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
Phase: PHASE4
Conditions: Pulmonary Arterial Hypertension
Sponsor: Actelion

 
 
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The information contained in this document, especially unpublished data, is the property of the sponsor of 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 
Protocol AC-065A404 
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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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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 
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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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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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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]:  
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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® 
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Pulmonary arterial hypertension 
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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 
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Pulmonary arterial hypertension 
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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. 
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Pulmonary arterial hypertension 
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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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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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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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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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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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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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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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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.  
 
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Pulmonary arterial hypertension 
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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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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. 
 
 
 
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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