standard deviation (SD), first and third quartiles, minimum and 
maximum. The cumulative distribution of exposure time by different class intervals will 
be tabulated to show the number and percentage of patients in each class interval. Count 
and percentages of patients within each HTD and IMD dose class will be tabulated by 
treatment group. 
11.3.6 Baseline characteristics and concomitant medications 
Continuous baseline variables and disease characteristics (e.g., age, height, weight, BMI, 
BP, pulse rate, 6MWT, Borg Dyspnea index and time from PAH diagnosis) will be 
summarized by treatment group using mean, median, SD, first and third quartiles, 
minimum and maximum. 
Qualitative baseline variables and disease characteristics (e.g., gender and race, etiology 
of PAH, WHO FC, medical history, previous and concomitant medications) will be 
summarized by treatment group using counts and percentages. Individual patient listings 
will be provided by treatment group. 
Previous and concomitant medications will be coded according to the latest available 
version of the WHO drug code and the anatomic therapeutic chemical class code. They 
will be summarized by type (i.e., previous and concomitant) and treatment group by 
tabulating the number and percentages of patients having received each treatment.  
11.4 Interim analyses 
Not applicable. 
11.5 Sample size 
There are no longitudinal data available for actigraphy variables in PAH patients. 
Therefore the study is designed as exploratory and the sample size is based on enrolment 
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capabilities: 100 patients will be randomized in total (50 in placebo group and 50 in 
selexipag group). 
One of the primary variables is the difference between the two groups for the change 
from baseline to Week24/EOT for the number of daily minutes spent in non-sedentary 
activity. A number of 100 patients will provide an acceptable precision for associated 
width of 95% CI (assuming normal distributions) given scenarios of common SD ranging 
from 30 to 90 minutes [Table 4 below]. Calculations were made using software FAST 
version 4. 
Table 4 
Confidence interval (2-sided 5%) width assuming different scenarios 
of SD 
Common SD for change from baseline in 
time spent (minutes) in non-sedentary 
activity 
Confidence interval (2-sided 5%) width for difference 
between two groups for time spent (minutes) in non-
sedentary activity 
30 
± 11.76 
40 
± 15.68 
50 
± 19.6 
60 
± 23.52 
70 
± 27.44 
80 
± 31.36 
90 
± 35.28 
SD, standard deviation. 
Those CI widths are indicative only, and the main analysis for actigraphy variables will 
be based on ANCOVA including terms for treatment and region, and baseline values as 
covariates. 
12 DATA HANDLING 
12.1 Data collection 
The investigator/delegate is responsible for ensuring the accuracy, completeness and 
timelines of the data reported. All source documents should be completed in a neat, 
legible manner to ensure accurate interpretation of the data. Data reported in the eCRF 
derived from source documents must be consistent with the source documents. 
eCRF data will be captured via electronic data capture (using the Rave system provided 
by Medidata Solutions, Inc, a web-based tool). The investigator and site personnel will be 
trained to enter and edit the data via a secure network, with secure access features 
(username, password, and identification – an electronic password system). A complete 
electronic audit trail will be maintained. The investigator/delegate will approve the data 
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(i.e., confirm the accuracy of the data recorded) using an electronic signature (ref. to US 
21 CFR Part 11). 
Entries recorded by the patient in the PAH-SYMPACT® questionnaire are considered 
source data. Site personnel will review and ensure completeness of the patients’ entries. 
Patient screening and randomization data will be completed for all patients (i.e., eligible 
and non-eligible) through the IRT system and eCRF. 
For each patient who enters the screening period of the study, an eCRF must be 
completed and signed by the investigator/delegate. If a patient withdraws from the study, 
the reason must be noted on the eCRF. 
12.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On the 
eCRF or other documents (e.g., documents attached to SAE forms / Pregnancy forms) 
submitted to Actelion and any CROs, patients must be identified only by number and 
never by their name or initials, date of birth, hospital numbers, or any other identifier. 
The investigator/delegate must keep a patient identification code list at the site, showing 
the screening/randomization number, the patient’s name, date of birth, and address or any 
other locally accepted identifiers. Documents identifying the patients (e.g., signed ICFs) 
must not be sent to Actelion, and must be kept in strict confidence by the 
investigator/delegate. 
The external service provider for actigraphy (ActiGraph) will not have access to 
personally identifiable patient information. The external service provider for the ePRO 
(ExcoIntouch) can receive personally identifiable information (private mobile phone 
number) if the patient agrees to this. This information is used to send study related 
messages (sent by ExcoIntouch) to the patient’s private mobile phone. However, 
ExcoIntouch is obliged to keep the private mobile phone number confidential and not to 
share with anyone else, including Actelion. 
12.3 Database management and quality control 
eCRFs will be used for all patients. The investigators will have edit 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 patient status at any time point during the course of 
the study. 
While entering the data, the investigator/delegate will be instantly alerted to data queries 
by validated programmed checks. Additional data review will be performed by Actelion 
personnel on an ongoing basis to look for unexpected patterns in data and for study 
monitoring. If discrepant data are detected, a query specifying the problem and requesting 
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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/or a response from the investigator/delegate to clarify the queried data directly in the 
eCRF, or simply a data correction in the eCRF. The investigator/delegate must, on 
request, supply Actelion with any required background data from the study 
documentation or clinical records. This is particularly important when errors in data 
transcription are suspected. In the case of health authority queries, it is also necessary to 
have access to the complete study records, provided that patient confidentiality is 
protected. 
This process will continue until database closure. 
Laboratory samples will be processed through a central laboratory and the results will be 
electronically sent to Actelion. 
Data collected by the vendors of the ePRO and actigraphy device are owned by Actelion 
Pharmaceuticals Ltd. The data will be transferred to Actelion at the end of the study. The 
vendors will not use the data for any purpose not related to the conduct of the clinical 
study AC-065A404.  
AEs are coded according to the latest MedDRA used by Actelion. 
After the database has been declared complete and accurate, the database will be closed. 
Any changes to the database after that time may only be made as described in the 
appropriate Actelion QS docs. After database closure, the investigator will receive the 
eCRFs of the patients of his/her site (including all data changes made) on electronic 
media or as a paper copy. 
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, respectively, ICH-GCP Guidelines, the principles of the 
“Declaration of Helsinki” (currently 2013 version), and with the laws and regulations of 
the country in which the study is conducted. 
13.2 Independent Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document(s) provided to the 
patient (such as the ICF) to an IEC/IRB. Approval from the committee/board must be 
obtained before starting the study, and must be documented in a dated letter to the 
investigator, clearly identifying the study, the documents reviewed, and the date of 
approval. 
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Modifications made to the protocol or the ICF after receipt of the approval must also be 
submitted as amendments by the investigator to the IEC/IRB in accordance with local 
procedures and regulations [see Section 13.6]. 
A list of members participating in the IEC/IRB meetings must be provided, including the 
names, qualifications, and functions of these members. If that is not possible, the attempts 
made to obtain this information along with an explanation as to why it cannot be obtained 
or disclosed must be documented in the study documentation.  
If a member of the study personnel was present during an IEC/IRB meeting, it must be 
clear that this person did not vote. 
13.3 Informed consent 
It is the responsibility of the investigator/delegate to obtain informed consent according 
to the latest versions of the ICH-GCP and Declaration of Helsinki guidelines and local 
regulations from each individual participating in this study and/or legally designated 
representative. The investigator/delegate must explain to patients that they are completely 
free to refuse to enter the study, or to voluntarily withdraw from the study at any time for 
any reason without having to provide any justification. Special attention shall be paid to 
the information needs of specific patient populations and of individual patients, as well as 
to the methods used to give the information. Adequate time shall be given for the patient 
and/or legally designated representative to consider his or her decision to participate in 
the study and it shall be verified that the patient has understood the information (e.g., by 
asking the patient to explain what is going to happen). 
The ICF will be provided in the country local language(s). 
Site personnel authorized to participate in the consent process and/or to obtain consent 
from the patient and/or legally designated representative will be listed on the Delegation 
of Authority form supplied by Actelion. A study physician must always be involved in 
the consent process. 
The patient and/or legally designated representative and authorized site personnel listed 
on the Delegation of Authority form supplied by Actelion must sign, personally date, and 
time (if the first study-mandated procedure is to be performed on the same day informed 
consent is obtained) the ICF before any study-related procedures (i.e., any procedures 
required by the protocol) begin.  
A copy of the signed and dated ICF is given to the patient and/or legally designated 
representative; the original is filed in the site documentation. The informed consent 
process must be fully documented in the patient’s medical records. This must include at a 
minimum the study reference, the patient number, the date and, if applicable, time when 
the patient was first introduced to the study, the date and, if applicable, time of consent, 
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who participated in the consent discussion, who consented the patient, and any additional 
person present during the consent process (e.g., patient’s family member[s]), and the 
information that a copy of the signed ICF was given to the patient / legally designated 
representative. 
If the site intends to recruit patients who are considered as vulnerable (e.g., patient cannot 
read or write, does not speak or understand the ICF language), additional measures must 
be implemented in order to ensure patient’s rights are respected and the consent obtained 
is legally valid. Actelion, the regulatory authorities (if applicable), and the IEC/IRB must 
be informed prior to the recruitment. The consent process (e.g., involvement of an 
impartial witness) must be fully described, submitted to, and approved by the IEC/IRB, 
according to procedures and before patients are recruited. 
13.4 Compensation to patients 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 patient 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 IEC/IRB and/or the 
regulatory authority-approved version of the protocol and must not implement any 
deviation/change from the protocol, except when deviation is necessary to eliminate an 
immediate hazard to the patient. 
If a protocol deviation occurs, the investigator/delegate will inform Actelion or its 
representative in a timely manner. The investigator/delegate must document and explain 
any deviation from the approved protocol. Deviations considered to be a violation of 
ICH-GCP must be reported to the IEC/IRB and regulatory authorities according to 
Actelion or (overruling) local requirements. 
All protocol deviations will be reported in the Clinical Study Report (CSR). IECs/IRBs 
will be provided with listings of protocol deviations as per local requirements. 
13.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. An 
amended protocol must be submitted to the IEC/IRB and regulatory authorities, 
according to their requirements. 
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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 
patients’ source documents. 
These records must be kept by the investigator for as long as is necessary to comply with 
Actelion’s requirements (i.e., as specified in the clinical study agreement), and national 
and/or international regulations, whichever would be the longest period. If the 
investigator cannot guarantee this archiving requirement at the site for any or all of the 
documents, special arrangements, respecting the data confidentiality, must be made 
between the investigator and Actelion to store these documents outside the site, so that 
they can be retrieved in case of a regulatory inspection. No study document should be 
destroyed without prior written approval from Actelion. Should the investigator wish to 
assign the study records to another party, or move them to another location, Actelion 
must be notified in advance. 
If the site is using an electronic/computerized system to store patient medical records, it 
can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 
or equivalent standard) and if the CRA has been provided personal and restricted access 
to study patients 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 patient medical records but 
it could not be confirmed that the system is validated or if the CRA could not be provided 
access to the system, the site is requested to print the complete set of source data needed 
for verification by the CRA. The print-outs must be numbered, stapled together with a 
coversheet, signed and dated by the investigator/delegate to confirm that these certified 
copies are exact copies having the same information as the original source data. The 
printouts will be considered as the official clinical study records and must be filed either 
with the patient’s medical records or with the patient’s eCRF. 
In order to verify that the process the site uses to prepare certified copies is reliable, the 
CRA must be able to observe this process and confirm that the comparison of the source 
documents and the certified copy did not reveal inconsistencies. The CRA does not need 
to verify this process for all data of all patients but at least for some of them (e.g., first 
patient; regular check during the study of critical data like inclusion/exclusion criteria, 
endpoints for some patients) as per Actelion’s instructions. If it were not possible for the 
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CRA to observe this process, it would not be possible to rely on the site’s certified copies 
and therefore the site cannot be selected for the clinical study. 
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 SIV. 
The SIV must be completed before the site can start the screening of study patients. 
Following the SIV, a copy of the completed initiation visit report and follow-up letter 
will be provided to the PI and filed in the ISF. 
During the study, the CRA will contact and visit the site regularly and must be permitted, 
on request, to have access to study facilities and all source documents needed to verify 
adherence to the protocol and the completeness, consistency, and accuracy of the data 
being entered in the eCRFs and other protocol-related documents. Actelion monitoring 
standards require full verification that informed consent has been provided, verification 
of adherence to the inclusion/exclusion criteria, documentation of SAEs, and the 
recording of the main efficacy, safety, and tolerability endpoints. Additional checks of 
the consistency of the source data with the eCRFs will be performed according to the 
study-specific monitoring guidelines. The frequency of the monitoring visits will be 
based on patient recruitment rate and critical data-collection times. 
The PI must ensure that the eCRF is completed after a patient’s visit (site visit or 
telephone call), and that all requested patient files (e.g., ICFs, medical notes/charts, other 
documentation verifying the activities conducted for the study) are available for review 
by the CRA. The required site personnel must be available during monitoring visits and 
allow adequate time to meet with the CRA to discuss study-related issues. 
The investigator agrees to cooperate with the CRA(s) to ensure that any issues detected in 
the course of these monitoring visits are resolved. If the patient 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 
patients and all follow-up issues have been resolved. In case a site does not enroll any 
patients, the close-out visit may be performed prior to study database closure at the 
discretion of Actelion. 
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13.9 Investigator Site File 
Each site will be provided with an ISF prior to the SIV. It will contain all the essential 
documents that are required to be up-to-date and filed at site as per ICH-GCP section 8. 
The ISF will include a table of content listing the essential documents. All study-related 
documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the CRA regarding the filing of the study 
documents outside the ISF. It should be clearly documented where each document is 
filed. This note to file should be present in the specific tab of the document in the ISF. 
The ISF must be stored in a secure and access-restricted area during and after the study. It 
must be kept by the site for as long as needed to comply with any applicable rules and 
regulations, ICH-GCP, as well as instructions from Actelion. If the site needs to transfer 
the ISF to another location and/or if site facility can no longer store the ISF, the PI must 
immediately inform Actelion. 
If the PI will change, or if the site will relocate, the CRA must be notified as soon as 
possible. 
13.10 Audit 
Actelion’s/CRO’s representatives may audit the investigator site (during the study or 
after its completion). The purpose of this visit will be to determine the investigator’s 
adherence to ICH-GCP, the protocol, and applicable regulations; adherence to Actelion’s 
requirements (e.g., standard operating procedures) will also be verified. Prior to initiating 
this audit, the investigator will be contacted by Actelion to arrange a time for the audit. 
The investigator and site personnel must cooperate with the auditor(s) and allow access to 
all study documentation (e.g., patient records) and facilities. 
13.11 Inspections 
Health authorities and/or IEC/IRB may also conduct an inspection of this study (during 
the study or after its completion) at the site. 
Should an inspection be announced by a health authority and/or IEC/IRB, the investigator 
must immediately inform Actelion (usually via the CRA) that such a request has been 
made. 
The investigator and site personnel must cooperate with inspector(s) and allow access to 
all study documentation (e.g., patient records) and study facilities. 
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13.12 Reporting of study results and publication 
Actelion will post the key elements of this protocol and the summary of results on 
Actelion’s Clinical Trial Register and within the required timelines on publically 
accessible databases (e.g., clinicaltrials.gov, EU database), as required by law and 
regulation. 
Study results will be documented in a CSR that will be signed by Actelion representatives 
and the Coordinating Investigator (or PI for single-center studies). 
In accordance with the Good Publication Practices and ethical practice, the results of the 
study will be submitted for publication in a peer-reviewed journal. Study results can be 
submitted for presentation at a congress before submission to a peer-reviewed journal. 
The Coordinating Investigator and the Steering Committee will review the analysis of the 
data and discuss the interpretation of the study results with Actelion personnel prior to 
submission to a peer-reviewed journal or presentation at a congress. 
Authorship will be determined in accordance with the International Committee of Journal 
Editors criteria, and be based on: 
• substantial contributions to the conception or design of the study, or the acquisition, 
analysis, or interpretation of data; and 
• drafting of the publication or critical review for important intellectual content; and 
• providing final approval of the version to be published; and 
• agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
The list of authors of any publication of study results may include representatives of 
Actelion and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted 
to Actelion for review at least 30 days prior to submission for publication or presentation 
at a congress. Upon review, Actelion may provide comments, and may also request 
alterations and/or deletions for the sole purpose of protecting its confidential information 
and/or patent rights. Neither the institution nor the investigator should permit publication 
during such a review period. 
Actelion’s Policy on Scientific Publications can be found at: 
http://www.actelion.com/documents/corporate/policies-charters/policy-scientific-
publications.pdf. 
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14 REFERENCES 
[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. 
[FDA 2009] Food and Drug Administration. Guidance for Industry. Patient-reported 
outcome measures: use in medical product development to support labeling claims. 
December 2009. Available from: 
http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf. Accessed 
8 February 2017. 
[Freedson 1998] Freedson PS, Melanson E, Sirard J. Calibration of the Computer Science 
and Applications, Inc. accelerometer. Med Sci Sports Exerc. 1998;30:777-81. 
[Galiè 2015a] Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the 
diagnosis and treatment of pulmonary hypertension. The Joint Task Force for the 
Diagnosis and Treatment of Pulmonary Hypertension of the European Society of 
Cardiology (ESC) and the European Respiratory Society (ERS) Endorsed by: 
Association for European Paediatric and Congenital Cardiology (AEPC), 
International Society for Heart and Lung Transplantation (ISHLT). Eur Resp J 
2015;46:903-975. 
[Galiè 2015b] Galiè N, Barberà JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin 
VV, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial 
Hypertension. N Engl J Med. 2015;373:834-44. 
[Godfrey 2008] Godfrey A, Conway R, Meagher D, OLaighin G. Direct measurement of 
human movement by accelerometry. Med Eng Phys. 2008;30:1364-86. 
[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. 
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[Humbert 2004] Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial 
hypertension. New Engl J Med. 2004;351:142-136.  
[ICH M3] ICH M3(R2) Guideline: Guidance on non-clinical safety studies for the 
conduct of human clinical trials and marketing authorization for pharmaceuticals. 
11 June 2009 
[Kylhammar 2014] Kylhammar D, Persson L, Hesselstrand R, Rådegran G. Prognosis 
and response to first-line single- and combination therapy in pulmonary arterial 
hypertension. Scand Cardiovasc J. 2014;10:1-23. 
[Marvisi 2013] Marvisi M, Balzarini L, Mancini C, Mouzakiti P. Thyroid gland and 
pulmonary hypertension. What’s the link? Panminerva Med. 2013; 55:93-7. 
[Mainguy 2011] Mainguy V, Provencher S, Maltais F, Malenfant S, Saey D. Assessment 
of daily life physical activities in pulmonary arterial hypertension. PLoS One. 2011; 
6(11):e27993. 
[McCollister 2016] McCollister D, Shaffer S, Badesch DB, Filusch A, Hunsche E, 
Schüler R, et al. Development of the Pulmonary Arterial Hypertension-Symptoms 
and Impact (PAH-SYMPACT®) questionnaire: a new patient-reported outcome 
instrument for PAH. Respir Res. 2016;17:72. 
[McKenna 2006] McKenna SP, Doughty N, Meads DM, et al. The Cambridge Pulmonary 
Hypertension Outcome Review (CAMPHOR): A measure of health-related quality 
of life and quality of life for patients with pulmonary hypertension. Qual Life Res. 
2006;15:103–115. 
[Okumus 2016] Okumus G, Aslan GK, Arseven O, Ongen G, Issever H, Kıyan E. The 
role of an activity monitor in the objective evaluation of patients with pulmonary 
hypertension. Clin Respir J. 2016; Epub 2016 May 5. 
[Oudiz 2013] Oudiz RJ. Death in pulmonary arterial hypertension. Am J Respir Crit Care 
Med. 2013;188(3):269-70. 
[Pugh 2012] Pugh ME, Buchowski MS, Robbins IM, Newman JH, Hemnes AR. Physical 
activity limitation as measured by accelerometry in pulmonary arterial 
hypertension. CHEST 2012;142:1391-1398. 
[Pulido 2013] Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani HA, 
et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N 
Engl J Med. 2013;369:809-18. 
[Selexipag 
IB] 
Investigator’s 
brochure 
for 
selexipag, 
version 
13. 
Actelion 
Pharmaceuticals Ltd, September 2018. 
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[Sitbon 2015] Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galiè N, et al. 
Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 
2015;373:2522-33.  
[Ulrich 2012] Ulrich S, Fischler M, Speich R, Bloch KE. Wrist actigraphy predicts 
outcome in patients with pulmonary hypertension. Respiration. 2013;86:45-51. 
 
 
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15 APPENDICES 
Appendix 1 
Actelion guidelines for 6-minute walk test 
Please note: Per study requirement, patients must be at trough levels for study treatment. 
Trough level of study treatment (selexipag) is defined as: the last dose has been taken not 
less than 8 hours prior to the 6MWT. 
Background 
This document is an adaptation from the American Thoracic Society (ATS) guideline on 
the 6MWT (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit 
Care Med. 2002;166:111-17).  
Tool description 
• A self-paced test that measures the distance that a subject can quickly walk on a 
flat, hard surface in a period of 6 minutes (the 6MWD). 
• Assesses the submaximal level of functional capacity. 
• Evaluates the global and integrated responses of all the systems involved during 
exercise, including the pulmonary and cardiovascular systems, systemic 
circulation, peripheral circulation, blood, neuromuscular units, and muscle 
metabolism. 
Contraindications and safety issues 
Absolute contraindications for the 6MWT include: 
• Unstable angina and/or myocardial infarction during the previous month. Stable 
exertional angina is not an absolute contraindication for a 6MWT, but subjects 
with these symptoms must perform the test after using their antiangina 
medication, and rescue nitrate medication must be readily available. 
Relative contraindications include: 
• Resting HR of more than 120 beats/min after 10 minutes of rest. 
• Uncontrolled hypertension: SBP of >180 mm Hg +/− DBP > 100 mm Hg. 
A physician is not required to be present during the test. However, the technician 
administering the test must be certified in cardiopulmonary resuscitation, and training in 
related health care fields is desirable. 
Testing needs to be performed in a location where rapid appropriate response to 
emergency is possible and a mean is in place enabling to call for help if needed. Access 
to a crash cart, as well as medications to treat angina, bronchospasm, and severe 
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shortness of breath must be available (e.g., aspirin, subligual nitroglycerine, oxygen, 
albuterol metered dose inhaler or nebulizer). 
Care must be taken to evaluate safety in ambulation prior to the 6MWT, to ensure that the 
subject is safe to proceed. 
Reasons for immediately stopping a 6MWT include the following: (1) chest pain, 
(2) intolerable dyspnea, (3) leg cramps, (4) staggering, (5) diaphoresis, and (6) pale or 
ashen appearance. Any reason for discontinuing the test needs to be recorded. 
Pulse oximetry is optional. If it is performed, measure and record baseline HR and 
oxygen saturation and follow manufacturer’s instructions to maximize the signal and to 
minimize motion artifact. The oxygen saturation must not be used for constant 
monitoring during the exercise (no intra-test measurements). The technician must not 
walk with the patient to observe the oxygen saturation. 
General Instructions 
The 6MWT needs to be performed indoors, along a long, flat, straight, enclosed corridor 
with a hard surface that is seldom traveled. The walking course must be free of obstacles. 
If a suitable indoor corridor cannot be found, the test may be performed outdoors if the 
weather is comfortable. A permanent, dedicated course is ideal. The use of treadmill and 
a continuous course is not allowed.  
The walking distance used for the test needs to be 30 meters (not shorter than 20 meters) 
in length. This distance needs to be marked every 3 meters. The turnaround point must be 
marked with a cone. A starting line, which marks the beginning and the end of each 60–m 
lap, needs to be marked on the floor using brightly colored tape. Ensure that the subject 
walks the same course on each re-test. 
The staff member administering the 6MWT needs to stand near the starting line during 
the test and must not walk with the subject, and not get distracted during the conduct of 
this test (e.g., talk to anyone). Intermittent rest periods are allowed if the subject can no 
longer continue. If the subject needs to rest, he/she may pause, lean against the wall and 
continue walking whenever he/she feels able. The 6-minute timer must continue to run 
even if the subject stops to rest. The test can be stopped at any moment as outlined under 
contraindications and safety issues. 
The 6MWT is a non-encouraged test. An even tone of voice must be used when using the 
standard phrases of encouragement. No other instructions or words of encouragement is 
given during the test, other than the pre-scripted phrases. Eye contact and body language 
signaling the subject to speed up must be avoided during the test.  
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For an individual subject, repeat testing must always be conducted under the same 
conditions throughout the clinical trial (e.g., same corridor). Whenever possible, repeat 
testing for an individual subject needs to be conducted by the same tester, and preferably 
at about the same time of the day to minimize variability. A warm up period before the 
test must not be performed.  
Training tests 
For subjects who have never performed a 6MWT previously, a training test is 
recommended before the 6MWT, due to a learning effect when performing the test.  
Timing 
The interval between training tests must be at least 1 hour, and the interval between 
training and Screening tests must be at least 2 hours. More than two 6MWTs cannot be 
performed on the same day.  
Required equipment 
Emergency call tool 
Countdown timer (or stop watch)  
Mechanical lap counter  
Two small cones to mark the turnaround points  
A chair that can be easily moved along the walking course  
Worksheets on a clipboard  
Sphygmomanometer  
Automated electronic defibrillator  
Source of oxygen  
Oximeter (optional) 
Subject preparation 
Medications type, dose and number of hours taken before the test must be recorded. 
Restrictions in medications need to be described. Certain medications need to be stable 
prior to the test (oxygen, diuretics, etc.). 
The subject needs to wear comfortable clothing and appropriate walking shoes.  
The meals preceding the test need to be light, and the subject must not have exercised 
vigorously within 2 hours of beginning the test.  
The subject needs to sit at rest for at least 10 minutes before the test starts.  
Subjects must receive their usual medication on the day of the test. If the subject is used 
to taking bronchodilators before a walk, he/she must take them 5–30 min before the test.  
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If a subject is oxygen dependent, it is recommended that oxygen is delivered in the same 
way (i.e., same application route and/or delivery device and same way of carrying the 
delivery device) and the flow rate remains constant. However, from 1 hour prior to each 
6MWT, until the completion of all assessments after the 6MWT, the flow rate must 
remain constant. Additionally, the same oxygen flow rate as the one administered during 
the 6MWT at screening, must be maintained throughout the clinical trial for each 6MWT, 
as well as the same way of carrying the delivery device.  
Have the subject stand and rate their baseline dyspnea using the Borg scale and 
instructions. 
Measurements 
Measurement of the 6MWD – Instructions to the subject  
The person administering the test uses the following exact dialogue with the subject:  
“The object of this test is to walk as far as possible for 6 minutes. You will walk back and 
forth in this hallway. Six minutes is a long time to walk, so you will be exerting yourself. 
You will probably get out of breath or become exhausted. You are permitted to slow 
down, to stop, and to rest as necessary. You may lean against the wall while resting, but 
resume walking as soon as you are able.  
You will be walking back and forth around the cones. You should pivot briskly around 
the cones and continue back the other way without hesitation. Now I’m going to show 
you. Please watch the way I turn without hesitation.”  
(The tester demonstrates the walking and pivots around a cone briskly).  
“Are you ready to do that? I am going to use this counter to keep track of the number of 
laps you complete. I will click it each time you turn around at this starting line. 
Remember the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don’t run or 
jog. I will tell you when 2 minutes, 4 minutes have elapsed. Keep walking when I talk.”  
After these instructions are given to the subject, the person administering the test then 
asks:  
“Do you have any questions about the test?”  
“Please explain what you are going to do.”  
“Are you ready?”  
“Start now, or whenever you are ready.”  
As soon as the subject starts to walk, the tester starts the timer and writes down start time.  
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The tester tells the subject the time elapsed by saying:  
“You have 4 minutes to go.”  
“You have 2 minutes to go.”  
When the timer is 15 seconds from completion, the tester says:  
“In a moment I’m going to tell you to stop. When I do, just stop right where you are and I 
will come to you.”  
When the timer alarm rings the tester says:  
“Stop!” 
If the subject stops walking during the test and needs a rest, the tester says: 
“You can lean against the wall if you would like; then continue walking whenever you 
feel able.” Do not stop the timer. 
The tester walks over to the subject, marks the spot where the subject stopped, records 
the total distance walked in the worksheet and congratulates the subject on good effort. 
Ask subject: “What, if anything, kept you from walking farther?” 
Record the post-walk Borg dyspnea index using the Borg scale and instructions. 
If using a pulse oximeter, measure oxygen saturation and pulse rate from the oximeter. 
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Appendix 2 Borg dyspnea index  
The Borg scale must be printed in well readable font size on paper. 
At the beginning of the 6-minute walk test, show the scale to the subject and ask the 
subject this: “Please grade your level of shortness of breath using this scale.”  
As soon as possible following the walk test, remind the subject of the breathing grade that 
he/she chose before the exercise and ask him/her to rate his/her shortness of breath using 
the scale again. The tester uses the following dialog:  
“I would like to use the following scale to indicate the maximal shortness of breath you 
had during the walk test (indicate the Borg scale).  
If there was no shortness of breath at all you would point to 0;  
if the shortness of breath was not very great you would choose from 0.5 to 2;  
if you were somewhat more short of breath you would select 3;  
and if the breathing was getting very difficult, you would choose 4 to 9, depending on 
just how hard it was; 10 represents the greatest shortness of breath you have ever 
experienced in your life.” 
Borg rating 
Perceived exertion 
0 
0.5 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Nothing at all 
Very, very slight (just noticeable) 
Very slight 
Slight (light) 
Moderate 
Somewhat severe 
Severe (heavy) 
 
Very severe 
 
 
Very, very severe (maximal) 
 
 
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Appendix 3 WHO Functional Classification of pulmonary hypertension 
Class I 
Patients with pulmonary hypertension but without resulting limitation of 
physical activity. Ordinary physical activity does not cause undue dyspnea 
of fatigue, chest pain or near syncope. 
Class II 
Patients with pulmonary hypertension resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical activity 
causes undue dyspnea or fatigue, chest pain or near syncope. 
Class III 
Patients with pulmonary hypertension resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary activity 
causes undue dyspnea or fatigue, chest pain or near syncope. 
Class IV 
Patients with pulmonary hypertension with inability to carry out any 
physical activity without symptoms. These patients manifest signs of right 
heart failure. Dyspnea and/or fatigue may even be present at rest. 
Discomfort is increased by any physical activity. 
 
 
 
NCT03078907


Selexipag (ACT-293987) 
Pulmonary arterial hypertension 
Protocol AC-065A404 
Version 2 
5 December 2018, page 99/105 
Confidential 
EudraCT 2017­000216­42 
Doc No D-18.398 
 
Appendix 4 PAH-SYMPACT® Questionnaire  
Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) 
Questionnaire 
 
The questionnaire and a patient manual will be available in the local language(s). 
 
DAY 1 
 
INSTRUCTIONS 
 
Each day you will answer questions about your Pulmonary Arterial Hypertension symptoms over 
the PAST 24 HOURS. Please select the answer that best describes your experience with your 
symptoms.   
 
On the 7th day you will answer questions about your Pulmonary Arterial Hypertension symptoms 
over the PAST 24 HOURS and additional questions about how your life was affected by 
Pulmonary Arterial Hypertension in the PAST 7 DAYS.   
 
Please do not skip any questions. There are no right or wrong answers to any of the questions.  
 
 
DAYS 2-6 (Subsequent days prior to last day in week) 
 
INSTRUCTIONS 
 
Today you will answer questions about your Pulmonary Arterial Hypertension symptoms over the 
PAST 24 HOURS. Please select the answer that best describes your experience with your 
symptoms.   
 
Please do not skip any questions. There are no right or wrong answers to any of the questions.  
 
 
DAY 7 (Last day of week) 
 
INSTRUCTIONS 
 
Today you will answer questions about your Pulmonary Arterial Hypertension symptoms over the 
PAST 24 HOURS and additional questions about how your life was affected by Pulmonary 
Arterial Hypertension in the PAST 7 DAYS.   
 
Please do not skip any questions. There are no right or wrong answers to any of the questions. 
 
NCT03078907


Selexipag (ACT-293987) 
Pulmonary arterial hypertension 
Protocol AC-065A404 
Version 2 
5 December 2018, page 100/105 
Confidential 
EudraCT 2017­000216­42 
Doc No D-18.398 
 
SYMPTOMS 
 
1. In the past 24 hours … 
 
Did you use oxygen?  
0  No 
1  Yes 
If yes: How many hours? _______ 
 
 
Answer the questions that follow based on your experiences regardless of whether you were 
using oxygen or not. 
 
2. In the past 24 hours … 
 
How would you rate your shortness of breath? 
0  No shortness of breath at all 
1  Mild 
2  Moderate 
3  Severe 
4  Very Severe 
 
 
3. In the past 24 hours … 
 
How would you rate your fatigue? 
0  No fatigue at all 
1  Mild 
2  Moderate 
3  Severe 
4  Very Severe 
 
 
4. In the past 24 hours … 
 
How would you rate your lack of energy? 
0  No lack of energy at all 
1  Mild 
2  Moderate 
3  Severe 
4  Very Severe 
 
 
 
NCT03078907


Selexipag (ACT-293987) 
Pulmonary arterial hypertension 
Protocol AC-065A404 
Version 2 
5 December 2018, page 101/105 
Confidential 
EudraCT 2017­000216­42 
Doc No D-18.398 
 
 
5. In the past 24 hours … 
 
How would you rate the swelling in your ankles or legs? 
0  No swelling in ankles or legs at all 
1  Mild 
2  Moderate 
3  Severe 
4  Very Severe 
 
 
6. In the past 24 hours … 
 
How would you rate the swelling in your stomach area? 
0  No swelling in stomach area at all 
1  Mild 
2  Moderate 
3  Severe 
4  Very Severe 
 
 
7. In the past 24 hours … 
 
How would you rate your cough? 
0  No cough at all 
1  Mild 
2  Moderate 
3  Severe 
4  Very Severe 
 
 
8. In the past 24 hours … 
 
How would you rate your heart palpitations (heart fluttering)? 
0  No heart palpitations (heart fluttering) at all 
1  Mild 
2  Moderate 
3  Severe 
4  Very Severe 
 
 
9. In the past 24 hours … 
 
How would you rate your rapid heartbeat? 
0  No rapid heartbeat at all 
1  Mild 
2  Moderate 
3  Severe 
4  Very Severe 
 
 
NCT03078907


Selexipag (ACT-293987) 
Pulmonary arterial hypertension 
Protocol AC-065A404 
Version 2 
5 December 2018, page 102/105 
Confidential 
EudraCT 2017­000216­42 
Doc No D-18.398 
 
10. In the past 24 hours … 
 
How would you rate your chest pain? 
0  No chest pain at all  
1  Mild 
2  Moderate 
3  Severe 
4  Very Severe 
 
 
11. In the past 24 hours … 
 
How would you rate your chest tightness? 
0  No chest tightness at all  
1  Mild 
2  Moderate 
3  Severe 
4  Very Severe 
 
 
12. In the past 24 hours … 
 
How would you rate your lightheadedness? 
0  No lightheadedness at all 
1  Mild 
2  Moderate 
3  Severe 
4  Very Severe 
 
NCT03078907


Selexipag (ACT-293987) 
Pulmonary arterial hypertension 
Protocol AC-065A404 
Version 2 
5 December 2018, page 103/105 
Confidential 
EudraCT 2017­000216­42 
Doc No D-18.398 
 
IMPACTS 
 
 
For the following questions, please select the answer that best describes how your life was 
affected by Pulmonary Arterial Hypertension in the PAST 7 DAYS.  Answer the questions based 
on your experiences regardless of whether you were using oxygen or not. 
 
 
1. In the past 7 days … 
 
Were you able to walk slowly on a flat surface? 
0  Yes, with no difficulty at all 
1  Yes, with a little difficulty  
2  Yes, with some difficulty 
3  Yes, with much difficulty 
4  No, not able at all 
 
 
2. In the past 7 days … 
 
Were you able to walk quickly on a flat surface? 
0  Yes, with no difficulty at all 
1  Yes, with a little difficulty  
2  Yes, with some difficulty 
3  Yes, with much difficulty 
4  No, not able at all 
 
 
3. In the past 7 days … 
 
Were you able to walk uphill? 
0  Yes, with no difficulty at all 
1  Yes, with a little difficulty  
2  Yes, with some difficulty 
3  Yes, with much difficulty 
4  No, not able at all 
 
 
4. In the past 7 days … 
 
Were you able to carry things, such as bags or baskets? 
0  Yes, with no difficulty at all 
1  Yes, with a little difficulty  
2  Yes, with some difficulty 
3  Yes, with much difficulty 
4  No, not able at all 
 
 
 
NCT03078907


Selexipag (ACT-293987) 
Pulmonary arterial hypertension 
Protocol AC-065A404 
Version 2 
5 December 2018, page 104/105 
Confidential 
EudraCT 2017­000216­42 
Doc No D-18.398 
 
 
5. In the past 7 days … 
 
Were you able to do light indoor household chores, such as preparing food, cleaning 
surfaces, or tidying up? 
0  Yes, with no difficulty at all 
1  Yes, with a little difficulty  
2  Yes, with some difficulty 
3  Yes, with much difficulty 
4  No, not able at all 
 
 
6. In the past 7 days … 
 
Were you able to wash or dress yourself? 
0  Yes, with no difficulty at all 
1  Yes, with a little difficulty  
2  Yes, with some difficulty 
3  Yes, with much difficulty 
4  No, not able at all 
 
 
7. In the past 7 days … 
 
How much did you need help from others? 
0  Not at all 
1  A little bit 
2  Some 
3  Quite a bit 
4  Very much 
 
 
8. In the past 7 days … 
 
Were you able to think clearly? 
0 Yes, with no difficulty at all 
1  Yes, with a little difficulty  
2  Yes, with some difficulty 
3  Yes, with much difficulty 
4  No, not able at all 
 
 
 
NCT03078907


Selexipag (ACT-293987) 
Pulmonary arterial hypertension 
Protocol AC-065A404 
Version 2 
5 December 2018, page 105/105 
Confidential 
EudraCT 2017­000216­42 
Doc No D-18.398 
 
 
9. In the past 7 days … 
 
How sad did you feel? 
0  Not at all 
1  A little bit 
2  Somewhat 
3  Very 
4  Extremely 
 
 
10. In the past 7 days … 
 
How worried did you feel? 
0  Not at all 
1  A little bit 
2  Somewhat 
3  Very 
4  Extremely 
 
 
11. In the past 7 days … 
 
How frustrated did you feel? 
0  Not at all 
1  A little bit 
2  Somewhat 
3  Very 
4  Extremely 
 
NCT03078907

SAP_001.pdf: 
TPL-000241 v02
STATISTICAL ANALYSIS PLAN
FOR CSR OF PROTOCOL AC-065A404
A multi-center, double-blind, placebo-controlled, Phase 4 study in patients with 
pulmonary arterial hypertension to assess the effect of selexipag on daily life 
physical activity and patient’s self-reported symptoms and their impacts (TRACE)
Purpose of Analysis
Clinical Study Report
Investigational Drug
Selexipag / ACT-293987 / JNJ 67896049
Protocol Number
AC-065A404 (TRACE)
Actelion Document Number
D-19.409
Document Status/Version Number
Final 3.0 Amendment 2
Date
27 February 2020
Author
 CRO Trial Statistician
Author
, Actelion Trial Statistician
Reviewer
, Senior Director Post approval 
studies, medical information & training
Reviewer
, Principal Clinical Scientist
Reviewer
, Medical Safety Officer
Reviewer
, Project Statistician 
Reviewer
, Statistical Programmer
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
NCT03078907


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Study AC-065A404
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Confidential 
Statistical Analysis Plan
Doc No D-19.409
TPL-000241 v02
TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND ACRONYMS.................................................8
1
INTRODUCTION .........................................................................................11
1.1
Study documents..............................................................................11
2
STUDY DESIGN AND FLOW......................................................................11
2.1
Study design ....................................................................................11
2.2
Study visit and assessment schedule.................................................12
3
OBJECTIVES................................................................................................12
3.1
Primary objective(s).........................................................................12
3.2
Secondary objectives........................................................................12
3.3
Other objectives ...............................................................................13
4
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL ....................................................................................13
4.1
Changes to the analyses planned in the study protocol......................13
4.1.1
Concomitant therapies ..........................................................13
4.1.2
Treatment emergent definition and 30 days safety follow-up 13
4.1.3
Sub-group analyses...............................................................13
4.2
Changes in the conduct of the study / data collection........................13
4.3
Clarifications concerning endpoint definitions and related variables or 
statistical methods............................................................................14
4.3.1
Windowed actigraphy data analysis ......................................14
4.3.2
DLPA actigraphy endpoints..................................................14
4.3.2.1
Daily time spent in non-sedentary activity ............................14
4.3.2.2
Total DLPA in counts/min....................................................15
4.3.2.3
Sleep ....................................................................................16
5
DEFINITIONS OF VARIABLES ..................................................................16
5.1
Screening failures.............................................................................16
5.2
Patient characteristics.......................................................................16
5.2.1
Demographics.......................................................................16
5.2.2
Baseline disease characteristics.............................................16
5.2.3
Medical history.....................................................................17
5.2.4
Previous and concomitant therapies ......................................17
5.2.4.1
Previous therapies.................................................................17
5.2.4.2
Baseline concomitant therapies.............................................17
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Study AC-065A404
27 February 2020, page 3/74
Confidential 
Statistical Analysis Plan
Doc No D-19.409
TPL-000241 v02
5.2.4.3
Concomitant therapies initiated during the study treatment 
period ...................................................................................17
5.2.4.4
PAH specific previous or concomitant therapies ...................17
5.3
Study treatment exposure and compliance........................................18
5.3.1
Exposure...............................................................................18
5.3.1.1
Individual maximum tolerated dose (IMTD).........................18
5.3.1.2
Individual maintenance dose (IMD)......................................19
5.3.2
Compliance with study treatment..........................................19
5.3.3
Study treatment discontinuation............................................19
5.3.4
Study treatment adjustments or interruptions.........................20
5.4
Study discontinuation.......................................................................20
5.5
Efficacy variables.............................................................................20
5.5.1
Primary efficacy variables.....................................................20
5.5.1.1
Actigraphy DLPA endpoints in protocol...............................20
5.5.1.2
DLPA actigraphy endpoints..................................................21
5.5.1.3
Sleep endpoints.....................................................................23
5.5.2
Secondary efficacy variables.................................................25
5.5.2.1
PAH-SYMPACT® domain scores:........................................25
5.5.2.2
WHO functional class...........................................................25
5.5.2.3
6-minute walk test ................................................................25
5.5.2.4
N-terminal pro b-type natriuretic peptide (NT-pro BNP).......26
5.5.3
Variables used for correlation analyses .................................26
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.....................26
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
Adverse events leading to discontinuation of study treatment27
5.6.5
Other significant adverse events............................................27
5.6.5.1
AEs of special interest (AESIs) based on the selexipag risk 
management plan (RMP) ......................................................27
5.6.5.2
AEs typical of prostanoid treatments.....................................27
5.6.5.3
Non-serious AEs...................................................................27
5.6.6
Vital signs and body weight..................................................27
5.6.7
Electrocardiogram ................................................................28
5.6.8
Laboratory............................................................................28
5.7
Quality of life variables....................................................................28
6
DEFINITION OF PROTOCOL DEVIATIONS .............................................28
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7
ANALYSIS SETS..........................................................................................29
7.1
Definitions of analysis sets...............................................................29
7.1.1
Screened analysis set ............................................................29
7.1.2
Full analysis set ....................................................................29
7.1.3
Per-protocol analysis set .......................................................29
7.1.4
Safety analysis set.................................................................29
7.1.5
Other analysis sets ................................................................30
7.2
Usage of the analysis sets.................................................................30
8
DEFINITION OF SUBGROUPS ...................................................................31
9
GENERAL STATISTICAL METHODOLOGY ............................................32
9.1
Statistical models for continuous data...............................................32
9.1.1
Analysis of covariance..........................................................32
9.1.2
Mixed model analysis with repeated measures......................32
10 STATISTICAL ANALYSES .........................................................................33
10.1
Overall testing strategy.....................................................................33
10.2
General rules for data presentations..................................................33
10.2.1
General guidelines for table contents ....................................33
10.2.2
General guidelines for table layout and formats ....................34
10.3
Display of patient disposition, protocol deviations and analysis sets.34
10.3.1
Patient disposition.................................................................34
10.3.2
Protocol deviations ...............................................................34
10.3.3
Analysis sets.........................................................................34
10.4
Analyses of patient characteristics....................................................35
10.4.1
Demographics.......................................................................35
10.4.2
Baseline disease characteristics.............................................35
10.4.3
Medical history.....................................................................35
10.4.4
Previous baseline concomitant and concomitant therapies.....35
10.5
Analysis of study treatment exposure and compliance ......................36
10.5.1
Exposure...............................................................................36
10.5.2
Compliance with study treatment..........................................36
10.5.3
Study treatment discontinuation............................................36
10.5.4
Study treatment adjustments and interruptions ......................36
10.6
Analysis of the primary efficacy variables........................................37
10.6.1
Hypothesis and statistical model ...........................................37
10.6.2
Main analysis........................................................................37
10.6.2.1
Analysis of DLPA actigraphy endpoints ...............................37
10.6.2.2
Analysis of Sleep endpoints..................................................38
10.6.3
Handling of missing data ......................................................39
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Statistical Analysis Plan
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10.6.4
Supportive/sensitivity analyses .............................................40
10.6.4.1
Supportive analyses ..............................................................40
10.6.4.2
Sensitivity analyses...............................................................40
10.6.4.3
Subgroup analyses ................................................................40
10.6.4.4
Compliance of DLPA endpoints ...........................................41
10.7
In case of notable unbalanced in compliance of DLPA, sensitivity 
analysis will be performed as mentioned in Section 10.6.4.2. In 
addition, the impact of weekday and weekend activities may be 
explored on a few of actigraphy DLPA endpoints (e.g., top 3 DLPA 
actigraphy parameters shown stronger difference between treatment 
arms).  Analysis of the secondary efficacy variables.........................41
10.7.1
Secondary endpoints.............................................................41
10.7.1.1
Hypothesis and statistical model...........................................41
10.7.1.2
Statistical analysis ................................................................41
10.7.1.3
Handling of missing data ......................................................42
10.7.1.4
Supportive/sensitivity analyses .............................................43
10.7.1.5
Subgroup analyses ................................................................43
10.8
Correlation Analysis.........................................................................43
10.9
Analysis of safety variables..............................................................43
10.9.1
Adverse events .....................................................................44
10.9.2
Deaths, other serious adverse events .....................................44
10.9.2.1
Death....................................................................................44
10.9.2.2
Serious adverse events..........................................................44
10.9.2.3
Adverse events leading to study treatment discontinuations ..45
10.9.2.4
Other significant adverse events............................................45
10.9.2.5
Summaries of AEs for Clinical Trial data disclosure.............45
10.9.3
Laboratory tests ....................................................................46
10.9.3.1
Laboratory tests over time.....................................................46
10.9.3.2
Marked laboratory abnormalities ..........................................46
10.9.3.3
Marked laboratory hepatic abnormalities ..............................48
10.9.4
Vital signs and body weight..................................................48
10.9.4.1
Vital signs and body weight over time ..................................48
10.9.4.2
Marked blood pressure abnormalities....................................48
10.10
Analysis of quality of life variables ..................................................49
11 GENERAL DEFINITIONS AND DERIVATIONS........................................49
11.1
Study treatment start- and end date...................................................49
11.2
Treatment emergent assessments or events.......................................49
11.3
Study days .......................................................................................49
11.4
Duration in months...........................................................................49
11.5
Baseline definition ...........................................................................49
11.6
Visit windows ..................................................................................49
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11.7
Handling of selexipag/placebo dose titrations between morning and 
evening dose ....................................................................................50
11.8
Derivation of DLPA actigraphy endpoints........................................51
11.9
Scoring the PAH-SYMPACT® questionnaire ...................................52
11.9.1
Symptoms.............................................................................52
11.9.2
Impact ..................................................................................53
12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS .....54
12.1
Imputation of previous/concomitant medication and therapy dates ...55
12.1.1
Previous/concomitant medication and therapy start date........55
12.1.2
Previous/concomitant medication and therapy end date.........55
12.2
Imputation of AE start and end dates................................................55
12.2.1
AE start date.........................................................................55
12.2.2
AE end date..........................................................................56
12.3
Imputation of other date fields..........................................................56
12.3.1
Date of PAH diagnosis..........................................................56
13 REFERENCES ..............................................................................................57
14 APPENDICES ...............................................................................................58
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LIST OF TABLES
Table 1
ActiGraph’s wrist-to-hip count conversion ..................................................15
Table 2
PAH-specific therapies................................................................................18
Table 3
Summary of primary endpoints....................................................................24
Table 4
Overview of the different analysis sets and their usage ................................30
Table 5
Actigraphy assessment time windows..........................................................38
Table 6
Time windows for analysis of association between DLPA endpoints and 
secondary endpoints ....................................................................................43
Table 7
Definition of marked laboratory abnormalities.............................................47
Table 8
Time windows for efficacy assessments, at the exception of actigraphy.......50
Table 9
Time windows for treatment-emergent safety assessments...........................50
Table 10
Illustrative example for handling of selexipag/placebo dose titrations over day
....................................................................................................................51
Table 11
Symptom scores domains ............................................................................53
Table 12
Impact scores domains.................................................................................54
Table 13
Study periods, visits at study site and assessments.......................................69
LIST OF FIGURES
Figure 1
Study design................................................................................................12
Figure 2
Possible patterns of PAH-SYMPACT® period at baseline............................71
LIST OF APPENDICES
Appendix 1 Protocol synopsis and study visit assessment schedule ..............................58
Appendix 2 Baseline for PAH-SYMPACT® Scores......................................................71
Appendix 3 Adverse events of special interest..............................................................73
Appendix 4 Document history......................................................................................74
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LIST OF ABBREVIATIONS AND ACRONYMS
6MWD
6-minute walk distance
6MWT
6-minute walk test
ADaM
Analysis data model
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ANCOVA 
Analysis of covariance
AST
Aspartate aminotransferase 
b.i.d.
Twice daily
BMI
Body mass index
CI
Confidence interval
CRO
Contract Research Organization
CSR
Clinical study report
CYP
Cytochrome P450
DBP
Diastolic blood pressure
DLPA
Daily life physical activity
eCRF
Electronic case report form
EOS
End-of-study
EOT
End-of-treatment
ePRO
Electronic patient reported outcomes
ERA
Endothelin receptor antagonist
EudraCT
European union drug regulating authorities clinical trials
FAS
Full Analysis Set
FC
Functional class
GGT
Gamma-glutamyltransferase
HIV
Human immunodeficiency virus
HTD
Highest tolerated dose
IMD
Individual maintenance dose
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IMTD
Individual maximum tolerated dose
LDH
Lactate dehydrogenase
LOCF
Last observation carried forward
LVEDP
Left ventricular end diastolic pressure
MedDRA
Medical Dictionary for Regulatory Activities
METs
Metabolic equivalents
MMRM
Mixed model of repeated measures
mPAP
Mean pulmonary arterial pressure
MVPA
Moderate-to-vigorous physical activity (Freedson ‘98)
NT-proBNP
N-terminal pro b-type natriuretic peptide 
PAH
Pulmonary arterial hypertension
PAWP
Pulmonary arterial wedge pressure
PD
Protocol deviation
PDE5i
Phosphodiesterase-5 inhibitor
PDID
Protocol deviation identifier
PPS
Per-Protocol Analysis Set
PT
Preferred term
PVR
Pulmonary vascular resistance
q.d.
Once daily 
RBC
Red blood cell count 
RHC
Right heart catheterization
RMP
Risk management plan
SAE
Serious adverse event
SAF
Safety Analysis Set
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SD
Standard deviation
SDTM
Study data tabulation model 
sGC
Soluble guanylate cyclase
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SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamate-pyruvate transaminase
SMQ
Standardized MedDRA query
SOC
System organ class
TST
Total sleep time
ULN
Upper limit of the normal range
VM
Vector magnitude
WASO
Wake after sleep onset
WBC
White blood cell count 
WHO
World Health Organization
WHO FC
WHO functional class
WHODRUG
WHO drug dictionary
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1
INTRODUCTION
This statistical analysis plan (SAP) describes in detail the derivation of efficacy and safety 
endpoints, the analyses and the presentation of analysis results and data for the clinical 
study report (CSR) of study AC-065A404 (TRACE). 
Study data tabulation model (SDTM) datasets are provided by data management and are 
considered source data. 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-065A404, Final Version 2, dated 5 December 2018

Electronic Case Report Form (eCRF), Version 009, dated 11 April 2019

Protocol deviation code list, Version 4.0, dated 5 February 2020

Pulmonary Arterial Hypertension - Symptoms and Impacts® (PAH-SYMPACT®) 
User Guide Version 1, dated March 2017 

Data Transfer Agreement (ActiGraph), Revision N, dated 21 November 2019

Data Transfer Agreement (Laboratory), Version 8.0, dated 18 September 2019

Data Transfer Agreement (ePRO: PAH-SYMPACT), Version 4.0, dated 13 
September 2019

Selexipag (Uptravi®) EU Risk Management Plan Version 7, dated 7 June 2019

Definition of Marked Abnormalities in Laboratory Data (OTH-000005), Version 09, 
dated 1 November 2017
2
STUDY DESIGN AND FLOW
This section describes the general design aspects of the study. Further details can be found 
in the protocol synopsis in Appendix 1.
2.1
Study design
This is a multi-center, double-blind, placebo-controlled, Phase 4 study in patients with 
pulmonary arterial hypertension to assess the effect of selexipag on daily life physical 
activity and patient’s self-reported symptoms and their impacts.
After signing informed consent, establishing study eligibility and a 14-day screening phase, 
patients will provide baseline efficacy data for 14 days before they return to the site for the 
baseline visit. At baseline visit, patients will be randomized in a 1:1 ratio to either selexipag 
or placebo double-blind treatment. Study drug will be up-titrated in weekly intervals to the 
highest tolerated dose, i.e., individual maximum tolerated dose (IMTD) after 12 weeks of 
treatment. At Week 16, the interim visit, and Week 24, the end of treatment (EOT) visit, 
the patients will return to the study center for efficacy and safety assessments. At Week 24, 
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during the EOT visit, study treatment will be discontinued. If the investigator believes that 
it is in the best patient’s interest to transition to commercial selexipag (Uptravi®), in order 
to maintain the study treatment allocation blinded the patient will initiate Uptravi according 
to recommendations in the country specific approved labelling and Uptravi will be 
re-up-titrated under clinician’s guidance. An end-of-study phone call will be made at the 
end of the safety follow-up phase 30 days after the EOT visit.
Figure 1
Study design
2.2
Study visit and assessment schedule
For the detailed visit assessment schedule refer to Table 13 in Appendix 1.
3
OBJECTIVES
3.1
Primary objective(s)
The primary objective of this study is to evaluate the effect of selexipag on daily life 
physical activity (DLPA) of patients with PAH.
3.2
Secondary objectives
The secondary objectives of this trial are:

To evaluate the effect of selexipag on PAH symptoms and the impact on patients’
daily life
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
To evaluate the effect of selexipag on exercise capacity and disease severity in 
patients with PAH 

To evaluate the safety and tolerability of selexipag in patients with PAH
3.3
Other objectives
Other objectives of this trial are to:

Explore potential association between traditional efficacy outcomes and DLPA

Explore the levels and level changes of biomarkers potentially associated with PAH
4
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN 
THE STUDY PROTOCOL 
4.1
Changes to the analyses planned in the study protocol
4.1.1
Concomitant therapies
Protocol section 5.2.1 defines concomitant therapies as study concomitant therapies, i.e.,
all therapy given at or after signature of informed consent are considered concomitant. An 
analysis using this definition would consider medications taken during the screening period 
as concomitant, which provides little scientific value. In this analysis, previous (i.e., ending 
prior to first study treatment intake), baseline concomitant, and concomitant (i.e., starting 
after first study treatment intake) medications will be analyzed. This approach is better 
suited to describing the population in terms of background therapy additional to study 
treatment and changes to the therapy during study drug intake [see details in Section 5.2.4].
4.1.2
Treatment emergent definition and 30 days safety follow-up 
According to protocol section 6.2, adverse events (AEs) and serious adverse events (SAEs) 
from screening and up to 30 days after study treatment discontinuation are collected. The 
treatment-emergent AE definition refers to an AE which starts after study drug initiation 
and up to 3 days after end of study treatment, which is in line with the selexipag standard
treatment emergent definition based on the consideration of the pharmacological half-life 
of selexipag’s major metabolite (6.2–13.5 hours) and the analyses of previous selexipag 
clinical trials.
4.1.3
Sub-group analyses
Protocol section 11.3.2.5 defines the subgroup analyses that will be performed by region 
as a randomization stratification factor, i.e., and North America versus Europe/rest of the 
world. However, most patients are enrolled in the UK. The subgroup analyses will be based 
on UK versus non-UK. The originally planned subgroup by region North America versus 
Europe/rest of the world analysis will not be performed nor used in ANCOVA model.
4.2
Changes in the conduct of the study / data collection
None.
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4.3
Clarifications concerning endpoint definitions and related variables or 
statistical methods
4.3.1
Windowed actigraphy data analysis
Protocol section 11.3.2 states that actigraphy data collected after Day 168/EOT will not be 
used in the tabular summaries. This time limit does not include the allowed assessment 
window of −4 to +14 days during which the Week 24 visit should be conducted. For the
actigraphy analysis, the EOT value of the actigraphy values will be the average of the last 
14 days prior to the last dose of study drug, regardless of when the last dose is taken, i.e., 
before, at, or after EOT.
4.3.2
DLPA actigraphy endpoints
The protocol lists various actigraphy DLPA endpoints derived from the ActiGraph GT9X 
Link accelerometer data. The ActiGraph accelerometer measures accelerations in 3 axes
(x-, y-, z-axis) at a sampling rate of 30 Hz. These raw acceleration data are processed in 
epochs of 60-seconds to generate activity counts per minute for each axis and for vector 
magnitude (sqrt [countsx2 + countsy2 + countsz2]) by ActiGraph’s proprietary algorithms. 
The activity counts per minute are further summarized to daily values for each patient. In 
addition, each minute is classified as “wear” or “non-wear” and as well as for “awake” or 
“asleep”. Wear time and non-wear time are classified by applying the Troiano algorithm
[Troiano 2008]. Time awake and time asleep are classified by applying the Tudor-Locke 
algorithm [Tudor-Locke 2014].
The daily values, defined in the Data Transfer Agreement between ActiGraph and 
Actelion, are the basis for all DLPA endpoints including those for sleep.
4.3.2.1
Daily time spent in non-sedentary activity 
For the purpose of the analyses, sedentary behavior is defined by an energy expenditure of 
≤1.5 metabolic equivalents (METs) [Tremblay 2010]. Accordingly, non-sedentary 
activities considered all activities that are characterized by an energy expenditure of 
> 1.5 METs. Two thresholds for accelerometer-based activity counts corresponding to 
non-sedentary activities, i.e., > 1.5 METs, have been previously established:

≥ 100 y-axis counts per minute measured by a single-axis hip-worn ActiGraph 
accelerometer [Matthews 2008]. This is often referred to as one of the Freedson 98 
thresholds in addition to those for light, moderate, vigorous and very vigorous 
activities [Freedson 1998].

≥ 1853 vector magnitude (VM) counts per minute measured by a triaxial ActiGraph 
accelerometer worn at the non-dominant wrist [Koster 2016].
In TRACE, the ActiGraph accelerometer is worn at the non-dominant wrist. Therefore,
ActiGraph will apply a conversion algorithm from wrist counts to hip counts before
applying the Freedson thresholds. The conversion algorithm is shown in Table 1:
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Table 1
ActiGraph’s wrist-to-hip count conversion
Wrist counts (WC)
Equivalent (hip) counts (EC)
WC as a function of EC 
0 – 644 
WC × 0.5341614
EC / 0.5341614
645 – 1272 
WC × 1.7133758 – 759.414013
(EC+759.414013) / 1.7133758
1273 – 3806 
WC × 0.3997632 + 911.501184
(EC-911.501184) / 0.3997632
3807 – infinity 
WC × 0.0128995 + 2383.904505
(EC-2383.904505) / 0.0128995
Color coding: each color corresponds to a different Conversion Rule 
Adapted from https://actigraphcorp.force.com/support/s/article/What-does-the-Worn-on-Wrist-option-do-in-the-
Scoring-tab
The measurement of physical activity (PA) at the hip excludes manual PA, which may be 
a surrogate for QoL and mental health. Therefore, PA measured at the wrist is different 
from PA measured at the hip. It is unclear how well the wrist-to-hip conversion of activity 
counts takes the inherent difference between hip and wrist PA into account. No conversion 
is required for the 1853-VM count threshold. Since TRACE is an exploratory study, time 
spent in non-sedentary activity will be analyzed using both thresholds.
4.3.2.1.1 Daily time spent in moderate-to-vigorous physical activity 
Time spent in moderate-to-vigorous physical activity (MVPA) is a fraction of time spent 
in non-sedentary activity. A recent communication by Bellerophon Therapeutics on the 
positive outcome of a Phase 2b clinical trial using the endpoint of daily time spent in 
MVPA [Nathan 2019] led to the decision to analyze MVPA in TRACE. Bellerophon’s trial 
used a wrist-worn ActiGraph accelerometer, and MVPA was determined based on the 
Freedson 98 thresholds after count conversion from wrist to hip (see above). The threshold 
for MVPA is ≥ 1952 y-axis hip activity counts per minute corresponding to ≥2603 y-axis 
wrist activity counts per minute. 
4.3.2.2
Total DLPA in counts/min
Total DLPA refers to the daily total activity counts obtained during the awaking time while 
the device was worn. To consider the acceleration data obtained from the wrist for all 
3 axes, VM counts per minute will be analyzed.
4.3.2.2.1 Total DLPA in counts/min performed in non-sedentary activities
Total DLPA performed in non-sedentary activities is a fraction of the total DLPA in 
counts/min. Total DLPA performed in non-sedentary activities refers to the daily total VM 
activity counts per minute obtained during each minute of awaking time for which the 
device was worn and the VM counts per minute were ≥ 1853 counts [Koster 2016].
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4.3.2.2.2 Total DLPA in steps per day
A recent study in 30 patients with PAH found that the change in daily step count correlated 
with a change in 6MWD (r = 0.43, p = 0.05) [Sehgal 2019]. ActiGraph’s proprietary step 
counting algorithm will be used to analyze number of steps per day.
4.3.2.3
Sleep
Various algorithms are applied by ActiGraph to derive sleep variables. 
Sleep episodes are determined by the Cole-Kripke Sleep Scoring Algorithm and may occur 
throughout the day [Cole 1992]. Sleep episodes of the night may be more relevant for the 
evaluation of sleep characteristics due to the circadian rhythm. Therefore, only sleep 
episodes starting from 7:00 pm to 06:59 am and ending no later than 11:59 am are 
considered in the analyses. To exclude non-wear time during sleep, each sleep episode 
must include at least 15 epochs with non-zero activity counts. The sleep variables, i.e., total 
sleep time, wake after sleep onset, and sleep efficiency, are obtained by applying the 
Tudor-Locke algorithm to each minute of a sleep episode [Tudor-Locke 2014].  
5
DEFINITIONS OF VARIABLES
5.1
Screening failures
Screened patients are patients who received a patient number. Screen failures are patients 
who received a patient number but are not randomized. 
If a patient is screened but not randomized, the reason for screen failure has to be collected 
in the eCRF. If a patient is re-screened and fails again, only the last reason for screening 
failure is analyzed.
5.2
Patient characteristics
5.2.1
Demographics
Demographics is collected at baseline and comprise age, sex, race, ethnicity, geographical 
region, systolic blood pressure (SBP), diastolic blood pressure (DBP), height and weight. 
Body-mass index (BMI) will be computed. 
5.2.2
Baseline disease characteristics
Etiology of PAH, association of PAH with other diseases, and WHO functional class 
(WHO FC) are collected at baseline. The time since the initial diagnosis of PAH at the 
randomization date will be computed.
The documented results from the most recent right heart catheterization (RHC) confirming 
the diagnosis of PAH are collected: Mean pulmonary arterial pressure (mPAP), pulmonary 
arterial wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP), and 
pulmonary vascular resistance (PVR). The time since the most recent RHC at the 
randomization will be computed.
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A 6-minute walk test (6MWT) is performed at baseline. The Borg dyspnea score is assessed 
at the end of the test.
The baseline concomitant PAH specific therapy [see Section 5.2.4.2] will be summarized 
by category [see Table 2] in addition.
5.2.3
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 is ongoing at screening visit or not.
Previous diseases are diseases which ended prior to the screening visit. 
Study concomitant diseases are diseases which started prior to screening visit but were 
ongoing at the date of screening visit.
Medical history terms are coded using the most current version of the MedDRA dictionary 
at the time of the database closure.
5.2.4
Previous and concomitant therapies
All previous/concomitant therapies are coded using the WHODRUG dictionary.
5.2.4.1
Previous therapies
Previous therapies are any treatments for which the end date of treatment is prior to the 
first dose of study treatment. 
All therapies which ended within 90 days prior to signature of informed consent are entered 
in the eCRF.
5.2.4.2
Baseline concomitant therapies
Baseline concomitant therapies are treatments that are initiated prior to start of study 
treatment and ongoing at the start date of study treatment.
5.2.4.3
Concomitant therapies initiated during the study treatment period
Concomitant therapies initiated during the study treatment period are therapies which were 
started with the study treatment or therapies which were started after the start of study 
treatment and before the last dose of study treatment.
5.2.4.4
PAH specific previous or concomitant therapies
All PAH specific previous or concomitant therapies are categorized by their mode of action
(i.e., subcategory) as specified in Table 2 below. 
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Table 2
PAH-specific therapies
Category
Subcategory
(mode of action)
Ingredient names
Antihypertensives for 
pulmonary arterial hypertension
ERAs
Ambrisentan, Bosentan, Sitaxentan, Macitentan 
PDE-5 inhibitors
Sildenafil, Tadalafil, Vardenafil
sGC stimulator
Riociguat 
Prostanoids 
Epoprostenol, Treprostinil, Iloprost, Beraprost  
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.
Sitaxentan has been removed from the market due to concerns about liver toxicity.
5.3
Study treatment exposure and compliance
Selexipag and placebo administered in double-blind fashion are considered as study drugs 
for this analysis. 
5.3.1
Exposure
Study treatment is administered through two dosing periods. 

A titration period that starts at the day of randomization with the evening dose of a 
twice daily (b.i.d.) oral dose of 200 mcg, which is up-titrated on a weekly basis 
thereafter until the IMTD (maximum possible dose at 1600 mcg b.i.d.) is reached. 
The titration period ends at Day 86.

A maintenance period, that follows the titration period, during which the dose of 
Selexipag/Placebo is maintained constant except dose adjustment for safety. The 
maintenance period starts at Day 87 and ends with the last dose of study treatment.
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 and the last dose of selexipag/placebo medication, regardless of 
interruptions or titrations.
5.3.1.1
Individual maximum tolerated dose (IMTD)
The IMTD with unit mcg b.i.d is defined as the study drug dose taken by the patient at 
Day 87. If patients with study drug discontinuation prior to Day 87: 1) IMTD is defined as 
the highest daily dose (b.i.d) without reason for stop this dose level "dose reduction" or 
"discontinuation", or 2) If the daily dose (b.i.d) is only 200 mcg (i.e. no up-titration 
attempted) with the above reasons, IMTD is defined as zero.
If different doses of study drug are used on Day 87, the average dose is considered. If a 
patient receives study drug once daily (q.d.) instead of b.i.d., the following rule will be 
applied:
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
During the concomitant treatment of moderate cytochrome P450 (CYP) 2C8 inhibitor
(e.g., drug categorized in moderate or higher in the standardized drug grouping ): 
Dose X mcg q.d. will be considered as equivalent to X mcg b.i.d. due to the drug-
drug interaction.

No concomitant treatment of moderate CYP2C8 inhibitor: Dose X mcg q.d. will be 
considered as equivalent to X/2 mcg b.i.d.
5.3.1.2
Individual maintenance dose (IMD)
For patients who enter the maintenance period, the IMD is defined as the daily study drug 
dose (mcg b.i.d.) to which the patient is exposed to for the longest time (i.e., maximum 
number of days including the interruptions) during the maintenance period, i.e., after 
Day 87. If more than one study drug dose corresponds to the maximum number of days 
during maintenance period, the highest dose is analyzed.
For patients with the last study drug dose intake prior to the maintenance period, the IMD 
is the highest study drug dose which did not lead to study drug discontinuation or down 
titration, regardless of the reasons for study treatment dose end on dose record(s) before or 
after the highest dose.
For patients who received only the lowest study drug dose level of 200 mcg b.i.d., the IMD 
is 200 mcg if study drug was not discontinued prematurely; otherwise it is set to 0 mcg.
For each patient, the following study drug doses (mcg b.i.d.) will be analyzed:

Highest and weighted-average study drug dose in the titration period

Highest and weighted-average study drug dose in the maintenance period (for patients 
who entered this period)

Highest and weighted-average study drug dose in the entire treatment period.

IMTD

IMD
Weighted-average dose is computed with weighting on the amount of time exposed to each 
study drug dose according to the drug log eCRF.
5.3.2
Compliance with study treatment
Compliance will be assessed as described in the study protocol. Compliance below 80% or 
above 120% will be reported as a protocol deviation based on the monitoring methodology.
5.3.3
Study treatment discontinuation 
Patients who completed study [see Section 5.4] and who did not discontinue study drug 
prematurely are considered study treatment completers.
Premature discontinuations of study drug are recorded on a specific page in the eCRF. The 
primary reason for study drug discontinuation will be collected as well.
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5.3.4
Study treatment adjustments or interruptions
The study treatment log eCRF page collects start date, end date, dose and frequency of 
study treatment. The reason for study drug adjustments, interruptions or discontinuations 
is recorded for the termination of each dose record.
5.4
Study discontinuation
Patients completing study will be derived from the SDTM DS data panel. 
For patients who prematurely discontinue the study, the associated reason(s) is entered in 
the eCRF.
5.5
Efficacy variables
Actigraphy assessments will be generated for each day by Actigraph® algorithms and 
included in the SDTM datasets.
Scores from the PAH-SYMPACT® electronic patient reported outcomes (ePRO) diary will 
be included in the SDTM datasets. Domain scores will be generated by analysis 
programming.
Results from the 6MWT and WHO FC are entered by the investigator in the eCRF. 
N-terminal pro b-type natriuretic peptide (NT-proBNP) is assessed by the central lab.
These will be transferred in the SDTM 
5.5.1
Primary efficacy variables
5.5.1.1
Actigraphy DLPA endpoints in protocol
The study is designed as exploratory, and all actigraphy variables are listed under primary 
endpoints.
The primary efficacy variables, as defined in the protocol, include the change from baseline 
to Week 24 or EOT in actigraphy-assessed DLPA as measured by:

Daily time spent (minutes) in non-sedentary activity (≥100 counts per minute). 

Percentage of daily time spent in non-sedentary activity (≥100 counts per minute)

Total DLPA in counts/min

Sleep: Total sleep time (TST; minutes), wake after sleep onset (WASO; minutes), 
number of awakenings, sleep efficiency (percentage)
The protocol defined thresholds based on the Freedson’s the uniaxial hip worn 
accelerometer counts [Freedson 1998]. This study is using the wrist worn accelerometer at 
the non-dominant wrist, and a conversion factors are applied according to Table 1.
The measurement of physical activity (PA) may not fully measure hand movement-related
PA, which could capture relevant information for QoL and mental health. Therefore, PA 
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measured at the wrist may differ from PA measured at the hip, despite existing conversion 
rules.
On the other hand, no conversion is required for the Koster’s non-sedentary activity
threshold, which is measured by a triaxial ActiGraph accelerometer worn at the 
non-dominant wrist. 
Since TRACE is an exploratory study, time spent in non-sedentary activity will be analyzed 
using both Freedson and Koster algorithms.
In addition, a recent communication by Bellerophon Therapeutics on the positive outcome 
of a Phase 2b clinical trial using the endpoint of daily time spent in MVPA led to the 
decision to analyze MVPA in TRACE. In response to FDA feedback for another Actelion 
studies, i.e., AC-055H301 (RUBATO) and macitentan 75 mg in CTEPH (NDA 204410), 
the volume of non-sedentary activity, including number of steps, has also been added to 
the TRACE CSR SAP and will be analyzed [see details in Section 4.3.2].
The full details of the actigraphy additional DLPA endpoints are provided in the next 
section and summarized in table 3. 
5.5.1.2
DLPA actigraphy endpoints
The following primary efficacy endpoints are used in this SAP.
1)
Change from Baseline to Week 24/EOT in daily time spent in non-sedentary activities 
(minutes) – Freedson
Definition: Daily time spent in non-sedentary activities (minutes) defined as ≥100 y-
axis hip counts per minute (i.e., ≥ 187 y-axis wrist converted counts per minute). This 
is the sum of time spent (minutes) in light, moderate, vigorous, and very vigorous 
activities during wear and awake time per day.
2)
Change from Baseline to Week 24/EOT in daily time spent in MVPA (minutes) –
Freedson
Definition: Daily time spent in MVPA (minutes) defined as ≥1952 y-axis hip counts 
per minute (i.e., ≥ 2603 y-axis wrist converted counts per minute). This is the sum of 
time spent (minutes) in moderate, vigorous, and very vigorous activities during wear 
and awake time per day.
3)
Change from Baseline to Week 24/EOT in daily time spent non-sedentary activities 
(minutes) – Koster
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Definition: Daily time spent in non-sedentary activities (minutes) defined as 
≥1853 triaxial vector magnitude (VM) counts per minute. This is the sum of time 
spent (minutes) in non-sedentary activities during wear and awake time per day.
4)
Change from Baseline to Week 24/EOT in percentage of daily time spent in non-
sedentary activities – Freedson
Definition: Percentage of daily time spent in non-sedentary activities (≥ 187 y-axis
wrist converted counts per minute) defined as the sum of time spent (minutes) in light, 
moderate, vigorous, and very vigorous activities during wear and awake time divided
by daily total wear and awake minutes.
5)
Change from Baseline to Week 24/EOT in percentage of daily time spent in MVPA –
Freedson
Definition: Percentage of daily time spent in non-sedentary activities (≥ 2603 y-axis
wrist converted counts per minute) defined as the sum of time spent (minutes) in 
moderate, vigorous, and very vigorous activities during wear and awake time divided 
by daily total wear and awake minutes.
6)
Change from Baseline to Week 24/EOT in percentage of daily time spent in 
non-sedentary activities – Koster
Definition: Percentage of daily time spent in non-sedentary activities (≥1853 triaxial
VM counts per minute) defined as the sum of time spent (minutes) in non-sedentary 
activities during wear and awake time divided by daily total wear and awake minutes.
7)
Change from Baseline to Week 24/EOT in volume of total activity (counts/minutes)
Definition: Volume of total activity counts/minute defined as sum of triaxial vector 
magnitude counts during wear and awake time per day divided by daily total wear and 
awake minutes.   
8)
Change from Baseline to Week 24/EOT in volume of non-sedentary activity during 
awake time (counts, computed over one day [24 hours]) – Koster
Definition: Volume of non-sedentary activities defined as sum of counts above the 
sedentary threshold (≥ 1853 triaxial VM counts per minute) during wear and awake 
time per day.  
9)
Change from Baseline to Week 24/EOT in volume of non-sedentary activity during 
awake time, per awake time (counts/minute, computed over one day [24 hours]) –
Koster
Definition: Volume of non-sedentary activities defined as sum of counts above the 
sedentary (≥ 1853 triaxial VM counts per minute) during wear and awake time per day 
divided by daily total wear and awake minutes.
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10) Change from Baseline to Week 24/EOT in number of steps during awake time (step 
counts, computed over one day [24 hours])
Definition: Number of steps during wear and awake time per day.
11) Change from Baseline to Week 24/EOT in number of steps during awake time, per 
awake time (step counts/minute, computed over one day [24 hours])
Definition: Number of steps during wear and awake time per day divided by daily total
wear and awake minutes.
The detailed analysis methods of the DLPA actigraphy endpoints are specified in 
Section 10.6. The derivation of DLPA actigraphy endpoints from the ActiGraph daily 
summary parameters are specified in Section 11.8
5.5.1.3
Sleep endpoints 
The following sleep variables are used:
12) Change from Baseline to Week 24/EOT in TST (minutes)
13) Change from Baseline to Week 24/EOT in WASO (minutes)
14) Change from Baseline to Week 24/EOT in number of awakenings (counts)
15) Change from Baseline to Week 24/EOT in sleep efficiency (percentage)
Sleep endpoints will be provided on a by-episode basis by the Actigraphy provider. To 
capture the impact of the study medication on night-time sleep endpoints, only sleep 
episodes beginning between 7:00 pm and 6:59 am and ending no later than 11:59 am will 
be used as valid episodes at night for the definition of the sleep endpoints. 
Some patients may have multiple sleep episodes in a night. For TST, WASO, and number 
of awakenings, the assessments of eligible episodes will be summed up for each night.  The 
sleep efficiency endpoint will be assigned to an analysis night as described before. Sleep 
efficiency will be summarized on a sleep episode basis but will not be summed up for a 
nightly value. 
This algorithm is, however, exploratory, as no known literature data currently provide 
robust information about the derivation of actigraphy sleep-related endpoints. This might 
lead to be biased results, and this will be further discussed in the final report. The sleep 
endpoints may show less association with the secondary endpoints. All sleep endpoints will 
be only summarized descriptively. 
The summary of primary endpoints shows in the Table 3.
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Table 3
Summary of primary endpoints
Primary endpoints (in SAP)
Unit
Algorithm
DLPA/
Sleep
Rationale
Endpoints 
(as 
per 
written 
in 
protocol) 
1) Change from Baseline to 
Week 24/EOT in daily time 
spent in non-sedentary 
activities
min
Freedson 
1998
DLPA
As per 
protocol
Change from baseline to Week
24/EOT in actigraphy-assessed DLPA 
as measured by daily time spent 
(minutes) in non-sedentary activity 
(≥100 activity counts per minute)
2) Change from Baseline to 
Week 24/EOT in daily time 
spent in MVPA
min
Freedson
1998
DLPA
Same as 
Bellerophon
n.a.
3) Change from Baseline to 
Week 24/EOT in daily time 
spent non-sedentary activities
min
Koster 2016
DLPA
More 
reliable 
n.a.
4) Change from Baseline to 
Week 24/EOT in percentage 
of daily time spent in non-
sedentary activities
%
Freedson 
1998
DLPA
As per 
protocol
Change from baseline to Week 
24/EOT in actigraphy-assessed DLPA 
as measured by percentage of daily 
time spent in non-sedentary activity 
(≥100 activity counts per minute)
5) Change from Baseline to 
Week 24/EOT in percentage 
of daily time spent in MVPA
%
Freedson 
1998
DLPA
same as 
Bellerophon
n.a.
6) Change from Baseline to 
Week 24/EOT in percentage 
of daily time spent in non-
sedentary activities
%
Koster 2016
DLPA
more 
reliable 
n.a.
7) Change from Baseline to 
Week 24/EOT in volume of 
total activity counts/minutes
counts
/ min
n.a.
DLPA
As per 
protocol
Change from baseline to Week 
24/EOT in actigraphy-assessed DLPA 
as measured by total DLPA in 
counts/min
8) Change from Baseline to 
Week 24/EOT in volume of 
non-sedentary activity during 
awake time (counts, computed 
over one day [24 hours])
counts
Koster 2016
DLPA
FDA 
feedback in 
other studies
n.a.
9) Change from Baseline to 
Week 24/EOT in volume of 
non-sedentary activity during 
awake time, per awake time 
(counts/minutes, computed 
over one day [24 hours])
counts
/ min
Koster 2016
DLPA
FDA 
feedback in 
other studies
n.a.
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Primary endpoints (in SAP)
Unit
Algorithm
DLPA/
Sleep
Rationale
Endpoints 
(as 
per 
written 
in 
protocol) 
10) Change from Baseline to 
Week 24/EOT in number of 
steps during awake time 
(counts, computed over one 
day [24 hours])
steps
n.a.
DLPA
FDA 
feedback in 
other studies
n.a.
11) Change from Baseline to 
Week 24/EOT in number of 
steps during awake time, per 
awake time (counts/minutes, 
computed over one day [24 
hours])
steps/ 
min
n.a.
DLPA
FDA 
feedback in 
other studies
n.a.
12) Change from Baseline to 
Week 24/EOT in TST 
min
n.a.
sleep
As per 
protocol
Change from baseline to Week 
24/EOT in actigraphy-assessed DLPA 
as measured by Sleep: TST (minutes), 
WASO 
(minutes), 
number 
of 
awakenings, efficiency (percentage)
13) Change from Baseline to 
Week 24/EOT in WASO 
min
n.a.
sleep
As per 
protocol
14) Change from Baseline to 
Week 24/EOT in number of 
awakenings
counts
n.a.
sleep
As per 
protocol
15) Change from Baseline to 
Week 24/EOT in sleep 
efficiency
%
n.a.
sleep
As per 
protocol
DLPA = daily life physical activity; EOT = End-of-Treatment; MVPA = n.a. = not applicable; TST = total sleep time; 
WASO = wake after sleep onset; Moderate to Vigorous Physical Activity (Freedson ‘98).
5.5.2
Secondary efficacy variables
5.5.2.1
PAH-SYMPACT® domain scores:
Change from baseline to Week 24 or EOT in:

Cardiovascular symptom domain score

Cardiopulmonary symptom domain score

Physical impact domain score

Cognitive/emotional impact domain score
5.5.2.2
WHO functional class
Shift from baseline to Week 24 or EOT in WHO FC.
5.5.2.3
6-minute walk test
Change from baseline to Week 24 or EOT for following variables:

6-minute walk distance (6MWD)

Borg dyspnea index during 6MWT
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5.5.2.4
N-terminal pro b-type natriuretic peptide (NT-pro BNP)
Change from baseline to Week 24 or end of treatment for NT-proBNP.
The detailed analysis methods for secondary efficacy variables are specified in 
Section 10.7.
5.5.3
Variables used for correlation analyses
These variables will consist of:

Actigraphy DLPA variables and other secondary efficacy endpoints. For this CSR,
correlations between secondary efficacy endpoints and DLPA actigraphy endpoints 
are planned (detailed analysis methods are specified in Section 10.8). A more detailed 
analysis of associations (i.e., anchoring variables) will be described in a separate 
document.
5.6
Safety variables
Safety endpoints as stipulated in the protocol comprise:

Treatment-emergent AEs and treatment-emergent SAEs up to 3 days after study 
treatment discontinuation.

AEs leading to discontinuation of study treatment.

Change from baseline in vital signs (systolic and diastolic arterial blood pressure and 
pulse rate) and body weight from baseline to all assessed time points during the study.

Treatment-emergent marked laboratory abnormalities up to 3 days after study 
treatment discontinuation.

SAEs and Deaths up to 30 days after study treatment discontinuation. 
5.6.1
Adverse events
All AEs will be coded using the MedDRA dictionary in its latest version at time of database 
closure. 
5.6.1.1
Treatment-emergent adverse events
Treatment-emergent AEs are defined as those AEs occurring from study treatment start up 
to 3 days after end of study treatment.
5.6.1.2
Frequency of treatment-emergent adverse events
Treatment-emergent AEs reported more than once within a patient, are counted in the 
frequency table once. 
5.6.1.3
Intensity of treatment-emergent adverse events
For treatment-emergent AEs reported more than once within a patient, the worst intensity
is considered.
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5.6.1.4
Relationship of treatment-emergent adverse events
Relationship to study treatment is defined as ‘related’ or ‘not related’ as judged by the 
investigator. For treatment-emergent AEs reported more than once within a patient, the 
worst relationship is considered (i.e., related). Adverse events with missing relationship are 
considered in any analysis as related.
5.6.2
Deaths
The primary reason for death is reported on a specific eCRF page. SAEs leading to death 
are marked on the AE eCRF form. 
5.6.3
Serious adverse events
SAEs are all AEs that have been marked as serious by the investigator or where the 
seriousness assessment is missing in the database.
5.6.4
Adverse events leading to discontinuation of study treatment
AEs where action taken with study treatment is “Drug withdrawn” are analyzed as AEs 
leading to discontinuation of study treatment.
5.6.5
Other significant adverse events
5.6.5.1
AEs of special interest (AESIs) based on the selexipag risk management plan 
(RMP)
The adverse events of special interest (AESIs) will be retrieved using preferred terms (PTs) 
or standardized MedDRA queries (SMQs). The latest available categories are described in
Appendix 3. A list of MedDRA terms for the identified/potential risks of selexipag will be 
provided by Actelion drug safety for each update of the RMP and/or MedDRA version.
5.6.5.2
AEs typical of prostanoid treatments
The AEs typical of prostanoid treatments will be retrieved from the database 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.
5.6.5.3
Non-serious AEs
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. 
5.6.6
Vital signs and body weight
Body weight, SBP, DBP, and pulse rate are collected at each study visit at the site. BMI 
will be derived at each visit.
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Treatment-emergent vital signs and body weight assessments up to 3 days after study 
treatment discontinuation will be analyzed.
5.6.7
Electrocardiogram
Not applicable.
5.6.8
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 or 
emergency 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. 
In the analysis only central laboratory values will be used. If a central laboratory value is 
not available but a local laboratory assessment is available, the local laboratory value will 
be used to account for lost or non-analyzable samples in the central laboratory. 
A basic panel for hematology and biochemistry will be evaluated:
Hematology: White blood cell count (WBC), Hemoglobin, Hematocrit, Red blood cell 
count (RBC), Platelet count, Differential (% and absolute).
Clinical chemistry: Sodium, Potassium, Chloride, Bicarbonate, BUN/Urea, Creatinine, 
Glucose, Calcium, Phosphorus, Magnesium, Total Protein, Albumin, Total Bilirubin, 
Direct Bilirubin, Indirect Bilirubin, AST (SGOT), ALT (SGPT), GGT, Alkaline 
Phosphatase, LDH
Treatment emergent laboratory assessments up to 3 days after study treatment 
discontinuation will be analyzed. Additional laboratory variables collected will be listed 
but not used in summaries.
Marked abnormal laboratory data are determined according to Document OTH-000005
[see Section 1.1].
The detailed analysis methods for safety variables are specified in Section 10.9.
5.7
Quality of life variables
Quality of life endpoints are efficacy endpoints and described in Section 5.5.
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 and databased prior to 
unblinding to the study.
PDs are described in the PD list referred in Section 1.1.
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7
ANALYSIS SETS
7.1
Definitions of analysis sets
7.1.1
Screened analysis set
This analysis set will include all patients who were screened and received a patient number.
7.1.2
Full analysis set 
The Full Analysis Set (FAS) will include all patients randomly assigned to a study 
treatment. In order to adhere to the intention-to-treat principle as much as possible, analyses 
on the FAS will use the following rules:

Patients will be evaluated according to the study treatment they have been assigned to 
(which may be different from the study treatment they have received).

All available data will be included (e.g., including assessments after study treatment 
discontinuation).
7.1.3
Per-protocol analysis set 
The Per-Protocol Analysis Set (PPS) will comprise all patients who received study 
treatment and who complied with the protocol sufficiently to allow assessment of the 
treatment effects. 
Criteria for sufficient compliance include sufficient exposure to treatment, availability of 
measurements and absence of major PDs that have an impact on the treatment effect.
Patients will be excluded from the PPS if they meet at least one of the following criteria:

Patient is not randomized or received treatment different from the treatment it was 
randomized to

Patient prematurely discontinued treatment 

Patient was not consented properly or violated inclusion or exclusion criteria: 
Protocol deviation identifier (PDID) 101, 202 – 247

Patient had insufficient treatment compliance: PDID 405

Forbidden concomitant medication used: PDID 501, 511, 521
Subjects will be evaluated according to the study drug to which they were assigned to.
Patients will be evaluated according to the study drug to which they were assigned to.
Exclusions from the PPS will be identified from the protocol deviation SDTM panel for all 
PDs which have PDIDs. All other exclusions from the PPS will be programmed.
7.1.4
Safety analysis set 
The Safety Analysis Set (SAF) will include all patients who received at least one dose of 
study treatment. The analysis will be based on the actual treatment received. If a patient
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received both selexipag and placebo treatments in error, the patient will be analyzed in the 
selexipag arm.
7.1.5
Other analysis sets
Not applicable.
7.2
Usage of the analysis sets
The usage of the analysis sets is summarized in Table 4 below.
Table 4
Overview of the different analysis sets and their usage
Analyses/Data Displays
Screened analysis 
set
Full analysis 
set
Safety 
analysis set
Per protocol 
set
Patient disposition

Demographics


Baseline characteristics


Medical history

Previous and concomitant 
therapies

Treatment exposure


Efficacy: Primary endpoint


Efficacy: Secondary 
endpoints


Efficacy: Exploratory 
endpoints


Safety endpoints

All other patient listings1

1Unless indicated otherwise
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8
DEFINITION OF SUBGROUPS
Subgroup analyses will be conducted based on relevant demographics or baseline disease 
characteristics.
The following subgroup variables will be used for the analyses:

Region [see Section 4.1.3]
–
UK
–
non-UK

Sex
–
Male
–
Female

WHO functional class at baseline
–
I/II
–
III/IV

Age at screening
–
<65 years
–
≥65 years
Other subgroup variables, in accordance with the AC065A302 (GRIPHON) trial, will be 
used for the analyses if at least 15 patients are contained in each subgroup category:

Baseline concomitant PAH specific therapy
–
No PAH specific therapy
–
Endothelin receptor antagonist (ERA) monotherapy
–
Phosphodiesterase-5 inhibitor (PDE5i) or soluble guanylate cyclase (sGC)
stimulator monotherapy
–
ERA and PDE5i (or sGC stimulator) combination therapy
NOTE: Concomitant use of PDE5is and sGC stimulators is not allowed. 

Race
–
Caucasian
–
Asian
–
Black
–
Other/Unknown

PAH etiology at baseline (group 1)
–
Idiopathic
–
Associated with connective tissue disease
–
Others (i.e. heritable, drug- or toxin-induced, associated with HIV infection, and 
associated with congenital heart disease with simple systemic-to-pulmonary shunt 
≥ 1 year after surgical repair)

PAH etiology at baseline (group 2)
–
Associated with connective tissue disease
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–
Others (i.e. Idiopathic, heritable, drug- or toxin-induced, associated with HIV 
infection, and associated with congenital heart disease with simple systemic-to-
pulmonary shunt ≥ 1 year after surgical repair).
9
GENERAL STATISTICAL METHODOLOGY
All statistical analyses are run by the CRO Datamap GmbH, Freiburg, Germany using 
SAS 9.4 or higher on a SUN Solaris system. 
The analyses of the study data will comprise univariate and multivariate exploratory 
analyses to generate hypotheses on new endpoints. Thus, no difference will be made 
between primary and secondary efficacy analyses.
The methodology below describes the minimum set of planned analyses; the list may be 
expanded depending on data driven findings.
9.1
Statistical models for continuous data
9.1.1
Analysis of covariance
An analysis of covariance model (ANCOVA) including terms for treatment as factor, and 
baseline value as covariate will be fitted to all continuous primary and secondary endpoints 
(except of sleep parameters). The differences in least square means between selexipag and 
placebo, corresponding 2-sided 95% confidence interval (CI), and p-value will be 
provided.
SAS code as shown below will be used; for analysis_dataset, treatment, response, and
baseline the corresponding dataset and variable names will be inserted. 
The stratification factor (i.e., North America versus Europe/Rest of the World) was planned 
to be added to the above ANCOVA model as per protocol. However, only a very few
North Americans were enrolled in this study. In the preceding AC-065A302/GRIPHON 
study, regional differences were only observed in the distribution of PAH-specific 
medication at baseline. Therefore, the stratification factor of North America versus 
Europe/Rest of the world will be removed from the ANCOVA model.  
PROC MIXED DATA=analysis_dataset;
CLASS treatment ;
MODEL response = treatment baseline;
LSMEANS treatment /PDIFF CL ALPHA=0.05;
RUN;
9.1.2
Mixed model analysis with repeated measures
A mixed model analysis of repeated measures (MMRM) will be fitted to continuous DLPA 
related primary endpoints. The model will include terms for baseline value, treatment, visit, 
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and treatment by visit interaction as covariates. Visits will be repeated measures within 
patients with an unstructured covariance matrix. Fixed effect tests will be computed using 
the Kenward-Rogers method to determine the degrees of freedom of the denominator. An 
unstructured variance-covariance matrix will be used for observations clustered by patient. 
In case of convergence problems, alternative variance-covariance structures will be 
evaluated in the following order, with the first structure that converges being used in the 
analysis: heterogeneous Toeplitz, standard Toeplitz, and AR(1) with separate patient
random effect.
The overall and by-visit differences in least square means between selexipag and placebo, 
corresponding 2-sided 95% CI, and p-value will be provided using appropriate contrasts.
SAS code as shown below will be used; for analysis_dataset, visit, patient id, treatment, 
response and baseline, the corresponding dataset and variable names will be inserted. 
PROC MIXED DATA=analysis_dataset;
CLASS treatment visit subj_id;
MODEL response = treatment visit treatment*visit baseline /DDFM=KR;
REPEATED visit / SUBJECT=patient_id TYPE=UN;
LSMEANS treatment /cl;
LSMEANS treatment*visit /cl
RUN;
10 STATISTICAL ANALYSES
10.1 Overall testing strategy
This study is designed as exploratory with the purpose to generate hypotheses on new 
endpoints. All analyses performed will be descriptive with summary statistics and 
associated 95% CIs provided when applicable. Any p-value provided as result of a 
statistical model is to be considered as exploratory only.
No adjustment for multiplicity will be performed.
10.2 General rules for data presentations
10.2.1 General guidelines for table contents
Summary statistics for continuous variables will include number of non-missing 
observations (n), mean, standard deviation (SD), median, 1st and 3rd quartiles, minimum,
and maximum. For discrete variables, the number of patients in the respective category and 
the relative frequency (percentage) will be shown. Missing values will be shown as a 
separate category and included in the computation of percentages.
All summaries are presented by treatment arm in the respective population. The order of 
the treatment arms will be ‘Selexipag’ and then ‘Placebo’. Patient disposition, 
demographics, baseline characteristics and exposure summaries will additionally be 
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presented with a ‘Total’ treatment column to convey a summary of the total population 
assessed in this study.
10.2.2 General guidelines for table layout and formats
The guidelines in the Biostatistics Standards Document of the Actelion Standardization 
Project Standard outputs are followed.
Summaries of continuous variables will be 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 standard 
deviation. P-values are presented with 4 decimals. P-values smaller than 0.0001 are 
presented as ‘<0.0001’.
Individual patient listings are ordered by treatment arm (in order “Selexipag”, “Placebo”
and “Not randomized”) country, center, patient number, and assessment date.
10.3 Display of patient disposition, protocol deviations and analysis sets
10.3.1 Patient disposition
The following information will be presented on the screened analysis set:

Number of patients screened for inclusion and reason for screen failures

Number of patients randomized

Number of patients treated with study treatment

Number of patients who completed and discontinued study treatment

Reasons for study treatment discontinuation

Number of patients who completed and discontinued the study

Reasons for study discontinuation.
Reasons for screen failure will be listed on the screened set. Treatment completion status 
and study completion status (i.e., completed or withdrawn together with reason for 
withdrawal) as well as randomization information will be listed on the FAS.
10.3.2 Protocol deviations
The number and percentage of patients with PDs (PDs leading to exclusion from the PPS, 
important PDs, and all PDs) will be summarized as defined in Section 6 on the FAS. 
All PDs will be listed on the screened set. PDs leading to exclusion from an analysis set 
will be flagged.
10.3.3 Analysis sets
The number and percentage of patients included in each analysis set will be summarized 
on the FAS. The reasons for exclusion from any analysis set will be presented.
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10.4 Analyses of patient characteristics
Patient characteristics will be analyzed on the FAS and PPS.
10.4.1 Demographics
Baseline demographics as described in Section 5.2.1 will be summarized with descriptive 
statistics. Age will be analyzed as a continuous variable and as a categorical variable with 
categories < 18 (if applicable), 18–64, ≥ 65 years. 
The summary will be conducted for all patients and by subgroup. All demographics will 
be listed.
10.4.2 Baseline disease characteristics
Baseline disease characteristics as described in Section 5.2.2 will be summarized 
descriptively. The time since the initial PAH diagnosis will be summarized in months as a 
continuous variable.
The baseline concomitant PAH specific treatment will be summarized by the number of 
medications taken concomitant to baseline (one, two, ≥three and the categories shown in 
Table 2.
Results from the most recent RHC will be converted into standard units, if necessary. The 
time since the most recent RHC will be summarized in months.
Baseline 6MWD (in meters) and the Borg dyspnea score will be summarized as a 
continuous variable.
Baseline concomitant therapies and PAH specific therapies will be summarized [see 
Section 10.4.4].
The summary will be conducted for all patients and by subgroup. All baseline disease 
characteristics will be listed.
10.4.3 Medical history
Previous diseases will be summarized by MedDRA system organ class (SOC) and PT. 
SOCs and PTs within SOCs will be ordered by descending frequency. A second summary 
will be prepared on the PT level only.
Study concomitant diseases will be analyzed in the same way as previous diseases.
10.4.4 Previous baseline concomitant and concomitant therapies
For study reporting purposes, all previous and study-concomitant therapies are reported in 
the patient listings. 
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Previous therapies, baseline concomitant therapies and concomitant therapies initiated 
during the study treatment period are summarized by therapeutic organ class and preferred 
term. A second summary is prepared by preferred term only.
Previous, baseline concomitant and concomitant PAH specific therapies initiated during 
the study treatment period are summarized by mode of action category [see Table 2] and 
WHODRUG preferred term. 
10.5 Analysis of study treatment exposure and compliance
All exposure analyses are conducted on the SAF and PPS.
10.5.1 Exposure
The definition of the variables analyzed for exposure is given in Section 5.3.1.
Exposure to study treatment will be summarized in days. Furthermore, the number and 
percentage of patients being exposed at least 1, 14, 28, 56, 84, 112, 140, and 168 days will 
be given in categories.
Exposure will be summarized graphically as inverse cumulative distribution function.
The maximum and weighted-average selexipag dose will be summarized as a continuous 
variable for:

The titration period

The maintenance period (for patients entering the maintenance period)

Entire treatment period.
The study drug IMTD and IMD will be summarized with number and percentage of 
patients by each dose category (0 mcg, 200–400 mcg b.i.d., 600–1000 mcg b.i.d., and 
1200–1400 mcg b.i.d.) and each dose level. Study drugs’ IMTD and IMD will also be 
summarized as continuous variable.
Exposure analyses will be presented by subgroup.
10.5.2 Compliance with study treatment
Deviations from treatment compliance will be summarized as PD [see Section 10.3.2].
10.5.3 Study treatment discontinuation 
Study treatment discontinuation is summarized within the patient disposition [see 
Section 10.3.1].
10.5.4 Study treatment adjustments and interruptions
The study drug administration log (start and end dates, dose) will be listed. Reasons for 
study drug interruptions and discontinuations as entered in the eCRF will be given.
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10.6 Analysis of the primary efficacy variables
This is an exploratory study. All actigraphy variable analyses are listed as primary efficacy 
variables in Section 5.5.1.
All actigraphy variables collected between informed consent and end-of-study (EOS) will 
be presented in patient listings.
10.6.1 Hypothesis and statistical model
There will be no confirmatory hypotheses testing in the analysis of this trial.
All statistical testing procedures used, if any, will provide exploratory p-values. CIs will 
be two-sided at the 95% level. No adjustment for multiplicity will be made.
10.6.2 Main analysis
10.6.2.1 Analysis of DLPA actigraphy endpoints
All actigraphy DLPA endpoints (i.e., the endpoints 1 to 11 in Section 5.5.1.2) are treated 
as continuous variables. These are expected to be approximately normally distributed. 
Should there be relevant deviations from normality, appropriate transformation of the data 
(e.g., log transformation, inverse logit, …) may be applied before analysis.
All actigraphy endpoints will be aggregated into 14-day windows for analysis. Baseline 
will be the average of the last 14 days prior to first dose of study drug (Day −1 to Day −14); 
post baseline assessments will be aggregated in 14-day intervals as shown in Table 5.
Likewise, the last 14 days prior to the last dose of study treatment will be used for 
determination of the EOT value. All subjects will have the EOT value, unless subject 
withdrew within a week of treatment start or no actigraphy data available after the study 
Day 7 [see Section 10.6.3 for handling of missing data]. 
If enough valid data have been collected in a time window at an analysis visit [see 
Section 10.6.3 for handling of missing data], the average of the values assessed within the 
time window will be used as analysis value. 
Actigraphy data collection will be independent of actual study visits, e.g., Week 16 data 
will be always be averages between Day 99 and 112, regardless of when the actual study 
visit took place. 
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Table 5
Actigraphy assessment time windows
Analysis Visit
Start Day
End Day
Baseline
−14
−1
Week 2 
1
14
Week 4
15
28
Week 6
29
42
Week 8
43
56
Week 10
57
70
Week 12
71
84
Week 14
85
98
Week 16
99
112
Week 18
113
126
Week 20
127
140
Week 22
141
154
Week 24
155
168
EOT1
Last study treatment
−14 days*
Last study treatment
−1 day*
1 EOT value will be computed out of the last two weeks prior to last study treatment, regardless if the last study 
treatment date was before, at, or after Day 168. 
* EOT will have a valid value. If EOT value based on the period (EOT-14, EOT-1) is missing (not valid), the EOT
period will be rolled back by one day, i.e., (EOT-15, EOT -2), (EOT-16, EOT-3), and so on until a non-missing 
(valid) value is available. The period can be rolled back until (1, 14).
EOT = End-of-Treatment. 
The actigraphy DLPA endpoints will be summarized descriptively for each analysis visit
together with the respective absolute and percentage change from baseline. The number of 
patients with a missing of actigraphy assessments (include invalid assessments) at any 
given visit will be presented as well.
The main analysis, change from baseline to Week 24/EOT in the DLPA actigraphy 
endpoints, will be analyzed using an ANCOVA model with treatment baseline value of the 
actigraphy parameter as covariates. Least squares means of treatment group differences of 
the actigraphy DLPA endpoints as well as the corresponding 95% confidence intervals will 
be provided. Imputation rules are described in Section 10.6.3. The ANCOVA model will 
be applied on the imputed Week 24/EOT values.
The main analysis will be conducted on the FAS.
The sensitivity/supportive analyses and subgroup analyses will be conducted [see details 
in Section 10.6.4 and Section 10.6.4.3].
10.6.2.2 Analysis of Sleep endpoints
The sleep parameters (i.e., the endpoints 12 to 15 in Section 5.5.1.3) are provided on a 
by-episode basis by Actigraph, before being derived for the analysis.
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For the derivation of sleep endpoints, the by-episode data will be transformed for each 
night using the following algorithm: All sleep episodes starting between 7:00 pm and 6:59
am (next day) and ending no later than 11:59 am (next day) will be used. The data for each
actigraphy sleep endpoint will be aggregated to form one single night assessment, with an 
allocated analysis visit day corresponding to the day of evening starting that night, e.g., all 
eligible assessments starting from Day X −1 at 7:00 pm up to Day X 06:59 am will be 
summed up and assigned to the night of Day X −1. Then, baseline and post-baseline night 
assessments will be aggregated into bi-weekly windows for analysis as described in 
Table 5.
For the sleep efficiency, when patients have multiple episodes in a night, the time between 
episodes could be considered as a long awakening period, and it would introduce low 
efficiency per night. However, the device used for this study does not enable patients to 
register their bed-in and bed-out times. The above algorithm may not be reflecting patients’
real sleep patterns. In this SAP, sleep efficiency will be summarized on a sleep episode 
basis, and will not be summed up for a nightly value. Consequently, sleep efficiency per 
analysis visit will be based on all (possibly more than 14) episodes during the 14 nights.
For the sleep endpoints, no ANCOVA model, sensitivity/supportive analysis, nor subgroup 
analyses will be performed. 
10.6.3 Handling of missing data
Actigraphy variables will be considered valid (non-missing) for a specific time window if 
the data are available for at least 7 complete days (consecutive or not) within that time 
window of assessment. 
For DLPA actigraphy endpoints, a complete day is defined as a record of at least 7 awake 
hours of data. If less than 7 complete days are available, the value of the time window will 
be set to missing.
For sleep endpoints, at least one valid episode of any length must be present for each night 
to obtain a valid assessment. Sleep endpoints must be present for at least 7 nights 
(consecutive or not) within each 14-day window; otherwise the value of the time window 
will be set to missing. 
In case of premature discontinuation of study drug, the average of the last non-missing 
14-day window prior to the last dose of study treatment will always be used as an EOT 
value. If the EOT value corresponding to the period (EOT-14, EOT-1) is missing (not 
valid), the EOT period will be rolled back by one day, i.e., (EOT-15, EOT-2), (EOT-16, 
EOT-3), until a non-missing (valid) value is available. This corresponds to a last 
observation carried forward (LOCF) up to Week 24/EOT approach. If no post-baseline 
actigraphy data have been collected for at least 7 days over a 14-day time window, no EOT 
value will be computed, and the post-baseline value will be set as missing.
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10.6.4 Supportive/sensitivity analyses
Supportive and sensitivity analyses will be performed for DLPA actigraphy endpoints. 
10.6.4.1 Supportive analyses
For the endpoints based on Freedson algorithm (i.e., the endpoints 1, 2, 4, and 5 in 
Section 5.5.1.2), the daily time spent and percentage of daily time spent will be also 
summarized descriptively according to activity categories “sedentary”, “light”, 
“moderate”, “vigorous”, and “very vigorous” on the FAS. 
10.6.4.2 Sensitivity analyses
All ANCOVA analyses on the primary efficacy actigraphy endpoints for DLPA will be 
repeated on the PPS.
The additional following sensitivity analyses will be performed on the FAS: all actigraphy
DLPA endpoints will additionally be analyzed using a MMRM model with baseline value, 
treatment, analysis visit, and interaction between treatment and analysis visit as covariates. 
Treatment group differences contrasts will be computed overall and for each analysis visit
(i.e., Week 2, Week 4, Week6, …, Week 24) and displayed with the respective 95% CIs. 
No imputed values will be used for the MMRM analysis. These sensitivity analyses assume
missing at random. 
In case of multiple or notably unbalanced discontinuations or missing data (i.e., 15% more 
missing in one group as compared to the other), additional methods such as multiple 
imputation models may be explored to further assess the impact of missing values on the 
main actigraphy DLPA endpoints (e.g., top 3 DLPA actigraphy parameters shown stronger 
correlation with 6MWD). These potential sensitivity analyses assuming not missing at 
random will be performed using Tipping Point Analyses.
10.6.4.3 Subgroup analyses
Subgroup analyses for the change from baseline to Week 24/EOT for all DLPA actigraphy 
endpoints (the endpoints 1 to 11) will be conducted on the subgroup variables listed in 
Section 8, based on the FAS. The analyses are conducted to assess consistency of the 
overall treatment effect across subgroup variables.
The above main ANCOVA analyses will be repeated with each subgroup variables tested 
separately. Treatment group differences of least squares means as well as the corresponding 
95% confidence intervals within each subgroup level will be presented.
The treatment-by-subgroup interaction p-value will be estimated using a separate model 
including treatment, baseline actigraphy value, subgroup, and treatment-by-subgroup 
interaction term(s). Interactions with p-value < 0.01 will be investigated further to 
determine the nature of the interaction (quantitative of qualitative) and the association with 
other subgroups. 
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Results are presented in a summary table and in forest plot for each endpoint. The forest 
plot will display the “overall” treatment effect, based on the main ANCOVA analysis, as a 
reference line. Least squares means of the treatment group differences, the corresponding 
95% confidence intervals, and the numbers of patients in the subgroup levels will be 
presented in the forest plot.  
10.6.4.4 Compliance of DLPA endpoints
DLPA endpoints are required at least 7 complete days (i.e. at least 7 awake hours per day) 
within 14-day time window as per protocol. The different cut-off of awake hours and/or 
number of complete days will be affected on results, if there are some imbalance between 
the treatment groups. The number of valid days (at least 7 hours of wear and awake hours 
per day), and daily wear and awake time (hours) in the 14day time-window as defined in 
Table 5 will be summarized descriptively. For the Week 2 – Week 24, if a day of DLPA 
recodes are missing before the EOT, the day will be handled as zero awake and wear hour. 
10.7 In case of notable unbalanced in compliance of DLPA, sensitivity 
analysis will be performed as mentioned in Section 10.6.4.2. In addition, 
the impact of weekday and weekend activities may be explored on a few 
of actigraphy DLPA endpoints (e.g., top 3 DLPA actigraphy parameters 
shown stronger difference between treatment arms). Analysis of the 
secondary efficacy variables
All analyses of secondary efficacy variables will be based on the FAS.
All secondary efficacy variables collected between informed consent and EOS will be 
presented in patient listings.
10.7.1 Secondary endpoints
10.7.1.1 Hypothesis and statistical model 
There will be no confirmatory hypotheses testing in the analysis of this trial.
All statistical testing procedures used, if any, will provide exploratory p-values. CIs will 
be two-sided at the 95% level. No adjustment for multiplicity will be made.
10.7.1.2 Statistical analysis
PAH-SYMPACT® domain scores
The four PAH-SYMPACT® questionnaire domain scores will be derived using the scoring 
algorithm described in Section 11.9.
The four domain scores, cardiovascular symptom domain score, cardiopulmonary 
symptom domain score, physical impact domain score, and cognitive/emotional impact 
domain score, will be derived for three seven-day periods corresponding to the following
study visits: Baseline period, Week 16, and Week 24/EOT [see details in Appendix 2].
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The four domain scores at baseline, absolute value and absolute change from baseline at 
Week 16 and Week 24/EOT by treatment group will be summarized using the descriptive 
statistics. For the change from baseline to Week 24/EOT, treatment group difference will 
be estimated using the ANCOVA model as described in Section 9.1.1.  
WHO functional class
The WHO functional class will be analyzed descriptively by presenting a summary at each 
study visit and a shift table from baseline to Week 16 and Week 24/EOT. Additionally, the 
shift from baseline to the highest and lowest post-baseline value will be presented. The 
analysis will be presented for all patients and by subgroup.
6MWD and Borg dyspnea index
The 6MWD and Borg dyspnea index (as a continuous variable) at baseline, and absolute 
value and change from baseline at Week 16 and Week 24/EOT will be analyzed using the 
descriptive methods. For the change from baseline to Week 24/EOT, treatment group 
differences will be estimated using the ANCOVA model as described in Section 9.1.1.
NT-proBNP
NT-proBNP will be analyzed descriptively as described for the primary efficacy endpoints 
in Section 10.6.2. 
For the ANCOVA model, NT-proBNP will be log-transformed as NT-proBNP 
assessments follow more closely a log-normal distribution.
The change of log-transformed NT-proBNP values from baseline to Week 24/EOT will be 
analyzed using an ANCOVA model with treatment and log transformed baseline 
NT-proBNP and other covariates. Least squares means of the treatment group differences
as well as the corresponding 95% CIs will be back transformed before being presented, 
thus providing a geometric mean ratio between the treatment groups.
10.7.1.3 Handling of missing data
Handling of missing data for the derivation of PAH-SYMPACT® scores is described in 
Section 11.9.
To account for missed assessments and unscheduled visits, all assessments of secondary 
efficacy data (except PAH SYMPACT scores) will be assigned to the most appropriate 
timepoint using Table 8 in Section 11.6.
For all secondary efficacy endpoints, a LOCF approach will be used: If the Week 24 
domain score is not available, the last post-baseline value is carried forward. The 
ANCOVA models will be performed using on the imputed data using LOCF.
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10.7.1.4 Supportive/sensitivity analyses
The analyses of secondary endpoints described above will be repeated on the PPS.
10.7.1.5 Subgroup analyses
Descriptive analyses of secondary efficacy variables will be conducted by subgroup as 
described in Section 8. 
10.8 Correlation Analysis
The association between actigraphy DLPA endpoints (the endpoints 1 to 11 in 
Section 5.5.1.2) and the other efficacy endpoints (PAH-SYMPACT® domain scores, 
6MWD, NT-proBNP, WHO-FC) will be evaluated. Scatter plots of change from baseline 
to EOT of the actigraphy DLPA endpoints (at Week 24/EOT) [see Section 5.5.1.2] versus 
change from baseline of the other efficacy endpoints ate Week 24/EOT with the 
corresponding Pearson correlation coefficients will be presented. In addition, the Pearson 
correlation coefficient for the changes from baseline to Week16 and Week 24, and absolute 
value at Baseline, Week 16, and Week 24 will be tabulated. NT-proBNP data will be log 
transformed for the correlation analysis. 
Table 6
Time windows for analysis of association between DLPA endpoints 
and secondary endpoints
Analysis 
Visit
Target 
Day
6MWD, WHO FC, NT-proBNP, and 
PAH-SYMPACT®
Actigraphy assessment 
period
Lower limit 
of study day
Upper limit 
of study day
Assessment 
date*
Start date
End date
Baseline
1
Latest assessment before or at 
Day 1
XBL
−14
−1
Week 16
113
2
141
X16
X16 −14
X16 −1
Week 24
169
142
EOS
X24
X24 −14
X24 −1
EOT
EOT (Last 
assessment)
2
EOS
XEoT
XEoT −14
XEoT −1
* For PAH-SYMPACT®, the date of the 7th day will be used to determine the actigraphy assessment period.
6MWD = 6-minute walk distance; EOT = end of treatment; NT-proBNP = N-terminal pro b-type natriuretic peptide; 
PAH-SYMPACT® = Pulmonary Arterial Hypertension Symptoms and Impact questionnaire; WHO FC = World 
Health Organization functional class. EOS = end of study (Secondary endpoints are measured a few days after 
EOT)
10.9 Analysis of safety variables
The safety endpoints in this study are defined in Section 5.6. 
All safety analyses will be based on the SAF except where stated otherwise.
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10.9.1 Adverse events
All AEs captured from signature of informed consent up to EOS are reported in the patient
listings. 
Treatment-emergent AEs, including SAEs, will be summarized for each treatment groups 
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 (at the PT level). 
The display will be ordered by descending order of incidence of SOCs and PTs within 
SOCs in the (double-blind) selexipag group.
The analysis will be repeated by presenting for each treatment group, the number and 
percentage of patients having any AE, and having each individual AE (at the PT level). 
The display will be ordered in descending order of incidence of PTs.
Furthermore, treatment-emergent AEs, including SAEs, will be summarized by severity, 
SOC, and PT. For each patient, SOC, and PT the highest severity will analyzed.
All AEs collected in the eCRF, i.e., AEs starting between signature of informed consent 
and the day prior to the first dose of study treatment, will be listed. The listing will be based 
on the screened patients set and will also include AEs of patients who were screened but 
not randomized. Some patients will start using commercial selexipag after end of study 
treatment. AEs occurring during the commercial selexipag will be indicated in the listings.  
10.9.2 Deaths, other serious adverse events
10.9.2.1 Death
All study deaths will be listed together with the primary reason for study death as entered 
on the specific eCRF page will be listed.
A second listing will be prepared displaying all AEs leading to death as entered in the AE 
eCRF page.
10.9.2.2 Serious adverse events
Treatment emergent SAEs (+3 days after treatment discontinuation) will be summarized 
by presenting a summary by SOC and PT and by PT as described in Section 10.9.1.
A separate summary will be presented for SAEs occurring between first day of study drug 
and up to +30 days after treatment discontinuation.
SAEs prior to first dose of study treatment and occurring later than 30 days after the end 
of treatment will be presented in listings if entered in the clinical database.
A separate listing will be prepared presenting all SAEs, regardless of relationship to study 
drug.
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10.9.2.3 Adverse events leading to study treatment discontinuations
AEs leading to study treatment discontinuation will be summarized by SOC and PT and 
by PT as described in Section 10.9.1. 
A separate listing will be prepared for all AEs leading to study treatment discontinuation. 
10.9.2.4 Other significant adverse events
AEs related to study drug
Treatment-emergent AEs which are related to study drug as judged by the investigator will 
be summarized by SOC and PT.
AESIs based on the selexipag Risk Management Plan (RMP)
Treatment-emergent AESIs based on the selexipag RMP will be summarized by treatment 
group for each AESI category, including:

the number and percentage of patients having an AESI

the relative risk compared to placebo (only on the safety set)

patients with at least one AESI leading to discontinuation of study drug, serious 
AESIs, fatal AESIs

Number and annualized rate of recurrent events

Observed PTs

Maximum severity
AEs typical of prostanoid treatments 
AEs typical of prostanoid treatments [see Section 5.6.5.2] will be summarized for each 
treatment group, by presenting the number and percentage of patients having any AE, and 
having each individual AE (at the PT level). The display will be ordered in descending 
order of incidence of PTs of the selexipag treatment arm.
10.9.2.5 Summaries of AEs for Clinical Trial data disclosure
For the disclosure of the results to EudraCT and ClinicalTrials, treatment-emergent (S)AEs 
will be summarized for each treatment group, displaying counts and percentages of patients 
with at least one treatment-emergent event plus the number of events (counted exactly the 
number of times they occurred also within a patient) by SOC and individual PT. The 
summary table is presented in descending order according to the incidence in the selexipag
treatment group (i.e., SOC and individual preferred term within each SOC with the highest 
number of occurrences appears first). Equal frequency of different individual preferred 
terms is 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 
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
Summary of treatment emergent SAEs judged to be treatment related by the 
investigator

Summary of treatment emergent SAEs with fatal outcome

Summary of treatment emergent SAEs with fatal outcome judged to be treatment 
related by the investigator

Summary of treatment emergent non-serious AEs with an incidence of 5% or higher 
in any treatment group
10.9.3 Laboratory tests
Laboratory data, regardless if from scheduled or unscheduled visits will be used for 
analysis. 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 [see Section 5.6.8].
The laboratory data will be assigned to the most appropriate analysis time point using time 
windows as described in Table 9 in Section 11.6.
10.9.3.1 Laboratory tests over time
Hematology and biochemistry values will be summarized by treatment group and by visit 
in their respective SI unit together with the respective changes from baseline for Week 16 
and Week 24. Only treatment emergent (i.e., up to 3 days after last dose of study treatment) 
laboratory tests will be used for summaries. 
All laboratory values will be listed.
10.9.3.2 Marked laboratory abnormalities 
Actelion internal guidelines (OTH-000005) 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 their correspondence to scheduled or unscheduled assessments. 
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Table 7
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 (10E9/L)
<75
<50
>600
>999
Leucocytes (10E9/L)
<3
<2
>20
>100
Neutrophils (10E9/L)
<1.5
<1.0
-
-
Eosinophils (10E9/L)
-
-
>5
-
Lymphocytes (10E9/L)
<0.8
<0.5
>4
>20
ALT/SGPT
-
-
>3 ULN
>5 ULN
AST/SGOT
-
-
>3 ULN
>5 ULN
GGT
-
-
>2.5 ULN
>5 ULN
Alkaline Phosphatase
-
-
>2.5 ULN
>5 ULN
Total Bilirubin
-
-
>2 ULN
>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
Magnesium (mmol/L)
<0.5
<0.4
-
>1.23
Phosphate (mmol/L)
<0.8
<0.6
-
-
Urate (µmol/L)
-
-
>590
>720
Albumin (g/dL)
<30
<20
-
-
Creatinine Clearance (mL/min)
<60
<30
-
-
BUN
-
-
>2.5 ULN
>5 ULN
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; GGT = gamma-
glutamyltransferase; SGOT = Serum glutamic oxaloacetic transaminase; SGPT = Serum glutamate-pyruvate 
transaminase; ULN = upper limit of normal. 
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The number and percentage of patients with treatment-emergent (i.e., up to 3 days after
last dose) post-baseline laboratory abnormalities will be tabulated by treatment group.
10.9.3.3 Marked laboratory hepatic abnormalities 
The incidence of the following important treatment-emergent (i.e., up to 3 days after last 
dose) laboratory hepatic abnormality will be tabulated by treatment group:

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)
10.9.4 Vital signs and body weight
10.9.4.1 Vital signs and body weight over time
Weight, BMI, pulse rate, systolic and diastolic blood pressure will be summarized together 
with the respective changes from baseline for all scheduled study visits.
Treatment emergent vital signs assessments within 3 days of the last dose of study 
treatment will be used for summaries. All data, regardless if from scheduled or unscheduled 
visits are used; vital signs assessments will be assigned to the most appropriate analysis 
time point using time windows as described in Table 9 in Section 11.6.
10.9.4.2 Marked blood pressure abnormalities 
The number and percentage of patients with treatment-emergent (i.e., within 3 days of last 
dose) post-baseline blood pressure abnormalities will be tabulated by treatment group. All 
blood pressure assessments are taken into account, regardless of association to scheduled 
or unscheduled visits.
The incidence of the following notable treatment emergent blood pressure values post 
baseline will be tabulated: 

SBP < 90 mmHg

DBP < 50 mmHg

Decrease of > 40 mmHg in SBP from baseline

Decrease of > 20 mmHg in DBP from baseline

All four notable criteria fulfilled.
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10.10 Analysis of quality of life variables
The analysis of the PAH-SYMPACT® questionnaire is described as a secondary endpoint
[see Section 10.7.1.2].
11 GENERAL DEFINITIONS AND DERIVATIONS
11.1 Study treatment start- and end date
Study treatment is selexipag or placebo. Thus, the date of the first dose of 
selexipag/placebo is study treatment start date and the date of the last dose of 
selexipag/placebo is the study treatment end date (EOT date). 
11.2 Treatment emergent assessments or events
Treatment emergent assessments or events are assessments made or events experienced 
between the study treatment start date and 3 days after the last dose of study treatment. 
11.3 Study days
Study days are relative to the date of first study treatment. The date of first study treatment
is Day 1. There is no Day 0, i.e., the Day before Day 1 is Day −1.
11.4 Duration in months
Number of months between two study dates will be computed by counting the number of 
days between the two dates (including the dates) and dividing be 30.4.; i.e.,
Duration (months) = (End date - Start date + 1) / 30.4
11.5 Baseline definition
The last value prior to or on the date of the first dose of study treatment 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.
For patients randomized but not treated with study treatment, the last value prior to or on 
the date of randomization is considered baseline. All assessments made on the day of 
randomization are considered as prior to randomization for the determination of baseline.
Note that AEs starting on Day 1 are considered as on study treatment unless ‘Onset prior 
to first dose of study treatment’ on the eCRF page is ticked ‘Yes’.
For PAH-SYMPACT®, the baseline definition is shown in Appendix 2.
11.6 Visit windows 
To account for unscheduled visits, missed or postponed assessments all study site based 
assessments will be mapped to the most appropriate visit. The assessment closest to the 
target date will be used. If two assessments are equally close to the target date, the earlier 
assessment will be used. 
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Table 8
Time windows for efficacy assessments, at the exception of 
actigraphy
Analysis Visit
Target Day
Lower limit of study 
day
Upper limit of study 
day
Baseline
1
Latest assessment before or at Day 1
Week 16
113
2
141
Week 24
169
142
EOS
EOT
EOT (Last assessment)
2
EOS
EOT = end of treatment. EOS = end-of-study (Some of secondary endpoints are measured a few days after EOT)
Table 9
Time windows for treatment-emergent safety assessments
Analysis Visit
Target Day
Lower limit of study 
day
Upper limit of study 
day
Baseline
1
Latest assessment before or at Day 1
Week 16
113
2
141
Week 24
169
142
EOT + 3 days
EOT = end-of-treatment. 
11.7 Handling of selexipag/placebo dose titrations between morning and 
evening dose
In some patients, dose changes (up- or down-titration) may be conducted over the day in
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 recorded with the same 
date as the start date of the new regimen. To account for the actual daily dose the 
following handling convention will be used:
1.
The end date of the old dose regimen will be reduced by one day
2.
The start date of the new dose regimen will be increased by one day
3.
A record with the average dose will be created for the day of dose change, i.e. the 
overlapping date
An example from the selexipag/placebo dosage log is shown in Table 10.
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Table 10
Illustrative example for 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.
11.8 Derivation of DLPA actigraphy endpoints 
All activity counts collected during the time of patient was awake and wore the Actigraphy 
device will be provided on a daily summary basis by the Actigraphy provider (ActiGraph).
The following derivations will be used for each DLPA actigraphy endpoint. The variable 
names are based on “Data Transfer Agreement (ActiGraph), Revision N, dated 
21 November 2019” with horizontal database structure. The names will be changed in 
SDTM according to SDTM’s vertical data structure. 
1)
For daily time spent in non-sedentary activities (minutes – based on Freedson
algorithm), the values of ‘WFAwakeCutpointsLight’, 
‘WFAwakeCutpointsModerate’, ‘WFAwakeCutpointsVigorous’, 
‘WFAwakeCutpointsVeryVigorous’ will be summed up. 
2)
For daily time spent in MVPA (minutes – based on Freedson algorithm), the values 
of ‘WFAwakeCutpointsModerate’, ‘WFAwakeCutpointsVigorous’, 
‘WFAwakeCutpointsVeryVigorous’ will be summed up. 
3)
For total daily time spent in non-sedentary activity (minutes – based on Koster 
algorithm), the value of ‘WFAwakeKosterNonSedentary’ will be used.
4)
For percentage of daily time spent in non-sedentary activity (% – based on Freedson 
algorithm), the sum of ‘WFAwakeCutpointsLight’, ‘WFAwakeCutpointsModerate’, 
‘WFAwakeCutpointsVigorous’, ‘WFAwakeCutpointsVeryVigorous’ will be divided 
by ‘WearAwakeMinutes’.
5)
For percentage of daily time spent in MVPA (% – based on Freedson algorithm), the 
sum of ‘WFAwakeCutpointsModerate’, ‘WFAwakeCutpointsVigorous’, 
‘WFAwakeCutpointsVeryVigorous’ will be divided by ‘WearAwakeMinutes’.
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6)
For percentage of time spent in in non-sedentary activity (% – based on Koster 
algorithm), the value of ‘WFAwakeKosterNonSedentary’ will be divided by 
‘WearAwakeMinutes’.
7)
For total DLPA (counts / minute), the values of ‘WFAwakeTotalVectorMagnitude’
will be divided by ‘WearAwakeMinutes’.
8)
For volume of non-sedentary activity during awake time (counts – based on Koster 
algorithm), the values of ‘WFATotalVectorMagnitude-K-NS’ will be used. 
9)
For volume of non-sedentary activity during awake time, per awake time (counts –
based on Koster algorithm), the values of ‘WFATotalVectorMagnitude-K-NS’
divided by ‘WearAwakeMinutes’.
10) For number of steps during wake time (steps), variable 
‘WearFilteredAwakeTotalSteps’ will be used.
11) For number of steps during awake, per awake minute (steps / min), the value of 
‘WearFilteredAwakeTotalSteps’ divided by ‘WearAwakeMinutes’.
The Actigraph device must be worn for at least seven awake hours on any given day in 
order to provide a valid DLPA assessment, i.e., the mean DLPA count will only be 
computed if wear and awake time is greater or equal 7 × 60 = 420 minutes. If the wear time 
is below 420 minutes on a specific day, the DLPA count will be set to missing [see also 
Section 10.6.3].
11.9 Scoring the PAH-SYMPACT® questionnaire
The PAH-SYMPACT® is composed of two parts: the Symptoms part (11 items), which is 
assessed daily for seven days; and the Impacts part (11 items), which is assessed once at 
the end of a seven-day period. 
11.9.1 Symptoms
Each item is scored daily on a Likert Scale ranging from 0 (best) to 4 (worst). The average
score across the seven-day period for each symptom item will be computed, if at least 
4 days of valid answers are available. Otherwise the item score will be set to missing.
Then the weekly averages will be aggregated into domain scores by taking the arithmetic 
mean of the average weekly item scores of all symptom items belonging to a domain [see 
Table 11]. 
Domains with an even number of item scores will be scored if at least half of the item 
scores are non-missing; domains with an odd number of item scores will be scored if at 
least half of the item scores plus one item are non-missing. Otherwise the domain score 
will be left as missing.
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Table 11
Symptom scores domains
Domain
Item
Cardiopulmonary Symptoms 
Domain
How would you rate your shortness of breath?
How would you rate your fatigue?
How would you rate your lack of energy?
How would you rate the swelling in your ankles or legs?
How would you rate the swelling in your stomach area?
How would you rate your cough?
Cardiovascular Symptoms 
Domain
How would you rate your heart palpitations (heart fluttering)?
How would you rate your rapid heartbeat?
How would you rate your chest pain?
How would you rate your chest tightness?
How would you rate your lightheadedness?
11.9.2 Impact
Each item is scored once for the past seven days on a Likert Scale ranging from 0 (best) to 
4 (worst). 
Domain scores will be computed by taking the arithmetic mean of the item scores of all 
symptom items belonging to a domain [see Table 12]. 
Domains with an even number of item scores will be scored if at least half of the item 
scores are non-missing; domains with an odd number of item scores will be scored if at 
least half of the item scores plus one item are non-missing. Otherwise the domain score 
will be left at missing.
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Table 12
Impact scores domains
Domain
Item
Physical Impacts Domain
Were you able to walk slowly on a flat surface?
Were you able to walk quickly on a flat surface?
Were you able to walk uphill?
Were you able to carry things, such as bags or baskets?
Were you able to do light indoor household chores such as preparing food, 
cleaning surfaces, or tidying up?
Were you able to wash or dress yourself?
How much did you need help from others?
Cognitive/Emotional Impacts 
Domain
Were you able to think clearly?
How sad did you feel?
How worried did you feel?
How frustrated did you feel?
12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS
Missing and incomplete date and time fields should be avoided as far 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 will be employed. 
Dates are split in 3 parts: year, month, and day. Year is the top level, month is medium 
level, and day is low level. Missing date parts will be imputed into acceptable non-missing 
values in a way depending on the type of date to be replaced.
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.
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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 study 
treatment AND
Medication stop date not collected or with 
the upper limit after the study treatment
start AND 
The treatment start day falls in the range 
of possible dates.
In which case it is the study treatment
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 treatment
start or missing AND 
Upper limit is after the study treatment
start AND 
Not tagged as ongoing at start of study 
treatment AND
Not tagged as ongoing at last visit
In which case it is 1 day before study
drug start
No replacement (considered ongoing)
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 treatment, 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.
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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: 30th of 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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13 REFERENCES
[Cole 1992] Cole RJ1, Kripke DF, Gruen W, Mullaney DJ, Gillin JC. Automatic 
sleep/wake identification from wrist activity. Sleep. 1992;15:461-469.
[Freedson 1998] Freedson PS, Melanson E, Sirard J. Calibration of the Computer Science 
and Applications, Inc. accelerometer. Med Sci Sports Exerc. 1998;30:777-781.
[Koster 2016] Koster A, Shiroma EJ, Caserotti P, Matthews CE, Chen KY, Glynn NW, 
Harris TB. Comparison of sedentary estimates between activPAL and hip and 
wrist-worn ActiGraph. Med Sci Sports Exerc. 2016;48:1514-1522.
[Matthews 2008] Matthews CE, Chen KY, Freedson PS, et al. Amount of time spent in 
sedentary behaviors in the United States, 2003-2004. Am J Epidemiol. 
2008;167:875-881.
[Nathan 2019] Nathan SD, Flaherty K, Glassberg MK, Raghu G, Swigris J, Alvarez R, 
et al. Actigraphy as a clinically meaningful endpoint to detect change after treatment 
with iNO (30 mcg/kg-IBW/hr) in patients at risk of Pulmonary Hypertension 
associated with Pulmonary Fibrosis. 13th Annual Pulmonary Vascular Research 
Institute World Congress on Pulmonary Vascular Disease, January 31 to February 3, 
2019, Barcelona, Spain.
[Sehgal 2019] Sehgal S, Chowdhury A, Rabih F, Gadre A, Park MM, Li M, et al. 
STep-count using an Accelerometer for Monitoring PAH—STAMP Study. Lung.
2019;197:501-508. 
[Tremblay 2010] Tremblay MS, Colley RC, Saunders TJ, Healy GN, Owen N. 
Physiological and health implications of a sedentary lifestyle. Appl Physiol Nutr 
Metab. 2010;35(6):725-740.
[Troiano 2008] Troiano RP, Berrigan D, Dodd KW, Mâsse LC, Tilert T, McDowell M: 
Physical activity in the United States measured by accelerometer. Med Sci Sports 
Exerc. 2008;40:181-188.
[Tudor-Locke 2014] Tudor-Locke C, Barreira TV, Schuna JM Jr., Mire EF, 
Katzmarzyk PT. Fully automated waist-worn accelerometer algorithm for detecting 
children’s sleep-period time separate from 24-h physical activity or sedentary 
behaviors. Appl Physiol Nutr Metab. 2014;39:53-57.
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14 APPENDICES
Appendix 1
Protocol synopsis and study visit assessment schedule
TITLE
A multi-center, double-blind, placebo-controlled, Phase 4 
study in patients with pulmonary arterial hypertension to assess 
the effect of selexipag on daily life physical activity and 
patient’s self-reported symptoms and their impacts
ACRONYM
TRACE: EffecT of selexipag on daily life physical activity 
assessed by a weaRAble deviCE
OBJECTIVES
Primary objective
Evaluate the effect of selexipag on daily life physical 
activity (DLPA) of patients with pulmonary arterial 
hypertension (PAH).
Secondary objectives
Evaluate the effect of selexipag on PAH symptoms and 
their impacts in patients’ daily life.
Evaluate the effect of selexipag on exercise capacity, and 
disease severity in patients with PAH.
Evaluate the safety and tolerability of selexipag in patients 
with PAH.
Other objectives
Explore potential association between traditional efficacy 
outcomes and DLPA. 
Explore the levels and level changes of biomarkers 
potentially associated with PAH.
DESIGN
A prospective, multi-center, double-blind, randomized, 
placebo-controlled, parallel-group, exploratory Phase 4 study.
PERIODS
Screening period (duration up to 14 days): The period 
includes the informed consent process and assessments 
determining patient eligibility at Visit 1. Some of the 
assessments provide baseline data. At Visit 1 the devices for 
the assessment of DLPA and PAH-SYMPACT® are given to 
the patient for outpatient use. Visit 2 defined as Day 1 is being 
scheduled.
Baseline period (duration 14–28 days): The period starts at 
the end of Visit 1 and ends with randomization at Visit 2 on 
Day 1. The actigraphy device is worn for the entire period, 
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24 hours per day (except during charging) for the collection of 
baseline DLPA. The recording of DLPA starts on the day of 
Visit 1. The PAH-SYMPACT® is assessed daily over a period 
of 7 days starting on Day −14. The start of the 
PAH-SYMPACT® can be delayed until Day −11, if the start 
on Day −14 has been missed. Valid baseline data for DLPA 
and PAH-SYMPACT® are required for eligibility. 
Treatment period (duration 24 weeks): For eligible patients 
with valid baseline data for DLPA and PAH-SYMPACT®, the 
period starts on Day 1 (Visit 2) with confirmation of eligibility 
and randomization to one of the two double-blind treatment 
arms. Patients will receive the first dose of study treatment on 
Day 1. From Day 1 up to end of Week 12 (Day 85) study 
treatment will be titrated to the highest individually tolerated 
dose. Patients will be called weekly by the site staff to guide 
the titration process, assess safety/tolerability, and support 
compliance with the actigraphy device. From Week 13 to 
Week 24 the individualized highest tolerated dose (HTD) is 
intended to be maintained (individualized maintenance dose 
[IMD]). Change of study treatment dose is allowed if needed 
for efficacy or tolerability reasons. 
Patients will continue to wear the actigraphy device during the 
whole 24-week period. At Week 15 and Week 23, 
PAH-SYMPACT® is assessed by the patient at their actual 
location (home, vacation, etc.). Patients will be called by the 
site staff on the first day of each PAH-SYMPACT® assessment 
period (Week 15 and Week 23) and at Week 20, to assess 
safety/tolerability, and to support compliance with the 
actigraphy device and the PAH-SYMPACT®. Visits at the 
study site are scheduled on Day 1 (Visit 2), Week 16/Day 113 
(Visit 3), and Week 24/Day 169 (Visit 4). An unscheduled visit 
is required for study treatment dispensing if dose is increased 
after Visit 3. At Visit 4, study treatment is terminated (end-of-
treatment, EOT). Upon premature discontinuation of study 
treatment prior to Week 24, the Visit 4 assessments should be 
performed within 10 days. Patient and investigator remain 
blinded regarding study treatment. 
Post-treatment safety follow-up period (duration 30 days):
This period starts 1 day after EOT, defined as the last day of 
intake of study drug. Patients will be followed by telephone 
regarding ongoing and new adverse events (AEs) at 
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investigator’s discretion. The period is completed by an end-
of-study (EOS) telephone call 30 days after EOT. This 
telephone call represents the end of the patient’s study 
participation.
At any time during the study, unscheduled telephone calls or 
visits at the study site may be conducted if medically indicated 
at the discretion of the investigator.
PLANNED DURATION
Approximately 20 months from first patient, first visit to last 
patient, last visit.
SITE(S)
/ COUNTRY(IES)
The study will be conducted at approximately 45 sites in 
approximately 12 countries.
SUBJECTS / GROUPS
Approximately 100 patients will be randomized in a 1:1 ratio 
to the two treatment groups (approximately 50 patients per 
group), stratified by region (Europe/rest of the world versus 
North America).
INCLUSION CRITERIA
1. Signed informed consent prior to initiation of any study 
mandated procedure.
2. Male and female patients with symptomatic PAH, aged 
from 18 years to 75 years inclusive. A woman of 
childbearing potential [see definition in Section 4.5.1] is 
eligible only if the following applies:
a) Negative serum pregnancy test at Screening Visit 1 and 
a negative urine pregnancy test at randomization,
AND
b) Agreement to undertake monthly urine pregnancy tests 
during the study up to 30 days after study treatment 
discontinuation
AND
c) Agreement to use an acceptable method of contraception 
[see definition in Section 4.5.2] from screening to 
30 days after study treatment discontinuation.
3. Diagnosis of PAH belonging to one of the following 
subgroups of Group 1 pulmonary hypertension (PH) 
according 
to 
the 
updated 
clinical 
classification 
[Galiè 2015a]: 
1.1. Idiopathic (IPAH)
1.2. Heritable (HPAH)
1.3. Drugs or toxins induced
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1.4. Associated (APAH) with one of the following:
1.4.1. Connective tissue disease
1.4.2. Human 
immunodeficiency 
virus 
(HIV) 
infection
1.4.4. Congenital heart disease with simple systemic-
to-pulmonary 
shunt 
(atrial 
septal 
defect, 
ventricular septal defect, patent ductus arteriosus) 
≥ 1 year after surgical repair.
4. Documented hemodynamic diagnosis of PAH by right 
heart catheterization (RHC). Prior to randomization the 
most recently performed RHC at rest showing:
a)
Mean 
pulmonary 
arterial 
pressure 
(mPAP) 
≥25 mmHg; and
b)
Resting 
pulmonary 
vascular 
resistance 
(PVR) 
≥240 dyn•s•cm-5 or 3 Wood Units; and
c)
Pulmonary artery wedge pressure (PAWP) or left 
ventricular 
end 
diastolic 
pressure 
(LVEDP) 
≤15 mmHg.
5. Treatment with an endothelin receptor antagonist (ERA) 
for at least 90 days and on a stable dose for 30 days prior to 
randomization. 
6. Possible treatment with a phosphodiesterase-5 (PDE-5) 
inhibitor or soluble guanylate cyclase (sGC) stimulator 
must be ongoing for at least 90 days and on a stable dose 
for 30 days prior to randomization.
7. WHO functional class (FC) II or III at randomization.
8. 6-minute walk distance (6MWD) ≥100 m at Visit 1.
9. Ability to walk without a walking aid.
10. Valid baseline data at Visit 2 for DLPA and 
PAH-SYMPACT® defined as:
a)
DLPA: Within the last 14 days (excluding Day 1), at 
least 9 days each with a minimum of 14 hours wear 
time;
b)
PAH-SYMPACT®: Of the 7-day PAH-SYMPACT®
assessment period, 5 days with complete data of the 
symptom part and 1 day with complete data of the 
impact part.
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EXCLUSION CRITERIA
1. PH Groups 2–5 according to the updated clinical 
classification [Galiè 2015a], and PAH Group 1 subgroups 
that are not covered by the inclusion criterion 3.
2. Patients on a PAH-specific monotherapy targeting the 
nitric oxide pathway (i.e., PDE-5 inhibitor or sGC 
stimulator).
3. Patients treated with prostacyclin, prostacyclin analog, or 
prostacyclin receptor agonist) at any time prior to Day 1 
(administration for vasoreactivity testing is permitted; 
previous prostacyclin / prostacyclin analogs used 
intermittently for the treatment of digital ulcers or 
Raynaud’s 
phenomenon 
are 
permitted 
if 
stopped 
> 6 months prior to Day 1).
4. Any hospitalization during the last 30 days prior to Visit 1.
5. Worsening in WHO FC during the last 30 days prior to 
Visit 1.
6. Severe coronary heart disease or unstable angina.
7. Myocardial infarction within the last 6 months.
8. Decompensated cardiac failure.
9. Ongoing severe arrhythmias.
10. Cerebrovascular events (e.g., transient ischemic attack, 
stroke) within the last 3 months.
11. Congenital or acquired valvular defects with clinically 
relevant myocardial function disorders not related to PH. 
12. Presence of one or more of the following signs of relevant 
lung disease at the last examination any time up to Visit 1:
a) Diffusing capacity of the lung for carbon monoxide 
< 40% of predicted UNLESS computed tomography 
reveals no or mild parenchymal lung disease; OR
b) Forced vital capacity < 60% of predicted1; OR
c) Forced expiratory volume in one second < 60% of 
predicted1.
                                               
1 Pulmonary function tests may be performed either with or without the use of bronchodilators, as per local clinical 
practice.
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13. Documented severe hepatic impairment (with or without 
cirrhosis) at Visit 1, defined as Child-Pugh Class C.
14. Documented severe renal insufficiency at Visit 1, defined 
as estimated creatinine clearance < 30 mL/min, or serum 
creatinine > 2.5 mg/dL.
15. Hemoglobin < 80 g/L (< 4.96 mmol/L) at Visit 1.
16. Known or suspected uncontrolled hyperthyroidism.
17. Known or suspected pulmonary veno-occlusive disease.
18. Ongoing or planned dialysis.
19. Body mass index above 40 kg/m2 at Visit 1.
20. Sitting systolic blood pressure below 90 mmHg at Visit 1.
21. Treatment 
with 
a 
strong 
inhibitor 
of 
CYP2C8 
(e.g., gemfibrozil).
22. Receiving or having received any investigational drugs 
within 90 days prior to Visit 1.
23. Participation in a cardio-pulmonary rehabilitation program 
based on exercise training within 8 weeks prior to Visit 1. 
Such program must not be started during the course of the 
study.
24. Concomitant life-threatening disease with a life expectancy 
of less than 12 months.
25. Known hypersensitivity to any of the excipients of the 
study treatment formulation.
26. Pregnancy, breastfeeding, or intention to become pregnant 
during the study.
27. Any factor or condition likely to impair adherence to 
protocol mandated procedures, as
judged by the 
investigator.
STUDY TREATMENTS
Investigational treatment
Selexipag (ACT-293987) 200 mcg oral tablet twice daily 
(b.i.d.).
Comparative treatment
Matching placebo 200 mcg oral tablet b.i.d.
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Study treatments will be provided as film-coated tablets in 
childproof bottles of 120 tablets. Store below 25 °C (77 °F). 
Keep the bottle tightly closed in order to protect from moisture.
Individualized dose titration (Weeks 1 to 12)
Each patient should be titrated to the individualized HTD, 
which can range from 200 mcg b.i.d. to 1600 mcg b.i.d.
The starting dose is 200 mcg b.i.d., approximately 12 hours 
apart. The dose is increased in increments of 200 mcg b.i.d., 
usually at weekly intervals. At the beginning of treatment and 
at each up-titration step it is recommended to take the first dose 
in the evening. During dose titration some adverse reactions, 
reflecting the mode of action of the study treatment (such as 
headache, diarrhea, nausea and vomiting, jaw pain, myalgia, 
pain in extremity, arthralgia, and flushing), may occur. They 
are usually transient or manageable with symptomatic 
treatment. However, if a patient reaches a dose that cannot be 
tolerated or managed, the dose should be reduced to the 
previous dose level. In patients in whom up-titration was 
limited by reasons other than adverse reactions reflecting the 
mode of action of study treatment, a second attempt to continue 
up-titration to the HTD up to a maximum dose of 1600 mcg 
b.i.d. may be considered until Week 12.
Individualized maintenance dose (Weeks 13 to 24)
The individualized maintenance dose is the HTD reached 
during individualized dose titration and should be maintained 
from Week 13 to Week 24. Change of study treatment dose is 
allowed if needed for efficacy or safety/tolerability reasons. If 
the therapy over time is less tolerated at a given dose, 
symptomatic treatment and/or a dose reduction to the next 
lower dose should be considered. The dose may be increased 
(to a maximum dose of 1600 mcg b.i.d.) if the patient may 
benefit from a higher dose, as judged by the investigator. 
ENDPOINTS
Primary endpoints

Change from baseline to Week 24/EOT in actigraphy-
assessed DLPA as measured by:
o Daily time spent (minutes) in non-sedentary activity 
(> 100 activity counts per minute)
o Percentage of daily time spent in non-sedentary activity 
(> 100 activity counts per minute)
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o Total DLPA in counts/min
o Sleep: Total sleep time; minutes, wake after sleep onset; 
minutes, number of awakenings, efficiency (percentage) 
The study is designed as exploratory, and therefore all 
actigraphy variables are listed under primary endpoints.
Secondary endpoints

Change from baseline to Week 24/EOT for following 
PAH-SYMPACT® domain scores:
o Cardiovascular symptom domain score
o Cardiopulmonary symptom domain score
o Physical impact domain score
o Cognitive/emotional impact domain score

Change from baseline to Week 24/EOT for following 
variables:
o WHO FC
o 6MWD
o Borg dyspnea index at 6MWT
o N-terminal pro b-type natriuretic peptide (NT-proBNP)
Other endpoints

Change from baseline to Week 24/EOT for blood 
biomarkers associated with, e.g., PAH worsening, right/left 
ventricle function, inflammation.

Association between actigraphy variables and other 
efficacy endpoints (PAH-SYMPACT®, 6MWD, etc.)
Safety endpoints

Treatment-emergent AEs and serious AEs up to 30 days 
after study treatment discontinuation.

AEs leading to discontinuation of study treatment.

Change from baseline in vital signs (systolic and diastolic 
arterial blood pressure and pulse rate) and body weight 
from baseline to all assessed time points during the study.

Treatment-emergent marked laboratory abnormalities up to 
30 days after study treatment discontinuation.
ASSESSMENTS
Refer to the schedule of assessments in Table 1.
STATISTICAL 
METHODOLOGY
All statistical analyses will be conducted by Actelion or by 
designated CRO supervised by Actelion. A Statistical Analysis 
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Plan (SAP) will provide full details of the analyses, data 
displays, and algorithms to be used for data derivations.
Analysis sets:
The Screened Analysis Set includes all patients who are 
screened and have a patient identification number.
The Full Analysis Set (FAS) includes all patients randomly 
assigned to a study treatment. In order to adhere to the 
intention-to-treat principle as much as possible: 

Patients are evaluated according to the study treatment they 
have been assigned to (which may be different from the 
study treatment they have received),

All available data are included.
The Per-protocol Analysis Set comprises all patients who 
received study treatment and who complied with the protocol 
sufficiently to allow assessment of the treatment effects. 
Criteria for sufficient compliance include exposure to 
treatment, availability of measurements and absence of major 
protocol deviations that have an impact on the treatment effect. 
The full list of criteria will be detailed in the SAP before 
making the full randomization information available.
The Safety Set includes all patients who received at least one 
dose of study treatment, and the analysis will be based on the 
actual treatment received.
Primary analysis:
This study is designed as exploratory with the purpose to 
generate hypotheses on new endpoints. All analyses performed 
will be descriptive in nature with summary statistics and 
associated 95% confidence intervals (CI) provided when 
applicable. Any p-value provided as result of a statistical 
model is to be considered as exploratory only. 
No adjustment for multiplicity will be performed. There will 
be no interim analysis. 
All actigraphy variables will be summarized by period of 
14 days: Baseline (last 14 days before first dose), Week 2 
(Day 1–14), Week 4 (Day 15–28), and so on until Week 24 
(Day 155–168) or EOT (last 14 days period on study treatment) 
in case of premature discontinuation. Any actigraphy data 
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recorded after Day 168/EOT will not be considered in 
summary statistics and will be listed only.
For all actigraphy variables (continuous), change from baseline 
to Week 24/EOT will be analyzed (on the FAS) using an 
analysis of covariance including terms for treatment and 
region, and baseline values as covariates. The differences in 
least square means between treatment and placebo, 
corresponding 2-sided 95% CI and p-value will be provided.
All actigraphy variables will be also reported overtime with 
actual values, absolute change and percentage change from 
baseline at each time point (14 days periods). 
Daily time spent and percentage of daily time spent will be also 
displayed according to activity categories “sedentary”, “light”, 
“moderate”, “vigorous” and “very vigorous” based on the 
Freedson Adult algorithm [Freedson 1998].
Secondary/exploratory analyses:
PAH-SYMPACT® domain scores and others PAH-related 
variables (6MWD, Borg dyspnea index, NT-proBNP) will be 
analyzed similarly as actigraphy variables (as continuous). 
WHO FCs will be described by shift tables from baseline to 
each time point. The association between actigraphy variables 
and others efficacy endpoints (PAH-SYMPACT® domain 
scores, 6MWD, NT-proBNP) will be described using 
correlations, scatter plots and regressions. Details will be 
provided in the SAP. 
Safety analysis:
All safety analyses will be performed on the Safety Set using 
descriptive statistics.
Sample size:
There are no longitudinal data available for actigraphy 
variables in PAH patients. Therefore, the study is designed as 
exploratory and sample size is based on enrolment capabilities: 
100 patients will be randomized in total (50 in placebo group 
and 50 in selexipag group). 
STUDY COMMITTEES
A Steering Committee has been appointed by Actelion to 
contribute to the design of the protocol, the oversight of study 
conduct, the evaluation of results, and the support in 
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publication. The committee is governed by a Steering 
Committee charter.
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Table 13
Study periods, visits at study site and assessments
PERIOD
(DURATION)
SCREENING 
(up to 14 
days)
BASELINE 
(at least 14 
days)
TREATMENT
(24 weeks)
FOLLOW-UP
(30 days)
VISIT
Number
1
2
3
4
U1, U2, …
P16
Name
Screening
Actigraphy,
ePRO period
Randomization1
ePRO period
Intermediate 
visit
ePRO period
End-of-
treatment
Unscheduled 
visits3
End-of-study 
telephone call
Time 
(Time window)
Days
−28 to −15
Days
−14 to −1
Day 
1
Week 15
Days 99 to 105
(+3 days)
Week 16 
Day 113
(−4 to +7 days)
Week 23
Days 155 to 161 
(+3 days)
Week 242
Day 169
(−4 to +14 
days)
Any day between 
Day 1 and 
EOT+30 days
End-of-Treatment 
+30 days
(+10 days)
Informed consent4
X
IRT interaction
X
X
X
X
X11
Eligibility
X
X
Demographics, PAH
X
Medical history
X
Prev./conc. therapies
X
X5
X5
X5
X5
X5
Vital signs (BP, HR, body 
weight, height6)
X
X
X
X
X
WHO FC
X
X
X
X
X
6MWT/Borg index
X
X
X
X
NT-proBNP, biomarkers
X13
X
X
X
Hematology, chemistry
X
X
X
Contraceptive methods used, 
pregnancy test7, 8
X
X
X
X
X
X
Actigraphy9
E v e r y  d a y ,  2 4  h o u r s  p e r  d a y
PAH-SYMPACT®10
X
X
X
Study treatment dose
X
X5
X5
X5, 11
Study treatment 
dispensing/return
X
X
X
X11
AE and SAE12
X
X
X
X
X
X
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1)
All assessments are to be done prior to first intake of study drug.
2)
In case of premature study treatment discontinuation, this visit with all assessments should be performed within 10 
days after end-of-treatment, if possible.
3)
Unscheduled visits may be performed at any time during the study and may include all, some or additional assessments, 
based on the judgment of the investigator. Study assessments must be entered in the eCRF.
4)
Prior to any study mandated assessments.
5)
Only the changes are recorded.
6)
Height is measured at Visit 1 only.
7)
Serum pregnancy tests performed by central laboratory at Visit 1, Visit 3 (Week 16) and Visit 4 (Week 24). 
8)
Urine pregnancy tests performed at study site during Visit 2 and by patient at home within 3 days prior to the telephone 
call at EOT + 30 days.
9)
Actigraphy data are collected starting at Visit 1, uploaded by patients daily, AND by the site at all site visits.
10) The PAH-SYMPACT® questionnaire is being completed daily during each of the 3 7-day ePRO periods starting on 
Day −14, Day 99 (Week 15), and Day 155 (Week 23).
11) An unscheduled visit is required for study treatment dispensing if dose is increased after Visit 3. 
12) All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after EOT must be recorded 
in the eCRF. SAEs must be reported to Actelion drug safety on an SAE form.
13) No sampling for blood biomarkers at re-screening, if collected at initial screening.
6MWT, 6-minute walk test; AE, adverse event; BP, blood pressure; eCRF, electronic Case Report Form; EOT, end-of-
treatment; ePRO, electronic patient-reported outcome; HR, heart rate; IRT, interactive response technology; NT-proBNP, 
N-terminal pro b-type natriuretic peptide; PAH, pulmonary arterial hypertension; PAH-SYMPACT®, Pulmonary Arterial 
Hypertension Symptoms and Impact questionnaire; SAE, serious adverse event; WHO FC, World Health Organization 
functional class. 
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Appendix 2
Baseline for PAH-SYMPACT® Scores
1)
Check the existence of “impact” assessment before study treatment start.
2)
If yes, check the latest assessment date on “impact” questionnaire items before study 
treatment start. This assessment date will be handled as an anchor date for the baseline 
ePRO (=Day -Xi).  
If no, check the latest assessment date on “symptom” questionnaire items before study treatment 
start. This date will be handled as an anchor date for the baseline ePRO (=Day -Xs).   
3)
The anchor date will be considered as the last date of the baseline ePRO. 
Therefore, the baseline ePRO assessment period will be:
a.
[ Day - (Xi + 6), Day - Xi] for symptoms, with corresponding impacts assessment at Day - Xi
b.
[ Day - (Xs + 6), Day - Xs] for symptoms, without corresponding impacts assessment. 
Figure 2
Possible patterns of PAH-SYMPACT® period at baseline
The cells with “S” and “I” indicate the “symptom” and “impact” assessments in the baseline ePRO. The orange arrows indicate the 7 
days baseline ePRO period.  The yellow cells indicate the valid scores at baseline, these values will be used for calculation of baseline 
domain scores.  White cells will not be used for domain score. These values will be used for listing only.  
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In the post-baseline ePRO periods, some patients might have more than 7 days assessments in a 
period. If so, the same concept will be applied. i.e., check the existence of “impact” assessment 
in a period, and set up the 7 days assessment period based on the last impact assessment date, 
or last symptom assessment date (when impact is missing). The patients are allowed to enter the 
assessment until the next day 02.00 AM.  
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Appendix 3
Adverse events of special interest
The following adverse events of special interest will be used for selexipag. These are based 
on the important identified and potential risks in the latest Risk Management Plan and 
on-going discussion with Pharmacovigilance Risk Assessment Committee.  
AE Special Interest Category
Anaemia
Bleeding events
Gastrointestinal disturbances denoting intestinal intussusception (manifested as ileus or obstruction)
Hyperthyroidism
Hypotension
Light-dependent non-melanoma skin malignancies
Major adverse cardiovascular events (MACE)
Medication errors
Ophthalmological effects associated to retinal vascular system
Pregnancy
Pulmonary venoocclusive disease associated with pulmonary oedema
Renal function impairment / acute renal failure
Thrombocytopenia
Prostacyclin associated reactions*
*Prostacyclin associated reactions will be summarized separate from other AESIs
Adverse events of special interest are defined per the file available in the ICE folder:
root/Selexipag/Selexipag_across_indications/AC-065_Standard/BIOS/val/val_meddra/doc_aesi 
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Appendix 4
Document history
Version
Effective Date
Reason
1.0
10-Jan-2017
New
2.0
16-Dec-2019
New findings on ActiGraph primary endpoints, and modifications 
are necessary [details in Section 4]
3.0
27-Feb-2020
Based on the FDA type C meeting:
- Section 10.6.4.4. Compliance of DLPA endpoint was newly added.
In line with the (standard) documents or latest dictionaries: 
- Section 1.1. Updated study documents 
- Section 5.3.1.1. IMTD detailed definition in line with RMP.
- Section 5.3.1.1. IMTD, CYP2C8 category was modified according 
to the latest version of Standardized Drug Groupings
Others, e.g. fine tuning, precisions etc.: 
- Section 4.1.3. Subgroup analyses.  Add explanation of UK vs non-
UK will not considered in ANCOVA.  
- Section 5.5.1.2.  DLPA endpoint 7) was modified from “total 
DLPA” to “volume of total activity”.  Because it’s the volume and 
link with endpoints 8) and 9). 
- Section 5.5.1.3. conflicting information was deleted. 
- Section 7.2. Table 4. Delete the PPS on exploratory endpoints.
- Section 8. Subgroup of PAH etiology.  Updated as per clinical 
interest and reasonable numbers in each group during the blinded 
data review. 
- Section 9.1.1.  Remaining “region” was deleted (Other than this 
section, region has already been deleted in the SAP version 2.0)
- Section 10.6.2.1. Duplicated sentence was deleted.  Sentence for 
listing was deleted (due to the size of data, listing is not meaningful). 
- Section 10.8. Table 6. “EOT (Last assessment)” and footnote were 
added for giving the precise definitions.  
- Section 11.6. Table 8 added the EOT in line with Table 6.
- Section 11.8. Derivation of Actigraphy endpoints 8) and 9) were 
updated based on the blinded data received from the vendor 
(ActeGraph).
- Appendix 2. Assessment window was extended based on blinded 
data. 
- Appendix 3. Off label use was deleted, because it’s not expected in 
clinical trial.
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