Conditions: Chronic Thromboembolic Pulmonary Hypertension
Keywords: CTEPH selexipag
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 128
Healthy volunteers: no

Brief summary:
Selexipag is available in many countries for the treatment of pulmonary arterial hypertension (PAH). Due to the similarities between PAH and chronic thromboembolic pulmonary hypertension (CTEPH) and the observed efficacy of other PAH medicines in CTEPH, it is believed that selexipag could benefit to patients with CTEPH. This study aims to assess the efficacy and safety of selexipag in participants with inoperable or persistent/recurrent CTEPH.

Detailed description:
Participants will be recruited in two sequential cohorts: approximately the first 90 randomized participants will undergo a right heart catheterization (RHC) (and left heart catheterization LHC, if needed) with measurement of pulmonary vascular resistance (PVR) at Week 20 and will constitute the hemodynamic cohort; the remaining participants will constitute the non-hemodynamic cohort; who do not require a post-baseline hemodynamic assessment. They will undergo the same overall study assessments as the hemodynamic cohort excepted for RHC at Week 20.

Arms:
arm 1: During the double blind treatment period, participants in this group will receive selexipag. Each participant will start with one oral tablet of selexipag 200 µg in the evening of Day 1 and will continue with 200 µg twice daily (b.i.d.) on Day 2. If this dose is well-tolerated, selexipag is up-titrated with weekly increments of 200 µg until reaching the individual maximal tolerated dose (iMTD) in the range of 200 to 1600 µg b.i.d. The up-titration period up to Week 12 is followed by a stable maintenance treatment period from Week 12 to Week 26, at the iMTD. After Week 26, further up-titration can be allowed (but not above 1600 µg b.i.d.). arm 2: During the double-blind treatment period, participants in this group will receive the oral matching placebo, twice daily. A (mock) up-titration scheme will be followed. arm 3: All participants who completed the double-blind treatment period, whether they received placebo or selexipag during the double-blind period, will receive selexipag during the open-label extension period, using the same up-titration schedule as in the double-blind period.

Interventions: intervention 1: Selexipag intervention 2: Placebo
Intervention descriptions: intervention 1: oral tablets containing 200 µg of selexipag. Depending on the iMTD, participants will receive 1 to 8 tablets at each administration intervention 2: Oral tablets without active compound

Protocol document:
Prot_002.pdf: 
Actelion Pharmaceuticals Ltd 
(a Janssen Pharmaceutical Company of Johnson & Johnson)* 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary Hypertension 
Protocol AC-065B302 
SELECT: SELExipag in inoperable or persistent/recurrent Chronic 
Thromboembolic pulmonary hypertension 
A multicenter, randomized, double-blind, placebo-controlled, parallel-group, group-sequential, 
adaptive, Phase 3 study with open-label extension period to assess the efficacy and safety of 
selexipag as an add-on to standard of care therapy in subjects with inoperable or persistent/recurrent 
after surgical and/or interventional treatment Chronic Thromboembolic Pulmonary Hypertension. 
Study Phase: 
3 
EudraCT Number: 
2018-002823-41 
Status and version: 
Final Version 4 
Date: 
29 September 2020 
Document type: 
Amended Global Protocol 
Actelion document number (Doc No.): 
D-20.234 
*Actelion Pharmaceuticals Ltd (“Actelion”) is a global organization that operates through different legal
entities in various countries. Therefore, the legal entity acting as the sponsor for Actelion studies may vary,
such as, but not limited to Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; or
Janssen Research & Development, LLC. The term “sponsor” is used throughout the protocol to represent
these various legal entities; the sponsor is identified on the Contact Information page that accompanies the
protocol.
Confidentiality statement 
The information provided herein contains Company trade secrets, commercial or financial information that 
the Company customarily holds close and treats as confidential. The information is being provided under the 
assurance that the recipient will maintain the confidentiality of the information under applicable statutes, 
regulations, rules, protective orders or otherwise. 
NCT03689244


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 2/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
SPONSOR CONTACT DETAILS 
Sponsor 
 
Actelion 
Pharmaceuticals 
Ltd*, 
a 
Janssen 
Pharmaceutical Company of Johnson and Johnson 
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 
 
 
 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 3/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
CONTRACT RESEARCH ORGANIZATION INFORMATION 
CENTRAL LABORATORY 
 
Covance Central Laboratory Services, LP 
8211 Scicor Drive 
Indianapolis, IN 46214, USA 
CENTRAL RANDOMIZATION 
Almac Clinical Technologies, LLC  
25 Fretz Road  
Souderton, PA 18964, USA  
CENTRAL IMAGE 
PROCESSING CENTER 
World Care Clinical, LLC (WCC) 
7 Bulfinch Place 
Boston, MA 02114, USA 
INDEPENDENT STATISTICAL 
SUPPORT GROUP (SSG) 
Frontier 
Science 
and 
Technology 
Research 
Foundation,440 Science Drive, Suite 401 
Madison WI 53711, USA 
ACTIGRAPHY 
Actigraph LLC 
49 East Chase Street 
Pensacola, FL 3502, USA 
ELECTRONIC PATIENT-
REPORTED OUTCOME 
DEVICE 
ERT  
Peterborough Business Park, Lynch Wood  
Peterborough, PE2 6FZ, UK 
PARAXEL INTERNATIONAL, 
CORP. 
195 West Street, Waltham 
MA 02451, USA 
A list of site-specific contact details for Contract Research Organizations (CROs) can 
be found in the Investigator Site File. 
 
 
 




Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 5/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
Selexipag / ACT-293987 
Indication 
Chronic Thromboembolic Pulmonary Hypertension 
Protocol number, study acronym, study title 
AC-065B302, SELECT: A multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, group-sequential, adaptive, Phase 3 study with open-label extension period 
to assess the efficacy and safety of selexipag as an add-on to standard of care therapy in 
subjects with inoperable or persistent/recurrent after surgical and/or interventional 
treatment Chronic Thromboembolic Pulmonary Hypertension. 
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 subjects (other than those procedures necessary for the 
well-being of the subjects). 
United States (US) sites of this study will be conducted under US Food & Drug 
Administration Investigational New Drug (IND) regulations (21 CFR Part 312). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, 
and applicable regulations and laws. I will obtain approval by an Independent Ethics 
Committee or Institutional Review Board (IEC/IRB) prior to study start and signed 
informed consent from all subjects included in this study. If an amendment to the protocol 
is necessary, I will obtain approval by an 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 subjects (if applicable). I will allow direct access to 
source documents and study facilities to sponsor representative(s), particularly Site 
Manager(s) (SM[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 subjects 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 subject. I confirm 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 6/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
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 
Town 
Date 
 
Signature 
Principal 
Investigator 
 
 
 
 
 
 
 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 7/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment 3, Version 4 
29-Sep-2020 
Amendment 2, Version 3 
16-Apr-2020 
Amendment 1, Version 2 
09-Jan-2019 
Original Protocol, Version 1 
30-Jul-2018 
Amendment 3, Version 4 (29 September 2020) 
Overall Rationale for the Amendment: The overall rationale for the amendment is to 
update the information regarding the resolutions made to biostatistical evaluation section 
in response to Food and Drug Administration (FDA) queries, to update safety reporting 
requirements to align with Janssen process as well as to make minor updates, corrections, 
and editorial document formatting revisions.  
Section Number 
and Name 
Description of Change 
Brief Rationale 
Synopsis;  
3.1 Study design 
The number of study sites was updated 
to 195 (earlier 175).  
To update the number of 
study sites. 
Synopsis;  
3.1.2 Study duration;  
3.2.2 Rationale for the 
duration of the study; 
10.6.3 Time to clinical 
worsening (according to the 
CHMP definition) 
The maximum duration for double 
blind (DB) phase is revised to 59 
months from previous 52 months. 
 
 
 
The maximum duration of participation 
of a subject in the study is updated to 
approximately 74 months (earlier 67 
months). 
The required number of 
clinical worsening events is 
increased due to the smaller 
alpha level in the new testing 
strategy. 
 
To update duration of study 
participation. 
 
Synopsis;  
4.3 Inclusion criteria 
It was clarified that subjects with 
persistent/recurrent chronic 
thromboembolic pulmonary 
hypertension (CTEPH) after balloon 
pulmonary angioplasty (BPA) are also 
to be deemed inoperable. 
Reworded to avoid 
misunderstanding towards 
the following stratification 
group: "inoperable [with or 
without BPA]". 
5.1.6 Unblinding 
Figure 3 of study analyses and the 
footnote is revised. 
To update information about 
unblinding. 
5.1.11 Study-specific criteria 
for interruption / premature 
discontinuation of study 
treatment 
It is clarified that in case of premature 
study treatment discontinuation due to 
interruptions exceeding 14 consecutive 
days (or 28 consecutive doses if bid 
regimen or 14 consecutive doses if qd 
regimen), the premature End-of-
Clarified as in that case the 
instructions in section 7.1 to 
perform EDBT/EOLT visit 
no later than 7 days after the 
last dose of study treatment is 
not applicable. 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 8/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Double-Blind-Treatment/ End-of-
Open-Label-Treatment (EDBT/EOLT) 
visit must occur within 7 days of the 
discontinuation criteria being met. 
5.1.12 Treatment of overdose 
Information regarding treatment in case 
of selexipag overdose is included. 
To be consistent with Janssen 
protocol template and 
processes. 
Synopsis;  
6.1.2 Secondary efficacy 
endpoints; 
10.2.2 Secondary efficacy 
variables 
 
Definition of ‘Time to clinical 
worsening (TTCW)’ was rephrased. 
Editorial clarification. 
6.1.3 Other efficacy 
endpoints; 
 
Information about efficacy endpoints 
being captured by actigraphy 
assessment is updated. 
Actigraphy endpoints are not 
yet established for pulmonary 
hypertension (PH) subjects. 
Additional evaluations are 
being conducted in another 
study.  
7.2.3.5 Daily life physical 
activity (DLPA); 
10.2.3 Other efficacy 
variables 
Information about actigraphy raw data 
to be derived by vendor as per Data 
Transfer Agreement is updated. 
Table 5 Visit and assessment 
schedule for subjects entering 
the PTOP 
Post-treatment observation period-end 
of study (PTOP-EOS) visit timing is 
corrected.  
PTOP-EOS is not applicable 
for premature EDBT visit. 
Inconsistency from protocol 
amendment 2 (version 3) 
corrected.  
7.2.6.1 PAH-SYMPACT® 
questionnaire 
Pulmonary arterial hypertension 
Symptoms and Impact® Questionnaire 
(PAH-SYMPACT®) mobile device 
returning time is updated as Week 52 / 
Visit 7 (earlier Week 39/Visit 6) 
To update the information as 
per new revised study 
duration. 
9.1.1 Definition of adverse 
events 
Statement related to AEs associated 
with overdose and study treatment error 
was deleted. 
Captured under Section 9.5 
to follow Janssen template 
9.2.5 Reporting procedures 
Information about reporting procedures 
for serious adverse events (SAEs) and 
product quality complaint (PQC) is 
updated.  
To be consistent with Janssen 
protocol template and 
processes. 
 
9.3.1 Reporting of 
pregnancy; 
9.3.2 Follow-up of pregnancy 
Information about reporting and 
follow-up procedures for pregnancy is 
updated. 
9.4 Product quality 
complaints 
A new section is included to define 
product quality complaints and the 
procedure for reporting. 
9.5 Special reporting 
situations 
A new section is included to define 
special reporting situations. 
10.1.7 Usage of the analysis 
sets 
Footnote of Table 6 is revised. 
Editorial clarification. 


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Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
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EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
10.2.1 Primary efficacy 
variable;  
10.3.2.2 Handling of missing 
data 
Information about use of left 
ventricular end diastolic pressure 
(LVEDP) for pulmonary vascular 
resistance (PVR) calculation in absence 
of pulmonary artery wedge pressure 
(PAWP) measurement is updated. 
To clarify that if the PAWP 
measurement is not available, 
then LVEDP will be used in 
the calculation of PVR. 
Synopsis; 
10.3.1 Overall testing 
strategy; 
10.3.3 Analysis of secondary 
efficacy variable(s); 
10.4 Interim analysis 
Testing strategy in Section 10.3.1 for 
secondary endpoints is changed; a new 
Table 7 of analysis time points of the 
primary and secondary efficacy 
endpoints for double-blind treatment 
period is included; Figure 4 is revised; 
the analyses in Sections 10.3.3 and 10.4 
are revised accordingly; all these 
changes have been aligned in Synopsis 
as well. 
To allow declaring success if 
either 6-minute walk distance 
(6MWD) or TTCW is 
statistically significant 
Synopsis; 
10.3.1 Overall testing 
strategy; 
13 References 
New reference in context to weighted 
Bonferroni-Holm method [Holm 
1979].is included and updated in 
reference list as well. 
To support the use of 
employed statistical method. 
Synopsis;  
5.1.6.1 Timing of study 
analyses;  
10.4 Interim analysis 
Figure 5 (Flow of decision making) and 
description of analysis time points are 
revised. 
To align with change in 
testing strategy. 
Synopsis;  
10.3.5 Subgroup analyses 
Predefined subgroup analyses based on 
race were removed from the protocol. 
To allow definition of the 
subgroup in the statistical 
analysis plan (SAP) based on 
race depending on the 
number within each race 
category 
10.6.3 Time to clinical 
worsening (according to the 
CHMP definition) 
• Two-sided type I error is revised to 
2.5%. 
• Event number is revised to 148. 
• Number of months to observe 148 
events after the randomization of 
the last subject is updated to 17 
months. 
• Minor changes made to improve the 
clarity of the matter. 
Updated according to the 
new testing strategy 
13 References 
References are updated. 
To align with Janssen style 
guide. 
14.10 Appendix 10: Child-
Pugh classification; 
13 References 
 
The Child-Pugh classification is 
included, and the corresponding 
reference is updated. 
To provide detailed 
information for the 
assessment of severity of 
liver diseases. 
Throughout the protocol 
• Independent statistical analysis 
center (ISAC) is replaced with 
To improve the clarity of 
subject matter; to align with 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
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Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Statistical support group (SSG). 
• Right heart failure related 
symptoms-worsening is included 
in TTCW efficacy endpoint.  
•  The term ‘Global Drug Safety 
Department’ is deleted. 
•  Minor grammatical, formatting, 
spelling and abbreviation-related 
changes are made. 
 
Janssen terminology. 
 
 


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Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
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EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
TABLE OF CONTENTS 
SPONSOR CONTACT DETAILS ......................................................................................2 
CONTRACT RESEARCH ORGANIZATION INFORMATION ......................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ................................7 
TABLE OF CONTENTS ...................................................................................................11 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................19 
PROTOCOL SYNOPSIS AC-065B302 ............................................................................23 
PROTOCOL ......................................................................................................................40 
1 
BACKGROUND .........................................................................................................40 
1.1 
Indication ......................................................................................................40 
1.2 
Study treatment(s) .........................................................................................41 
1.3 
Purpose and rationale of the study ................................................................41 
1.4 
Summary of known benefits and potential risks ..........................................42 
1.4.1 
Benefits .............................................................................................42 
1.4.2 
Possible risks .....................................................................................43 
2 
STUDY OBJECTIVES ...............................................................................................44 
2.1 
Primary objective ..........................................................................................44 
2.2 
Secondary objectives ....................................................................................44 
2.3 
Other efficacy objective ................................................................................45 
2.4 
Safety objective ............................................................................................45 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................45 
3.1 
Study design .................................................................................................45 
3.1.1 
Study periods ....................................................................................46 
3.1.1.1 
Screening period ......................................................................46 
3.1.1.2 
Treatment periods ....................................................................46 
3.1.1.3 
Follow-up period .....................................................................46 
3.1.1.4 
Post-treatment observation period ...........................................46 
3.1.2 
Study duration ...................................................................................49 
3.2 
Study design rationale ..................................................................................50 
3.2.1 
Rationale for the use of placebo .......................................................50 


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Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
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Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
3.2.2 
Rationale for the duration of the study .............................................50 
3.2.3 
Rationale for the post-treatment observation period .........................51 
3.3 
Site personnel and roles ................................................................................51 
3.3.1 
Heart catheterization .........................................................................51 
3.3.2 
6-minute walk test .............................................................................52 
3.4 
Study committees .........................................................................................52 
3.4.1 
Steering committee ...........................................................................52 
3.4.2 
Independent Data Monitoring Committee ........................................52 
3.4.3 
Adjudication committees ..................................................................52 
3.4.4 
Clinical Event Committee .................................................................53 
4 
SUBJECT POPULATION ..........................................................................................53 
4.1 
Subject population description .....................................................................53 
4.1.1 
Adjudication procedure .....................................................................53 
4.2 
Rationale for the selection of the study population ......................................55 
4.3 
Inclusion criteria ...........................................................................................55 
4.4 
Exclusion criteria ..........................................................................................57 
4.4.1 
Exclusion criteria related to the disease ............................................57 
4.4.2 
Exclusion criteria related to comorbidities .......................................58 
4.4.3 
Exclusion criteria related to selexipag use ........................................58 
4.4.4 
General exclusion criteria .................................................................58 
4.5 
Criteria for women of childbearing potential ...............................................59 
4.5.1 
Definition of childbearing potential ..................................................59 
4.5.2 
Acceptable methods of contraception ...............................................59 
5 
TREATMENTS ..........................................................................................................60 
5.1 
Study treatment .............................................................................................60 
5.1.1 
Investigational treatment and matching placebo: Description 
and rationale ......................................................................................60 
5.1.2 
Study treatment administration .........................................................60 
5.1.3 
Study treatment up-titration ..............................................................60 
5.1.3.1 
Double-blind study treatment up-titration ...............................61 
5.1.3.2 
Open-label study treatment up-titration ..................................62 
5.1.4 
Treatment assignment .......................................................................63 
5.1.5 
Blinding ............................................................................................64 
5.1.6 
Unblinding ........................................................................................64 
5.1.6.1 
Timing of study analyses .........................................................64 
5.1.6.2 
Unblinding for IDMC ..............................................................67 
5.1.6.3 
Unblinding for analysis time points 1, 2, and 3 .......................67 


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Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
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Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
5.1.6.4 
Unblinding for the fourth analysis time point 
(end-of-double-blind-treatment period) ..................................67 
5.1.6.5 
Unblinding for suspected unexpected serious adverse 
reactions ..................................................................................67 
5.1.6.6 
Emergency procedure for unblinding ......................................67 
5.1.7 
Study treatment supply .....................................................................68 
5.1.7.1 
Study treatment packaging and labeling .................................68 
5.1.7.2 
Study treatment distribution and storage .................................68 
5.1.7.3 
Study treatment dispensing .....................................................68 
5.1.7.4 
Study treatment return and destruction ...................................69 
5.1.8 
Study treatment accountability and compliance with study 
treatment ...........................................................................................69 
5.1.8.1 
Study treatment accountability ................................................69 
5.1.8.2 
Study treatment compliance ....................................................69 
5.1.9 
Study treatment dose adjustments and interruptions ........................70 
5.1.10 
Premature discontinuation of study treatment ..................................71 
5.1.11 
Study-specific criteria for interruption / premature 
discontinuation of study treatment ....................................................73 
5.1.11.1 
Tolerability issues / AEs ..........................................................73 
5.1.11.2 
Hepatic impairment .................................................................73 
5.1.11.3 
Pulmonary edema due to PVOD .............................................73 
5.1.11.4 
Initiation of prohibited medications ........................................74 
5.1.11.5 
Pregnancy ................................................................................74 
5.1.12 
Treatment of overdose ......................................................................74 
5.2 
Previous and concomitant medications ........................................................74 
5.2.1 
Definitions ........................................................................................74 
5.2.2 
Recording of previous/concomitant medications / auxiliary 
medicinal products / procedures in the eCRF ...................................75 
5.2.3 
Auxiliary medicinal products ............................................................75 
5.2.4 
Allowed concomitant therapy ...........................................................75 
5.2.5 
Forbidden concomitant therapy ........................................................76 
6 
STUDY ENDPOINTS ................................................................................................76 
6.1 
Efficacy endpoints ........................................................................................76 
6.1.1 
Primary efficacy endpoint(s) ............................................................76 
6.1.2 
Secondary efficacy endpoints ...........................................................76 
6.1.3 
Other efficacy endpoints ...................................................................77 
6.2 
Safety endpoints ...........................................................................................78 


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Chronic Thromboembolic Pulmonary 
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Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
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7 
VISIT SCHEDULE AND STUDY ASSESSMENTS ................................................78 
7.1 
General information ......................................................................................78 
7.1.1 
Screening/rescreening .......................................................................79 
7.1.2 
Unscheduled visits ............................................................................79 
7.2 
Study assessments .........................................................................................88 
7.2.1 
Demographics / baseline characteristics ...........................................89 
7.2.2 
Assessments for diagnosis of CTEPH and judgment of 
inoperability ......................................................................................89 
7.2.3 
Efficacy assessments .........................................................................90 
7.2.3.1 
Right heart catheterization (and left heart catheterization, 
if needed) .................................................................................90 
7.2.3.2 
Exercise capacity .....................................................................91 
7.2.3.3 
Post-6MWT Dyspnea ..............................................................92 
7.2.3.4 
WHO FC ..................................................................................92 
7.2.3.5 
Daily life physical activity (DLPA) ........................................92 
7.2.3.6 
Clinical worsening ...................................................................93 
7.2.3.7 
NT-proBNP .............................................................................93 
7.2.3.8 
Clinician reported outcomes ....................................................93 
7.2.3.9 
Survival follow-up ...................................................................93 
7.2.4 
Safety assessments ............................................................................94 
7.2.4.1 
Physical examination ...............................................................94 
7.2.4.2 
Vital signs ................................................................................94 
7.2.4.3 
Weight and height ...................................................................94 
7.2.4.4 
Electrocardiogram assessment ................................................94 
7.2.5 
Laboratory assessments ....................................................................95 
7.2.5.1 
Type of laboratory ...................................................................95 
7.2.5.2 
Laboratory tests .......................................................................96 
7.2.6 
Patient-reported outcomes ................................................................97 
7.2.6.1 
PAH-SYMPACT® questionnaire ............................................97 
7.2.6.2 
EQ-5D-5L ................................................................................98 
7.2.6.3 
WPAI©: GH V2.0 ....................................................................98 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL 
CARE ..........................................................................................................................98 
8.1 
Study completion as per protocol .................................................................98 
8.2 
Premature withdrawal from study ................................................................99 
8.3 
Premature termination or suspension of the study ......................................100 
8.4 
Medical care of subjects after study completion ........................................100 


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Chronic Thromboembolic Pulmonary 
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Amendment 3, Version 4 
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9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS .........................101 
9.1 
Adverse events ............................................................................................101 
9.1.1 
Definition of adverse events ...........................................................101 
9.1.2 
Intensity of adverse events ..............................................................101 
9.1.3 
Relationship to study treatment ......................................................102 
9.1.4 
Reporting of adverse events ............................................................102 
9.1.5 
Follow-up of adverse events ...........................................................102 
9.2 
Serious adverse events ................................................................................103 
9.2.1 
Definitions of serious adverse events .............................................103 
9.2.2 
Reporting of serious adverse events ...............................................103 
9.2.3 
Follow-up of serious adverse events ...............................................103 
9.2.4 
After EOS .......................................................................................104 
9.2.5 
Reporting procedures ......................................................................104 
9.3 
Pregnancy ...................................................................................................104 
9.3.1 
Reporting of pregnancy ..................................................................105 
9.3.2 
Follow-up of pregnancy ..................................................................105 
9.4 
Product Quality Complaints .......................................................................105 
9.4.1 
Definition ........................................................................................105 
9.4.2 
Procedures .......................................................................................105 
9.5 
Special reporting situations ........................................................................105 
9.6 
Study safety monitoring ..............................................................................106 
10 STATISTICAL METHODS .....................................................................................106 
10.1 
Analysis sets ...............................................................................................107 
10.1.1 
Screened Analysis Set .....................................................................107 
10.1.2 
Full Analysis Set .............................................................................107 
10.1.3 
Hemodynamic Set ...........................................................................107 
10.1.4 
Per-protocol Analysis Sets ..............................................................107 
10.1.4.1 
PVR Per-protocol Analysis Set .............................................108 
10.1.4.2 
6MWD Per-protocol Analysis Set .........................................108 
10.1.4.3 
TTCW Per-protocol Analysis Set ..........................................108 
10.1.5 
Safety Analysis Set .........................................................................108 
10.1.6 
Selexipag-initiated Set ....................................................................108 
10.1.7 
Usage of the analysis sets ...............................................................108 
10.2 
Variables .....................................................................................................110 
10.2.1 
Primary efficacy variable ................................................................110 
10.2.2 
Secondary efficacy variables ..........................................................110 
10.2.3 
Other efficacy variables ..................................................................111 
10.2.4 
Safety variables ...............................................................................112 


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Chronic Thromboembolic Pulmonary 
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Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
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Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
10.3 
Description of statistical analyses ...............................................................113 
10.3.1 
Overall testing strategy ...................................................................113 
10.3.2 
Analysis of the primary efficacy variable .......................................116 
10.3.2.1 
Hypotheses and statistical model ..........................................116 
10.3.2.2 
Handling of missing data .......................................................117 
10.3.2.3 
Supportive/sensitivity analyses .............................................118 
10.3.3 
Analysis of secondary efficacy variable(s) .....................................118 
10.3.3.1 
Handling of missing data .......................................................121 
10.3.4 
Analysis of the safety variable(s) ....................................................122 
10.3.4.1 
Adverse events, serious adverse events, deaths and 
premature discontinuation of study treatment .......................122 
10.3.4.2 
Laboratory parameters ...........................................................123 
10.3.4.3 
Vital signs and body weight ..................................................123 
10.3.5 
Subgroup analyses ..........................................................................123 
10.4 
Interim analysis ...........................................................................................124 
10.5 
Double-blind and open-label analyses ........................................................126 
10.6 
Sample size .................................................................................................126 
10.6.1 
PVR .................................................................................................127 
10.6.2 
6MWD ............................................................................................129 
10.6.3 
Time to clinical worsening (according to the CHMP definition) ...131 
10.6.4 
Design operating characteristics .....................................................131 
11 DATA HANDLING ..................................................................................................131 
11.1 
Data collection ............................................................................................131 
11.2 
Maintenance of data confidentiality ...........................................................132 
11.3 
Database management and quality control .................................................132 
12 PROCEDURES AND GOOD CLINICAL PRACTICE ...........................................133 
12.1 
Ethics and Good Clinical Practice ..............................................................133 
12.2 
Independent Ethics Committee / Institutional Review Board ....................133 
12.3 
Informed consent ........................................................................................134 
12.4 
Indemnification, compensation and refund of expenses to subjects and 
investigators ................................................................................................135 
12.5 
Protocol adherence/compliance ..................................................................135 
12.6 
Protocol amendments .................................................................................136 
12.7 
Essential documents and retention of documents .......................................136 
12.8 
Monitoring ..................................................................................................137 
12.9 
Investigator Site File ...................................................................................138 
12.10 
Audit ...........................................................................................................138 


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Chronic Thromboembolic Pulmonary 
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Amendment 3, Version 4 
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12.11 
Inspections ..................................................................................................139 
12.12 
Reporting of study results and publication .................................................139 
13 REFERENCES ..........................................................................................................141 
14 APPENDICES ...........................................................................................................145 
14.1 
Appendix 1 Actelion heart catheterization guidance ..................................145 
14.1.1 
Heart Catheterization procedures ....................................................145 
14.1.1.1 
Conditions .............................................................................145 
14.1.1.2 
‘Zeroing’ ................................................................................145 
14.1.1.3 
Oxygen ..................................................................................145 
14.1.2 
Heart catheterization measurements ...............................................146 
14.1.2.1 
Right Heart Catheterization measurements ...........................146 
14.1.2.2 
Left Heart Catheterization measurement ...............................147 
14.1.2.3 
Other measurements ..............................................................147 
14.1.3 
Documentation ................................................................................148 
14.1.3.1 
Tracings .................................................................................148 
14.1.3.2 
Heart catheterization worksheet ............................................148 
14.2 
Appendix 2 Marked laboratory abnormalities ............................................149 
14.3 
Appendix 3 Actelion 6MWT guidance ......................................................150 
14.3.1 
Instructions ......................................................................................150 
14.3.1.1 
General ..................................................................................150 
14.3.1.2 
Training tests .........................................................................151 
14.3.1.3 
Timing ...................................................................................151 
14.3.2 
Test requirements ............................................................................151 
14.3.2.1 
Participant ..............................................................................151 
14.3.2.2 
Equipment to perform the test ...............................................151 
14.3.3 
Performing the 6MWT ....................................................................152 
14.3.3.1 
Instructions to the participant during the 6MWT ..................152 
14.3.3.2 
Assessments after the 6MWT ................................................153 
14.3.4 
6MWT worksheet ...........................................................................153 
14.4 
Appendix 4 Borg dyspnea index (BDI) scale .............................................154 
14.5 
Appendix 5 Borg CR10 scale® ...................................................................155 
14.5.1 
Instructions ......................................................................................155 
14.5.2 
Borg CR10 Scale® ..........................................................................157 
14.6 
Appendix 6 WHO function classification of Pulmonary Hypertension .....158 
14.7 
Appendix 7 PAH-SYMPACT® questionnaire ............................................159 
14.8 
Appendix 8 EQ-5D-5L ...............................................................................166 


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Chronic Thromboembolic Pulmonary 
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Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
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Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
14.9 
Appendix 9 Work Productivity and Activity Impairment 
Questionnaire: General Health (WPAI©: GH) V2.0 ...................................168 
14.10 
Appendix 10 Child-Pugh classification ......................................................170 
14.11 
Appendix 11 Protocol amendment history .................................................171 
 
LIST OF TABLES 
Table 1 
Data required for adjudication procedure .......................................................54 
Table 2 
Double-blind dosing scheme ...........................................................................62 
Table 3 
Double-blind treatment period: visit and assessment schedule ......................81 
Table 4 
Open-label treatment period: visit and assessment schedule ..........................84 
Table 5 
Visit and assessment schedule for subjects entering the PTOP ......................86 
Table 6 
Analysis sets and their usage at each analysis time point .............................109 
Table 7 
Analysis time points of the primary and secondary efficacy endpoints 
during the double-blind treatment period .....................................................115 
Table 8 
Estimates of treatment effect in PVR ............................................................128 
Table 9 
Sample sizes for PVR under different scenarios with two-sided 5% 
type I error rate and 90% power using t-test for ratio of means ...................129 
Table 10 
Estimates of treatment effect in 6MWD .......................................................130 
Table 11 
Child-Pugh Classification .............................................................................170 
 
LIST OF FIGURES 
Figure 1 
Study design ....................................................................................................48 
Figure 2 
Titration phase design .....................................................................................49 
Figure 3 
Study analyses .................................................................................................66 
Figure 4 
Testing strategy for primary and secondary endpoints (two-sided type I 
error rate, α = 5%) .........................................................................................113 
Figure 5 
Flow of decision-making. .............................................................................126 
 
 
 
 


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Chronic Thromboembolic Pulmonary 
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Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
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EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
LIST OF ABBREVIATIONS AND ACRONYMS 
6MWD  6-minute walk distance 
6MWT  6-minute walk test 
AC  Adjudication committees 
AE  Adverse event 
ANCOVA  Analysis of covariance 
BDI  Borg dyspnea index 
bid  Twice daily 
Borg CR10®  Borg category-ratio 10 Scale® 
BPA  Balloon pulmonary angioplasty 
CAC  Central Adjudication Committee 
CEC  Clinical Event Committee 
CGI-C  Clinician Global Impression of Change 
CGI-S  Clinician Global Impression of Severity 
CHMP  Committee for medicinal products for human use 
CI  Cardiac index 
CL  Confidence limits 
CO  Cardiac output 
CRO  Contract Research Organization 
CSAC  Country-specific Adjudication Committee 
CSR  Clinical Study Report 
CTEPH  Chronic thromboembolic pulmonary hypertension 
CTPA  Computed tomography pulmonary angiogram 
CTT  Clinical Trial Team 
CYP2C8  Cytochrome P-450 2C8 
DB  Double-blind 
DLPA  Daily life physical activity 
dPAP  Diastolic pulmonary artery pressure 
ECG  Electrocardiogram 
eCRF  Electronic Case Report Form 


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Chronic Thromboembolic Pulmonary 
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Amendment 3, Version 4 
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CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
EDBT  End-of-Double-Blind-Treatment 
EOLT  End-of-Open-Label-Treatment 
EOS  End-of-Study 
EOT  End-of-Treatment 
EQ-5D-5L  Euro Quality of life-5-Dimension-5-Level 
ERA  Endothelin receptor antagonist 
EU  European Union 
FAS  Full Analysis Set 
FC  Functional class  
FWER  Family-wise error rate 
GCP  Good Clinical Practice 
HC  Heart catheterization 
HES  Hemodynamic set 
HR  Heart rate 
HSD  Hwang, Shih and DeCani’s 
IA  Interim analysis 
IB  Investigator’s Brochure 
ICH  International Council for Harmonisation 
ICF  Informed Consent Form 
IDMC  Independent Data Monitoring Committee 
IEC  Independent ethics committee 
iMTD  Individual maximum tolerated dose 
IP receptor  Prostacyclin receptor  
IRB  Institutional review board 
IRT  Interactive Response Technology 
ISF  Investigator Site File 
LHC  Left Heart Catheterization 
LVEDP  Left ventricular end diastolic pressure 
MedDRA  Medical Dictionary for Regulatory Activities 
mPAP  Mean pulmonary artery pressure 


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Chronic Thromboembolic Pulmonary 
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Amendment 3, Version 4 
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CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
mPAWP  Mean pulmonary arterial wedge pressure  
mRAP  Mean right atrial pressure 
MRA  Magnetic resonance angiography 
NT-proBNP  N-terminal pro b-type natriuretic peptide 
OF  O’Brien and Fleming 
OL  Open label 
PA  Pulmonary angiography 
PAH  Pulmonary arterial hypertension 
PAH-SYMPACT®  Pulmonary Arterial Hypertension Symptoms and Impact® 
Questionnaire 
PAWP  Pulmonary artery wedge pressure 
PDE-5  Phosphodiesterase type-5 
PE  Pulmonary embolism 
PEA  Pulmonary endarterectomy 
PH  Pulmonary hypertension 
PI  Principal Investigator 
PPS  Per-protocol Analysis Set 
PPS1  PVR Per-protocol Analysis Set 
PPS2  6MWD Per-protocol Analysis Set 
PQC  Product quality complaint 
PRO  Patient-reported outcome 
PTOP  Post-treatment observation period 
PVOD  Pulmonary veno-occlusive disease 
PVR  Pulmonary vascular resistance 
qd  Once daily 
QS  Quality System 
RHC  Right heart catheterization 
RSI  Reference safety information  
SAE  Serious adverse event 
SAF  Safety Analysis Set  
SAP  Statistical analysis plan 


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Amendment 3, Version 4 
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Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
SBP  Systolic blood pressure 
SC  Steering Committee 
SD  Standard deviation 
SDO  Secure data office 
SFU  Safety follow-up 
sGC  Soluble guanylate cyclase 
SI  International System of Units 
SIV  Site initiation visit 
SM  Site manager 
SOC  System organ class 
sPAP  Systolic pulmonary artery pressure 
SSG  Statistical Support Group 
SUSAR  Suspected unexpected serious adverse reaction 
SvO2  Mixed venous oxygen saturation 
T3  Tri-iodothyronine  
T4  Thyroxin 
TSH  Thyroid stimulating hormone 
TST  Total sleep time 
TTCW  Time to clinical worsening 
US  United States 
V/Q  Ventilation/perfusion 
WASO  Wake after sleep onset  
WHO  World Health Organization 
WPAI©: GH  Work Productivity and Activity Impairment: General Health  
 
 
 


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Chronic Thromboembolic Pulmonary 
Hypertension 
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Amendment 3, Version 4 
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EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
PROTOCOL SYNOPSIS AC-065B302 
TITLE 
A multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, group-sequential, adaptive, Phase 3 study with 
open-label extension period to assess the efficacy and safety of 
selexipag as an add-on to standard of care therapy in subjects 
with inoperable or persistent/recurrent after surgical and/or 
interventional treatment Chronic Thromboembolic Pulmonary 
Hypertension (CTEPH). 
ACRONYM 
SELECT 
SELExipag in inoperable or persistent/recurrent Chronic 
Thromboembolic pulmonary hypertension 
OBJECTIVES 
Primary objective(s) 
To evaluate the effect of selexipag on pulmonary vascular 
resistance (PVR) versus placebo in subjects with inoperable 
CTEPH (ie, technically non-operable) and persistent/recurrent 
CTEPH after surgical (pulmonary endarterectomy [PEA]) 
and/or interventional (balloon pulmonary angioplasty [BPA]) 
treatment at Week 20. 
Secondary objectives 
To evaluate the effects of selexipag versus placebo on: 
• Exercise capacity.  
• Time to clinical worsening (TTCW). 
• All-cause death or hospitalizations related to Pulmonary 
Hypertension (PH) worsening. 
• World Health Organization (WHO) functional class (FC). 
• Patient-reported outcomes. 
• Dyspnea.  
• N-terminal pro b-type natriuretic peptide (NT-proBNP).  
Other objectives 
Other objectives are described in Sections 2.3 and 2.4.  
DESIGN 
A prospective, 
multicenter, 
randomized, double-blind, 
placebo-controlled, add-on to standard of care, parallel-group, 
group-sequential, adaptive Phase 3 study with an open-label 
extension period.  


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Chronic Thromboembolic Pulmonary 
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Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
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Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Up to 280 subjects will be randomized in a 1:1 ratio to receive 
either selexipag or placebo during the double blind (DB) 
period. Subjects completing the DB period will enter the 
open-label extension period and will receive selexipag. 
Subjects will be recruited in two sequential cohorts. 
Approximately the first 90 randomized subjects will constitute 
the hemodynamic cohort who, in addition to the overall study 
assessments, will undergo an right heart catheterization (RHC) 
(and left heart catheterization [LHC], if needed) at Week 20. 
The remaining subjects will constitute the non-hemodynamic 
cohort who do not require a post-baseline hemodynamic 
assessment. Both cohorts are combined for the evaluation of 
secondary efficacy endpoints. Treatment allocation will be 
stratified by: 
• Treatment with PH-specific therapies (ie, endothelin 
receptor antagonists [ERAs], phosphodiesterase type-5 
inhibitor 
(PDE-5i), 
soluble 
guanylate 
cyclase 
stimulator [riociguat]; one versus two versus naive 
[naive capped at 40%]) and  
• CTEPH population (inoperable [with or without BPA] 
versus persistent/recurrent after PEA [including PEA 
followed by BPA]).  
The database will be locked and analyzed at five time points 
during the study: 
• Time point 1: when approximately 90 randomized subjects, 
the hemodynamic cohort, have completed the Week 20 
RHC (and LHC, if needed) or prematurely discontinued 
from the study, the final analysis for the PVR endpoint will 
be performed by an independent Statistical Support Group 
(SSG) for the Independent Data Monitoring Committee 
(IDMC). 
• Time point 2: when approximately 160 randomized 
subjects have completed the Week 26 6-minute walk 
distance (6MWD) assessment or prematurely discontinued 
from the study, an interim analysis (IA) for the 6MWD 


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Chronic Thromboembolic Pulmonary 
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Amendment 3, Version 4 
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CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
endpoint and the TTCW endpoint will be performed by the 
independent SSG for the IDMC. 
• Time point 3: when all (up to 280) randomized subjects 
have completed the Week 26 6MWD assessment or 
prematurely discontinued from the study, the final analysis 
for the 6MWD endpoint and an IA for the TTCW endpoint 
will be performed by the independent SSG for the IDMC. 
• Time point 4: when all (up to 280) randomized subjects 
have completed the DB treatment period or the post-
treatment observation period (PTOP) or prematurely 
discontinued from the study, the DB database will be 
locked, the data extract will be performed and unblinding 
will occur. The final analysis for all endpoints will be 
performed by the sponsor. 
• Time point 5: when all (up to 280) randomized subjects 
have performed their End-of-Study (EOS) visit, an analysis 
including OL period data will be performed by the sponsor.  
PERIODS 
Screening period: Lasts at least 14 days and up to 60 days; 
starts with the signature of the informed consent and ends with 
the subject’s randomization at Visit 2, Day 1.  
Double-blind 
treatment 
period: 
Starts 
with 
the 
administration of the first dose of DB study treatment in the 
evening of the day of randomization (Visit 2) (except in case 
of once daily [qd] dosing, where the subjects must take the 
study treatment in the morning) and with a titration phase of up 
to 12 weeks. It ends on the day of the last dose of DB study 
treatment with the End-of-Double-Blind-Treatment (EDBT) 
visit. The EDBT visit will occur shortly (within 4 weeks) after 
the announcement of end-of-double-blind period, for all 
subjects who have not discontinued study treatment 
prematurely. The end-of-double-blind period will be 
announced by the sponsor when the overall target number of 
clinical 
worsening 
events 
has 
been 
reached 
[see 
Section 10.6.3], or earlier following recommendation of the 
IDMC [see Section 10.4] or sponsor’s decision [see 
Section 8.3].  
Open-label treatment extension period: For subjects who 
completed the DB treatment period, the OL treatment 


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Chronic Thromboembolic Pulmonary 
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Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
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CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
extension period will last at least until the DB period results 
release and up to a maximum of 26 weeks after the DB period 
results release. It starts with the first dose of the OL study 
treatment in the evening of the day of the last dose of DB study 
treatment, ie, the EDBT visit (except in case of qd dosing, 
where the subjects must take the study treatment in the 
morning). All subjects will have a titration phase of up to 12 
weeks. It ends with the End-of-Open-Label-Treatment (EOLT) 
visit that occurs any time within 26 weeks of the DB period 
results release.  
Follow-up period: Starts on the day after the last dose of OL 
study treatment and ends 30–35 days thereafter with the safety 
follow-up telephone call. 
Post-treatment 
observation 
period: 
Subjects 
who 
prematurely discontinue the DB treatment period will enter a 
PTOP and will continue to perform the visits and assessments 
as scheduled until the PTOP-EOS visit [see Section 5.1.10], 
provided the subject’s consent for this limited participation in 
the study has not been withdrawn [see Section 8.2].  
PLANNED DURATION 
The maximum duration of participation of a subject in the 
study will be approximately 74 months. 
SITE(S) 
/ COUNTRY(IES) 
Approximately 195 sites in 40 countries (planned). 
SUBJECTS / GROUPS 
Up to 280 subjects in two groups; randomized in a 1:1 ratio to 
receive either selexipag or placebo during the DB period. 
Subjects will be recruited in two sequential cohorts. 
Approximately the first 90 randomized subjects will constitute 
the hemodynamic cohort and, in addition to the overall study 
assessments, will undergo an RHC (and LHC, if needed) at 
Week 20 [see Section 7.2.3.1.2]. The remaining subjects will 
constitute the non-hemodynamic cohort.  
INCLUSION CRITERIA 
1. Signed and dated Informed Consent Form. 
2. Male and female subjects ≥18 (or the legal age of consent 
in the jurisdiction in which the study is taking place) 
and ≤85 years old at Screening (Visit 1).  


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Amendment 3, Version 4 
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3. Subjects with diagnosis of CTEPH and inoperability 
confirmed 
by 
the 
corresponding 
Adjudication 
Committee 
(AC; 
Country-specific 
Adjudication 
Committee 
[CSAC] 
or 
Central 
Adjudication 
Committee [CAC]) [see Section 3.4.3], defined as one 
of the following options: 
a. Inoperable CTEPH (ie, technically non-operable) with:  
– Diagnosis of CTEPH based on at least two of the 
following assessments performed in the 14-month 
period prior to randomization (Visit 2): 
o ventilation/perfusion (V/Q) scan,  
o pulmonary angiography (PA),  
o computed 
tomography 
pulmonary 
angiogram (CTPA), and/or  
o magnetic resonance angiography (MRA). 
– RHC (and LHC, if needed) 1 performed at least 
90 days after start of full anticoagulation, showing: 
o PVR at rest ≥400 dyn.sec/cm5 or ≥5 Wood 
units for the hemodynamic cohort and PVR 
at rest ≥300 dyn.sec/cm5 or ≥3.75 Wood 
units for the non-hemodynamic cohort, 
o Mean pulmonary arterial pressure (mPAP) 
≥25 mmHg, 
o Pulmonary arterial wedge pressure (PAWP) 
≤15 mmHg or, if not available or unreliable, 
a left ventricular end diastolic pressure 
(LVEDP) ≤15 mmHg. 
b. Persistent/recurrent CTEPH after BPA, and deemed 
inoperable with: 
– Diagnosis of CTEPH based on at least one of the 
following assessments performed in the 14-month 
period prior to randomization (Visit 2) and after last 
interventional 
(BPA) 
treatment: 
ventilation/perfusion (V/Q) scan, PA, CTPA or 
MRA. 
– RHC (and LHC, if needed)1 performed at least 
90 days after last interventional (BPA) treatment 
and at least 90 days after start of full 
anticoagulation, showing: 


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o PVR at rest ≥400 dyn.sec/cm5 or ≥5 Wood 
units for the hemodynamic cohort and PVR 
at rest ≥300 dyn.sec/cm5 or ≥3.75 Wood 
units for the non-hemodynamic cohort,  
o mPAP ≥25 mmHg, 
o PAWP ≤15 mmHg, or, if not available or 
unreliable, an LVEDP ≤15 mmHg. 
c. Persistent/recurrent CTEPH after PEA (including PEA 
followed by BPA) with: 
– Diagnosis of CTEPH based on at least one of the 
following assessments performed in the 14-month 
period prior to randomization (Visit 2) and after last 
surgical (PEA) or interventional (BPA) treatment: 
V/Q scan, PA, CTPA or MRA. 
– RHC (and LHC, if needed)1 performed at least 
90 days after last surgical (PEA) or interventional 
(BPA) treatment and at least 90 days after start of 
full anticoagulation, showing: 
o PVR at rest ≥400 dyn.sec/cm5 or ≥5 Wood 
units for the hemodynamic cohort and PVR 
at rest ≥300 dyn.sec/cm5 or ≥3.75 Wood 
units for the non-hemodynamic cohort, 
o mPAP ≥25 mmHg, 
o PAWP ≤15 mmHg, or, if not available or 
unreliable, an LVEDP ≤15 mmHg. 
4. PH in WHO FC I–IV. 
5. Subject able to perform the 6MWT with a minimum 
distance of 100 m and a maximum distance of 450 m at 
Screening Visit (Visit 1). 
6. A woman of childbearing potential [see definition in 
Section 4.5.1] is eligible only if all the following applies: 
a. Negative serum pregnancy test at Screening and a 
negative urine pregnancy test at randomization. 
b. Agreement to undertake monthly urine pregnancy tests 
during the study and up to at least 30 days after study 
treatment discontinuation. 
c. Agreement to use one of the methods of birth control 
described in Section 4.5 from Screening visit up to at 
least 30 days after study treatment discontinuation. 


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1 For the hemodynamic cohort, a historical RHC/LHC is allowed, provided it was 
performed within 30 days prior to Screening*, at least 90 days after last 
change in PH-specific therapies (ie, change in dose or initiation of new class 
of drugs) and as per guidance in Appendix 1. 
 
For the non-hemodynamic cohort, a historical RHC is allowed, provided it 
was performed within 6 months prior to Screening*.  
 
* In case of rescreening in the hemodynamic cohort within 6 months of the 
first Screening Visit, the first screening RHC (and LHC, if needed) can be 
used, provided there have been no changes in PH-specific therapy(ies) since 
the first Screening Visit. In case of rescreening in the non-hemodynamic 
cohort within 6 months of the first Screening Visit, the first screening RHC 
(and LHC if needed) can be used. 
 
If no historical results are available, an RHC (and LHC, if needed) must be 
performed during the Screening period (as per guidance in Appendix 1 for the 
hemodynamic cohort). 
 
EXCLUSION CRITERIA 
Exclusion criteria related to the disease 
1. Planned BPA within 26 weeks after randomization. 
2. Change in dose or initiation of new PH-specific therapy 
within 90 days prior to the baseline RHC (and LHC, if 
needed) qualifying for enrollment for the hemodynamic 
cohort and within 90 days prior to randomization (Visit 2) 
for the non-hemodynamic cohort.  
3. Treatment with prostacyclin (epoprostenol), prostacyclin 
analogs (ie, treprostinil, iloprost, beraprost) or prostacyclin 
receptor agonists (ie, selexipag/Uptravi) within 90 days 
prior to randomization (Visit 2), except those given at 
vasodilator testing during RHC.  
4. Change in dose or initiation of new diuretics and/or 
calcium channel blockers within 1 week prior to baseline 
RHC (and LHC, if needed). 
Exclusion criteria related to comorbidities 
5. Severe coronary heart disease or unstable angina as 
assessed by the investigator. 
6. Myocardial infarction within the last 6 months prior to or 
during Screening. 
7. Decompensated cardiac failure if not under close 
supervision. 


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8. Severe arrhythmias as assessed by the investigator. 
9. Cerebrovascular events (eg, transient ischemic attack, 
stroke) within the last 3 months prior to or during 
screening. 
10. Congenital or acquired valvular defects with clinically 
relevant myocardial function disorders not related to PH. 
11. Known or suspicion of pulmonary veno-occlusive disease.  
Exclusion criteria related to selexipag use 
12. Known and documented severe hepatic impairment, eg, 
Child-Pugh Class C2. 
13. Severe renal failure (estimated glomerular filtration rate 
<30 mL/min/1.73 m2 or serum creatinine >2.5 mg/dL or 
221 μmol/L) at Screening. 
14. Known or suspected uncontrolled thyroid disease as per 
investigator judgment. 
15. Pregnant, planning to be become pregnant or lactating. 
16. Treatment with strong inhibitors of cytochrome P-450 2C8 
(CYP2C8; eg, gemfibrozil) or moderate inducers of 
CYP2C8 (eg, rifampicin) within 14 days prior to 
randomization. 
17. Systolic blood pressure <90 mmHg at Screening (Visit 1) 
or at randomization (Visit 2).  
18. Known hypersensitivity to selexipag or drugs of the same 
class, or any of their excipients. 
General exclusion criteria 
19. Planned or current treatment with another investigational 
treatment up to 3 months prior to randomization. 
20. Any co-morbid condition that may influence the ability to 
perform a reliable and reproducible 6MWT, including use 
of walking aids (cane, walker, etc.).  
21. Any known factor or disease that might interfere with 
treatment compliance, study conduct or interpretation of 
the results, such as drug or alcohol dependence or 
psychiatric disease. 
22. Known concomitant life-threatening disease with a life 
expectancy <12 months. 
 


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2 The assessment of hepatic impairment (Child-Pugh Score as per Appendix 10) 
must be fully documented for patients who have clinical signs and evidence 
(from central and/or local lab) of hepatic impairment.  
STUDY TREATMENTS 
Investigational treatment 
DB and OL selexipag 200 µg, oral tablets in childproof bottles, 
up-titrated to allow each subject to reach their individual 
maximum tolerated dose (iMTD), in the range of 200 μg to 
1600 μg. 
Dosing frequency will be twice daily (bid), with an interval of 
approximately 12 hours. For subjects with moderate hepatic 
impairment (Child-Pugh B) or who are concomitantly taking a 
moderate CYP2C8 inhibitor (eg, clopidogrel, deferasirox, 
teriflunomide), the dosing frequency is once daily (qd) [see 
Section 5.1.9]. 
The DB study treatment refers to either DB selexipag 200 µg 
or the matching placebo, administered during the DB treatment 
period. The OL study treatment refers to OL selexipag 200 µg, 
administered during the OL period. If not otherwise specified, 
study treatment refers to both DB and open-label study 
treatments. 
Depending on the iMTD, a single dose of study treatment will 
consist of 1–8 tablets (200–1600 μg). 
Comparator and/or placebo 
Matching placebo, bid or qd. 
AUXILIARY MEDICINAL 
PRODUCTS  
All subjects must receive full anticoagulation treatment, as per 
local practice, from 90 days prior to the baseline RHC (and 
LHC, if needed) assessment and up to EOS. 
ENDPOINTS 
Primary efficacy endpoint 
PVR at Week 20, assessed at rest, within 2–5 hours post-dose, 
expressed as a percent of baseline PVR. 
Secondary efficacy endpoints 
• Change from baseline in 6MWD to Week 26 (key 
secondary endpoint). 
• Time to clinical worsening (key secondary endpoint), 
where clinical worsening is defined (adapted from the 


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Committee for medicinal products for human use [CHMP] 
definition [EMEA 2008]) as at least one of the following 
components, confirmed by the clinical event committee 
(CEC), when applicable: 
o All-cause death 
o Non-planned PH-related hospitalization  
o PH-related deterioration identified by at least one of 
the following: 
o Increase from baseline in WHO FC3; 
o Deterioration from baseline by at least 15% in 
exercise capacity as measured by the 6MWD3; 
o New or worsening of signs or symptoms of right 
heart failure defined as a reported adverse event 
(AE) with one of the following preferred terms: 
“CTEPH”, “pulmonary hypertension”, “right 
ventricular 
failure”, 
“right 
ventricular 
dysfunction” and “acute right ventricular 
failure”. 
• All-cause death or hospitalizations related to PH 
worsening. 
• Improvement in WHO FC from baseline to Week 26. 
• Change from baseline to Week 26 in Pulmonary arterial 
hypertension symptoms and impact questionnaire (PAH-
SYMPACT®) cardiopulmonary symptoms domain and 
cardiovascular symptoms domain. 
• Change from baseline to Week 26 in the Borg dyspnea 
index/Borg CR10®. 
• Change from baseline to Week 26 in NT-proBNP.  
3 Confirmed by a second measurement performed on a different day within 14 days 
Other efficacy endpoints 
Other efficacy endpoints are described in Section 6.1.3. 
Safety endpoints 
• Treatment-emergent AEs 5 up to 3 days after study 
treatment discontinuation at each analysis time point [see 
Section 5.1.6.1]. 


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• Serious adverse events (SAEs) up to 30 days after study 
treatment discontinuation at each analysis time point 
[see Section 5.1.6.1]. 
• AEs leading to premature discontinuation of study 
treatment at each analysis time point [see Section 5.1.6.1]. 
• Change 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 at each analysis 
time point [see Section 5.1.6.1]. 
• Treatment-emergent marked laboratory abnormalities up 
to 3 days after study treatment discontinuation, as detailed 
in Appendix 2, at each analysis time point [see 
Section 5.1.6.1]. 
• Treatment-emergent AEs5 of special interest (eg, 
hypotension, anemia, hyperthyroidism) up to 3 days after 
study treatment discontinuation at each analysis time point 
[see Section 5.1.6.1]. 
5 A treatment-emergent AE is any AE temporally associated with the use of study 
treatment (from study treatment start until 3 days after study treatment 
discontinuation), whether or not considered by the investigator as related to study 
treatment. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 3, Table 4 and 
Table 5. 
STATISTICAL 
METHODOLOGY 
There will be up to five analysis time points: 
  
At analysis time point 1, the analysis of the primary efficacy 
endpoint PVR will be conducted on the Hemodynamic Set 
(HES). If the analysis of PVR is statistically significant, the 
study will proceed as planned; otherwise, the study will be 
terminated. The IDMC will review the results and make 
corresponding recommendations in line with the IDMC 
charter. The independent SSG will make unblinded results 
available to the IDMC. 
At analysis time point 2, unblinded IA for 6MWD and TTCW 
will be conducted on the Full Analysis Set (FAS). If both 
6MWD and TTCW are futile, then the study will be terminated 
prematurely. If at least one of 6MWD and TTCW is 
statistically significant, the study will be terminated due to 


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overwhelming efficacy and subject recruitment will be 
stopped, but subjects already enrolled will remain on DB 
treatment as planned until all subjects have completed Week 
26 assessments or prematurely discontinued from the study. 
Otherwise, the study will proceed as planned. The IDMC will 
review the results and make corresponding recommendations 
in line with the IDMC charter. The independent SSG will make 
unblinded results available to the IDMC. 
At analysis time point 3, an unblinded final analysis for 6MWD 
and an unblinded IA for TTCW will be conducted on the FAS. 
If 6MWD is not statistically significant and TTCW is futile, 
then the study will be terminated prematurely. If at least one of 
6MWD and TTCW is statistically significant, the study will be 
terminated due to overwhelming efficacy. Otherwise, the study 
will proceed as planned. The IDMC will review the results and 
make corresponding recommendations in line with the IDMC 
charter. The independent SSG will make unblinded results 
available to the IDMC. 
At analysis time point 4, the DB database will be locked, the 
data extract will be performed and unblinding will occur. This 
final analysis of the DB treatment period will be conducted by 
the sponsor.  
At analysis time point 5, the data from all subjects enrolled in 
the OL treatment extension period will be summarized and 
reported. The analysis at this time point will be considered the 
final analysis of the study and will correspond to the 
completion of the OL treatment extension period. 
Primary efficacy variable 
The primary efficacy variable is the percent of baseline PVR at 
Week 20, defined as: 
(PVR (dyn.sec/cm5) at Week 20 / PVR (dyn.sec/cm5) at 
baseline) × 100 
The hypotheses for the primary endpoint are formulated in 
terms of geometric mean of percent of baseline PVR at 
Week 20 in subjects treated with selexipag versus placebo: 


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Ho: GMselexipag = GMplacebo 
HA: GMselexipag ≠GMplacebo 
where: 
GMselexipag and GMplacebo are the geometric means of percent of 
baseline PVR at Week 20 for subjects treated with selexipag 
and placebo, respectively. 
The null hypothesis for the primary efficacy variable will be 
tested on the hemodynamic cohort by means of an analysis of 
covariance (ANCOVA) model on the loge transformed percent 
of baseline PVR at Week 20 (including imputed values). 
Model covariates will include randomized treatment, 
stratification factors (PH-specific therapies and CTEPH 
population), and the loge-transformed baseline PVR value. The 
resulting arithmetic mean and 95% confidence limits (CL) of 
the natural logarithm of the ratio: PVR at Week 20 / PVR at 
baseline will be inversely transformed using the exponential 
function and multiplied by 100 to provide the geometric mean 
of the ratio and corresponding 95% CL, expressed as a percent, 
by treatment group. 
Imputation methods for the primary endpoint, PVR at 
Week 20, are described in Section 10.3.2.2. 
At analysis time point 1 the primary endpoint PVR will be 
tested in the hemodynamic cohort at full two-sided alpha of 
5%. Failure to meet success on the primary endpoint in this 
analysis will lead to termination of the study for futility, as no 
remaining alpha is available to test secondary endpoints.  
Key secondary variables 
There are two key secondary variables, 6MWD and TTCW. To 
allow for the declaration of study success if the test of at least 
either 6MWD or TTCW reaches statistical significance, a 
graphical testing strategy based on weighted Bonferroni-Holm 
method [Holm 1979; Bretz 2009] will be implemented, 
controlling the family-wise error rate (FWER) at a two-sided 
significance level of α=5% for the primary and secondary 


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efficacy variables. The significance level is initially split 
equally to 6MWD and TTCW. 
The 6MWD efficacy variable is the change from baseline to 
Week 26 in 6MWD (in meters) as defined by:  
(6MWD [m] at Week 26 − 6MWD [m] at baseline). 
The null hypothesis is that there is no difference between 
selexipag and placebo for change from baseline to Week 26 in 
6MWD. The analysis will be an ANCOVA (with baseline 
6MWD, all stratification factors, treatment group as 
covariates). Least squares estimates for each treatment group 
and for the placebo-corrected treatment effect will be 
displayed. This endpoint will be tested at analysis time points 
2 and 3 on the FAS. To preserve the type I error rate, the 
Hwang, Shih and DeCani’s error spending function with 
parameter γ=−4 [Hwang 1990] will be applied. The alpha to be 
spent in the IA depends on the fraction of available information 
on 6MWD at time of the IA. 
The TTCW efficacy variable (according to the CHMP 
definition) is calculated from date of randomization to the date 
of onset of the first component event. 
The null hypothesis is that there is no difference between 
selexipag and placebo for the distribution of time to the first 
CHMP-defined clinical worsening event. A two-sided 
stratified (for the stratification factors) log-rank test will be 
applied. Kaplan-Meier point and interval estimates for the 
survival functions will be provided. The hazard ratio will be 
estimated using a Cox model, including treatment group and 
all stratification factors as covariates. This endpoint will be 
tested at analysis time points 2, 3 and 4 on the FAS. To 
preserve the type I error rate, the O’Brien and Fleming-type 
error spending function will be applied [Lan 1983]. The alpha 
to be spent in the IA depends on the fraction of available 
information on TTCW at time of the IA. 
Safety variables 


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Safety variables: treatment-emergent AEs, SAEs, AEs leading 
to 
permanent 
discontinuation 
of 
study 
treatment, 
treatment-emergent AEs of special interest, reasons for 
premature discontinuation of study treatment, number of and 
reason 
for 
deaths, 
changes 
in 
vital 
signs 
and 
treatment-emergent marked laboratory abnormalities will be 
listed and summarized by frequency tables. 
Subgroup analyses 
Subgroup analyses will be conducted to assess results 
consistency on the primary endpoint and on selected secondary 
endpoints, based on the following baseline characteristics:  
• Stratification factor 1: PH-specific therapies (one versus 
two versus naive);  
• Stratification factor 2: CTEPH population (inoperable 
[with or without BPA] versus persistent-recurrent after 
PEA [including PEA followed by BPA]);  
• Participation in the hemodynamic cohort;  
• Gender;  
• Race (as defined in the statistical analysis plan [SAP]);  
• Geographic region (as defined in the SAP).  
An additional subgroup analysis on the primary endpoint and 
on selected secondary endpoints will be conducted by dose 
group (low [200–400 µg bid], medium [600, 800 and 1000 µg 
bid] and high [1200, 1400 and 1600 µg bid]). 
Sample size 
Up to 280 subjects are planned to be randomized in this study. 
The study will consist of two cohorts: approximately the first 
90 subjects will be randomized in the hemodynamic cohort, 
targeting the primary endpoint of PVR. The remaining subjects 
will be randomized to enrich information on all secondary 
endpoints. 


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A sample size of 90 subjects will provide a power of >90% at 
two-sided alpha 5% for the primary endpoint (PVR) under the 
assumed effect of a 30% relative improvement in geometric 
mean as compared to placebo at Week 20 and a coefficient of 
variation of 35–50%.  
The sample size of 280 subjects will provide a power of 90% 
at two-sided alpha 2.5% for the key secondary endpoint 
6MWD under the assumed effect of a 34 m difference in 
6MWD at a standard deviation of 80 m with one IA, and a 
power of 80% at two-sided alpha 2.5% for the key secondary 
endpoint TTCW under the assumed hazard ratio of 0.6, a no-
event rate of 0.7 at 12 months in the placebo arm and a total of 
148 events, with two IAs. [Section 10.6].  
STUDY COMMITTEES 
A Steering Committee has been appointed by the sponsor to 
contribute to the design of the protocol, oversee the conduct of 
the study, evaluate the results and support publications.  
An IDMC has overall responsibility for safeguarding the 
interests of subjects by monitoring safety and efficacy data 
obtained 
in 
the 
study 
and 
making 
appropriate 
recommendations based on the reported data, thus ensuring 
that the study is conducted with the highest scientific and 
ethical standards. It will interpret the results of the planned 
analyses at analysis time points 1, 2, and 3. The IDMC will be 
fully operational prior to enrollment of the first subject into the 
study.  
Two sets of independent ACs are established to confirm the 
inoperability and the persistence/recurrence of PH of CTEPH 
subjects considered eligible for study inclusion by the 
investigational sites: 
• CSAC and  
• CAC for countries without a CSAC. 
These committees will review predefined data for each subject 
and 
assess 
whether 
CTEPH 
diagnosis 
and 
persistence/recurrence of PH (when applicable) are confirmed 
and the inoperability criterion is met prior to randomization. In 
addition, the ACs will confirm the scientific and medical 


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plausibility of all Week 20 hemodynamic parameters as 
compared to the baseline values. 
Clinical Event Committee 
A CEC has been appointed by the sponsor to adjudicate, in a 
blinded fashion, components of the clinical worsening events. 
 


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PROTOCOL 
1 
BACKGROUND 
1.1 Indication 
Pulmonary hypertension (PH) is a rare pathophysiological disorder that may involve 
multiple clinical conditions and can complicate several cardiovascular and respiratory 
diseases such as left ventricular dysfunction and chronic obstructive pulmonary disease.  
Chronic thromboembolic pulmonary hypertension (CTEPH) most commonly develops 
from the obstruction of pulmonary artery branches following episodes of acute or recurrent 
pulmonary embolism (PE) with incomplete thrombus resolution, formation of fibrosis and 
remodeling of pulmonary blood vessels. Based on the European CTEPH registry, a large 
contemporary, international, prospective registry that included 679 newly diagnosed 
CTEPH patients, the majority of patients evaluated for CTEPH had been previously 
diagnosed with acute PE. Specifically, a history of deep venous thrombosis and acute PE 
was observed in 56% and 75%, respectively, of patients with CTEPH in this registry 
[Pepke-Zaba 2011].  
CTEPH is one of the leading causes of severe PH, categorized by the World Health 
Organization (WHO) and the Nice Classification as Group 4 [Galiè 2016]. CTEPH is 
defined as precapillary PH (resting mean pulmonary arterial pressure [mPAP] ≥25 mmHg, 
mean pulmonary arterial wedge pressure [mPAWP] ≤ 15 mmHg) in the presence of non-
resolving organized thromboemboli that are located proximally or more distally in the 
pulmonary arterial tree (main, lobar, segmental, subsegmental pulmonary arteries) and that 
persist at least 3 months after the onset of anticoagulant therapy [Gopalan 2016]. The 
arteriopathy observed in CTEPH has a histopathology indistinguishable from that observed 
in pulmonary arterial hypertension (PAH) and affects vascular territories beyond those 
affected by unresolved thromboemboli. 
Pulmonary endarterectomy (PEA) surgery is the treatment of choice for patients with 
symptomatic, operable CTEPH, which means CTEPH is a potentially curable form of PH. 
However, if left untreated, because it is unrecognized or inoperable, CTEPH leads to 
progressively increasing pulmonary vascular resistance (PVR) and eventually right 
ventricle failure and death [Jenkins 2013]. Balloon pulmonary angioplasty (BPA) is an 
emerging therapeutic option for patients diagnosed with inoperable CTEPH that is 
currently being assessed for the treatment of CTEPH, as it is likely to address changes in 
medium- to small-sized pulmonary arteries[Galiè 2016]. 
PVR represents a relevant assessment in CTEPH with direct implications for patient 
management, given that baseline values have been shown to be linked to outcome. A high 


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PVR (>584 dyn.sec/cm5) and a high mPAP (>40 mmHg) are prognostic for increased 
mortality [Saouti 2009]. 
1.2 Study treatment(s) 
Selexipag (ACT-293987) is an orally available, selective and long-acting non-prostanoid 
agonist of the prostacyclin receptor (IP receptor) approved and commercially available for 
the treatment of patients with PAH in the US, EU, Japan and other countries. 
Selexipag is currently under development in Japan for CTEPH and arteriosclerosis 
obliterans with intermittent claudication. 
For detailed information, refer to the Investigator’s Brochure [Selexipag IB]. 
1.3 Purpose and rationale of the study 
This study will be the first global, randomized, controlled study to explore the efficacy and 
safety of an oral IP-receptor agonist in an inoperable or persistent/recurrent CTEPH 
population treated with standard of care and, as such, will address the role of the oral 
IP-receptor agonist selexipag in a first-line and add-on setting. The purpose of this study is 
to obtain registration of selexipag in the studied indication and population. 
This study assesses important data intended to guide clinical decision making and support 
the filing for regulatory approval, including but not limited to hemodynamics, 6-minute 
walk distance (6MWD) and clinical worsening. 
The rationale for this study rests in the observed efficacy of PH-specific therapies such as 
riociguat and macitentan in inoperable and persistent/recurrent CTEPH. This is further 
supported by shared histopathologic findings including endothelial cell dysfunction and 
distal pulmonary arterial remodeling between PAH and CTEPH [Humbert 2010].  
Selexipag Phase 2 study in CTEPH 
Study AC-065B201 was a Phase 2 study conducted in Japanese patients with inoperable 
and/or persistent/recurrent CTEPH. A total of 34 patients were enrolled in this study and 
assigned to treatment with placebo or selexipag with a ratio of 1:3. Patients were treated 
following an up-titration regimen, based on the tolerability of each subject, starting at a 
dose of 100 μg twice daily (bid) up to a maximum dose of 800 μg bid. Concomitant use of 
either an endothelin receptor antagonist (ERA) or a phosphodiesterase type-5 (PDE-5) 
inhibitor was allowed in this study. In the Per-protocol Set (N=28), selexipag treatment 
was associated with a mean change from baseline to Week 17 in PVR of −104 dyn.sec/cm5 
(95% confidence limits [CL]: −191 and −17 dyn.sec/cm5) compared to an increase of 
26 dyn.sec/cm5 in the placebo group (95% CL: −140 and 192 dyn.sec/cm5). The treatment 
effect in percentage change from baseline to Week 17 in PVR over placebo with selexipag 


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was −16.3% (95% CL: −34.7 and 7.3%), with p-values of 0.1553 (Wilcoxon rank sum test) 
and 0.1260 (t-test). No effect on 6MWD was observed (−9 m, 95% CL=−57 to 39 m). The 
interpretability of this study is considered limited, given the cap on the maximal permitted 
dose at half of the currently approved maximum selexipag dose in PAH, which suggests 
that not all patients were on their individual maximal tolerated, and thus effective, dose. A 
post-hoc analysis in patients with and without notable prostacyclin-associated adverse 
events (AEs) suggested improved efficacy on both hemodynamic and exercise capacity 
parameters in patients who experienced prostacyclin-associated AEs (data on file). 
The data from study AC-065B201 support the current design despite the lack of an effect 
on 6MWD, given the observed hemodynamic effects in a study in which a potentially 
sub-maximal dose was given and in view of the observed treatment effect in patients who 
have likely reached their individual maximum tolerated dose (iMTD), as evidenced by the 
occurrence of relevant prostacyclin-associated AEs. 
1.4 Summary of known benefits and potential risks 
1.4.1 Benefits 
Selexipag, a non-prostanoid IP-receptor agonist, is an orally available medicine with 
pharmacokinetic characteristics suitable for bid dosing. 
Efficacy of selexipag in the treatment of adult patients with symptomatic PAH was 
demonstrated in the AC-065A302 (GRIPHON) study, the largest (N=1156) and only 
randomized long-term (mean duration 1.5 years and up to 4.2 years), controlled 
morbidity/mortality study conducted with an IP-receptor agonist [Sitbon 2015]. A highly 
statistically significant effect on the primary endpoint, risk of first morbidity or mortality 
event during treatment, was observed: the hazard ratio versus placebo was 0.60 (99% CL: 
0.46, 0.78; 1-sided unstratified log-rank p=0.0001), corresponding to a 40% relative risk 
reduction versus placebo. The treatment effect was consistent across WHO functional class 
(FC) II–III and was fully preserved in patients already treated with an approved 
PAH-specific medicine at baseline (80% of the study population), as well as in patients 
treated with two such medicines (30% of the study population). In all analyses, the effect 
of selexipag was established early and was sustained over this long-term study, in which 
the median duration of treatment was nearly 1.5 years. GRIPHON was the first study to 
demonstrate the long-term outcome benefit of an IP-receptor agonist, in particular when 
added sequentially to therapies acting on other pathogenic pathways in PAH (endothelin 
and nitric oxide pathways). The study outcome is reflected in the current consensus 
guidelines for PAH, where selexipag is the only IP-receptor agonist with a Class I evidence 
recommendation for sequential drug combination therapy [Galiè 2016]. 


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Given the pathophysiological and clinical similarities between CTEPH and PAH due to 
distal pulmonary arteriopathy, as well as the demonstrated efficacy of PAH-targeted 
therapies in inoperable CTEPH [Ghofrani 2013, Ghofrani 2017], it is believed that CTEPH 
patients could benefit from selexipag treatment, thus providing an alternate treatment 
option for these patients. 
1.4.2 Possible risks 
The tolerability and safety profile of selexipag administered to CTEPH patients is expected 
to be consistent with that in adult patients with PAH. 
The short and long-term safety profile of oral selexipag has been established in PAH 
patients in the GRIPHON study conducted in 1156 subjects and is mainly characterized by 
prostacyclin-associated AEs associated with the mode of action of selexipag. Such AEs 
typically occur during the initial phase of individualized dose titration, and the 
susceptibility varies between individuals. Adverse reactions, reflecting the mode of action 
of selexipag, included headache, diarrhea, nausea and vomiting, jaw pain, myalgia, pain in 
extremity, arthralgia and flushing.  
Hypotension was reported more frequently in the selexipag group than in the placebo group 
(5.0% and 3.1%, 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 the 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.  
The safety profile established in a Phase 2 study of selexipag in inoperable and 
persistent/recurrent CTEPH, conducted in Japanese patients [see Section 1.3], did not 
indicate any additional safety risk for selexipag in this indication. The risks associated with 
study participation beyond those described above for selexipag are limited to those 
associated with prolonged placebo treatment and those associated with study-specific 
procedures (eg, repeated blood sampling for safety assessments, right heart catheterization 
[RHC], etc.).  


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A potential risk is associated with the re-uptitration of subjects previously randomized to 
selexipag at the start of the OL study period, potentially resulting in a limited period of 
lower drug exposure in subjects. This measure is deemed necessary to preserve the blind 
prior to the analysis of endpoints assessed at the Week 52 time point. This potential risk is 
deemed low and acceptable given the demonstrated absence of any adverse outcomes 
following temporary interruption of selexipag treatment in the GRIPHON study 
[Preston 2018]. 
The following measures are taken to minimize the risks for the subjects participating in the 
study:  
• External adjudication of eligibility ensuring enrollment of subjects with a potential for 
benefit from medicinal treatment. 
• Exclusion of subjects with unstable PH condition or severe comorbidities [see 
Section 4.4]. 
• Allowed changes to PH-specific therapies following the Week 26 visit (new 
introduction or dose adjustments) and BPA to mitigate any risk associated with 
prolonged double-blind (DB) treatment. 
• Close monitoring of the study by an external Independent Data Monitoring Committee 
(IDMC) throughout the study. 
It is the investigator’s responsibility to monitor the individual risk-benefit ratio of study 
treatment administration, as well as the degree of distress caused by study procedures at an 
individual subject level, and to discontinue study treatment or the study if, on balance, 
he/she believes that continuation would be detrimental to the subject’s well-being. 
2 
STUDY OBJECTIVES 
2.1 Primary objective 
The primary objective of the study is to evaluate the effect of selexipag on PVR versus 
placebo in subjects with inoperable CTEPH (ie, technically non-operable) and 
persistent/recurrent CTEPH after surgical (PEA) and/or interventional (BPA) treatment at 
Week 20.  
2.2 Secondary objectives 
The secondary objectives of the study are to evaluate the effects of selexipag versus placebo 
on: 
• Exercise capacity.  
• Time to clinical worsening (TTCW). 
• All-cause death or hospitalizations related to PH worsening. 


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• WHO FC. 
• Patient-reported outcomes (PROs). 
• Dyspnea.  
• N-terminal pro b-type natriuretic peptide (NT-proBNP). 
2.3 Other efficacy objective 
The other objective of the study is to evaluate the effects of selexipag versus placebo on 
exploratory efficacy assessments. 
2.4 Safety objective 
The safety objective of the study is to evaluate the safety and tolerability of selexipag 
versus placebo in subjects with CTEPH. 
3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
This is a prospective, multicenter, randomized, double-blind, placebo-controlled, add-on 
to standard of care, parallel-group, group-sequential, adaptive Phase 3 study with an 
open-label extension period [Figure 1].  
Up to 280 subjects will be randomized in a 1:1 ratio to receive either selexipag or placebo 
during the DB period. Subjects completing the DB period will enter the open-label (OL) 
extension period and will receive selexipag [see Section 5.1.3.2 for open-label treatment 
initiation].  
Subjects will be recruited in two sequential cohorts. Approximately the first 90 randomized 
subjects will constitute the hemodynamic cohort and, in addition to the overall study 
assessments, will undergo an RHC (and left heart catheterization [LHC], if needed) at 
Week 20 [see Section 7.2.3.1.2]. The remaining subjects will constitute the 
non-hemodynamic cohort, who do not require a post-baseline hemodynamic assessment. 
Both cohorts are combined for the evaluation of secondary efficacy endpoints.  
Treatment allocation will be stratified by: 
• Treatment with PH-specific therapies (ie, ERAs, PDE-5 inhibitors, soluble guanylate 
cyclase [sGC] stimulators [riociguat]): one versus two versus naive [naive capped at 
40%]) and   
• CTEPH population: inoperable (with or without BPA) versus persistent/recurrent 
after PEA (including PEA followed by BPA).  
The study will be conducted in approximately 195 sites in 40 countries.  


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The database will be locked and analyzed at five time points during the study, as described 
in Section 5.1.6.1. Actions to be taken following these analyses are defined in Section 10.4. 
3.1.1 Study periods 
The study comprises the following consecutive periods for both cohorts: 
3.1.1.1 Screening period  
Lasts at least 14 days and up to 60 days; starts with the signature of the informed consent 
and ends with the subject’s randomization at Visit 2, Day 1.  
3.1.1.2 Treatment periods 
Double-blind treatment period: The DB treatment period starts with the administration 
of the first dose of DB study treatment in the evening of the day of randomization (Visit 2) 
(except in case of qd dosing; see Section 5.1.3.1) and with a titration phase of up to 
12 weeks. It ends on the day of the last dose of DB study treatment with the End-of-Double-
Blind-Treatment (EDBT) visit.  
The EDBT visit will occur shortly (within 4 weeks) after the announcement of end-of-
double-blind period, for all subjects who have not discontinued study treatment 
prematurely. The end-of-double-blind period will be announced by the sponsor when the 
overall target number of clinical worsening events has been reached [see Section 10.6.3], 
or earlier following recommendation of the IDMC [see Section 10.4] or sponsor’s decision 
[see Section 8.3].  
Open-label treatment extension period: For subjects who completed the DB treatment 
period, the OL treatment extension period will last at least until the DB period results 
release and up to a maximum of 26 weeks after the DB period results release. It starts with 
the first dose of the OL study treatment in the evening of the day of the last dose of DB 
study treatment, ie, the EDBT visit (except in case of qd dosing; see Section 5.1.3.2). All 
subjects will have a titration phase of up to 12 weeks. It ends with the End-of-Open-Label-
Treatment (EOLT) visit that occurs any time within 26 weeks of the DB period results 
release.  
3.1.1.3 Follow-up period  
Starts on the day after the last dose of OL study treatment and ends 30–35 days thereafter 
with the safety follow-up telephone call. 
3.1.1.4 Post-treatment observation period 
Subjects who prematurely discontinue the DB treatment period will enter a post-treatment 
observation period (PTOP) and will continue to perform the visits and assessments as 


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scheduled until the PTOP-EOS visit [see Section 5.1.10], provided the subject’s consent 
for this limited participation in the study has not been withdrawn [see Section 8.2].  
The visit schedule and protocol-mandated procedures for both hemodynamic and 
non-hemodynamic cohorts are performed according to the tables of assessments: Table 3 
for DB treatment period, Table 4 for OL treatment period, and Table 5 for subjects entering 
the PTOP, as presented in Section 7. 
The overall study design is depicted in Figure 1. The DB titration phase design is depicted 
in Figure 2. 
 
 


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Figure 1 
Study design  
 
bid = twice daily; BPA = balloon pulmonary angioplasty; DB = double-blind, EDBT = End-of-Double-Blind-
Treatment; EOLT = End-of-Open-Label-Treatment; EOS = End-of-Study; FU = follow-up, OL = open-label; PH = 
pulmonary hypertension; PTOP = post-treatment observation period, SFU = safety follow-up; V = visit; W = week.  
 
(1) End-of-double-blind period announcement: when the overall target number of clinical worsening events has been 
reached, or earlier following recommendation of the IDMC or sponsor’s decision. 
(2) EDBT visit to occur within 4 weeks of End-of-double-blind period announcement [see (1)]. 
(3) DB period results to be released approx. 6 months after last EDBT/PTOP-EOS visit. 
(4) Variable duration of OL treatment extension period for individual subjects depending on time randomization, with 
visits every 26 weeks ONLY FOR SUBJECTS WHO WERE TRANSITIONED TO THE OL TREATMENT EXTENSION 
PERIOD BEFORE IMPLEMENTATION OF THE AC-065B302 PROTOCOL AMENDMENT 2. 
(5) EOLT visit to occur any time within 26 weeks of the DB period results release [see (3)]. 
(6) PTOP-EOS visit to occur within 4 weeks of End-of-double-blind period announcement [see (1)]. 
(7) For subjects with moderate hepatic impairment (Child-Pugh B) or who are concomitantly taking a moderate CYP2C8 
inhibitor (eg, clopidogrel, deferasirox, teriflunomide), the dosing frequency of study treatment is once daily (qd), which 
must be taken in the morning [see Section 5.1.9]. 


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Figure 2 
Titration phase design 
  
bid = twice daily; D = day; iMTD = individual maximum tolerated dose; V = visit; W = week. 
 = weekly telephone 
calls.  
* For subjects with moderate hepatic impairment (Child-Pugh B) or who are concomitantly taking a moderate CYP2C8 
inhibitor (eg, clopidogrel, deferasirox, teriflunomide), the dosing frequency of the study treatment is once daily (qd), 
which must be taken in the morning [see Section 5.1.9]. 
If the dose regimen is not well tolerated or symptoms cannot be fully managed with symptomatic treatment, the duration 
of the titration step can be prolonged to two weeks [see Section 5.1.3].  
3.1.2 Study duration 
The study starts with the first act of recruitment (ie, first Informed Consent Form [ICF] 
signed) and ends with the last telephone call or visit of the last subject. 
The subjects will be treated in the DB treatment period for a variable duration depending 
on each subject’s individual date of randomization. The maximum duration is estimated to 
be approximately 59 months (the actual duration depends on actual accrual rate and clinical 
worsening event rate [see Section 10.6.3] as well as recommendation of the IDMC [see 
Section 10.4] and sponsor’s decision [Section 8.3]).  


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Subjects who complete the DB treatment period will enter the OL treatment extension 
period, which lasts at least until the release of results from the DB treatment period and up 
to a maximum of 26 weeks after the DB period results release.  
Subjects who were transitioned to the OL treatment extension period before 
implementation of the AC-065B302 Protocol amendment 2: Those subjects transitioned to 
the OL treatment extension period after 52 weeks of DB treatment will be treated in the OL 
treatment period for a variable duration depending on each subject’s individual date of 
randomization. They will remain in the OL treatment extension period until EOLT 
occurring anytime within 26 weeks of the DB period results release [see Figure 1 and 
Table 4]. 
Subjects who prematurely discontinue the DB study treatment will enter a PTOP and 
cannot enter the OL treatment extension period [see Section 3.1.1.4].  
For an individual subject, the EOS visit is defined as the last telephone call / visit performed 
in the study [see Section 8.1].  
The maximum duration of participation of a subject in the study will be approximately 
74 months. 
3.2 Study design rationale 
3.2.1 Rationale for the use of placebo 
A placebo-controlled study conducted in a randomized and DB fashion provides the most 
definite and rigorous method of evaluating treatment efficacy of a medical treatment and 
will allow establishment of the frequency and magnitude of changes in hemodynamic and 
clinical endpoints that may occur in the absence of active intervention. The use of placebo 
as a control will also allow proper evaluation of any safety-related events or abnormalities 
and disease progression observed during the study, and differentiation between events 
potentially related to the use of selexipag vs those related to the underlying disease.  
A placebo-controlled study is considered ethically acceptable due to the eligibility criteria 
restricting enrollment to stable CTEPH subjects as an add-on to standard of care. The use 
of background therapy with PH-specific therapies (excluding prostanoids) is allowed. In 
addition, treatment escalation of PH-specific therapies and BPA are allowed following the 
Week 26 visit (Visit 5). Furthermore, subjects who complete the DB treatment will receive 
selexipag in the OL treatment extension period.  
3.2.2 Rationale for the duration of the study 
Subjects will receive DB selexipag or placebo for a variable duration (up to a maximum of 
59 months) until EDBT visit. After the 90 subjects (approximately) of the hemodynamic 


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cohort have completed the Week 20 RHC (and LHC, if needed) (analysis time point 1), the 
primary endpoint (PVR) will be analyzed. If the study is not terminated prematurely for 
futility of PVR, the study will proceed as planned and the efficacy of selexipag on 6MWD 
(at Week 26), TTCW, and all-cause death or hospitalization related to PH-worsening, as 
well as other secondary endpoints will be assessed at specified time points [see 
Section 5.1.6.1] following the specified testing hierarchy [see Figure 4]. 
The results of the AC-055E201 (MERIT-1) study comparing macitentan to placebo showed 
a decrease in PVR of 16% when compared to placebo after 16 weeks of treatment and a 
significant increase in 6MWD after 24 weeks of treatment [Ghofrani 2017]. Exercise 
capacity increased gradually in this population, lagging behind hemodynamic 
improvements. Therefore, the durations of 20 and 26 weeks are considered to be sufficient 
to observe the effects on PVR and 6MWD, respectively, also allowing for titration to an 
iMTD. The variable follow-up time for individual subjects beyond Week 26 will allow for 
the assessment of the TTCW endpoint and the long-term safety and tolerability endpoints 
in a blinded fashion.  
Access to selexipag beyond completion of the DB treatment is ensured by including the 
OL treatment extension period in the study. The OL treatment extension period will allow 
investigators to make an informed decision on post-study therapy based on the DB 
treatment period results and the actual intervention received by the study subjects. It will 
also help in collecting further long-term efficacy, safety and tolerability information on 
selexipag and the survival status of subjects with CTEPH who have already completed the 
DB treatment period.  
3.2.3 Rationale for the post-treatment observation period 
In order to estimate the effect of treatment initially assigned at baseline, regardless of 
adherence to the planned course of treatment (intent-to-treat principle), subjects who 
prematurely discontinue the DB treatment period will be followed up until the end-of-
double-blind period, provided the subject’s consent for this limited participation in the 
study has not been withdrawn. 
3.3 Site personnel and roles 
3.3.1 Heart catheterization  
Detailed guidance on the conduct of RHC and LHC is provided in Appendix 1. Appropriate 
training(s) on the heart catheterization (HC) guidance must be completed and properly 
documented by site team members conducting the RHCs/LHCs. 


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3.3.2 6-minute walk test 
Appropriate training(s) on the sponsor’s 6-minute walk test (6MWT) guidelines 
[Appendix 3] must be completed and properly documented by site team members 
conducting the 6MWT. 
3.4 Study committees 
3.4.1 Steering committee 
A Steering Committee (SC) has been appointed by the sponsor to contribute to the design 
of the protocol, oversee the conduct of the study, evaluate the results and support 
publications. The committee is governed by a dedicated SC charter. 
3.4.2 Independent Data Monitoring Committee 
An IDMC has overall responsibility for safeguarding the interests of subjects by 
monitoring safety and efficacy data obtained in the study and making appropriate 
recommendations based on the reported data, thus ensuring that the study is conducted with 
the highest scientific and ethical standards. The IDMC will interpret the results of the 
planned analyses at time points 1, 2, and 3 (which will be performed by the independent 
statistical support group [SSG]) as outlined in Section 10.4. The IDMC will be fully 
operational prior to enrollment of the first subject into the study. The composition and 
operation of the IDMC is described in the IDMC charter. 
3.4.3 Adjudication committees 
The study population includes subjects with CTEPH who are diagnosed as inoperable (ie, 
technically non-operable) or with persistent/recurrent CTEPH after surgical (PEA) and/or 
interventional (BPA) treatment.  
In accordance with the European Society of Cardiology and the European Respiratory 
Society Guidelines for the diagnosis and treatment of PH [Galiè 2016], an operability 
assessment for CTEPH subjects should be performed by a multidisciplinary CTEPH team. 
Therefore, in addition to the CTEPH diagnosis, the inoperability and the 
persistence/recurrence of PH of CTEPH subjects considered eligible for study inclusion by 
the investigational sites will be confirmed by a multidisciplinary CTEPH team. For this 
purpose, two sets of independent adjudication committees (ACs) are established: 
• Country-specific Adjudication Committees (CSACs) and 
• Central Adjudication Committee (CAC) for countries without a CSAC. 
The establishment of the ACs is contingent on sound experience, as per the requirements 
outlined in the ACs’ charter. A CSAC may be established to review subjects’ data from 
selected countries within a specific geographical region. 


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These committees will review predefined data for each subject and assess whether the 
CTEPH diagnosis and persistence/recurrence of PH (when applicable) are confirmed and 
the inoperability criterion is met prior to randomization [see Section 4.1.1]. 
In addition to the eligibility review, the ACs will review the post-baseline RHC/LHC of 
each subject in the hemodynamic cohort in order to confirm the scientific and medical 
plausibility of all Week 20 hemodynamic parameters as compared to the baseline values. 
The ACs will provide the sponsor with feedback on the quality and plausibility. The 
plausibility check may lead to site querying from the sponsor of the values reported on the 
electronic Case Report Forms (eCRFs); no independent RHC/LHC values will be provided 
by the AC. Protocol deviations will be assigned for all Week 20 RHCs/LHCs not meeting 
the above quality criteria or any non-plausible Week 20 hemodynamic parameters. 
The composition and operation of these committees is described in the ACs’ charter. 
3.4.4 Clinical Event Committee 
A Clinical Event Committee (CEC) has been appointed by the sponsor to adjudicate, in a 
blinded fashion, components of the clinical worsening events. Full details for this procedure, 
as well as the composition and operation of the CEC, are described in the CEC charter. 
4 
SUBJECT POPULATION 
4.1 Subject population description 
This study will enroll adult male and female subjects aged ≥18 (or the legal age of consent 
in the jurisdiction in which the study is taking place) and ≤85 years with an established 
diagnosis of inoperable CTEPH (ie, technically non-operable) or persistent/recurrent 
CTEPH after surgical (PEA) and/or interventional (BPA) treatment, as confirmed by the 
corresponding ACs (CSAC or CAC) [see Section 3.4.3]. The subject must have PH in 
WHO FC I–IV due to CTEPH (Group 4.1 of PH). 
To minimize the number of screening failures, it is recommended to only screen subjects 
with available imaging and hemodynamic data, as described in Section 7.2.2 and 
Section 7.2.3.1. 
Eligible subjects must be able and willing to give informed consent for participation in the 
clinical study. 
4.1.1 Adjudication procedure 
Following the Screening visit, for subjects judged to have inoperable (ie, technically 
non-operable) or recurrent/persistent CTEPH after surgical (PEA) and/or interventional 
(BPA) treatment by the investigational site and fulfilling all other eligibility criteria, the 


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ACs (CSAC or the CAC) will receive anonymized data as outlined in Table 1 and detailed 
in the AC charter. 
Table 1 
Data required for adjudication procedure 
 
Inoperable 
CTEPH 
Persistent/recurrent 
CTEPH after BPA 
Persistent/recurrent 
CTEPH after PEAb 
RHC (and LHC, if 
needed)a 
X 
X 
X 
Imaging assessments 
≥2c 
≥1d 
≥1d 
Historical surgery & 
intervention report 
− 
X 
X 
Medical history form 
X 
X 
X 
BPA = balloon pulmonary angioplasty; CTEPH = chronic thromboembolic pulmonary hypertension; LHC = left heart 
catheterization; PEA = pulmonary endarterectomy; RHC = right heart catheterization. 
a. RHC (and LHC, if needed) must be performed at least 90 days after start of full anticoagulation and at least 90 days 
after last surgical (PEA) or interventional (BPA) treatment for subjects with persistent/recurrent CTEPH.   
For the hemodynamic cohort, a historical RHC (and LHC, if needed) is allowed, provided it was performed within 
30 days prior to Screening*, at least 90 days after last change in PH-specific therapies (ie, change in dose or initiation 
of new class of drugs) and as per guidance in Appendix 1. 
For the non-hemodynamic cohort, a historical RHC (and LHC, if needed) is allowed, provided it was performed 
within 6 months prior to Screening*.  
If no historical results are available, an RHC (and LHC, if needed) must be performed during the Screening period 
(as per guidance in Appendix 1 for the hemodynamic cohort). 
* In case of rescreening in the hemodynamic cohort within 6 months of the first Screening Visit, the first screening 
RHC (and LHC if needed) can be used, provided there have been no changes in PH-specific therapy(ies) since the 
first Screening Visit. In case of rescreening in the non-hemodynamic cohort within 6 months of the first Screening 
Visit, the first screening RHC (and LHC if needed) can be used. 
b. Includes PEA followed by BPA. 
c. Ventilation/perfusion (V/Q) scan, pulmonary angiography (PA), computed tomography pulmonary angiogram 
(CTPA), magnetic resonance angiography (MRA) performed in the 14-month period prior to randomization. 
d. V/Q scan, PA, CTPA, MRA performed in the 14-month period prior to randomization and after last surgical (PEA) 
and/or interventional (BPA) treatment.  
These data will be transferred from the investigational site to the corresponding AC via a 
central image processing center. Based on these data, the AC will assess the eligibility of 
each subject.  
The investigator will await the feedback from the AC concerning the final eligibility before 
informing the subject and performing the randomization visit.  
In addition to the eligibility review, the scientific and medical plausibility check will also 
be performed by the ACs via a central image processing center. 


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A separate manual is provided to the investigational sites for guidance through the 
adjudication procedure (eg, requested data, transfer of data to the central image processing 
center, etc.). 
4.2 Rationale for the selection of the study population 
The study population includes subjects with inoperable (ie, technically non-operable) or 
persistent/recurrent CTEPH after surgical (PEA) and/or interventional (BPA) treatment. 
This population is generally considered a good candidate for medicinal treatment to treat 
PH and accompanying right heart failure [Galiè 2016]. At present, the only approved 
treatment for CTEPH is riociguat, which is contraindicated in combination with a PDE-5 
inhibitor [Adempas® SmPC, Adempas® USPI]. The targeted study population was chosen 
as it represents a broad spectrum of CTEPH patients with and without PH-specific 
background therapies. Additionally, there is a medical need for an approved therapy in this 
indication acting on the prostacyclin pathway, allowing for combination therapy with other 
PH-specific therapies. 
4.3 Inclusion criteria 
For inclusion in the study, all of the following inclusion criteria must be fulfilled. It is not 
permitted to waive any of the criteria for any subject: 
1. Signed and dated ICF. 
2. Male and female subjects ≥18 (or the legal age of consent in the jurisdiction in which 
the study is taking place) and ≤85 years old at Screening (Visit 1).  
3. Subjects with diagnosis of CTEPH and inoperability confirmed by the corresponding 
AC (CSAC or CAC) [see Section 3.4.3], defined as one of the following options: 
a. Inoperable CTEPH (ie, technically non-operable) with:  
– Diagnosis of CTEPH based on at least two of the following assessments 
performed in the 14-month period prior to randomization (Visit 2): 
o ventilation/perfusion (V/Q) scan,  
o pulmonary angiography (PA),  
o computed tomography pulmonary angiogram (CTPA), and/or  
o magnetic resonance angiography (MRA). 


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– RHC (and LHC if needed)1 performed at least 90 days after start of full 
anticoagulation, showing: 
o PVR at rest ≥400 dyn.sec/cm5 or ≥5 Wood units for the hemodynamic 
cohort and PVR at rest ≥300 dyn.sec/cm5 or ≥3.75 Wood units for the 
non-hemodynamic cohort, 
o mPAP ≥25 mmHg, 
o Pulmonary arterial wedge pressure (PAWP) ≤15 mmHg or, if not 
available or unreliable, a left ventricular end diastolic pressure 
(LVEDP) ≤15 mmHg. 
b. Persistent/recurrent CTEPH after BPA, and deemed inoperable with: 
– Diagnosis of CTEPH based on at least one of the following assessments 
performed in the 14-month period prior to randomization (Visit 2) and after last 
interventional (BPA) treatment: V/Q scan, PA, CTPA or MRA. 
– RHC (and LHC, if needed)1 performed at least 90 days after last interventional 
(BPA) treatment and at least 90 days after start of full anticoagulation. showing: 
o PVR at rest ≥400 dyn.sec/cm5 or ≥5 Wood units for the hemodynamic 
cohort and PVR at rest ≥300 dyn.sec/cm5 or ≥3.75 Wood units for the 
non-hemodynamic cohort,  
o mPAP ≥25 mmHg, 
o PAWP ≤15 mmHg, or, if not available or unreliable, an LVEDP 
≤15 mmHg. 
c. Persistent/recurrent CTEPH after PEA (including PEA followed by BPA) with: 
– Diagnosis of CTEPH based on at least one of the following assessments 
performed in the 14-month period prior to randomization (Visit 2) and after last 
surgical (PEA) or interventional (BPA) treatment: V/Q scan, PA, CTPA or 
MRA. 
 
1 For the hemodynamic cohort, a historical RHC/LHC is allowed, provided it was performed within 30 days prior to 
Screening*, at least 90 days after last change in PH-specific therapies (i.e., change in dose or initiation of new class 
of drugs) and as per guidance in Appendix 1. 
For the non-hemodynamic cohort, a historical RHC/LHC is allowed, provided it was performed within 6 months 
prior to Screening*.  
* In case of rescreening in the hemodynamic cohort within 6 months of the first Screening Visit, the first screening 
RHC (and LHC if needed) can be used, provided there have been no changes in PH-specific therapy(ies) since the 
first Screening Visit. In case of rescreening in the non-hemodynamic cohort within 6 months of the first Screening 
Visit, the first screening RHC (and LHC if needed) can be used. 
If no historical results are available, an RHC/LHC must be performed during the Screening period (as per guidance 
in Appendix 1 for the hemodynamic cohort). 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
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Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
– RHC (and LHC, if needed)1 performed at least 90 days after last surgical (PEA) 
or interventional (BPA) treatment and at least 90 days after start of full 
anticoagulation, showing: 
o PVR at rest ≥400 dyn.sec/cm5 or ≥5 Wood units for the hemodynamic 
cohort and PVR at rest ≥300 dyn.sec/cm5 or ≥3.75 Wood units for the 
non-hemodynamic cohort, 
o mPAP ≥25 mmHg, 
o PAWP ≤15 mmHg, or, if not available or unreliable, an LVEDP 
≤15 mmHg. 
4. PH in WHO FC I–IV. 
5. Subject able to perform the 6MWT with a minimum distance of 100 m and a maximum 
distance of 450 m at Screening visit (Visit 1). 
6. A woman of childbearing potential [see definition in Section 4.5.1] is eligible only if 
all the following applies: 
a. Negative serum pregnancy test at Screening and a negative urine pregnancy test at 
randomization. 
b. Agreement to undertake monthly urine pregnancy tests during the study and up to 
at least 30 days after study treatment discontinuation. 
c. Agreement to use one of the methods of birth control described in Section 4.5 from 
Screening visit up to at least 30 days after study treatment discontinuation. If a 
hormonal contraceptive is chosen, it must be taken for at least 1 month prior to 
randomization. 
4.4 Exclusion criteria 
Subjects must not fulfill any of the following exclusion criteria. It is not permitted to waive 
any of the criteria for any subject: 
4.4.1 Exclusion criteria related to the disease 
1. Planned BPA within 26 weeks after randomization. 
2. Change in dose or initiation of new PH-specific therapy within 90 days prior to the 
baseline RHC (and LHC, if needed) qualifying for enrollment for the hemodynamic 
cohort and within 90 days prior to randomization (Visit 2) for the non-hemodynamic 
cohort.  
3. Treatment with prostacyclin (epoprostenol), prostacyclin analogs (ie, treprostinil, 
iloprost, beraprost) or prostacyclin receptor agonists (ie, selexipag/Uptravi®) within 
90 days prior to randomization (Visit 2), except those given at vasodilator testing 
during RHC.  
4. Change in dose or initiation of new diuretics and/or calcium channel blockers within 
1 week prior to baseline RHC (and LHC, if needed). 


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Amendment 3, Version 4 
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4.4.2 Exclusion criteria related to comorbidities 
5. Severe coronary heart disease or unstable angina as assessed by the investigator. 
6. Myocardial infarction within the last 6 months prior to or during Screening. 
7. Decompensated cardiac failure if not under close supervision. 
8. Severe arrhythmias as assessed by the investigator. 
9. Cerebrovascular events (eg, transient ischemic attack, stroke) within the last 3 months 
prior to or during Screening. 
10. Congenital or acquired valvular defects with clinically relevant myocardial function 
disorders not related to PH. 
11. Known or suspicion of pulmonary veno-occlusive disease (PVOD).  
4.4.3 Exclusion criteria related to selexipag use 
12. Known and documented severe hepatic impairment eg, Child-Pugh Class C.2 
13. Severe renal failure (estimated glomerular filtration rate <30 mL/min/1.73 m2 or serum 
creatinine >2.5 mg/dL or 221 μmol/L) at Screening. 
14. Known or suspected uncontrolled thyroid disease as per investigator judgment. 
15. Pregnant, planning to be become pregnant or lactating. 
16. Treatment with strong inhibitors of cytochrome P-450 2C8 (CYP2C8; eg, gemfibrozil) 
or moderate inducers of CYP2C8 (eg, rifampicin) within 14 days prior to 
randomization. 
17. SBP <90 mmHg at Screening (Visit 1) or at Randomization (Visit 2).  
18. Known hypersensitivity to selexipag or drugs of the same class, or any of their 
excipients. 
4.4.4 General exclusion criteria 
19. Planned or current treatment with another investigational treatment up to 3 months 
prior to randomization. 
20. Any co-morbid condition that may influence the ability to perform a reliable and 
reproducible 6MWT, including use of walking aids (cane, walker, etc.).  
21. Any known factor or disease that might interfere with treatment compliance, study 
conduct, or interpretation of the results, such as drug or alcohol dependence or 
psychiatric disease. 
22. Known concomitant life-threatening disease with a life expectancy <12 months. 
 
2 The assessment of hepatic impairment (Child-Pugh Score as per Appendix 10) must be fully documented for patients 
who have clinical signs and evidence (from central and/or local lab) of hepatic impairment. 


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Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
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EudraCT 2018-002823-41 
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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 [according to the ICH M3 definition]) 
• 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 eCRF. 
4.5.2 Acceptable methods of contraception 
To ensure compliance, the study personnel must remind women of childbearing potential 
at each visit to use the methods of contraception defined for this study. The reminders must 
be documented in the hospital chart.  
Women of childbearing potential [see definition in Section 4.5.1] must use one of the 
following methods of birth control from Screening visit up to at least 30 days after study 
treatment discontinuation: 
1. Diaphragm; female condom or cervical cap; or partner’s use of a condom, and any of 
these used in combination with a spermicide. 
2. Intra-uterine devices. 
3. Oral or injectable contraceptive agents, implants or transdermal contraceptive hormone 
patches. If a hormonal contraceptive is chosen, it must be taken for at least 1 month 
prior to randomization. For hormonal contraceptive initiated during the study, this must 
overlap for at least 1 month with the existing contraceptive method. 
4. Sterilization method (tubal ligation / occlusion or partner’s vasectomy). 
5. True abstinence from intercourse with a male partner, only when this is in line with the 
preferred lifestyle of the subject. 
Rhythm methods are not considered as acceptable methods of contraception for this study. 
The methods of birth control used (including non-pharmacological methods) must be 
recorded in the eCRF. 


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Chronic Thromboembolic Pulmonary 
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Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
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EudraCT 2018-002823-41 
Doc No D-20.234 
 
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5 
TREATMENTS 
5.1 Study treatment 
5.1.1 Investigational treatment and matching placebo: Description and rationale 
DB selexipag 200 µg, matching placebo and OL selexipag 200 µg will be provided as 
identical yellow, round, non-debossed, film-coated tablets in childproof bottles containing 
120 tablets.  
The DB study treatment refers to either DB selexipag 200 µg or the matching placebo, 
administered during the DB treatment period. The OL study treatment refers to OL 
selexipag 200 µg, administered during the OL treatment period. If not otherwise specified, 
study treatment refers to both DB and OL study treatments. 
5.1.2 Study treatment administration  
The study treatment is administered orally.  
The tablets should be swallowed whole with water. They should not be crushed, split or 
chewed.  
Dosing frequency will be twice daily (bid), with an interval of approximately 12 hours. For 
subjects with moderate hepatic impairment (Child-Pugh B) or who are concomitantly 
taking a moderate CYP2C8 inhibitor (eg, clopidogrel, deferasirox, teriflunomide), the 
dosing frequency is once daily (qd) [see Section 5.1.9]. 
At the beginning of each up-titration step, the first dose is to be taken in the evening in 
order to reduce the likelihood of the occurrence of IP-receptor-agonist-associated AEs [see 
Section 5.1.11.1]. In case of qd dosing, the subjects must take the study treatment in the 
morning.  
Tolerability may improve when study treatment is taken with food. To avoid fluctuations 
in drug exposure, it is recommended that study treatment is consistently taken either with 
or without food. In addition, side effects have been observed to respond to symptomatic 
treatment [see Section 5.1.11.1]. 
Depending on the iMTD, a single dose of study treatment will consist of 1–8 tablets 
(200-1600 μg). 
5.1.3 Study treatment up-titration 
The DB [Section 5.1.3.1] and OL [Section 5.1.3.2] study treatments must be up-titrated to 
allow each subject to reach their iMTD, in the range of 200–1600 μg bid/qd.  


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
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Amendment 3, Version 4 
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EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Any study treatment interruption of three consecutive days (or six consecutive doses if bid 
regimen or three consecutive doses if qd regimen) or more will require a new up-titration 
to avoid tolerability-limiting side effects [see Section 5.1.9].  
Any dose change must be documented in the eCRF. 
5.1.3.1 Double-blind study treatment up-titration 
The first intake of DB treatment could take place on-site or at home. Each subject will start 
with one tablet of DB study treatment, ie, selexipag (200 μg) or matching placebo, in the 
evening of Day 1 (randomization visit, Visit 2) and will continue with 200 μg bid on Day 2. 
Subjects with moderate hepatic impairment (Child-Pugh B) or who are concomitantly 
taking moderate CYP2C8 inhibitor(s) will start with 200 μg qd in the morning of Day 2. 
If the dose is well tolerated, the dose will be up-titrated in 200 μg bid/qd increments at 
weekly intervals during scheduled telephone calls or visits until reaching the iMTD 
[see Figure 2 and Table 2]. 
If the dose regimen is not well tolerated or symptoms cannot be fully managed with 
symptomatic treatment, the duration of the titration step can be prolonged to two or more 
weeks.  
The decision not to further up-titrate the dose will be at the discretion of the investigator’s 
medical judgment based on the occurrence and severity of typical pharmacological effects 
of IP-receptor agonists [see Section 5.1.11.1] and the subject’s individual tolerability. 
If needed, the dose can be reduced by 200 μg bid/qd. 
Although up-titration intervals can be flexible, the total time to reach the iMTD is 
12 weeks. At Week 12 (Visit 3), the dose reached for each subject is defined as the iMTD. 
This dose must be kept stable at least until Week 26 (Visit 5) but can be adjusted for safety 
and tolerability reasons. 
After Week 26, investigators will be allowed to up-titrate the dose of the subject further if 
needed (up to the maximum of 1600 μg bid/qd, as applicable) in 200 μg bid/qd increments 
and only at site visits (scheduled or unscheduled visits). Dose reduction for safety and 
tolerability reasons will also be allowed after Week 26. 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
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Doc No D-20.234 
 
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Table 2 
Double-blind dosing scheme 
Period  
Dose regimen 
Duration  
 
First dose 
200 μg  
On Day 1 in the evening (p.m.)  
1 tablet  
Up-titration 
200 μg bid*, § 
From Day 2 a.m. to Day 8 a.m.** 
1 tablet bid§  
 
400 μg bid*, § 
From Day 8 p.m. to Day 15 a.m.** 
2 tablets bid§  
 
600 μg bid*, § 
From Day 15 p.m. to Day 22 a.m.** 
3 tablets bid§  
 
800 μg bid*, § 
From Day 22 p.m. to Week 4 a.m.**  4 tablets bid§  
 
1000 μg bid*, § 
From Week 4 p.m. to Week 5 a.m.** 5 tablets bid§  
 
1200 μg bid*, § 
From Week 5 p.m. to Week 6 a.m.** 6 tablets bid§  
 
1400 μg bid*, § 
From Week 6 p.m. to Week 7 a.m.**  7 tablets bid§  
 
1600 μg bid*, § 
From Week 7 p.m. to Week 12 
a.m.**  
8 tablets bid§  
Maintenance  iMTD: 
200-1600 μg bid§ 
From Week 12 throughout the 
double-blind treatment period (or 
until Week 26) 
1–8 tablets bid §  
a m. = morning; bid = twice daily; iMTD = individual maximum tolerated dose; p m. = evening.  
* Or the iMTD until Week 12. 
** If the dose regimen is not well tolerated or symptoms cannot be fully managed with symptomatic treatment, the 
duration of the titration step can be prolonged to two or more weeks. If needed, the dose can be reduced by 200 μg 
bid/qd. 
§ For subjects with moderate hepatic impairment (Child-Pugh B) and who are concomitantly taking moderate CYP2C8 
inhibitors, the dosing frequency is once daily, which must be taken in the morning [see Section 5.1.9]. 
Beginning with the morning of Visit 3, and at each visit thereafter, subjects must take the 
morning dose before any visit-related procedure.  
5.1.3.2 Open-label study treatment up-titration 
The subjects, investigator and study personnel; site managers (SM); sponsor personnel; and 
Contract Research Organization (CRO) personnel will remain blinded to subjects’ 
treatment assignment at the time of transition to the OL period. Therefore, all subjects 
entering the OL study treatment period will have to up-titrate OL selexipag, irrespective of 
the previous treatment assignment. The last DB study treatment dose must be taken in the 
morning before performing EDBT visit.  
The first intake of OL treatment could take place on-site or at home. The OL study 
treatment up-titration will start with one tablet of OL selexipag (200 μg) in the evening of 
EDBT visit and with 200 μg bid on the day after. Subjects with moderate hepatic 
impairment (Child-Pugh B) or who are concomitantly taking moderate CYP2C8 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
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Amendment 3, Version 4 
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EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
inhibitor(s) will start with one tablet of OL selexipag (200 μg) in the morning of the day 
after EDBT visit. 
The up-titration procedure will then be similar to the one described in Section 5.1.3.1. 
Depending on the tolerability, the dose will be up-titrated by the investigator/delegate in 
200 μg bid/qd increments at weekly intervals during scheduled telephone calls until 
reaching the iMTD. The duration of the titration step can be prolonged to two or more 
weeks. Although up-titration intervals can be flexible, the total time to reach the iMTD is 
12 weeks. If needed, the dose can be reduced by 200 μg bid/qd. 
After OL-Week 12, investigators will be allowed to up-titrate the dose of the subject further 
if needed (up to the maximum of 1600 μg bid/qd, as applicable) in 200 μg bid/qd 
increments and only at site visits (scheduled or unscheduled visits). Dose reduction for 
safety and tolerability reasons will also be allowed after OL-Week 12. 
Beginning with the morning of OL-Week 12 Visit, and at each visit thereafter, subjects 
must take the morning dose before any visit-related procedure.  
5.1.4 Treatment assignment 
After the ICF has been signed, the investigator/delegate contacts the Interactive Response 
Technology (IRT) system at Visit 1 (Screening visit) to obtain a subject number. 
In case of rescreening, the subject number attributed at the time of first screening will be 
used for the rescreened subject. 
At Visit 2 (randomization visit), after having verified that the subject meets all inclusion 
criteria (including confirmation of CTEPH and inoperability by the corresponding AC 
[CSAC or CAC]) and none of the exclusion criteria, the investigator/delegate contacts the 
IRT system to randomize the subject. The IRT assigns a unique randomization number to 
the subject and assigns the treatment kit number, which matches the treatment arm assigned 
by the randomization list to the randomization number. The randomization list is generated 
by an independent CRO, Almac Clinical Technologies, using SAS® version 9.4. 
At randomization (Visit 2), treatment allocation will be stratified by treatment with 
PH-specific therapies (ie, ERAs, PDE-5 inhibitor, sGC stimulator [riociguat]; one versus 
two versus naive [capped at 40%]) and by CTEPH population (inoperable [with or without 
BPA] versus persistent-recurrent after PEA [including PEA followed by BPA]). Subjects 
will be randomized in a 1:1 ratio to either selexipag or placebo. Further details are provided 
in the IRT specification document.  


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Chronic Thromboembolic Pulmonary 
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Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
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EudraCT 2018-002823-41 
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5.1.5 Blinding 
The first treatment period of this study up to EDBT will be performed in a DB fashion. The 
investigator and study personnel, the subjects, the SMs, sponsor personnel and CRO 
personnel involved in the conduct of the study will remain blinded to the study treatment 
until the fourth analysis time point [see Section 5.1.6], ie, when all randomized subjects 
have completed EDBT/PTOP-EOS Visit or prematurely discontinued from the study, and 
when the DB database is locked and the data extract is performed, or when the study is 
terminated prematurely. Sponsor personnel responsible for clinical study supply 
distribution will need to be unblinded at a supply level to ensure adequate supply of study 
treatment. These persons will be clearly identified with their unblinding documented in the 
Trial Master File. A dedicated submission team, independent from the Clinical Trial Team 
(CTT), will be unblinded at analysis time points 2 and 3, as appropriate [see 
Section 5.1.6.3]. 
Until the time of sponsor unblinding [see Section 5.1.6], the randomization list is kept 
strictly confidential and accessible only to authorized persons (ie, an independent SSG and 
Secure Data Office [SDO]), 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. 
5.1.6 Unblinding 
5.1.6.1 Timing of study analyses 
The database will be locked, and the data will be extracted and analyzed at five planned 
analysis time points during the study [see Figure 3]: 
1) The first analysis time point will be when approximately 90 randomized subjects, the 
hemodynamic cohort, have completed the Week 20 RHC (and LHC, if needed) or 
prematurely discontinued from the study. The final analysis of the PVR endpoint will be 
performed by the independent SSG for the IDMC. Actions to be taken following this 
analysis are described in Section 10.4.  
2) The second analysis time point will be when approximately 160 randomized subjects 
have completed the Week 26 6MWD assessment or prematurely discontinued from the 
study. An interim analysis (IA) for the 6MWD endpoint and an IA for the TTCW endpoint 
will be performed by the independent SSG for the IDMC. Actions to be taken following 
these analyses are described in Section 10.4. If regulatory submissions are to be prepared, 
all available data will be analyzed according to the statistical analysis plan (SAP) for 
regulatory submissions by the sponsor’s dedicated submission team, independent from the 
CTT. 


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3) The third analysis time point will be when all (up to 280) randomized subjects have 
completed the Week 26 6MWD assessment or prematurely discontinued from the study. 
The final analysis of the 6MWD endpoint and an IA for the TTCW endpoint will be 
performed by the independent SSG for the IDMC. Actions to be taken following these 
analyses are described in Section 10.4. If regulatory submissions are to be prepared, all 
available data will be analyzed according to the SAP for regulatory submissions by the 
sponsor’s dedicated submission team, independent from the CTT. 
4) The fourth analysis time point will be when all (up to 280) randomized subjects have 
completed the DB treatment period, or the PTOP or prematurely discontinued from the 
study. The DB database will be locked, the data extract will be performed and unblinding 
will occur at this time point. This final analysis of the DB treatment period will be 
conducted by the sponsor. If regulatory submissions are to be prepared, all data will be 
analyzed according to the SAP for regulatory submissions by the sponsor. 
5) The fifth analysis time point will be when all (up to 280) randomized subjects have 
performed their EOS visit. An analysis including the OL period data will be performed by 
the sponsor. This analysis will be considered the final analysis of the study. 


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Amendment 3, Version 4 
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EudraCT 2018-002823-41 
Doc No D-20.234 
 
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Figure 3 
Study analyses 
 
 
 
6MWD = 6-minute walk distance; CRO = Contract Research Organization; EDBT = End-of-Double-Blind-Treatment; 
FSFV = First subject first visit; LHC = Left heart catheterization; LSLV = Last subject last visit; PTOP-EOS = Post-
treatment observation period end-of-study; PVR = pulmonary vascular resistance; RHC = Right heart catheterization; 
SM = Site manager; TTCW = Time to clinical worsening; W = week. 
The diagram is not to scale. 
 


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5.1.6.2 Unblinding for IDMC 
An independent SSG not otherwise involved in the design, conduct and analysis of the 
study will have access to the randomization code in order to prepare unblinded reports for 
review by the IDMC, as described in the IDMC charter. The randomization code will be 
made available to the independent SSG in accordance with the sponsor’s Quality System 
(QS) documents. 
5.1.6.3 Unblinding for analysis time points 1, 2, and 3 
For the first three analysis time points, full randomization information of all subjects 
randomized so far will be made available to the independent SSG for analysis 
[see Section 5.1.6.2]. In accordance with the IDMC charter, the IDMC will review the 
results and provide a recommendation on continuation or premature study termination. If 
regulatory submissions are to be prepared, randomization information will be made 
available to a sponsor’s independent team dedicated for submission. The safeguards taken 
to keep the dedicated submission team independent from the CTT will be described in a 
separate charter. 
5.1.6.4 Unblinding for the fourth analysis time point (end-of-double-blind-treatment 
period)  
Full randomization information will be made available for data analysis only after all 
randomized subjects have completed the DB treatment period or the PTOP or prematurely 
discontinued from the study, and when the DB part of the database is locked and the data 
extract is performed, in accordance with current standard operating procedures [see 
Figure 3]. Following each subject’s completion of the DB treatment period, they will enter 
the OL extension period. In order to preserve the blind of each individual subject until the 
DB database will be locked, all subjects will be up-titrated with OL selexipag 
[see Section 5.1.3.2].  
5.1.6.5 Unblinding for suspected unexpected serious adverse reactions 
If a suspected unexpected serious adverse reaction (SUSAR) occurs for a subject 
participating in the study, the sponsor Global Drug Safety will request the unblinding of 
the treatment assignment. The treatment assignment will not be communicated to site 
personnel or to the sponsor’s CTT. Unblinded SUSAR information will be provided to 
respective health authorities and independent ethics committees (IECs) or institutional 
review boards (IRBs) only. SUSARs will be reported to investigators in a blinded fashion. 
5.1.6.6 Emergency procedure for unblinding 
The investigator, study personnel and sponsor personnel must remain blinded to the 
subject’s treatment assignment up to the fourth analysis time point. The identity of the 
study treatment may be revealed only if the subject experiences a medical event, the 


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Amendment 3, Version 4 
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EudraCT 2018-002823-41 
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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 does not delay) any decision in the best 
interest of the subject, the investigator is invited to discuss the intended unblinding with 
sponsor personnel. 
The occurrence of any unblinding during the study must be clearly justified and explained 
by the investigator. In all cases, sponsor personnel must be informed as soon as possible 
before or after the unblinding. 
A subject may stay on study treatment after unblinding provided the following conditions 
are met: emergency unblinding for accidental or intentional overdose or medication error. 
The circumstances leading to unblinding must be documented in the Investigator Site File 
(ISF) and eCRF. 
5.1.7 Study treatment supply 
Manufacturing, labeling, packaging and supply of study treatment will be conducted 
according to Good Manufacturing 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. 
5.1.7.1 Study treatment packaging and labeling 
Study treatment is provided as tablets and supplied in childproof bottles. 
Study treatment is labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located. 
5.1.7.2 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 subjects will receive sufficient study treatment to cover the period up to the next 
scheduled visit. Subjects 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 the sponsor. The IRT 
will allow dispensation of study treatment outside the scheduled visit. An accurate record 


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of the date and amount of study treatment dispensed to each subject must be available for 
inspection at any time. 
5.1.7.4 Study treatment return and destruction 
Study treatment must be handled in strict accordance with the protocol and the container 
label, and must be stored at the study site in a limited-access area or in a locked cabinet 
under appropriate environmental conditions. Unused study treatment and study treatment 
returned by the subject must be available for verification by the sponsor’s study site 
monitor during on-site monitoring visits. The return to the sponsor of unused study 
treatment or used returned study treatment for destruction will be documented on the 
intervention return form. When the study site is an authorized destruction unit and study 
treatment supplies are destroyed on-site, this must also be documented on the intervention 
return form. 
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 subject 
(ie, study-treatment accountability) must be performed by site personnel on the day of the 
visit and before dispensing further study treatment. It is to be recorded by site personnel on 
the study treatment dispensing and accountability log and in the eCRF and checked by the 
SM during site visits and at the end of the study. The study treatment accountability log in 
the eCRF will include at least the following information for each study treatment unit (ie, 
bottle dispensed to the subject): 
• Dispensed bottles number 
• Date dispensed / number of tablets dispensed 
• Date returned / number of tablets returned 
All study treatment supplies, including partially used or empty bottles, must be retained at 
the site for review by the SM. 
If the subject forgets to bring the remaining study treatment to a study visit, he/she must be 
instructed to not take any tablets from the remaining study treatment 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 by site personnel at each visit using the below formula and 
entered in the eCRF: 


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Compliance = [(number of tablets dispensed − number of tablets returned) / total number 
of tablets that should have been taken during the period3] × 100. 
Between-visit and overall study compliance are expected to be between 80% and 120%. 
Compliance values outside of this range will be considered as a protocol deviation, which 
will be reported by the SM. The investigator must discuss any non-compliance with the 
subject to clarify the reasons and to take appropriate actions to avoid reoccurrence. This 
discussion and its outcome must be documented in the source documents. 
5.1.9 Study treatment dose adjustments and interruptions  
For subjects who are unable to tolerate the protocol-specified dosing scheme, dose 
adjustments must follow the down-titration instructions [see Sections 5.1.3.1 and 5.1.3.2]. 
Dosing frequency of the study treatment must be qd (study treatment to be taken in the 
morning), when the subject presents with moderate hepatic impairment (Child-Pugh B) or 
when a moderate CYP2C8 inhibitor (eg, clopidogrel, deferasirox, teriflunomide) is co-
administered. Dosing frequency must be changed to bid when moderate hepatic 
impairment resolves or when co-administration of the moderate CYP2C8 inhibitor is 
stopped. 
The effect of strong inhibitors of UGT1A3 and UGT2B7 (eg, valproic acid, probenecid, 
and fluconazole) on the exposure to selexipag and its active metabolite has not been 
studied. Caution is required when administering these medicinal products concomitantly 
with selexipag. A potential pharmacokinetic interaction with strong inhibitors of UGT1A3 
and UGT2B7 cannot be excluded [Selexipag IB].  
In case of concomitant administration of a moderate inducer of CYP2C8 (eg, rifampicin), 
dose adjustment of selexipag/placebo may be required because of drug-drug interactions. 
A drug-drug interaction study showed that rifampicin did not lead to a relevant change in 
exposure to selexipag, whereas exposure to the active metabolite decreased by half 
[Selexipag IB]. 
Study treatment may be temporarily interrupted in response to an AE, a diagnostic or 
therapeutic procedure, a laboratory abnormality, or for administrative reasons. 
Study-specific criteria for interruption of study treatment are described in Section 5.1.11. 
 
3 The period is defined as the number of days of treatment from the date of start of study treatment until the next 
accountability visit. The number of tablets that should have been taken is derived from the number of days in the 
corresponding period. Tablets that are not taken following study staff instructions to interrupt study treatment are 
not counted as tablets that should have been taken. 


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If study treatment is interrupted by the subject for any reason, she/he must immediately 
inform the investigator. 
Any study treatment interruption of three consecutive days (or six consecutive doses if bid 
regimen or three consecutive doses if qd regimen) or more will require a new up-titration 
to avoid tolerability-limiting side effects. Subjects will start again with one tablet of study 
treatment (200 μg) bid/qd as applicable. If this dose is well tolerated, the dose will be up-
titrated by the investigator/delegate in 200 μg increments up to the iMTD before study 
treatment interruption [see Section 5.1.3]. For each subject, the up-titration frequency will 
be up to the medical judgment of the investigator and based on his/her clinical evaluation 
of the subject’s tolerability of the study treatment prior to its interruption. 
Interruptions of study treatment must be kept as short as possible. If treatment is stopped 
for more than 14 consecutive days (or 28 consecutive doses if bid regimen or 14 
consecutive doses if qd regimen), re-introduction is not permitted and treatment must be 
permanently discontinued [see Section 5.1.10]. 
Study treatment dose adjustments / interruptions must be recorded in the eCRF. 
5.1.10 Premature discontinuation of study treatment  
The decision to prematurely discontinue study treatment may be made by the subject, the 
investigator or sponsor personnel. The main reason for discontinuation of study treatment 
and whether the decision was that of the subject (eg, due to an AE or lack of efficacy), the 
investigator (eg, due to pre-specified study treatment discontinuation criteria, an AE or lack 
of efficacy) or the sponsor (eg, study termination) must be documented in the eCRF. 
A subject has the right to prematurely discontinue study treatment at any time, without any 
justification, by withdrawal from study treatment only or by withdrawal from any further 
participation in the study (ie, premature withdrawal from the study [see Section 8.2]). 
Although a subject is not obliged to give his/her reason for prematurely withdrawing from 
the treatment or the study, the investigator will make a reasonable effort to ascertain the 
reason(s), while fully respecting the subject’s rights. 
The investigator must discontinue study treatment for a given subject if, on balance, he/she 
believes that continued administration would be contrary to the best interests of the subject. 
Study-specific criteria for discontinuation of study treatment are described in 
Section 5.1.11. 
A subject who prematurely discontinues study treatment is NOT considered 
withdrawn from the study:  


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• A subject who prematurely discontinues DB study treatment will enter a PTOP 
[see Section 3.1.1.4], provided the subject’s consent for this limited participation in 
the study has not been withdrawn [see definition in Section 8.2]. The subject will 
be asked to return for a premature EDBT visit within 7 days of last intake of DB 
study treatment and will be contacted for a safety follow-up call 30 (+5) days after 
the last intake of DB study treatment (PTOP- safety follow-up [SFU]) . At the 
premature EDBT visit, the assessments described for the regular EDBT visit are to 
be performed [see Table 3].  
Thereafter, the subject will continue to perform the visits and assessments as 
scheduled [see Table 5] until the PTOP-EOS, which occurs within 4 weeks after 
the end-of-double-blind period announcement, ie, within 4 weeks of reaching the 
overall target number of clinical worsening events, or earlier following 
recommendation of the IDMC [see Section 10.4], or sponsor’s decision [see 
Section 8.3]. 
If the premature EDBT visit or the PTOP- SFU call falls within the time window 
of any other scheduled visit, these visits can be combined, and assessments will not 
be repeated. 
• If a subject discontinues prematurely DB study treatment and does not agree 
to enter the PTOP (ie, continue to perform the visits and assessments as scheduled 
until the PTOP-EOS visit), he/she will be asked to return for the premature EDBT 
visit within 7 days of last intake of DB study treatment and will be contacted for a 
SFU phone call 30 (+5) days after the last intake of DB, provided the subject’s 
consent for this limited participation in the study has not been withdrawn.  
Long-term survival follow-up information [see Section 7.2.3.9] will then be 
collected yearly until death or end-of-double-blind period announcement (ie, within 
4 weeks of reaching the overall target number of clinical worsening events, or 
earlier following recommendation of the IDMC, or sponsor decision), provided the 
subject’s consent for this limited participation in the study has not been withdrawn. 
• A subject who prematurely discontinues OL study treatment will be followed 
up until 30 (+5) days after OL study treatment discontinuation, provided that the 
subject’s consent for this limited participation in the study has not been withdrawn. 
The subject will be asked to return for a premature EOLT visit within 7 days of last 
intake of OL study treatment and will be contacted for a safety follow-up call 
30 (+5) days after the last intake of OL study treatment. At the premature EOLT 
visit, the assessments described for the regular EOLT visit are to be performed [see 
Table 4]. 


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A subject who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered as withdrawn from the 
study. Subjects who die or are lost to follow-up are also considered to be withdrawn from 
the study. Withdrawal from the study and follow-up medical care of subjects withdrawn 
from the study is described in Sections 8.2 and 8.4, respectively. 
5.1.11 Study-specific criteria for interruption / premature discontinuation of study 
treatment 
Study treatment interruptions exceeding 14 consecutive days (or 28 consecutive doses if 
bid regimen or 14 consecutive doses if qd regimen) must lead to permanent discontinuation 
of study treatment. In that case, the premature EDBT/EOLT visit must occur within 7 days 
of the discontinuation criteria being met. 
Any study treatment interruption of three days (or six consecutive doses if bid regimen or 
three consecutive doses if qd regimen) or more will require new up-titration [see 
Section 5.1.9].  
Interruptions of one dose or more must be recorded on the study treatment log in the eCRF.  
5.1.11.1 Tolerability issues / AEs  
Adverse reactions associated with the mode of action of selexipag have been observed 
frequently, in particular during the phase of individualized dose titration. These included: 
headache, diarrhea, nausea and vomiting, jaw pain, myalgia, pain in extremity, arthralgia 
and flushing. In adult subjects with PAH, these effects were usually transient or 
manageable with symptomatic treatment. Gastrointestinal events have been observed to 
respond to antidiarrheal, antiemetic and anti-nausea medicinal products and/or medicinal 
products for functional gastrointestinal disorders. Pain-associated events have frequently 
been treated with analgesics (such as paracetamol/acetaminophen).  
However, if a subject reaches a dose that cannot be tolerated and is not manageable, the 
investigator should follow the instructions given in Sections 5.1.3.1 and 5.1.3.2. 
5.1.11.2 Hepatic impairment 
If hepatic impairment is suspected, a clinical assessment of severity (eg, Child-Pugh score) 
must be performed and fully documented. If a subject has developed severe hepatic 
impairment (Child-Pugh C, see Appendix 10) at any time during the study, the study 
treatment must be permanently discontinued.  
5.1.11.3 Pulmonary edema due to PVOD 
Should signs of pulmonary edema occur, the possibility of associated PVOD should be 
considered. If confirmed, the study treatment must be discontinued. 


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5.1.11.4 Initiation of prohibited medications 
Study treatment must be permanently discontinued if strong inhibitors of CYP2C8 
(eg, gemfibrozil) and/or any investigational treatments are started during the DB and/or 
OL treatment period. 
5.1.11.5 Pregnancy 
If a female subject becomes pregnant while on study treatment, study treatment must be 
discontinued, and the investigator should arrange for specific therapy as needed 
[Regitz-Zagrosek 2011]. For reporting of pregnancies, refer to Section 9.3.1. 
5.1.12 Treatment of overdose 
For this study, any single dose greater than 1600 µg or a total daily dose greater than 
3200 µg will be considered an overdose. For subjects with moderate hepatic impairment 
or who are concomitantly taking moderate (a) CYP2C8 inhibitor(s) the dosing frequency 
is once daily, and an overdose is defined by the intake of a dose greater than 1600 µg or a 
total daily dose greater than 1600 µg.  
Isolated cases of overdose up to 3200 μg micrograms have been reported. Mild, transient 
nausea was the only reported consequence. 
In the event of overdose, supportive measures must be taken as required. Dialysis is 
unlikely to be effective because selexipag and its active metabolite are highly protein 
bound. 
In the event of an overdose, the investigator or treating physician should: 
• Contact the sponsor immediately. 
• Evaluate the subject to determine, in consultation with the sponsor, whether study 
treatment should be interrupted or whether the dose should be reduced. 
• Closely monitor the subject for AE/SAE and laboratory abnormalities until selexipag 
can no longer be detected systematically (at least 3 days) 
• Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF. 
5.2 Previous and concomitant medications  
5.2.1 Definitions 
A previous medication / non-pharmacological therapy is any treatment for which the end 
date is prior to signing of informed consent. 


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A medication / non-pharmacological therapy that is study-concomitant is any treatment 
that is ongoing or initiated after signing of informed consent or initiated up to the EOS as 
defined in Section 8.1. 
A medication / non-pharmacological therapy that is study treatment-concomitant is any 
treatment that is either ongoing at the start of study treatment or is initiated during the DB 
and/or OL treatment period. 
An auxiliary medicinal product is a medicinal product used for the purpose of the clinical 
study but not as an investigational medicinal product (eg, a mandatory background therapy 
or a medicinal product used for a study-mandated procedure). 
5.2.2 Recording of previous/concomitant medications / auxiliary medicinal 
products / procedures in the eCRF  
The use of all study-concomitant medications (including contraceptives and traditional and 
alternative medicines, eg, plant-, animal- or mineral-based medicines) will be recorded in 
the eCRF. All previous medications must be recorded in the eCRF if discontinued less than 
30 days prior to signing of the informed consent. Any previous PH-specific therapies 
(ERA, PDE-5 inhibitors, riociguat) must be recorded in the eCRF if discontinued less than 
90 days prior to the baseline RHC (and LHC, if needed). The generic name, start/end dates 
of administration (as well as whether it was ongoing at start of treatment and/or EOS), 
route, dose, frequency and indication will be recorded in the eCRF. 
Information on the indication, start/end dates of procedures will be collected in the eCRF. 
5.2.3 Auxiliary medicinal products 
All subjects must receive full anticoagulation treatment, as per local practice, from 90 days 
prior to the baseline RHC (and LHC, if needed) assessment and up to EOS. During the 
study, the usual safety measures, as routinely used by the study site for cessation of 
anticoagulants drugs, prior to and after the RHC/LHC procedure, should be taken. 
Interruption of anticoagulant drugs due to an AE during the course of the study is allowed. 
5.2.4 Allowed concomitant therapy 
• BPA procedure after Week 26 (Visit 5). 
• Change in dose or initiation of new PH-specific therapies (ie, ERA, PDE-5 inhibitor, 
sGC stimulator) after Week 26 (Visit 5). 
• Single administration of prostacyclin or analogs during the RHC procedure for acute 
vasodilator testing.  
• Treatment with moderate inhibitors of CYP2C8 (eg, clopidogrel, deferasirox, 
teriflunomide) with study-treatment dose adjustment as described in Section 5.1.9. 


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5.2.5 Forbidden concomitant therapy 
• Change in dose or initiation of new PH-specific therapies (ie, ERA, PDE-5 inhibitor, 
sGC stimulator) from 90 days prior to randomization (Visit 2) and up to Week 26 
(Visit 5) for the non-hemodynamic cohort and from 90 days prior to the baseline RHC 
(and LHC, if needed) qualifying for enrollment and up to Week 26 (Visit 5) for the 
hemodynamic cohort. 
• Treatment with prostacyclin (epoprostenol), prostacyclin analogs (ie, treprostinil, 
iloprost, beraprost) or prostacyclin receptor agonists (ie, selexipag/Uptravi) within 
90 days prior to randomization (Visit 2) and up to study treatment discontinuation.  
• Change in dose or initiation of new diuretics and/or calcium channel blockers within 
1 week prior to baseline RHC (and LHC, if needed).  
• Treatment with strong inhibitors of CYP2C8 (eg, gemfibrozil) within 14 days prior to 
randomization and up to 30 days after study treatment discontinuation. 
6 
STUDY ENDPOINTS 
6.1 Efficacy endpoints 
6.1.1 Primary efficacy endpoint(s) 
The primary efficacy endpoint of this study is the PVR at Week 20, assessed at rest, within 
2–5 hours post-dose, expressed as percent of baseline PVR. 
This endpoint has been selected as it is of high prognostic value in the treatment and 
management of CTEPH [Hoeper 2009] and because high preoperative values are indicative 
of a significant risk of surgical mortality [Dartevelle 2004].  
6.1.2 Secondary efficacy endpoints 
The secondary efficacy endpoints of this study are: 
• Change from baseline in 6MWD to Week 26 (key secondary endpoint). 
• TTCW (key secondary endpoint), where clinical worsening is defined (adapted from 
the CHMP definition [EMEA 2008]) as at least one of the following components 
confirmed by the CEC, when applicable: 
– All-cause death 
– Non-planned PH-related hospitalization 
– PH-related deterioration identified by at least one of the following: 
o Increase from baseline in WHO FC4; 
o Deterioration from baseline by at least 15% in exercise capacity, as 
measured by the 6MWD4; 
 
4 Confirmed by a second measurement performed on a different day within 14 days. 


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o New or worsening of signs or symptoms of right heart failure, defined as a 
reported AE with one of the following preferred terms: “CTEPH”, 
“pulmonary hypertension”, “right ventricular failure”, “right ventricular 
dysfunction” and “acute right ventricular failure”. 
• All-cause death or hospitalizations related to PH worsening. 
• Improvement in WHO FC from baseline to Week 26. 
• Change from baseline to Week 26 in Pulmonary arterial hypertension-symptoms and 
impact questionnaire (PAH-SYMPACT®) cardiopulmonary symptoms domain and 
cardiovascular symptoms domain. 
• Change from baseline to Week 26 in Borg dyspnea index (BDI)/Borg CR10®. 
• Change from baseline to Week 26 in NT-proBNP.  
6.1.3 Other efficacy endpoints 
The other efficacy endpoints of this study are: 
• Changes in 6MWD, WHO FC and NT-proBNP from baseline to all regular collection 
timepoints up to the EDBT period. 
• Change from baseline up to EOS, by visit, in exercise capacity, as measured by the 
6MWD. 
• Rate of hospitalizations up to the EDBT period. 
• Mean number of hospital days for all-cause hospitalization.  
• Mean number of hospital days related to PH worsening.  
• Improvement in WHO FC from baseline up to EOS, by visit. 
• Change from baseline to Week 26 in actigraphy-assessed daily life physical activity 
(DLPA  
• ).Change from baseline up to Week 39, by visit, in PAH-SYMPACT® scores (including 
cardiopulmonary symptoms domain, cardiovascular symptoms domain, physical 
impacts domain, and cognitive/emotional impacts domain). 
• Change from baseline up to EOS, by visit, in BDI/Borg CR10® collected immediately 
at the end of each individual 6MWT.  
• Change from baseline up to Week 52, by visit, in Euro Quality of life-5-Dimension-5-
Level (EQ-5D-5L). 
• Change from baseline up to Week 52, by visit, in Work Productivity and Activity 
Impairment: General Health (WPAI©: GH) scores. 
• Change from baseline to all regular collection timepoints up to the EDBT period in the 
Clinician Global Impression of Severity (CGI-S) scores and in the Clinician Global 
Impression of Change (CGI-C) scores. 
• Change from baseline to Week 20 in other hemodynamic parameters (cardiac output 
[CO], cardiac index [CI] and mean right atrial pressure [mRAP]) measured at rest. 


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• Change from baseline to Week 20 in the number of low-risk criteria, defined as 
WHO FC I or II, 6MWD ≥440 m, NT-proBNP <300 ng/L and CI criteria 
≥2.5 L/min/m2 [Galiè 2016]. 
6.2 Safety endpoints 
• Treatment-emergent AEs5 up to 3 days after study treatment discontinuation at each 
analysis time point [see Section 5.1.6.1]. 
• Serious adverse events (SAEs) up to 30 days after study treatment discontinuation at 
each analysis time point [see Section 5.1.6.1]. 
• AEs leading to premature discontinuation of study treatment at each analysis time point 
[see Section 5.1.6.1]. 
• Change 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 at each analysis 
time point [see Section 5.1.6.1]. 
• Treatment-emergent marked laboratory abnormalities up to 3 days after study treatment 
discontinuation as detailed in Appendix 2 at each analysis time point [see 
Section 5.1.6.1]. 
• Treatment-emergent 
AEs5 
of 
special 
interest 
(eg, 
hypotension, 
anemia, 
hyperthyroidism) up to 3 days after study treatment discontinuation at each analysis 
time point [see Section 5.1.6.1]. 
7 
 VISIT SCHEDULE AND STUDY ASSESSMENTS 
7.1 General information 
The study visits are listed in Table 3, Table 4 and Table 5. For all visits, the subjects must 
be seen or called on the designated day with an allowed visit window indicated in Table 3, 
Table 4 and Table 5. A follow-up safety telephone call / visit must be performed 
30 (+5) days after intake of the last dose of study treatment. If it is not possible to complete 
all assessments on the same day, a visit may extend over more than 1 day within the 
allowed time window.  
In case of premature discontinuation of study treatment, the EDBT or the EOLT visit must 
take place as soon as possible and no later than 7 days after the last dose of study treatment. 
Subjects who prematurely discontinue study treatment or withdraw consent from further 
participation in the study for any reason will not be replaced. 
 
5 A treatment-emergent AE is any AE temporally associated with the use of study treatment (from study treatment start 
until 3 days after study treatment discontinuation), whether or not considered by the investigator as related to study 
treatment. 


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7.1.1 Screening/rescreening 
Screening starts with the signature of the ICF. The date on which the first screening 
assessment is performed corresponds to the date of the Screening visit. 
It is the responsibility of the investigator/delegate to obtain written informed consent from 
each subject participating in this study after adequate face-to-face explanation of the 
objectives, methods, and potential hazards of the study. The subjects who agree to 
participate in the study and the investigator/delegate must sign the ICF prior to any 
study-related assessment or procedure. 
Subjects who are in screening when the enrollment target has been met may still be 
randomized. 
It is permitted to re-screen subjects once if the reason for non-eligibility was transient (eg, 
abnormal laboratory test, insufficient wash-out period of a forbidden medication, subject’s 
condition changes). Informed consent [see Section 12.3] and all screening assessments 
must be repeated at the time of rescreening. If the screening V/Q scan, PA, CTPA, MRA 
and RHC (and LHC, if needed) were done as per timing requirements indicated in 
Sections 7.2.2 and 7.2.3.1.1, respectively, these do not need to be repeated. 
7.1.2 Unscheduled visits 
Unscheduled visits may be performed at any time during the study. Depending on the 
reason for the unscheduled visit (eg, AE), appropriate assessments will be performed based 
on the judgment of the investigator.  
The date of the visit and the reason for the visit, as well as data related to study-specific 
assessments performed at unscheduled visits, will be recorded in the eCRF. 
If any RHC (and LHC, if needed) is done at an unscheduled visit, this must be collected in 
the eCRF. 
During the DB treatment or the PTOP period: 
• an unscheduled visit must be performed within 14 days of the following occurring at 
an on-site visit: 
o Increase from baseline in WHO FC. 
o Deterioration from baseline by at least 15% in exercise capacity, as measured 
by the 6MWD. 
• an unscheduled visit must be performed within 14 days of site knowledge in case of the 
following occurring outside of a scheduled visit: 
o Suspected clinical worsening, defined as i) any new AE suggestive of right 
heart failure or disease progression, and ii) any new evidence of a decrease in 
exercise capacity or increase in dyspnea.  


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o Any change in dose/initiation of new PH-specific therapies and/or up-titration 
of DB study treatment beyond Week 12 (when applicable).  
In these cases, the following assessments must be performed: physical examination, vital 
signs (blood pressure, heart rate [HR]), weight, post-dose 6MWT/BDI or Borg CR10® and 
WHO FC. In addition, concomitant therapy and SAEs/AEs will be collected. Further 
assessments are performed at the discretion of the investigator.  
After an unscheduled visit, the regular scheduled study visits must continue according to 
the planned visit and assessment schedule. 


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Table 3 
Double-blind treatment period: visit and assessment schedule 
PERIODS 
Name 
SCREENING 
DOUBLE-BLIND TREATMENT 
 
 
Duration 
At least 14 days 
and up to 60 
days 
 
 
VISITS 
Number 
1 
2 
Titration 
phase 
3 
4 
5 
6 
7 
TC every  
26 weeks10 
Visit every  
26 weeks10 
 EDBT 
U1, 2, 3, etc. 
 
Name 
Screening/ 
Rescreening 
Randomiz
ation 
Week 12 Week 20 Week 26 Week 39 Week 52 Week 65, 91, 
117, etc. 
Week 78, 104, 
130, etc 
Announced11 or 
for premature 
EDBT within 
7 days after last 
DB dose 
Unscheduled 
visit1 
 
Time 
Day −60 to Day 
−14 
Day 1 
Weekly from 
Week 1 to 
Week 11 (± 3 
days) 
Day 85 
(± 7 days) 
Day 141 
(± 7 days) 
Day 183 
(± 7 days) 
Day 274 
(± 7 days) 
Day 365 
(± 7 days) 
Day 456, 638, 
820 etc.  
(± 7 days) 
Day 547, 729, 
911, etc. 
(± 7 days) 
Any time 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical history/ Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Previous/concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
W 
Physical examination* 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
W 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (BP, HR), Weight 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
W 
Local 12-lead ECG 
X 
 
 
 
 
 
 
X 
 
 
X 
(X) 
RHC (and LHC, if needed) 
X2 
 
 
 
X3,4 
 
 
 
 
 
 
(X) 
V/Q scan, PA, CTPA, MRA5 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology and clinical chemistry** 
X 
X6 
 
X 
X 
X 
X 
X 
 
X 
X 
(X) 
Serum pregnancy test** 
X 
 
 
 
 
 
 
 
 
 
 
(X) 
Urine pregnancy test* 
 
X 
monthly (±7 days ) 
(X) 
6MWT/BDI or Borg CR10® 
X 
X 
 
 
 
 
 
 
 
 
 
 
Post-dose 6MWT/BDI or Borg 
CR10®3 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
W 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 82/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
PERIODS 
Name 
SCREENING 
DOUBLE-BLIND TREATMENT 
 
 
Duration 
At least 14 days 
and up to 60 
days 
 
 
VISITS 
Number 
1 
2 
Titration 
phase 
3 
4 
5 
6 
7 
TC every  
26 weeks10 
Visit every  
26 weeks10 
 EDBT 
U1, 2, 3, etc. 
 
Name 
Screening/ 
Rescreening 
Randomiz
ation 
Week 12 Week 20 Week 26 Week 39 Week 52 Week 65, 91, 
117, etc. 
Week 78, 104, 
130, etc 
Announced11 or 
for premature 
EDBT within 
7 days after last 
DB dose 
Unscheduled 
visit1 
 
Time 
Day −60 to Day 
−14 
Day 1 
Weekly from 
Week 1 to 
Week 11 (± 3 
days) 
Day 85 
(± 7 days) 
Day 141 
(± 7 days) 
Day 183 
(± 7 days) 
Day 274 
(± 7 days) 
Day 365 
(± 7 days) 
Day 456, 638, 
820 etc.  
(± 7 days) 
Day 547, 729, 
911, etc. 
(± 7 days) 
Any time 
WHO FC 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
W 
Actigraphy** 
X 
Every day, 24 hours per day  
 
 
 
 
 
 
PAH-SYMPACT®**, 7 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
 
EQ-5D-5L, WPAI©: GH** 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
CGI-S 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
 
CGI-C 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
 
NT-proBNP** 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
(X) 
Dose titration 
 
 
8 
iMTD 
 
 
 
 
 
 
 
 
DB Study treatment 
dispensing/return 
– 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
 
SAEs/AEs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
W 
 
6MWT = 6-minute walk test; AE = adverse event; BDI = Borg dyspnea index; Borg CR10® = Borg category-ratio 10 Scale®; BP = blood pressure; BPA = balloon 
pulmonary angioplasty; CGI-C = Clinician Global Impression of Change; CGI-S = Clinician Global Impression of Severity; CT = computed tomography; 
CTPA = computed tomography pulmonary angiogram; DB = double-blind; ECG = electrocardiogram; eCRF = electronic Case Report Form; EDBT = End-of-Double-
Blind-Treatment; EOS = end of study; EQ-5D-5L = Euro Quality of Life-5-Dimension-5-Level; FC = functional class; HR = heart rate; IDMC = Independent data 
management committee; iMTD = individual maximum tolerated dose; LHC = left heart catheterization; MRA = magnetic resonance angiography; 
NT-proBNP = N-terminal pro b-type natriuretic peptide; PA = pulmonary angiography; PAH-SYMPACT® = Pulmonary arterial hypertension symptoms and impact 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 83/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
questionnaire; PEA = pulmonary endarterectomy; RHC = right heart catheterization; SAE = serious adverse event; V/Q scan = ventilation/perfusion scan; WHO = World 
Health Organization; WPAI©: GH = Work Productivity and Activity Impairment Questionnaire: General Health. 
 = telephone call. 
1 Unscheduled visits may be performed at any time during the DB treatment period. Assessments (marked with an ‘(X)’ or ‘W’ in Table 3) are performed at the 
discretion of the investigator.  
If the unscheduled visit is performed due to increase from baseline in WHO FC, deterioration from baseline by at least 15% in exercise capacity, as measured by the 
6MWD, suspicion of clinical worsening [as defined in Section 7.1.2], any change in dose, initiation of PH-specific therapies, or up-titration of DB study treatment 
beyond Week 12, the mandatory assessments to be performed are marked with a ‘W’. If an RHC (and LHC, if needed) is done at an unscheduled visit, this 
information must be collected in the eCRF. 
2 RHC (and LHC, if needed) must have been performed at least 90 days after full anticoagulation and at least 90 days after last surgical (PEA) or interventional (BPA) 
treatment for subjects with persistent/recurrent CTEPH. 
For the hemodynamic cohort, a historical RHC (and LHC, if needed) is allowed, provided it was performed within 30 days prior to Screening*, at least 90 days after 
last change in PH-specific therapies (ie, change in dose or initiation of new class of drugs) and as per guidance in Appendix 1.  
For the non-hemodynamic cohort, historical RHC (and LHC, if needed) is allowed, provided it was performed within 6 months prior to Screening*.  
If no historical results are available, RHC (and LHC, if needed) must be performed during the Screening period (as per guidance in Appendix 1 for the hemodynamic 
cohort). 
* In case of rescreening in the hemodynamic cohort within 6 months of the first Screening Visit, the first screening RHC (and LHC if needed) can be used, provided 
there have been no changes in PH-specific therapy(ies) since the first Screening Visit. In case of rescreening in the non-hemodynamic cohort within 6 months of the 
first Screening Visit, the first screening RHC (and LHC if needed) can be used. 
3 Assessment to be performed within 2–5 hours post-dose. 
4 Only for subjects in the hemodynamic cohort and must be done after the post-dose 6MWT. 
5 Performed in the 14-month period prior to randomization and after last surgical (PEA) and/or interventional (BPA) treatment for subjects with persistent/recurrent 
CTEPH [Section 7.2.2]. If no historical results are available, the assessments must be performed during the Screening period.  
6 If the results of the screening blood samples from the central laboratory are not available in time for randomization of the subject, an additional blood sample may be 
drawn to verify eligibility based on a local laboratory test.  
7 PAH-SYMPACT® questionnaire to be completed for the seven consecutive days following the visit at site (ie, starting the day following the visit day) for the symptom 
part, and on the seventh day of the symptoms diary data collection period, together with the symptom part (ie, in the evening) for the impact part.  
8 Scheduled telephone calls as per up-titration scheme [Section 5.1.3.1]. 
9 All AEs and SAEs that occur after signing the Informed Consent Form and until the EOS, as defined in Section 8.1, must be reported [see also Section 9]. 
10 After Week 52, the phone and on-site visits will be alternating every 13 weeks (~3 months). 
11 The EDBT visit occurs within 4 weeks after the end-of-double-blind period announcement, ie, within 4 weeks of reaching the overall target number of clinical 
worsening events, or earlier following recommendation of the IDMC, or sponsor’s decision. 
* Assessment not collected in eCRF.  
** Transferred electronically by an external service provider. 
 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 84/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Table 4 
Open-label treatment period: visit and assessment schedule  
PERIODS 
Name 
TRANSITION 
OPEN-LABEL TREATMENT 
SAFETY 
FOLLOW-UP 
 
Duration 
 
At least until the DB period results release or 
 up to a maximum of 26 weeks after the DB period results release 
30 days 
VISITS1 
Number 
 
EDBT 
Titration 
phase 
OL 1 
OL 2 
Visits every 26 weeks7 
 
EOLT 
 
Safety follow-up 
(Telephone call) 
 
Name 
OL-Week 12 
OL-Week 26 
OL-Week 52, 78, 104, 
etc 
 
Time 
Announced6 
Weekly from 
OL-Week 1 to 
OL-Week 11 
(± 3 days) 
Day 85 after 
EDBT  
(± 7 days) 
Day 183 after 
EDBT 
(± 7 days) 
Day 365, 547, 729 
after EDBT, etc  
(± 7 days) 
Any time within 26 weeks of the 
DB period results release  
or for premature EOLT within 
7 days after last OL dose 
30 (+ 5) days after last 
OL dose 
Previous/concomitant therapy 
 
X 
X 
X 
X 
X 
X 
Physical examination* 
 
 
X 
X 
X 
X 
 
Vital signs (BP, HR), Weight 
 
 
X 
X 
X 
X 
 
Hematology and clinical chemistry** 
 
 
X 
X 
X 
X 
 
Urine pregnancy test* 
 
monthly (±7 days) 
Post-dose 6MWT/BDI or Borg CR10®2 
 
 
 
X 
X 
X 
 
WHO FC 
 
 
 
X 
X 
X 
 
Dose titration 
 
3  
iMTD 
 
 
 
 
OL Study treatment dispensing/return 
X4 
 
X 
X 
X 
X 
 
SAEs/AEs5 
 
X 
X 
X 
X 
X 
X 
6MWT = 6-minute walk test; AE = adverse event; BDI = Borg dyspnea index; Borg CR10® = Borg category-ratio 10 Scale®; BP = blood pressure; CGI-C = Clinician 
Global Impression of Change; CGI-S = Clinician Global Impression of Severity; DB = double blind; eCRF = electronic Case Report Form; EDBT = End-of-Double-Blind-
Treatment; EOLT = End-of-Open-Label-Treatment; ,EOS = end of study; EQ-5D-5L = Euro Quality of life-5-Dimension-5-Level; FC = functional class; HR = heart rate; 
IDMC = Independent data management committee; iMTD = individual maximum tolerated dose; LHC = left heart catheterization; NT-pro BNP = N-terminal pro b-type 
natriuretic peptide; OL = open-label; PAH-SYMPACT® = Pulmonary arterial hypertension symptoms and impact questionnaire; PTOP-SFU = Post-treatment observation 
period-Safety follow-up; RHC = right heart catheterization; SAE = serious adverse event; WHO = World Health Organization. 
 = telephone call 
1 Unscheduled visits may be performed at any time during the OL treatment period. Assessments are performed at the discretion of the investigator. If any RHC (and 
LHC, if needed) is done at an unscheduled visit, this must be collected in the eCRF. 
2 Assessment to be performed within 2–5 hours post-dose. 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 85/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
3 Scheduled telephone calls as per up-titration scheme [see Section 5.1.3.2]. 
4 First OL dose to be taken on the evening of the EDBT visit or in the morning of the day after EDBT visit in case of qd regimen. [see Section 5.1.3.2]. 
5 All AEs and SAEs that occur after first dose of OL study treatment and up to 30 days after study treatment discontinuation must be reported [see also Section 9]. 
6 The EDBT visit occurs within 4 weeks after the end-of-double-blind period announcement ie within 4 weeks of reaching the overall target number of clinical worsening 
events, or earlier following recommendation of the IDMC, or sponsor’s decision. 
7 ONLY FOR SUBJECTS WHO WERE TRANSITIONED TO THE OL TREATMENT EXTENSION PERIOD BEFORE IMPLEMENTATION OF THE AC-065B302 
PROTOCOL AMENDMENT 2. 
* Assessment not collected in eCRF.  
** Transferred electronically by an external service provider. 
 
 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 86/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Table 5 
Visit and assessment schedule for subjects entering the PTOP 
PERIODS 
Name 
 
DOUBLE-BLIND PERIOD - OFF-TREATMENT1 
(after premature discontinuation of double-blind study treatment) 
SURVIVAL 
FOLLOW-UP 
VISITS 
Number 
 
 
 
 
 
 
TC every 
26 weeks8 
Visit every 
26 weeks8 
 PTOP-EOS 
SFU 1, 2, 3, etc 
 
Name 
PTOP-SFU2  
(telephone 
call) 
PTOP-
Week 12 
PTOP-
Week 20 
PTOP-
Week 26 
PTOP-
Week 39 
PTOP-
Week 52 
PTOP-
Week 65, 
91, 117, etc 
PTOP-
Week 78, 
104, 130, 
etc 
Announced5  Survival Follow-up 
 
Time 
30 (+5 days) 
after last DB 
dose 
Day 85 
(± 7 days) 
Day 141 
(± 7 days) 
Day 183 
(± 7 days) 
Day 274 
(± 7 days) 
Day 365 
(± 7 days) 
Day 456, 
638, 820 
etc.  
(± 7 days) 
Day 547, 
729, 911, 
etc. 
(± 7 days) 
Yearly after study 
discontinuation 
until death or 
announcement6 
Previous/concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination* 
 
X 
X 
X 
X 
X 
 
X 
X 
 
Vital signs (BP, HR), Weight 
 
X 
X 
X 
X 
X 
 
X 
X 
 
Local 12-lead ECG 
 
 
 
 
 
X 
 
 
X 
 
Hematology and clinical chemistry** 
 
X 
X 
X 
X 
X 
 
X 
X 
 
6MWT/BDI or Borg CR10® 
 
X 
X 
X 
X 
X 
 
X 
X 
 
WHO FC 
 
X 
X 
X 
X 
X 
 
X 
X 
 
Actigraphy** 
 
Every day, 24 hours per day 
 
 
 
 
 
 
PAH-SYMPACT®**, 3 
 
X 
X 
X 
X 
 
 
 
 
 
EQ-5D-5L, WPAI©: GH** 
 
X 
X 
X 
X 
X 
 
 
 
 
CGI-S 
 
X 
X 
X 
X 
X 
 
X 
X 
 
CGI-C 
 
X 
X 
X 
X 
X 
 
X 
X 
 
NT-proBNP** 
 
X 
X 
X 
X 
X 
 
X 
X 
 
SAEs/AEs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival 
 
 
 
 
 
 
 
 
 
X7 
6MWT = 6-minute walk test; AE = adverse event; BDI = Borg dyspnea index; Borg CR10® = Borg category-ratio 10 Scale®, PTOP = Post-Treatment Observation 
Period; FC = functional class; SAE = serious adverse event; SFU = safety follow-up; WHO = World Health Organization.  


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 87/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
1 Depending on the time point of premature double-blind treatment discontinuation, the sequence and/or the applicability of visits may change. If one of the site visits 
falls within the time window of the premature EDBT visit [as defined in Section 5.1.10], only the assessments of the premature EDBT are to be performed. 
2 If the PTOP-SFU falls within the time window of any of the other PTOP visits, then the PTOP-SFU is combined with the corresponding PTOP site visit. In this case, 
the PTOP-SFU assessments are to be done in addition to the assessments of the respective visit.  
3 PAH-SYMPACT® questionnaire to be completed for the seven consecutive days following the visit at site (ie, starting the day following the visit day) for the symptom 
part, and on the seventh day of the symptoms diary data collection period, together with the symptom part (ie, in the evening) for the impact part. 
4 All AEs and SAEs that occur after signing the Informed Consent Form and until the EOS, as defined in Section 8.1, must be reported [see also Section 9]. 
5 The PTOP-EOS visit occurs within 4 weeks after the end-of-double-blind period announcement, ie, within 4 weeks of reaching the overall target number of clinical 
worsening events, or earlier following recommendation of the IDMC, or sponsor’s decision. 
6 The end of the survival follow-up period for alive subjects will be announced and corresponds to the end-of-double-blind period announcement ie within 4 weeks of 
reaching the overall target number of clinical worsening events, or earlier following recommendation of the IDMC, or sponsor’s decision. 
7 Only for subjects who prematurely discontinue from DB study treatment and who disagree to continue to perform visits and assessments until the end of the PTOP, 
survival information will be collected yearly [see Section 7.2.3.9]. 
8 After Week 52, the phone and on-site visits will be alternating every 13 weeks (~3 months). 
* Assessment not collected in electronic Case Report Form.  
** Transferred electronically by an external service provider. 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 88/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
7.2 Study assessments 
The study assessments are listed in Table 3, Table 4 and Table 5. The assessments that are 
mandatory during a visit are marked with an ‘X’. Optional assessments are marked with an 
‘(X)’. Mandatory assessments at an unscheduled visit due to increase from baseline in 
WHO FC, deterioration from baseline by at least 15% in exercise capacity, as measured by 
the 6MWD, suspicion of clinical worsening, any change in dose, initiation of PH-specific 
therapies or up-titration of DB study treatment beyond Week 12 during the DB treatment 
period are marked with a ‘W’. 
All study assessments are performed by qualified study personnel (medical, nursing or 
specialist technical personnel) and are recorded in the eCRF, unless otherwise specified. 
Study assessments performed during unscheduled visits will also be recorded in the eCRF. 
The following order of assessments is recommended:  
• PRO completed at subject’s home: PAH-SYMPACT® 
• Investigator to complete CGI-S and CGI-C 
• PROs: EQ-5D-5L and WPAI©: GH 
• Safety assessments 
• WHO FC 
• 6MWT 
• BDI or Borg CR10® immediately after completion of the 6MWT 
• Blood samples for hematology and clinical chemistry tests and NT-proBNP (as 
applicable) 
• RHC (and LHC, if needed) at rest, as applicable 
If the Principal Investigator (PI) delegates any study procedure/assessment for a subject, 
eg, ECG, RHC (and LHC, if needed), V/Q scan, PA, CTPA, MRA, blood sampling to an 
external facility, he/she should inform the sponsor to whom these tasks are delegated. The 
set-up and oversight will be agreed upon with the sponsor. The supervision of any external 
facilities remains the responsibility of the PI. 
Evidence of equipment maintenance for the below-listed equipment used to perform study 
assessments must be available prior to the screening of the first subject. Evidence of 
equipment maintenance of other equipment must be available as per local requirements. 
• 
Temperature measurement devices for study treatment storage area and freezer. 
• 
RHC equipment. 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 89/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
7.2.1 Demographics / baseline characteristics 
Demographic and baseline characteristic data to be collected on all randomized subjects 
include: age, sex, race and ethnicity6, weight and height, date of the initial CTEPH 
diagnosis, WHO FC, smoking status (never, former, current), and dates of the V/Q scan, 
PA, CTPA and/or MRA used to confirm the diagnosis of CTEPH. 
All relevant medical history / current medical conditions based on the investigator’s 
judgment (eg, chronic and ongoing acute conditions, serious past conditions) present before 
and/or at the time of signing informed consent will be recorded on the medical history page. 
Where possible, diagnoses and not symptoms will be recorded. 
For all screened subjects, the use of PH-specific therapies (ERA, PDE-5 inhibitors, 
riociguat), as well as the reason for not prescribing those are collected (not available, not 
reimbursed, contraindicated / not tolerated, other). 
For subjects who failed screening, the following data will be recorded in the eCRF, if 
available: reason for screening failure, baseline data collected until confirmation of the 
screening failure (at a minimum, data that support the reason for screening failure).  
7.2.2 Assessments for diagnosis of CTEPH and judgment of inoperability 
A baseline RHC (and LHC, if needed) is mandatory for all subjects, as detailed in 
Section 7.2.3.1.1.  
V/Q scan, PA, CTPA and MRA assessments are mandatory for the diagnosis of CTEPH 
and judgment of inoperability as follows [see also Section 4.1.1]: 
• Subjects with inoperable CTEPH (ie, technically non-operable) will require a diagnosis 
of CTEPH based on at least two of these imaging assessments. 
• Subjects with persistent/recurrent CTEPH after PEA and/or BPA will require a 
diagnosis of CTEPH based on at least one of these imaging assessments and a 
historical surgery & intervention report. 
Historical results are accepted if the imaging assessment was performed within 14 months 
prior to randomization (Visit 2) and after last surgical (PEA) and/or interventional (BPA) 
treatment for subjects with persistent/recurrent CTEPH. If no historical results are 
available, the assessments must be performed during the Screening period. 
Results of these imaging assessments will not be collected in the eCRF (except for the type 
and date of test[s]) but must be filed at site in the subject’s file. In order to allow the AC to 
 
6 Race/ethnicity will be collected in the eCRF only where it is allowed. 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 90/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
confirm subject eligibility prior to randomization [see Section 4.1.1], the anonymized data 
(images and forms) will be transferred via a central image processing center to the AC. 
Incidental findings unrelated to CTEPH identified by central reading will be communicated 
by the central image processing center to the investigator, who is responsible for taking 
appropriate action. 
If the primary investigational site does not have the possibility to perform these imaging 
assessments, the sponsor could support the assessment at another specialized site [see 
Section 7.2]. The investigator at the primary site remains accountable for review and 
submission of V/Q scan, PA, CTPA and MRA data to the AC. 
7.2.3 Efficacy assessments 
7.2.3.1 Right heart catheterization (and left heart catheterization, if needed) 
Hemodynamic data will be assessed during the RHC (and LHC, if needed) procedures. 
Detailed guidance is provided in Appendix 1.  
For the hemodynamic cohort, the following hemodynamic parameters are to be collected 
in the eCRF: HR and peripheral systolic and diastolic blood pressure (sSAP / dSAP), 
PAWP (alternatively LVEDP when PAWP is not available or not reliable), mRAP, systolic 
/ diastolic pulmonary artery pressures (sPAP / dPAP), CO and mixed venous oxygen 
saturation (SvO2). 
For the non-hemodynamic cohort, the following hemodynamic parameters are to be 
collected in the eCRF: HR and sSAP / dSAP , PAWP (alternatively LVEDP when PAWP 
is not available or not reliable), mRAP, sPAP / dPAP / mean pulmonary artery pressures 
(mPAP), CO, mixed venous oxygen saturation (SvO2) and PVR. CI and total pulmonary 
resistance should be entered into the eCRF by the site if available. 
If the primary investigational site does not have the possibility to perform an RHC (and 
LHC, if needed), the sponsor could support the assessment at another specialized site [see 
Section 7.2]. The investigator at the primary site remains accountable for review and 
submission of RHC (and LHC, if needed) data to the AC. 
7.2.3.1.1 Baseline RHC (and LHC, if needed) 
All subjects must have an RHC (and LHC, if needed), performed at least 90 days after full 
anticoagulation, available to evaluate eligibility.  
For subjects with persistent/recurrent CTEPH after PEA and/or BPA, the RHC (and LHC, 
if needed) must be performed at least 90 days after last surgical (PEA) or interventional 
(BPA) treatment.  


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 91/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
For the hemodynamic cohort, a historical RHC (and LHC, if needed) is allowed provided 
it was performed within 30 days prior to Screening*, at least 90 days after last change in 
PH-specific therapies (ie, change in dose or initiation of new class of drugs) and as per 
guidance in Appendix 1. 
For the non-hemodynamic cohort, a historical RHC (and LHC, if needed) is allowed, 
provided it was performed within 6 months prior to Screening*.  
If no historical results are available, an RHC (and LHC, if needed) must be performed 
during the Screening period (as per guidance in Appendix 1 for the hemodynamic cohort).  
* In case of rescreening in the hemodynamic cohort within 6 months of the first Screening 
Visit, the first screening RHC (and LHC if needed) can be used, provided there have been 
no changes in PH-specific therapy(ies) since the first Screening Visit. In case of 
rescreening in the non-hemodynamic cohort within 6 months of the first Screening Visit, 
the first screening RHC (and LHC if needed) can be used. 
7.2.3.1.2 Week 20 RHC (and LHC, if needed) 
At Week 20, an RHC (and LHC, if needed) is required for the assessment of the primary 
endpoint and will be conducted in approximately the first 90 randomized subjects that 
enroll in the hemodynamic cohort. The RHC (and LHC, if needed) must be performed 
following the post-dose 6MWD assessment (if applicable) and within 2–5 hours post-dose. 
The time of the study treatment morning dose intake will be recorded in the eCRF. 
For the hemodynamic cohort, Week 20 RHC (and LHC, if needed) must be performed 
according to guidance detailed in Appendix 1. 
An RHC (and LHC, if needed) performed at any unscheduled visit must be entered into the 
eCRF. 
7.2.3.2 Exercise capacity 
Exercise capacity will be measured by the 6MWT. The 6MWT is a non-encouraged test 
that measures the distance walked in 6 minutes (6MWD). It is performed as indicated in 
Table 3, Table 4 and Table 5. 
Beginning with the morning of Visit 3, and at each visit thereafter, subjects must take the 
morning study treatment dose before any visit-related procedure. The post-dose 6MWT 
must be performed within 2–5 hours post-dose. The time of the study treatment morning 
dose intake will be recorded in the eCRF.  
Guidelines on correct execution of the 6MWT are provided in Appendix 3.  


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Before study start, it must be verified whether the site can comply with the 6MWT study 
guidance [see Appendix 3]. If a 6MWT cannot be performed at a scheduled visit beyond 
Visit 2 or at an unscheduled visit, a reason must be provided (ie, clinical worsening or 
other). 
The data related to 6MWT will be recorded in the eCRF. 
7.2.3.3 Post-6MWT Dyspnea 
The perception of dyspnea will be assessed by the BDI scale/Borg CR10 Scale® by each 
individual subject immediately after each 6MWT.  
Subjects enrolled before implementation of the AC-065B302 protocol amendment 2 must 
continue using the BDI scale in Appendix 4.  
Subjects enrolled after implementation of the AC-065B302 protocol amendment 2 must 
use the Borg CR10 Scale® in Appendix 5.  
The perception of dyspnea will be collected in the eCRF. 
7.2.3.4 WHO FC 
WHO FC [Appendix 6] will be assessed as indicated in Table 3, Table 4 and Table 5. 
WHO FC will be collected in the eCRF. 
7.2.3.5 Daily life physical activity (DLPA) 
The DLPA of subjects is assessed via an actigraphy device. The device is given to the 
subject at Visit 1 (Screening Visit), and the subject is instructed to wear the actigraphy 
device on the wrist of the non-dominant hand (ambidextrous subjects may wear it on either 
wrist) during the entire study, up to Week 26. Subjects are instructed on the use of the 
actigraphy device and accessories via a subject guide. Raw data will be uploaded 
automatically via Bluetooth or during charging of the actigraphy device as described in the 
subject guide. 
To ensure DLPA data quality, the site and the SM will have access to compliance data 
through a web portal and via weekly subject reports displaying subject’s adherence to 
DLPA assessment. Should corrective actions be necessary, the subject may be contacted 
from the site staff (eg, telephone call, text message).  
The actigraphy device does not display collected data, ie, the subjects do not have access 
to their activity measurements, as this could influence their behavior.  
The vendor will have raw data and derive datasets such as epoch dataset (per second or 
minute), DLPA daily summary dataset, and sleep dataset. Datasets will include relevant 


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parameters and will be transferred to the sponsor as described in the Data Transfer 
Agreement. 
Subjects must return the actigraphy device to the site at the Week 26 / Visit 5. The devices 
will be returned to the vendor. Upon request, the subject will be provided with a report (on 
paper) summarizing the subject’s individual activity levels during his/her participation in 
the study. 
7.2.3.6 Clinical worsening 
In case of suspicion of clinical worsening outside of a scheduled visit [see Section 7.1.2], 
any change in dose, initiation of PH-specific therapies, or up-titration of DB study 
treatment beyond Week 12 during the DB treatment period, an unscheduled visit must be 
performed as detailed in Table 3. Data related to study-specific assessments, any 
concomitant therapies and any SAEs/AEs will be recorded in the eCRF. 
7.2.3.7 NT-proBNP 
A blood sample for the analysis of NT-proBNP will be drawn as indicated in Table 3. 
Details regarding blood sampling procedures, collection and shipment of the samples are 
described in the central laboratory manual. 
7.2.3.8 Clinician reported outcomes 
7.2.3.8.1 Clinician Global Impression of Severity (CGI-S) 
The CGI-S is a six-point single item scale. The investigator/delegate will rate the overall 
severity of the participant’s disease on the day of administration with responses of none, 
very mild, mild, moderate, severe or very severe. 
The outcome of the CGI-S will be recorded in the eCRF. 
7.2.3.8.2 Clinician Global Impression of Change (CGI-C) 
The CGI-C is a seven-point single item scale. The investigator/delegate will rate the overall 
participant’s change of the participant’s disease since baseline with responses of very much 
better, moderately better, a little better, no change, a little worse, moderately worse or very 
much worse. 
The outcome of the CGI-C will be recorded in the eCRF. 
7.2.3.9 Survival follow-up 
For subjects who prematurely discontinue DB study treatment and do not agree to continue 
to perform the visits and assessments until the PTOP-EOS visit, long-term survival 
information will be collected yearly until death or the time of end-of-double-blind period 


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[see Section 5.1.10]. Subject’s vital status, ie, alive/dead/unknown (including last date 
known to be alive if unknown) as well as death information and concomitant PH-specific 
therapies when applicable will be collected in the eCRF. 
7.2.4 Safety assessments 
The definitions, reporting and follow-up of AEs, SAEs and pregnancies are described in 
Section 9. 
7.2.4.1 Physical examination 
Physical examination at Screening includes the examination of the general appearance, 
heart, lungs, abdomen, skin, extremities, eyes, ears, nose, throat, neck (including thyroid), 
lymph nodes and nervous system. At subsequent visits, physical examination includes the 
examination of heart, lungs, abdomen, and extremities. 
Other exams will be performed if indicated, based on medical history and/or symptoms. 
Information for all physical examinations must be included in the source documentation at 
the study site.  
The date of the physical examination will be collected in the eCRF. Clinically relevant 
findings (other than those related to CTEPH) that are present prior to signing of informed 
consent must be recorded on the Medical History eCRF page. Physical examination 
findings made after signing of informed consent, which meet the definition of an AE 
[Section 9.1.1], must be recorded on the AE page of the eCRF. 
7.2.4.2 Vital signs 
Vital signs will be assessed as indicated in Table 3 and Table 4. 
SBP, diastolic blood pressure and radial pulse measurements will be measured in a supine 
or sitting position. It is recommended to allow the subject to rest for at least 5 minutes and 
to use the same device, same position (supine or sitting), same arm, same operator and 
appropriate cuff size throughout the study for each individual subject. 
7.2.4.3 Weight and height 
Height will be measured at Screening.  
Body weight will be measured in indoor clothing but without shoes as indicated in Table 3 
and Table 4. 
7.2.4.4 Electrocardiogram assessment 
A standard 12-lead electrocardiogram (ECG) will be performed as indicated in Table 3. 


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The ECG will be interpreted locally and stored at the site.  
Clinically relevant ECG findings that are present prior to the initiation of study treatment 
must be documented in the Medical History section of the eCRF. Clinically relevant ECG 
findings found after the study treatment initiation that were not present at Screening or that 
worsened during the study must be reported as an AE [see Section 9.1.1] as appropriate. 
7.2.5 Laboratory assessments 
7.2.5.1 Type of laboratory 
A central laboratory (see central laboratory manual for contact details) will be used for all 
protocol-mandated laboratory tests, including re-tests due to laboratory abnormalities and 
laboratory tests performed at unscheduled visits. 
If the results from the central laboratory are not available in time for randomization of the 
subject, an additional blood sample may be drawn to verify eligibility based on a local 
laboratory test. The local laboratory results (with the corresponding normal ranges) must 
be recorded in the eCRF. 
Other exceptional circumstances that require recording of local laboratory results for the 
parameters described in Section 7.2.5.2 (with corresponding normal ranges) include 
hospitalization of the subject due to a medical emergency and missing central laboratory 
results from a scheduled or unscheduled visit. 
If central laboratory samples are lost or cannot be analyzed for any reason, the investigator 
will consider collecting an additional sample as soon as possible for repeat analysis, if 
deemed medically necessary. 
Central laboratory reports will be sent to the investigator. In case of specific (predefined) 
laboratory abnormalities, the central laboratory will alert sponsor personnel and concerned 
site personnel. Alert flags that will trigger such notifications are displayed in Appendix 2. 
All laboratory reports must be reviewed, signed and dated by the investigator or delegate 
and filed with the hospital chart. 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 9] and must be followed up until the value returns to within the 
normal range or is stable or until the change is no longer clinically relevant. 
Details about the collection, sampling, storage, shipment procedures and reporting of 
results and abnormal findings can be found in the laboratory manual. 


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7.2.5.2 Laboratory tests 
The subjects do not need to be fasted prior to the laboratory tests.  
Details about the collection, sampling, storage, shipment procedures and reporting of 
results and abnormal findings can be found in the laboratory manual.  
Hematology 
• Hemoglobin (SI Unit: g/L; conventional unit: g/dL) 
• Hematocrit (SI Unit: L/L; conventional unit: %) 
• Erythrocyte count (SI Unit: 1012/L; conventional unit: 106/μL) 
• Leukocyte count with differential counts (SI Unit: 109/L; conventional unit: 103/μL) 
• Platelet count (SI Unit: 109/L; conventional unit: 103/μL) 
Clinical chemistry 
• Alanine aminotransferase (U/L) 
• Aspartate aminotransferase (U/L) 
• Alkaline phosphatase (U/L) 
• Total and direct bilirubin (SI unit: μmol/L; conventional unit: mg/dL) 
• Creatinine (SI unit: μmol/L; conventional unit: mg/dL) 
• Sodium, potassium (mmol/L) 
• Glomerular filtration rate (mL/min/1.73m2), using the Modification of Diet in Renal 
Disease formula 
• Thyroid hormones:  
– Free tri-iodothyronine (T3) (SI unit: pmol/L; conventional unit: pg/dL) 
– Total T3 (SI unit: nmol/L; conventional unit: ng/dL) 
– Free thyroxin (T4) (SI unit: pmol/L; conventional unit: ng/dL) 
– Total T4 (SI unit: nmol/L; conventional unit: ng/dL) 
– Thyroid stimulating hormone (TSH; SI unit: mIU/L; conventional unit: µIU/dL) 
Pregnancy test 
A serum pregnancy test for women of childbearing potential will be performed at 
Screening.  
Urine pregnancy tests will be performed at randomization and monthly thereafter. Urine 
pregnancy tests are either performed on-site during a scheduled visit or at home with the 
pregnancy test validated kit provided by the site. The results of the urine pregnancy tests 
will not be collected in the eCRF. Results of pregnancy tests will be documented in the 
subject’s records (pregnancy test card). The date of the urine pregnancy test reported on 
the pregnancy card will be collected in the eCRF. 


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If pregnancy is suspected during the study, a serum pregnancy test must be performed 
immediately. 
7.2.6 Patient-reported outcomes 
The following PRO instruments will not be administered to illiterate subjects and will not 
be administered to a subject when the instrument is not available in a language that can be 
easily understood and read. 
7.2.6.1 PAH-SYMPACT® questionnaire 
The PAH-SYMPACT® [Appendix 7] questionnaire is a PRO instrument that was 
developed by Actelion Pharmaceuticals Ltd [McCollister 2016]. This questionnaire has 
been developed and validated for use in PAH patients. The clinical presentation and 
manifestation of symptoms appear to be consistent across subgroups of pulmonary 
hypertension (eg, PAH and CTEPH) [Galiè 2016]. Therefore, it was considered that the 
PAH-SYMPACT® would be the most appropriate disease-specific instrument and is now 
being validated in CTEPH patients. Site staff will explain to the subjects that this 
questionnaire is applicable to their disease. 
The PAH-SYMPACT® consists of two parts: 
• The symptom part is completed for the seven consecutive days following the visit at 
site (ie, starting the day following the visit day).  
• The impact part is completed once, on the seventh day of the symptoms diary data 
collection period, together with the symptom part (ie, in the evening).  
The PAH-SYMPACT® will be administered as indicated in Table 3.  
The PAH-SYMPACT® should be completed in the evening before bedtime. 
The PAH-SYMPACT® will be administered via a hand-held mobile device that subjects 
take home. Subjects will be trained on the mobile device by the site staff during Visit 1. 
Data will be transferred to an electronic database immediately upon completion of the 
questionnaire via a cellular connection to the vendor.  
To ensure PAH-SYMPACT® data quality, the site and the SM will have access to 
compliance data through a web portal and will be informed by the vendor if the 
questionnaire has not been completed per protocol. Should corrective actions be necessary, 
subjects may be contacted by the site staff (eg, telephone call, text message). 
The data from the mobile device will be collected by the vendor, who will send the results 
to the sponsor. 


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At Week 52 / Visit 7, subjects must return the mobile device to the site. The devices will 
be returned to the vendor. 
7.2.6.2 EQ-5D-5L 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcomes 
[Janssen 2013].  
The EQ-5D-5L [Appendix 8] will be administered as indicated in Table 3. Each individual 
subject will enter their scores on an electronic device. Subjects will be trained on the 
electronic device by the site staff during Visit 1. The data from the electronic device will 
be collected by the vendor, who will send the results to the sponsor. 
Actelion Pharmaceuticals Ltd has been granted a license agreement for the use of the 
EQ-5D-5L. 
7.2.6.3 WPAI©: GH V2.0  
The WPAI©: GH [Appendix 9] is a patient-reported quantitative assessment of the amount 
of absenteeism, presenteeism and daily activity impairment attributable to general health 
[Reilly 1993]. It has a recall period of 1 week. 
The WPAI©: GH will be administered as indicated in Table 3. Each individual subject will 
enter their scores on an electronic device. The data from the electronic device will be 
collected by the vendor, who will send the results to the sponsor. 
Written permission is neither required nor provided to researchers using the WPAI©: GH. 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE 
8.1 Study completion as per protocol  
Subjects who perform the EOS telephone call / visit are considered as study completers:  
• For subjects who complete their study treatment up to the EOLT visit, the EOS visit 
corresponds to the safety telephone call which occurs 30–35 days after last OL dose. 
• For subjects who prematurely discontinue the DB study treatment, the EOS visit 
corresponds to the last visit in the PTOP period, ie, the PTOP-EOS visit. It occurs 
within 4 weeks after the end-of-double-blind period announcement, ie, within 4 weeks 
of reaching the overall target number of clinical worsening events [Section 10.6.3], or 
earlier following recommendation of the IDMC [Section 10.4] and sponsor’s decision 
[Section 8.3].  
• For subjects who prematurely discontinue the OL study treatment, the EOS visit 
corresponds to the safety telephone call (ie, 30–35 days after last OL dose). 


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Subjects who prematurely withdraw from the study, per Section 8.2, are not considered as 
study completers: 
• For subjects who prematurely withdraw from the study, the EOS date is defined as the 
date of either death, last unsuccessful follow-up contact attempt, consent withdrawal, 
physician decision or sponsor decision, depending on the reason for study 
discontinuation. 
8.2 Premature withdrawal from study  
Subjects may voluntarily withdraw from the study without justification for any reason at 
any time. Subjects are considered withdrawn if they state an intention to withdraw further 
participation in all components of the study (ie, withdrawal of consent), die or are lost to 
follow-up. If a subject withdraws consent, no further data will be collected in the eCRF 
from the date of withdrawal onward. The investigator may withdraw a subject from the 
study (without regard to the subject’s consent) if, on balance, he/she believes that continued 
participation in the study would be contrary to the best interests of the subject. Withdrawal 
from the study may also result from a decision by the sponsor for any reason, including 
premature termination or suspension of the study. 
Subjects 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 subject being lost to follow-up (eg, document different ways of contact such as telephone 
number, home address, email address, person to be contacted in case the subject cannot be 
reached). If the subject cannot be reached, the site must make a reasonable effort to contact 
the subject, 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 (eg, a visit by site personnel to the subject’s home, consult with 
family members, contacting the participant’s other physicians, medical records, database 
searches, use of locator agencies at study completion), respecting the subject’s right to 
privacy. If the subject is still unreachable after all contact attempts listed above, he/she will 
be considered to be lost to follow-up. 
If premature withdrawal occurs for any reason, the reason (if known) for premature 
withdrawal from the study, along with who made the decision (subject, investigator, or 
sponsor personnel), must be recorded in the eCRF. 
If, for whatever reason (except death or loss to follow-up), a subject 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 subject, collect unused study treatment and 


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discuss follow-up medical care. Data obtained during this last appointment / telephone call 
will be recorded in the subjects’ medical records but will not be collected in the eCRF. The 
investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care, as described 
in Section 8.4. 
8.3 Premature termination or suspension of the study  
The sponsor reserves the right to terminate the study at any time globally or locally. 
Investigators can terminate the participation of their site in the study at any time. 
If the study is prematurely suspended or terminated, the sponsor will promptly inform the 
investigators, the IECs/IRBs and health authorities, as appropriate, and provide the reasons 
for the suspension or termination. 
If the study is suspended or prematurely terminated for any reason, the investigator – in 
agreement with the sponsor – must promptly inform all enrolled subjects and ensure their 
appropriate treatment and follow-up, as described in Section 8.4. The sponsor may inform 
the investigator of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the subjects’ interests. 
In addition, if the investigator suspends or terminates the study without prior agreement 
from the sponsor, the investigator must promptly inform sponsor personnel and the 
IEC/IRB, and provide both with a detailed written explanation of the termination or 
suspension. 
If the IEC/IRB suspends or terminates its approval / favorable opinion of the study, the 
investigator must promptly notify sponsor personnel and provide a detailed written 
explanation of the termination or suspension. 
Any suspension or premature termination of the study must be discussed with the IDMC 
and SC. 
8.4 Medical care of subjects after study completion  
After the subject’s study completion, the investigator/delegate will explain to subjects what 
treatment(s) / medical care is necessary and available according to local regulations. If 
indicated, the sponsor will provide subjects who completed the study and did not 
prematurely discontinue study treatment with OL study treatment until access to 
commercial selexipag is possible in this indication in the subject’s country of residence, 
according to local regulatory requirements. 


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9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
9.1 Adverse events 
9.1.1 Definition of adverse events  
An AE is any untoward medical occurrence, ie, any unfavorable and unintended sign, 
including an abnormal laboratory finding, symptom or disease that occurs in a subject 
during the course of the study, whether or not considered by the investigator as related to 
study treatment. 
A treatment-emergent AE is any AE temporally associated with the use of study treatment 
(from study treatment initiation until 3 days after study treatment discontinuation), whether 
or not considered by the investigator as related to study treatment 
AEs include: 
• Exacerbation of a pre-existing disease. 
• Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 
• Disease or medical condition detected or diagnosed during the course of the study, even 
though it may have been present prior to the start of the study. 
• Continuous persistent disease or symptoms present at study start that worsen following 
the signing of informed consent. 
• Abnormal assessments, eg, 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. 
9.1.2 Intensity of adverse events  
The intensity of clinical AEs is graded on a three-point scale – mild, moderate, severe – 
and is reported on specific AE pages of the eCRF. 
If the intensity of an AE worsens within the DB study period, 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.  
If there is a worsening in intensity for an ongoing AE occurring during the subsequent OL 
study period, this must be reported in the eCRF as a new AE with the onset date equal to 
the date of worsening. 


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The three categories of intensity are defined as follows: 
 Mild 
The event may be noticeable to the subject. It does not usually influence daily activities 
and normally does not require intervention. 
 Moderate 
The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed. 
 Severe 
The event may cause noticeable discomfort and usually interferes with daily activities. The 
subject may not be able to continue in the study, and treatment or intervention is usually 
needed. 
A mild, moderate or severe AE may or may not be serious [see Section 9.2.1]. These terms 
are used to describe the intensity of a specific event. Medical judgment should be used on 
a case-by-case basis. 
Seriousness, rather than intensity assessment, determines the regulatory reporting 
obligations. 
9.1.3 Relationship to study treatment  
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the study treatment administered DB or OL (as 
applicable) and reported as either related or not related. The determination of the likelihood 
that the study treatment caused the AE will be provided by the investigator. 
9.1.4 Reporting of adverse events  
All AEs with an onset after signing of informed consent and until the EOS, as defined in 
Section 8.1, must be recorded on specific AE pages of the eCRF. 
9.1.5 Follow-up of adverse events  
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and evaluations as medically indicated to elucidate the nature and causality 
of the AE, SAE, or product quality complaint (PQC) as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
AEs still ongoing beyond the EOS, as defined in Section 8.1, must be followed up until 
they are no longer considered clinically relevant or until stabilization. The follow-up 


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information obtained after the subject’s EOS telephone call / visit will not be collected by 
the sponsor. 
9.2 Serious adverse events  
9.2.1 Definitions of serious adverse events 
An SAE is defined by the ICH guidelines as any AE fulfilling at least one of the following 
criteria: 
• Fatal. 
• Life-threatening: Refers to an event in which the subject was at risk of death at the time 
of the event. It does not refer to an event that hypothetically might have caused death 
had it been more severe. 
• Requiring 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 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in the definitions above. 
The following reasons for hospitalization are not considered SAEs: 
• Hospitalization for cosmetic elective surgery, or social and/or convenience reasons. 
• Hospitalization for pre-planned (ie, planned prior to signing informed consent) surgery 
or standard monitoring of a pre-existing disease or medical condition that did not 
worsen, eg, hospitalization for coronary angiography in a subject with stable angina 
pectoris. 
However, complications that occur during hospitalization are AEs or SAEs (eg, if a 
complication prolongs hospitalization). 
9.2.2 Reporting of serious adverse events 
All SAEs occurring after signing of informed consent and until the EOS, as defined in 
Section 8.1, must be reported on AE pages in the eCRF and on an SAE form, regardless of 
the investigator-attributed causal relationship with study treatment. 
9.2.3 Follow-up of serious adverse events 
SAEs still ongoing beyond the EOS, as defined in Section 8.1, must be followed up until 
resolution or stabilization, or until the event outcome is provided. The follow-up 


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information obtained after the subject’s EOS telephone call / visit must be reported to the 
sponsor but is not recorded in the eCRF. 
9.2.4 After EOS  
New SAEs occurring after the EOS, as defined in Section 8.1, must be reported to the 
sponsor within 24 hours of the investigator’s knowledge of the event only if considered by 
the investigator to be causally related to previous exposure to the study treatment. 
9.2.5 Reporting procedures 
All SAEs must be reported by the investigator to the sponsor within 24 hours of the 
investigator’s first knowledge of the event. 
All SAEs must be recorded on an SAE form, irrespective of the study treatment received 
by the subject and whether or not this event is considered by the investigator to be related 
to study treatment. 
The SAE forms must be sent to the sponsor (contact details are provided on the SAE form). 
The investigator must complete the SAE form in English and must assess the event’s causal 
relationship to the study treatment. Any relevant information from source documents 
regarding the SAE (eg, hospital notes, discharge summaries, etc.) must be summarized on 
the SAE form. 
Follow-up information about a previously reported SAE must also be reported within 
24 hours of receiving it. The sponsor personnel may contact the investigator to obtain 
further information. 
If the subject is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE-relevant information and 
documentation. 
The expectedness of an adverse reaction is determined by the sponsor in the Reference 
Safety Information (RSI) section provided in the most recent version of the IB. Any SAE 
that is assessed as related and unexpected against the RSI is known as a SUSAR and must 
be reported by the sponsor to concerned health authorities (including the EudraVigilance 
database if the study is conducted in Europe), IECs/IRBs and investigators. 
9.3 Pregnancy  
If a woman becomes pregnant while on study treatment, study treatment must be 
discontinued. The investigator must counsel the subject and discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus. 


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9.3.1 Reporting of pregnancy 
All initial reports of pregnancy in female subjects or partners of male subjects must be 
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the 
event using the appropriate pregnancy notification form. Any subject who becomes pregnant 
during the study must discontinue further study treatment [see Section 5.1.11.5].  
9.3.2 Follow-up of pregnancy 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae 
in the infant will be required. 
Any AE associated with the pregnancy occurring before the EOS, as defined in Section 8.1, 
must be reported as a separate AE in the eCRF. Any SAE occurring during the pregnancy 
must be reported on an SAE form as described in Section 9.2.5. Abnormal pregnancy 
outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic 
pregnancy) are considered SAEs and must be reported on an SAE form as described in 
Section 9.2.5. 
9.4 Product Quality Complaints 
9.4.1 Definition 
A PQC is defined as any suspicion of a product defect related to manufacturing, labeling, 
or packaging, ie, any dissatisfaction relative to the identity, quality, durability, reliability, 
or performance of a distributed product, including its labeling, drug delivery system, or 
package integrity. A PQC may have an impact on the safety and efficacy of the product. In 
addition, it includes any technical complaints, defined as any complaint that indicates a 
potential quality issue during manufacturing, packaging, release testing, stability 
monitoring, dose preparation, storage or distribution of the product or the drug delivery 
system. 
9.4.2 Procedures 
All initial PQCs must be reported to the sponsor by the study site personnel within 24 hours 
after being made aware of the event. 
A sample of the suspected product should be maintained under the correct storage 
conditions until a shipment request is received from the sponsor. 
9.5 Special reporting situations 
Safety events of interest on a sponsor study treatment in an interventional study that may 
require expedited reporting or safety evaluation include, but are not limited to: 
• 
Overdose of a sponsor study treatment 


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• 
Suspected abuse/misuse of a sponsor study treatment 
• 
Accidental or occupational exposure to a sponsor study treatment 
• 
Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study 
treatment 
• 
Unexpected therapeutic or clinical benefit from use of a sponsor study treatment 
• 
Medication error, intercepted medication error, or potential medication error involving 
a sponsor medicinal product (with or without patient exposure to the sponsor medicinal 
product, eg, product name confusion, product label confusion, intercepted prescribing 
or dispensing errors) 
• 
Exposure to a sponsor study intervention from breastfeeding. 
Special reporting situations should be recorded in the CRF. Any special reporting situation 
that meets the criteria of a serious adverse event should be recorded on the serious adverse 
event page of the CRF. 
9.6 Study safety monitoring  
Study safety information (AEs, SAEs, laboratory values, ECGs, vital signs and 
study-specific examinations, as required) is monitored and reviewed on a continuous basis 
by the sponsor’s CTT (in charge of ensuring subjects’ safety as well as data quality). In 
addition, an IDMC is monitoring safety data [see Section 3.4.2]. The sponsor may request 
additional data pertaining to the diagnostic work-up of an AE or SAE (eg, medical imaging, 
local laboratory values) for the purpose of safety monitoring. Such additional data may be 
shared with external experts.  
10 STATISTICAL METHODS 
This study implements an adaptive group-sequential design with early futility and/or 
efficacy stopping rules for PVR, 6MWD and TTCW in the DB treatment period. The 
timing of interim and final analyses is shown in Figure 3 and detailed in Section 5.1.6.1.  
Conditional to positive outcome of the PVR results at analysis time point 1, all secondary 
efficacy endpoints will be evaluated at subsequent analysis time points according to the 
testing hierarchy [Section 10.3.1, Figure 4]. At final DB analysis (time point 4) and at final 
study analysis (time point 5), all endpoints will be summarized and analyzed with all 
available information.  
All statistical analyses will be conducted by the sponsor or by a designated CRO supervised 
by the sponsor, with the exception of the analyses at time points 1, 2 and 3, which will be 


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conducted by the independent SSG for the IDMC, and by the independent submission team, 
if applicable. 
Estimands, analyses, data displays, and algorithms to be used for data derivations will be 
fully detailed in the SAP.  
The SAP will also include the definition of the protocol deviations and the link between 
protocol deviations and the analysis sets. The protocol deviations will be identified before 
interim and final analyses and before study closure.  
Subgroup analyses, classifying subjects according to relevant demographic and baseline 
characteristics, will be further described in the SAP to evaluate efficacy and safety results. 
The SAP will be finalized in advance of the planned IA. 
10.1 Analysis sets 
10.1.1 Screened Analysis Set 
The Screened Analysis Set (SCR) includes all subjects who are screened and have a subject 
identification number. 
10.1.2 Full Analysis Set 
The Full Analysis Set (FAS) includes all subjects assigned to a study treatment. In order to 
adhere to the intention-to-treat principle as much as possible: 
• Subjects are evaluated according to the study treatment they have been assigned to 
(which may be different from the study treatment they have received); and 
• All available data are included. 
10.1.3 Hemodynamic Set 
The Hemodynamic Set (HES) comprises all randomized subjects in the hemodynamic 
cohort [Section 3.1]. In order to adhere to the intention-to-treat principle as much as 
possible: 
• Subjects are evaluated according to the study treatment they have been assigned to 
(which may be different from the study treatment they have received); and 
• All available data are included. 
10.1.4 Per-protocol Analysis Sets 
Three Per-protocol Analysis Sets (PPS) are defined separately for PVR (PPS1), 6MWD 
(PPS2) and TTCW (PPS3). Each PPS comprises all subjects who received study treatment 
and who complied with the protocol sufficiently to be likely to exhibit the treatment effects. 
Criteria for sufficient compliance include exposure to study treatment, availability of 


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measurements and absence of important protocol deviations that have an impact on the 
treatment effect. The full list of criteria will be detailed in the SAP. Each PPS includes 
observations up to the occurrence of the specified protocol deviations. Additional 
specifications of the three PPS’s are given below. 
10.1.4.1 PVR Per-protocol Analysis Set 
The PVR Per-protocol Analysis Set (PPS1) includes all subjects in the HES who do not 
have important protocol deviations that have an impact on treatment effect in PVR.  
10.1.4.2 6MWD Per-protocol Analysis Set 
The 6MWD Per-protocol Analysis Set (PPS2) includes all subjects in the FAS who do not 
have important protocol deviations that have an impact on treatment effect in 6MWD. 
10.1.4.3 TTCW Per-protocol Analysis Set 
The TTCW Per-protocol Analysis Set (PPS3) includes all subjects in the FAS who do not 
have important protocol deviations that have an impact on treatment effect in TTCW. 
10.1.5 Safety Analysis Set  
The Safety Analysis Set (SAF) includes all subjects who received at least one dose of study 
treatment. 
Subjects are evaluated according to the study treatment they have received (which may be 
different from the study treatment they have been randomized to): 
• if a subject has taken at least one dose of selexipag, she/he is assigned to the 
selexipag treatment group; 
• if a subject has taken only placebo, she/he is assigned to the placebo treatment group. 
10.1.6 Selexipag-initiated Set  
The Selexipag-initiated Set (SIS) analysis comprises all subjects initiated at any time 
during DB or OL treatment on selexipag. The baseline for this analysis set is the last 
assessment before selexipag initiation. 
10.1.7 Usage of the analysis sets 
Table 6 defines all analysis sets and their specific usage at all analysis time points. For 
decision making at analysis time point 1, PVR will be evaluated on the HES. All other 
efficacy analyses will be primarily evaluated on the FAS. The SIS will be used to evaluate 
subjects initiated at any time on selexipag. Safety endpoints will be primarily evaluated on 
the SAF. 


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If the study is stopped after an IA during the DB treatment period, the final DB analysis of 
all endpoints will be performed using all available data up to EDBT visit. 
Table 6 
Analysis sets and their usage at each analysis time point 
 
Analysis 
Time point 
Analysis  
Analysis Set 
FAS 
HES 
PPS 
SAF 
SIS 
1 
Final PVR 
 
X 
PPS1 
 
 
1 
Exposure and safety 
 
 
 
X 
 
1 
Others* 
X 
X 
 
 
 
2 
Interim 6MWD 
X 
 
PPS2 
 
 
2 
Interim TTCW 
X 
 
PPS3 
 
 
2 
Exposure and safety 
 
 
 
X 
 
2 
Others* 
X 
 
 
 
 
3 
Final 6MWD 
X 
 
PPS2 
 
 
3 
Interim TTCW 
X 
 
PPS3 
 
 
3 
Exposure and safety 
 
 
 
X 
 
3 
Others* 
X 
 
 
 
 
4 
Final TTCW 
X 
 
PPS3 
 
 
4 
Final DB  
X 
 
 
X 
 
5 
Final OL 
X 
 
 
X 
X 
 
* Demographic and baseline characteristics, medical history, previous and concomitant medications, efficacy endpoints 
other than PVR, 6MWD and TTCW. 
The “X” indicates the analysis sets to be used for the main analyses for the respective endpoints and time points.   
6MWD = 6-minute walk distance; DB = double-blind; FAS = Full Analysis Set; HES = Hemodynamic Set; 
OL = open-label; PPS = Per-protocol Analysis Set; PPS1 = PVR Per-protocol Analysis Set; PPS2 = 6MWD Per-protocol 
Analysis Set; PPS3 = TTCW Per-protocol Analysis Set; PVR = pulmonary vascular resistance; SAF = Safety Analysis 
Set; SIS = Selexipag-initiated Set; TTCW = Time to clinical worsening.  
 
 


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10.2 Variables 
10.2.1 Primary efficacy variable 
The primary efficacy variable is the percent of baseline PVR at Week 20 defined as: 
(PVR (dyn.sec/cm5) at Week 20 / PVR (dyn.sec/cm5) at baseline) × 100 
All observed data will be included. Imputations for missing data are specified in 
Section 10.3.2.2. PVR, mPAP, PAWP and CI as captured on the eCRF will only be 
displayed in listings. If the PAWP measurement is not available, then LVEDP will be used 
in the calculation of PVR. The results from the sponsor re-calculated PVR (in dyn.sec/cm5) 
in the analysis dataset are used for analysis.  
10.2.2 Secondary efficacy variables 
One key secondary efficacy variable is change from baseline to Week 26 in 6MWD (in 
meters) as defined by:  
(6MWD (m) at Week 26 − 6MWD (m) at baseline). 
The baseline reference value (baseline) for the 6MWD is the distance obtained from the 
last 6MWT performed prior to or at randomization.  
The other key secondary efficacy variable is TTCW, calculated from date of randomization 
to the date of onset of the first component event, where clinical worsening is defined 
(adapted from the CHMP definition [EMEA 2008]) as at least one of the following 
components confirmed by the CEC, when applicable: 
• All-cause death 
• Non-planned PH-related hospitalization 
• PH-related deterioration identified by at least one of the following: 
– Increase from baseline in WHO FC*; 
– Deterioration from baseline by at least 15% in exercise capacity, as measured by 
the 6MWD*; 
– New or worsening signs or symptoms of right heart failure, defined as a reported 
AE with one of the following preferred terms: “CTEPH”, “pulmonary 
hypertension”, “right ventricular failure”, “right ventricular dysfunction” and 
“acute right ventricular failure”. 
*Confirmed by a second measurement performed on a different day within 14 days. 
Other secondary variables evaluated at Week 26 are: 
• Improvement in WHO FC from baseline to Week 26 


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• Change from baseline to Week 26 in PAH-SYMPACT® cardiopulmonary symptoms 
domain and cardiovascular symptoms domain 
• Change from baseline to Week 26 in BDI/Borg CR10® 
• Change from baseline to Week 26 in NT pro-BNP 
Another secondary endpoint is: 
• All-cause death and hospitalizations related to PH worsening 
Figure 4 defines the hierarchical testing strategy for the primary, key secondary and other 
secondary efficacy endpoints.  
10.2.3 Other efficacy variables  
• Changes in 6MWD, WHO FC and NT-proBNP from baseline to all regular collection 
timepoints up to the EDBT period. 
• Change from baseline up to EOS, by visit, in exercise capacity as measured by the 
6MWD.  
• Rate of hospitalizations up to the EDBT period. 
• Mean number of hospital days for all-cause hospitalization. 
• Mean number of hospital days related to PH worsening.  
• Improvement in WHO FC from baseline up to EOS, by visit. 
• Change from baseline to Week 26 in actigraphy-assessed DLPA.  
• Change from baseline up to Week 39, by visit, in PAH-SYMPACT® scores (including 
cardiopulmonary symptoms domain, cardiovascular symptoms domain, physical 
impacts domain, and cognitive/emotional impacts domain). 
• Change from baseline up to EOS, by visit, in BDI/Borg CR10® collected immediately 
at the end of each individual 6MWT.  
• Change from baseline up to Week 52, by visit, in EQ-5D-5L. 
• Change from baseline up to Week 52, by visit, in WPAI©: GH scores. 
• Change from baseline to all regular collection timepoints up to the EDBT period in the 
CGI-S scores and in the CGI-C scores. 
• Change from baseline to Week 20 in other hemodynamic parameters (CO, CI and 
mRAP) measured at rest. 
• Change from baseline to Week 20 in the number of low-risk criteria, defined as 
WHO FC I or II, 6MWD ≥440 m, NT-proBNP <300 ng/L and CI ≥2.5 L/min/m2 
[Galiè 2016]. 
 
Further details regarding endpoint definitions and analyses will be presented in the SAP. 


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10.2.4 Safety variables  
• Treatment-emergent AEs up to 3 days after study treatment discontinuation at each 
analysis time point [see Section 5.1.6.1]. 
• Serious adverse events (SAEs) up to 30 days after study treatment discontinuation at 
each analysis time point [see Section 5.1.6.1]. 
• AEs leading to premature discontinuation of study treatment at each analysis time point 
[see Section 5.1.6.1]. 
• Change 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 at each analysis 
time point [see Section 5.1.6.1]. 
• Treatment-emergent marked laboratory abnormalities up to 3 days after study treatment 
discontinuation as detailed in Appendix 2 at each analysis time point [see 
Section 5.1.6.1]. 
• Treatment-emergent 
AEs 
of 
special 
interest 
(eg, 
hypotension, 
anemia, 
hyperthyroidism) up to 3 days after study treatment discontinuation at each analysis 
time point [see Section 5.1.6.1]. 
AE data: 
An AE is defined as any event that is recorded on the AE eCRF module, regardless of the 
onset date. An SAE is defined as any AE that is identified in the AE eCRF as serious. All 
coded AEs and SAEs will be considered as safety variables.  
Treatment-emergent AEs are those with onset date/time ≥ start date/time of study treatment 
and ≤3 days after study treatment discontinuation. 
Treatment-emergent AEs of special interest with onset date/time ≥ start date/time of study 
treatment and ≤3 days after study treatment discontinuation will also be tabulated.  
Laboratory data: 
Laboratory analyses are based on data received from the central laboratory. All transferred 
central laboratory data are considered regardless of whether they correspond to scheduled 
or unscheduled assessments. 
‘Baseline laboratory test’ refers to the latest laboratory test performed prior to the start of 
study treatment. Missing baseline values are imputed using the median of the 
corresponding baseline test from all subjects with non-missing baseline values. 
‘EOT laboratory test’ refers to the laboratory test performed at the EOT visit. If no 
laboratory data are available for the EOT visit, the results of the latest available 
post-baseline laboratory tests performed prior to EOT are used for the analysis. 


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Treatment-emergent marked laboratory abnormalities up to 3 days after last study 
treatment intake will be considered. 
10.3 Description of statistical analyses 
10.3.1 Overall testing strategy 
A graphical testing strategy [Bretz 2009] will be implemented, controlling the family-wise 
error rate (FWER) at a two-sided significance level of α = 5% for the primary and 
secondary efficacy endpoints [Figure 4]. 
Figure 4 
Testing strategy for primary and secondary endpoints (two-sided 
type I error rate, α = 5%) 
 
 


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6MWD = 6-minute walk distance; BDI = Borg dyspnea index; Borg CR10®= Borg category-ratio 10 Scale®; 
CHMP = Committee for Medicinal Products for Human Use; PAH-SYMPACT®= Pulmonary Arterial Hypertension 
Symptoms and Impact®; PH = pulmonary hypertension; PVR = pulmonary vascular resistance; TTCW = Time to clinical 
worsening; WHO FC = World Health Organization functional class. 
At analysis time point 1, the primary endpoint PVR will be tested in the HES at a full 
two-sided alpha of 5%. Failure to meet success on the primary endpoint will lead to 
termination of the study for futility, as no remaining alpha is available to formally test 
secondary endpoints.  
If the test of PVR is statistically significant at 5% alpha, then the study will continue, and 
the alpha will be split initially 50%:50% between 6MWD and TTCW following the 
weighted Bonferroni-Holm method [Holm 1979]. If the test of either 6MWD or TTCW is 
statistically significant at 2.5% alpha at any time point, then the other endpoint (TTCW or 
6MWD) can be re-tested at 5% alpha. Only when both 6MWD and TTCW reach statistical 
significance, can the tests of the remaining secondary efficacy endpoints in the hierarchy 
be formally performed at the respective significance level at analysis time point 4. The 
formal testing process will stop when a test is not statistically significant at the respective 
significance level. Success on a particular endpoint may only be claimed if all endpoints in 
the hierarchy above this particular endpoint resulted in success. 
There are four analysis time points during the DB treatment period. The applicability of 
analysis time points for the primary and secondary endpoints is summarized in Table 7. 


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Table 7 
Analysis time points of the primary and secondary efficacy endpoints 
during the double-blind treatment period 
Hierarchical 
order 
Endpoint 
Time point 1 
(90 subjects in 
HES 
completing 
20 weeks) 
Time point 
2 
(160 
subjects 
completing 
26 weeks) 
Time point 
3 
(All subjects 
completing 
26 weeks) 
Time point 
4 
(All subjects 
completing 
EDBT visit) 
1 
PVR at Week 20 
X 
 
 
 
2a 
6MWD at Week 26 
 
X 
X 
 
2b 
TTCW 
 
X 
X 
X 
3 
Time to death or 
PH-related 
hospitalization 
 
 
 
X 
4a 
Improvement in 
WHO FC at Week 
26 
 
 
 
X 
4b 
Change from 
baseline to Week 
26 in PAH-
SYMPACT® 
Cardiopulmonary 
Symptoms Domain 
 
 
 
X 
5 
Change from 
baseline to Week 
26 in PAH-
SYMPACT® 
Cardiovascular 
Symptoms Domain   
 
 
 
X 
6 
Change from 
baseline to Week 
26 in BDI or Borg 
CR10® 
 
 
 
X 
6MWD = 6-minute walk distance; BDI = Borg dyspnea index; Borg CR10® = Borg category-ratio 10 Scale®; 
DB = double-blind; EDBT = End-of-Double-Blind-Treatment; HES = Hemodynamic set; FC = Functional 
class; PAH-SYMPACT® = Pulmonary arterial hypertension symptoms and impact questionnaire; PH = 
pulmonary hypertension; PVR = pulmonary vascular resistance; TTCW = time to clinical worsening; 
WHO = World Health Organization.The “X” indicates the applicable analysis time point(s) for the primary 
and secondary endpoints. 
 


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For the repeated analysis of 6MWD at the two analysis timepoints, the Hwang, Shih and 
DeCani (HSD)’s error spending function with parameter 𝛾𝛾= −4 [Hwang 1990] will be 
applied [Section 10.4]. 
At the IA, the information fraction is the ratio of the number of subjects included in the IA 
to the target sample size 280 [Section 10.4]. 
For the repeated analysis of TTCW on the three analysis timepoints, the O'Brien and 
Fleming (OF) type error spending function [Lan 1983] will be applied [Section 10.4]. 
At each IA, the information fraction is the ratio of the number of events included in the IA 
to the target number of events 148 [Section 10.4]. 
The chance of both key secondary endpoints to be significant at an IA is considered to be 
low, therefore formal testing of all other secondary efficacy endpoints will be performed 
only at analysis time point 4, if applicable. 
Details on the statistical analysis are given in the SAP. Guidelines for premature study 
termination are defined in Section 10.4 and the IDMC charter. 
10.3.2 Analysis of the primary efficacy variable 
At analysis time point 1, the PVR endpoint will be tested on the HES at two-sided alpha of 
5%. Failure to meet success on the primary endpoint will lead to termination of the study 
for futility, as no remaining alpha is available to formally test secondary endpoints. 
10.3.2.1 Hypotheses and statistical model 
The hypotheses for the PVR endpoint are formulated in terms of geometric mean of percent 
of baseline PVR at Week 20 in subjects treated with selexipag versus placebo: 
Ho: GMselexipag = GMplacebo 
HA: GMselexipag ≠ GMplacebo 
where: 
GMselexipag and GMplacebo are the geometric means of percent of baseline PVR at Week 20 
for subjects treated with selexipag and placebo, respectively. 
The PVR endpoint will be tested by means of an analysis of covariance (ANCOVA) model 
on the loge transformed percent of baseline PVR at Week 20 (including imputed values). 
Model covariates will include randomized treatment, stratification factors (PH-specific 
therapies and CTEPH population) and the loge-transformed baseline PVR value. The 
resulting arithmetic mean and 95% CL of the natural logarithm of the ratio: PVR at 
Week 20 / PVR at baseline will be inversely transformed using the exponential function 


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and multiplied by 100 to provide the geometric mean of the ratio and corresponding 
95% CL, expressed as a percent, by treatment group. 
10.3.2.2 Handling of missing data 
Imputation methods for the primary endpoint, PVR at Week 20 expressed as percent of 
baseline PVR, will be specific to the reason for missing data. 
The baseline reference value for PVR is based on the last RHC (and LHC, if needed) 
performed prior to randomization, as defined in Section 7.2.3.1.1. 
If PVR cannot be calculated due to missing PAWP and LVEDP, the following conventions 
will be applied for the calculation at a visit at which both mPAP and CO are assessed: 
1. If PAWP and LVEDP are missing both at baseline and post-baseline, the missing 
PAWP is imputed using the median of all values observed at the respective time 
point in all subjects from the same randomized treatment group. 
2. If PAWP and LVEDP are missing either at baseline or at post-baseline, the 
available PAWP for the subject is used as a substitute for the missing PAWP. 
In the case of a missing PVR value at Week 20, the last available post-baseline value 
obtained before Week 20 is carried forward. It is assumed that this will mainly occur in 
subjects who have an unscheduled RHC (and LHC, if needed) performed at the time of a 
PH-related disease progression before Week 20. This imputation will be performed except 
in the following cases: 
• If a subject dies without a Week 20 value, then the Week 20 PVR is imputed using the 
largest percent deterioration of baseline PVR at Week 20 among all subjects in the 
same treatment group. 
• If the subject is alive and does not have a post-baseline value, the 50th percentile of the 
percent of baseline PVR at Week 20 from all subjects in the same treatment group will 
be used to impute the Week 20 PVR value. 
All observed values will be used to derive the imputed values. 
If available, the RHC (and LHC, if needed) at the time of progression / treatment 
discontinuation is used for the primary analysis.  
The main analysis will be carried out as described above on the HES. Absolute values at 
baseline and at Week 20 as well as absolute changes from baseline to Week 20 in PVR will 
be summarized using descriptive statistics for continuous variables. From the ANCOVA 
model, PVR at Week 20 expressed as a percent of baseline will be summarized by 
treatment group using covariate-adjusted geometric means and corresponding 95% two-
sided CL. The between-group ratio of geometric means with corresponding 95% two-sided 


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CL and p-value will be displayed for the placebo-corrected treatment effect. Additionally, 
the median percent change of the treatment effect and corresponding 95% CL will be 
displayed. 
10.3.2.3 Supportive/sensitivity analyses 
Sensitivity analyses will be conducted using alternative imputation rules on the primary 
endpoint data to assess the imputation assumptions of the main statistical analysis. These 
analyses will be outlined in the SAP. 
A sensitivity analysis on PPS1 will be carried out to assess the robustness of the results of 
the main statistical analysis against protocol deviations leading to exclusion from the PPS1.  
Further details will be included in the SAP.  
10.3.3 Analysis of secondary efficacy variable(s) 
Secondary efficacy variables and their analyses are described below, using analysis sets as 
specified in Table 6 and at analysis timepoints as specified in Table 7. All secondary 
efficacy variables will be sequentially tested in a graphical hierarchical approach 
[Bretz 2009] with alpha spent at different time points according to the specified error 
spending functions [as per Section 10.3.1]. The null hypothesis of a secondary efficacy 
endpoint is formally rejected if and only if the main analysis of that endpoint and all main 
analyses of preceding secondary efficacy endpoints result in rejection of the respective null 
hypotheses. This procedure preserves the family-wise type I error rate to the overall 
assigned two-sided alpha of 5% for the primary and secondary efficacy endpoints 
[Figure 4]. 
For each secondary endpoint, a repeated two-sided (1 −𝛼𝛼∗)% CL for treatment effect will 
be presented at each applicable analysis time point (where 𝛼𝛼∗ denotes the alpha level 
allocated to the respective endpoint). For the final analysis, the adjusted p-value, two-sided 
(1 −𝛼𝛼∗)% CL and the corresponding median unbiased estimate for the treatment effect 
will be presented. If formal testing is not allowed, the presented p-value will be for 
exploratory purposes only. 
• Change from baseline to Week 26 in 6MWD  
The hypotheses are formulated in terms of mean difference in the 6MWD change from 
baseline to Week 26 in subjects treated with selexipag versus placebo: 
H0: μselexipag = μplacebo 
HA: μselexipag ≠ μplacebo 
where: 


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μselexipag and μplacebo are the means in the change from baseline to Week 26 for subjects 
randomized to selexipag and placebo, respectively. The analysis will be an ANCOVA 
including treatment group, baseline 6MWD and all stratification factors as covariates. 
Least squares estimates for each treatment group (mean and 95% CL) and for the 
placebo-corrected treatment effect (means, (1 −𝛼𝛼∗)% CL, and the corresponding p-value) 
will be displayed. Depending on the results of the testing hierarchy specified in Figure 4, 
this endpoint will be tested at analysis time points 2 and 3 [see Table 7]. The allocated α* 
will be either 2.5% or 5%. 
• TTCW, where clinical worsening is defined (adapted from the CHMP definition 
[EMEA 2008]) as at least one of the following components confirmed by the CEC, 
when applicable: 
– All-cause death 
– Non-planned PH-related hospitalization 
– PH-related deterioration identified by at least one of the following: 
o Increase from baseline in WHO FC*; 
o Deterioration from baseline by at least 15% in exercise capacity, as 
measured by the 6MWD*; 
o New or worsening signs or symptoms of right heart failure, defined as a 
reported AE with one of the following preferred terms: “CTEPH”, 
“pulmonary hypertension”, “right ventricular failure”, “right ventricular 
dysfunction” and “acute right ventricular failure”. 
*Confirmed by a second measurement performed on a different day within 14 days. 
The TTCW will be calculated from the date of randomization to the date of onset of the 
first component event. The null hypothesis is that there is no difference between selexipag 
and placebo for the distribution of time to the first CHMP-defined clinical worsening event. 
A two-sided stratified (for the stratification factors) log-rank test will be applied and the 
resulting p-value will be presented. Kaplan-Meier estimates with 95% CL for the survival 
functions will be provided for each treatment group. The hazard ratio will be estimated 
with two-sided (1 −𝛼𝛼∗)% CL using a Cox model, including treatment group and all 
stratification factors as covariates. The frequency of each component event will also be 
presented. Depending on the results of the testing hierarchy specified in Figure 4, this 
endpoint will be tested at analysis time points 2, 3 and 4 [see Table 7]. The allocated α* 
will be either 2.5% or 5%. 
• All-cause death or hospitalizations related to PH worsening (confirmed by the CEC)  


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The main analysis will be performed for the time from randomization to the first event 
among all-cause death or hospitalizations related to PH worsening that is confirmed by the 
CEC. The null hypothesis is that there is no difference between selexipag and placebo for 
the distribution of time to the first event among all-cause death or hospitalizations related 
to PH worsening. A two-sided stratified (for the stratification factors) log-rank test will be 
applied and the resulting p-value will be presented. Kaplan-Meier estimates for the survival 
functions will be provided together with two-sided 95% CL for each treatment group. The 
hazard ratio will be estimated with two-sided 95% CL using a Cox model, including 
treatment group and all stratification factors as covariates. The frequency of each 
component event will also be presented. Depending on the results of the testing hierarchy 
specified in Figure 4, this endpoint will be tested at analysis time point4 [see Table 7]. 
A supportive analysis will be performed on the rate of all-cause death or hospitalizations 
related to PH worsening. The null hypothesis is that there is no difference between 
selexipag and placebo in the hospitalization rate per 100-subject years, calculated by 
dividing the total number of all-cause death or hospitalizations related to PH worsening by 
the cumulative exposure of all subjects in each treatment arm. A negative-binomial 
regression model including treatment group and all stratification factors as covariates and 
with over-dispersion will be used to analyze the data. The different durations of follow-up 
time across subjects will be considered in the offset variable. This distribution assumes that 
each subject has recurrent hospitalizations related to PH worsening / death according to an 
individual-specific Poisson event rate, and that the Poisson rates vary according to a 
gamma distribution. The adjusted rate ratio, two-sided 95% CL and p-value will be 
provided. Depending on the results of the testing hierarchy specified in Figure 4, this 
endpoint may be tested at the same time as the main analysis time point (analysis time 
point 4). 
• Improvement in WHO FC at Week 26 
Improvement from baseline to Week 26 in WHO FC is defined as decrease in FC as 
compared to WHO FC at baseline. Subjects in FC I at baseline are excluded from the 
analysis as, by definition, their FC cannot be improved.The null hypothesis of same 
probabilities for improvement for selexipag and placebo will be tested by a Cochran-
Mantel-Haenszel test adjusted by WHO FC at baseline, treatment and stratification factors. 
The common odds ratio with 95% CL will be estimated, provided there is no clear evidence 
against a common odds ratio across the strata (evaluated by the Breslow-Day test). 
Depending on the results of the testing hierarchy specified in Figure 4, this endpoint will 
be tested at analysis time point 4 [see Table 7] with total two-sided significance level 𝛼𝛼∗= 
3% or 5%. The point estimate with two-sided (1 −𝛼𝛼∗)% CL and p-value for the treatment 
effect will be presented.  


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• Change from baseline to Week 26 in PAH-SYMPACT® cardiopulmonary symptoms 
domain and cardiovascular symptoms domain 
Absolute change from baseline to Week 26 in each of the PAH-SYMPACT® symptoms 
domain scores is defined as: 
(Score at Week 26 − Score at baseline) 
For each score, the null hypothesis is that there is no difference between selexipag and 
placebo in the mean change from baseline to Week 26. The change from baseline to Week 
26 in each PAH-SYMPACT® score will be analyzed by means of an ANCOVA model and 
will include treatment, baseline score value and stratification factors as covariates. Least 
squares estimates for each treatment group will be displayed with means and 95% CL. 
Responder analyses will also be implemented on PAH-SYMPACT® scores and will be 
defined in the SAP. Depending on the results of the testing hierarchy specified Figure 4, 
each score may be tested at analysis time point 4 [see Table 7] with total two-sided 
significance level 𝛼𝛼∗= 2% or 5%. The mean with two-sided (1 −𝛼𝛼∗)% CL and p-value 
for the treatment effect will be presented. 
• Change from baseline to Week 26 in BDI/Borg CR10® 
Absolute change from baseline to Week 26 in BDI/Borg CR10® is defined as: 
BDI/Borg CR10® at Week 26 − BDI/Borg CR10® at baseline. 
The null hypothesis is that there is no difference between selexipag and placebo in the 
mean change from baseline to Week 26. The changes will be analyzed by means of an 
ANCOVA model and will include treatment, baseline index value and stratification factors 
as covariates. Least squares estimates for each treatment group will be displayed with 
means and 95% CL. Depending on the results of the testing hierarchy specified Figure 4, 
this endpoint may be tested at analysis time point 4 [see Table 7] with total two-sided 
significance level 𝛼𝛼∗= 2% or 5%. The mean with two-sided (1 −𝛼𝛼∗)% CL and p-value 
for the treatment effect will be presented. 
10.3.3.1 Handling of missing data 
For the key secondary efficacy endpoint 6MWD, the following rules will be applied.  
The Week 26 value is the one identified for the Week 26 analysis time window, as defined 
in detail in the SAP. The handling of missing data will be detailed in the SAP, which will 
be finalized before analysis time point 1. Imputation will be carried out as follows:  
For subjects without any 6MWD available at Week 26, the following main imputation 
algorithm is applied: 


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• Rule 1: For subjects unable to walk at Week 26, a zero (0) is imputed for 6MWD at 
Week 26. Note: For subjects unable to walk due to clinical worsening at scheduled 
visits, 0 m is entered in the eCRF. This includes:  
– subjects who died without any visit performed in the Week 26 analysis time 
window (see SAP); and 
– subjects for whom the Week 26 visit corresponds to an unscheduled visit and were 
unable to walk for PH-related reasons (ie, the reason is coded as ‘clinical 
worsening’). 
• Rule 2 (if Rule 1 does not apply): the second-lowest observed 6MWD value at Week 26 
in the same analysis set (FAS), according to treatment group, is imputed. 
Concerning the other key secondary endpoint TTCW, for subjects who have not 
experienced any event by the respective analysis cut-off date, their time will be right 
censored at the earliest date of the following: EDBT visit, the last PTOP visit, last contact, 
or analysis cut-off. 
Additional sensitivity analyses may be described in the SAP, as well as imputations for 
other secondary variables. 
10.3.4 Analysis of the safety variable(s) 
10.3.4.1 Adverse events, serious adverse events, deaths and premature discontinuation 
of study treatment 
All AEs and SAEs are coded using the latest available version of the Medical Dictionary 
for Regulatory Activities (MedDRA). 
Individual subject listings of all collected AEs will be provided by treatment group. The 
frequency and the crude incidence of subjects who experienced treatment-emergent AEs 
until 3 days after last study treatment intake will be tabulated by system organ class (SOC), 
individual preferred terms within each SOC and by treatment group (in descending order 
according to the incidence in the investigational study treatment group). 
Treatment-emergent AEs occurring up to 3 days after last study treatment intake will also 
be tabulated by severity and by relationship to study treatment and for selected subgroups, 
eg, gender and age (18–65 years, older than 65 years). 
AEs leading to permanent discontinuation of study treatment will be listed and summarized 
similarly to AEs.  
SAEs occurring up to 30 days after last study treatment intake will be listed and 
summarized similarly to AEs, separately for treatment-emergent SAEs and SAEs occurring 


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before study treatment initiation (only those related to study-mandated procedures) and 
after EOS. 
Reasons for treatment-emergent deaths occurring up to 3 days after last study treatment 
intake will be listed and summarized similarly to AEs. Deaths occurring before study 
treatment initiation (only those related to study-mandated procedures) or more than 3 days 
after last study treatment intake will be listed separately by treatment group. 
Reasons for premature discontinuation of study treatment will be listed and summarized 
by frequency tables. Individual subject listings will be provided by treatment group. 
Discontinuations will be tabulated overall and for the first 6 and 12 months of DB 
treatment. 
10.3.4.2 Laboratory parameters 
The frequency of subjects who experienced treatment-emergent marked laboratory 
abnormalities up to 3 days after study treatment discontinuation will be tabulated for each 
laboratory parameter by treatment group at each analysis time point. 
Values of numeric laboratory parameters will be transformed to respective standard units 
for summary statistics (mean, median, standard deviation [SD], first and third quartiles, 
minimum and maximum) tabulated by treatment group for both the absolute values and the 
changes from baseline. 
Individual subject listings will be provided by treatment group. 
The sponsor’s internal guidelines will be used for definition of marked laboratory 
abnormalities and for the standardization of numeric values obtained from different 
laboratory and/or using different normal ranges. 
10.3.4.3 Vital signs and body weight 
Vital signs (blood pressure and HR) and body weight will be summarized by tabulating 
mean, median, SD, first and third quartiles, minimum and maximum by treatment group 
for both the absolute values and the changes from baseline. 
Individual subject listings will be provided by treatment group. 
10.3.5 Subgroup analyses 
Subgroup analyses will be conducted to assess consistency of results on the primary 
endpoint (according to the ANCOVA method described in Section 10.3.2) and selected 
secondary endpoints, based on the following baseline characteristics: 
• Stratification factor 1: PH-specific therapies (one versus two versus naive) 


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• Stratification factor 2: CTEPH population (inoperable [with or without BPA] versus 
persistent/recurrent after PEA [including PEA followed by BPA]) 
• Participation in the hemodynamic cohort 
• Gender 
• Race (as defined in the SAP) 
• Geographic region (as defined in the SAP) 
An additional analysis of the primary and selected secondary endpoints will be conducted 
by dose group (low [200–400 µg bid], medium [600, 800 and 1000 µg bid] and high [1200, 
1400 and 1600 µg bid]). 
10.4 Interim analysis 
As specified in Section 5.1.6.1, there are three IA time points during the DB treatment 
period.  
At analysis time point 1, the analysis of the primary efficacy endpoint PVR will be 
conducted on the HES. If the analysis of PVR is statistically significant, the study will 
proceed as planned; otherwise, the study will be terminated. The IDMC will review the 
results and make corresponding recommendations in line with the IDMC charter. The 
independent SSG will make unblinded results available to the IDMC.  
At analysis time point 2, unblinded interim analyses for 6MWD and TTCW will be 
conducted on the FAS. If both 6MWD and TTCW are futile, then the study will be 
terminated prematurely. If at least one of 6MWD and TTCW is statistically significant, the 
study will be terminated due to overwhelming efficacy and subject recruitment will be 
stopped, but subjects already enrolled will remain on DB treatment as planned until all 
subjects have completed Week 26 assessments or prematurely discontinued from the study. 
Otherwise, the study will proceed as planned. The IDMC will review the results and make 
corresponding recommendations in line with the IDMC charter. The independent SSG will 
make unblinded results available to the IDMC. 
At analysis time point 3, an unblinded final analysis for 6MWD and an unblinded IA for 
TTCW will be conducted on the FAS. If 6MWD is not statistically significant and TTCW 
is futile, then the study will be terminated prematurely. If at least one of 6MWD and TTCW 
is statistically significant, the study will be terminated due to overwhelming efficacy. 
Otherwise, the study will proceed as planned. The IDMC will review the results and make 
corresponding recommendations in line with the IDMC charter. The independent SSG will 
make unblinded results available to the IDMC. 
For 6MWD, the HSD error spending function with parameter γ = −4 [Hwang 1990] will 
be implemented to control the overall allocated two-sided significance level, 𝛼𝛼. With 


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information fraction (IF) at Stage 𝑖𝑖, for 𝑖𝑖= 1, 2, based on number of subjects at that stage,  
𝑛𝑛𝑖𝑖, relative to the total sample size 𝑛𝑛2 = 280, i.e. 𝑡𝑡𝑖𝑖= 𝑛𝑛𝑖𝑖/𝑛𝑛2, the HSD(-4) error spending 
function is: 
𝛼𝛼𝐻𝐻𝐻𝐻𝐻𝐻(𝑡𝑡𝑖𝑖) = 𝛼𝛼 1 −e−𝛾𝛾𝑡𝑡𝑖𝑖
1 −𝑒𝑒−𝛾𝛾= 𝛼𝛼 1 −e4𝑡𝑡𝑖𝑖
1 −e4     
For TTCW, the overall allocated two-sided significance level, 𝛼𝛼 for analyses at different 
analysis timepoints will be spent according to the OF-type error spending function 
[Lan 1983]. With IF at Stage 𝑖𝑖, for 𝑖𝑖= 1, 2, 3, based on the number of observed events at 
that stage, 𝑑𝑑𝑖𝑖, relative to the total number of required events, i.e. 𝑡𝑡𝑖𝑖= 𝑑𝑑𝑖𝑖/𝑑𝑑3, the OF-like 
error spending function is: 
𝛼𝛼𝑂𝑂𝑂𝑂(𝑡𝑡𝑖𝑖) = 4 ቈ1 −Φ ቆ𝑧𝑧1−𝛼𝛼/4
ඥ𝑡𝑡𝑖𝑖
ቇ቉ 
where 𝑑𝑑3 = 148, Φ is the standard normal cumulative density function and 𝑧𝑧𝑥𝑥 is the xth 
quantile of the standard normal distribution. 
The end of DB period could occur and will be announced at different time points due to 
the following reasons: 
Timepoint 
Reason 
1 
Interim stop for futility due to failure of PVR  
2 
Interim stop for futility of both 6MWD and TTCW  
Interim stop (accrual) for efficacy if at least one of 6MWD and TTCW is 
successful  
3 
Interim stop for failure of 6MWD and futility of TTCW 
Interim stop for efficacy if at least one of 6MWD and TTCW is successful  
The required 148 clinical worsening events have been observed  
4 
The required 148 clinical worsening events have been observed 
Throughout 
the study 
IDMC recommendation 
Sponsor’s decision  
 
Detailed guidelines for interim decision-making are further described in the IDMC 
charter. Figure 5 describes the decision-making flow.  


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Figure 5 
Flow of decision-making. 
 
 
 
6MWD = 6-minute walk distance; DB = double-blind; PVR = pulmonary vascular resistance; TTCW = time to clinical 
worsening. 
For secondary endpoints other than 6MWD and TTCW, formal testing will be performed 
only at analysis time point 4, if applicable and the two-sided significance level, 𝛼𝛼 will be 
spent according to Figure 4. 
If the study is stopped early at an interim time point, a supportive DB wrap-up analysis 
will be performed using all available data collected up to the EDBT visit. 
10.5 Double-blind and open-label analyses 
If the study is not stopped early for futility or efficacy at analysis time points 1, 2, or 3, the 
study will continue and blinding will be maintained until all subjects have completed DB 
treatment. Once all subjects complete DB treatment, they are enrolled in the OL period of 
the study and offered OL selexipag. At the final DB analysis (analysis time point 4), all 
secondary endpoints will be evaluated and reported in full in a DB Clinical Study Report 
(CSR). The analyses will be carried out on the analysis sets as defined in Section 10.1.  
At the final study analysis (analysis time point 5), the data from all subjects enrolled in the 
OL extension period will be summarized and reported. Additionally, selected analyses will 
be carried out on the SIS, as defined in the SAP. 
10.6 Sample size 
The study will consist of two cohorts: approximately the first 90 subjects will be 
randomized in the hemodynamic cohort, targeting the primary endpoint of PVR. The 
remaining subjects will be randomized to enrich information on all secondary endpoints. 


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If subject enrollment is not terminated for efficacy or futility at analysis time points 1 or 2, 
the total sample size would be 280 subjects. 
10.6.1 PVR 
The estimates of treatment effect in PVR are obtained from three selexipag studies 
conducted in PAH (NS-304/-02 and TRITON [ongoing]) and CTEPH (AC-065B201) 
subjects, as well as in three other studies with different therapies in CTEPH [Table 8]. The 
NS-304/-02 study (N = 35 in PPS) confirmed a statistically significant treatment effect of 
selexipag versus placebo (30.3% geometric mean decrease, 95% CL: −44.7%, −12.2%; 
p = 0.0045) in PVR at Week 17 as primary endpoint. The AC-065B201 study (N = 28, 
PPS) showed a non-statistically significant 16.3% (95% CL: −34.7, +7.3) decrease from 
baseline in PVR in the selexipag group relative to placebo at Week 17. The IA of the 
ongoing study TRITON (AC-065A308) in PAH reveals an estimated coefficient of 
variation (CV) of 50% (blinded pooled estimate), which is larger than the values reported 
in other studies. 


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Table 8 
Estimates of treatment effect in PVR 
 
AC-065B201 
AC-065B201 
subset* 
NS-304/-02 
TRITON 
Indication 
CTEPH 
CTEPH 
PAH 
PAH 
PH-background 
therapy 
ERA, PDE5i 
ERA, PDE5i 
ERA, PDE5i 
ERA 
(macitentan) + 
PDE5i 
(tadalafil) 
Investigational drug 
Selexipag 
Selexipag 
Selexipag 
Selexipag 
Assessment time 
17 weeks 
17 weeks 
17 weeks 
26 weeks 
N (active: placebo) 
PPS 
Active: 21 
Placebo: 7 
Active: 11 
PPS 
Active: 29 
Placebo: 6 
238 (1:1) 
Enrollment 
ongoing 
CV 
Active: 29.3% 
Placebo: 24.3% 
 
 
50% (interim 
pooled estimate 
in 79 patients) 
Change from baseline 
± SD (dyn.sec/cm5) 
Active: −104 ± 191 
Placebo: +26 ± 180 
Active: −140 
Active: −168 ± 
241.6 
Placebo: +137.2 ± 
84.9 
 
% change from 
baseline 
Active: −13.4% 
Placebo: +2.1% 
 
Active: −19.3% 
Placebo: +15.9% 
 
Placebo-adjusted effect 
from baseline & 95% 
CL 
Ratio: 
−16.3%  
(−34.7%, 7.3%) 
Not applicable 
Ratio: 
−30.3% 
(−44.7%, −12.2%) 
 
 
 
 
 
 
 
CHEST-1 
MERIT-1 
BENEFIT 
 
Indication 
CTEPH 
CTEPH 
CTEPH 
 
PH-background 
therapy 
None 
PDE5i, oral/inh. 
Prostanoids 
None 
 
Investigational drug 
Riociguat 
Macitentan 
Bosentan 
 
Assessment time 
16 weeks 
16 weeks 
16 weeks 
 
N (active: placebo) 
261 (2:1) 
80 (1:1) 
157 (1:1) 
 
CV 
 
39.4% (mean) 
Active: 38.4% 
Placebo: 31.1% 
 
Change from baseline 
± SD (dyn.sec/cm5) 
Active: −226 ± 248 
Placebo: 23 ± 274 
Active: −206 ± 450.4 
Placebo: −85.8 ± 301.5 
 
 
% change from 
baseline 
Active: −28.6% 
Placebo: +3% 
 
Active: -22.5% 
Placebo: +2.2% 
 
Placebo-adjusted effect 
(difference) & 95% CL 
from baseline  
Ratio: −31.5% 
(approx.) 
Difference 
(dyn.sec/cm5): −246 
(−303, −190) 
Ratio: 
−16% 
(−30%, −1%) 
Ratio: 
−24.1% 
(−31.5%, −16.0%) 
 
CL = confidence limits; CTEPH = Chronic thromboembolic pulmonary hypertension; CV = coefficient of variation; 
ERA = endothelin receptor antagonist; PAH = pulmonary arterial hypertension; PDE5i = phosphodiesterase 5 inhibitor; 
PH = pulmonary hypertension; PPS = Per-protocol Analysis Set; SD = standard deviation.  
* Subjects with ≥3 prostacyclin-associated adverse events in the selexipag group. 
 


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Although the main analysis of PVR at Week 20 will be conducted using an ANCOVA 
model, calculations of sample sizes were approximated by t-test for superiority on the 
log-transformed PVR percent of baseline value at Week 20 using the software package 
EAST™ version 6.4.0.1 for ratio of means. A sample size of 90 subjects in the HES will 
provide a power of >90% for the treatment effect of a 30% relative improvement in 
geometric mean as compared to placebo with a CV of 35–50% and a two-sided significance 
level of 5% [Table 9]. 
Table 9 
Sample sizes for PVR under different scenarios with two-sided 5% type I 
error rate and 90% power using t-test for ratio of means 
Relative improvement over 
placebo in geomean 
CV 
35% 
40% 
45% 
50% 
20% 
100 
128 
158 
191 
25% 
61 
78 
96 
116 
30% 
41 
52 
63 
76 
35% 
29 
36 
44 
53 
CV = coefficient of variation. 
10.6.2 6MWD 
The estimates of treatment effect in 6MWD change from baseline in four CTEPH studies 
are summarized in Table 10. 


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Table 10 
Estimates of treatment effect in 6MWD  
 
CHEST-1 
(Riociguat) 
MERIT -1 
(Macitentan) 
AC-065B201 
(Selexipag) 
AC-065B201 
subset* 
(Selexipag) 
BENEFIT 
(Bosentan) 
Assessment 
time 
16 weeks 
24 weeks 
17 weeks 
17 weeks 
16 weeks 
Change from 
baseline: 
Active (mean 
± SD) 
39 ± 79 
35 ± 52 
 
19 ± 55 
24.7 
2.9  
(95% CL: 
−12.9, 18.8) 
Change from 
baseline: 
Placebo 
(mean ± SD) 
−6 ± 84 
1 ± 83 
27 ± 49 
NA 
0.8  
(95% CL: 
−18.1, 19.7) 
placebo-
adjusted 
change from 
baseline  
(mean,  
95% CL) 
46  
(25, 67) 
 
34 
(3, 65) 
 
  
 
−9 
(−57, 39) 
  
 
NA 
2.2  
(−22.5, 26.8) 
  
 
6MWD = 6-minute walk distance; CL = confidence limits; SD = standard deviation. 
* Subjects with ≥3 prostacyclin-associated adverse events in the selexipag group. 
Although the main analysis of 6MWD at Week 26 will be conducted using an ANCOVA 
model, calculations of power were approximated by t-test for superiority on the change in 
6MWD from baseline value at Week 26 using the software package EAST™ version 6.5 
for difference of means.  
To have an adequate power for TTCW, the sample size is determined by the need for 
TTCW (see below). With a sample size of 280 subjects and using the HSD error spending 
function with parameter γ=−4 [Hwang 1990] for one interim analysis of 6MWD at 
information fraction 160/280, the power will be 90% for the treatment effect of 34 m with 
a standard deviation of 80 m at two-sided alpha level 2.5%. 
 


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10.6.3 Time to clinical worsening (according to the CHMP definition) 
This type of endpoint was evaluated in PAH subjects in the GRIPHON study [D-13.361], 
with a selexipag versus placebo hazard ratio of 0.73 (99% CL 0.60 – 0.91) for TTCW 
according to CHMP definition and a hazard ratio of 0.60 (99% CL 0.46–0.78) for specific 
morbidity and mortality events.  
For this study, the assumptions for sample size of TTCW are a hazard ratio of 0.60, a no-
event rate of 0.70 at 12 months in the placebo arm, a two-sided type I error of 2.5% and a 
power of 80%. Using the software package EAST™ version 6.5 for log-rank test, this 
setting requires a total of 148 events with two interim analyses using the OF-type error 
spending 
function 
[Lan 1983]. 
With 
piecewise 
uniform 
accrual 
rates 
of 
3.313 subjects/month in the first 16 months and 9.125 subjects/month in the remaining 
time, the sample size of 280 subjects will be reached in about 41 months. The required 
number of events is expected to be observed 17 months after the randomization of the last 
subject. The estimated duration from the first subject randomized to the time when 
148 events are observed plus the time to the EDBT visit is about 59 months. The actual 
duration depends on the actual accrual rate, the actual clinical worsening event rate, 
recommendation of the IDMC at interim analyses [see Section 10.4, Figure 5 and IDMC 
Charter Section 8 and Appendix 6] and regular safety monitoring meetings, and sponsor’s 
decision [Section 8.3]. 
10.6.4 Design operating characteristics 
The set-up and results of simulations to evaluate design operating characteristics under the 
null and alternative hypotheses are presented in the IDMC charter. 
11 DATA HANDLING  
11.1 Data collection 
The investigator/delegate is responsible for ensuring the accuracy, completeness and 
timely entry of the data reported. All source documents should be completed in a neat, 
legible manner to ensure accurate interpretation of the data. Data reported in the eCRF 
derived from source documents must be consistent with the source documents. 
eCRF data will be captured via electronic data capture (using the Rave system provided by 
Medidata Solutions, Inc., a web-based tool). The investigator and site personnel will be 
trained to enter and edit the data via a secure network, with secure access features 
(username, password and identification – an electronic password system). A complete 
electronic audit trail will be maintained. The investigator/delegate will approve the data 
(ie, confirm the accuracy of the data recorded) using an electronic signature (ref. to US 21 
CFR Part 11). 


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Entries recorded by the subject in the PROs (PAH-SYMPACT®, EQ-5D-5L, WPAI©: GH) 
[electronic format], submitted to the central image processing center and recorded via the 
actigraphy device are considered source data.  
Subject screening and enrollment data will be completed for all subjects (ie, eligible and 
non-eligible) through the IRT system and eCRF. 
For each subject enrolled, regardless of study treatment initiation, an eCRF must be 
completed and signed by the investigator/delegate. This also applies to those subjects who 
fail to complete the study. If a subject withdraws from the study, the reason must be 
recorded in the eCRF. 
11.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On eCRFs or 
other documents (eg, documents attached to SAE forms / Pregnancy Notification form) 
submitted to the sponsor and any CROs, subjects must be identified only by number and 
never by their name or initials, date of birth, hospital numbers or any other identifier. 
Subject identifiers might be submitted to the central image processing center. In that case, 
the central image processing center is contracted by the sponsor to anonymize data before 
submission to ACs [see Section 4.1.1]. The investigator/delegate must keep a subject 
identification code list at the site, showing the screening/randomization number, the 
subject’s name, date of birth and address or any other locally accepted identifiers. 
Documents identifying the subjects (eg, signed ICFs) must not be sent to the sponsor, and 
must be kept in strict confidence by the investigator/delegate. 
11.3 Database management and quality control 
The investigators and site personnel will have access to the site eCRF data until the 
database is closed. Thereafter, they will have read-only access. The eCRF must be kept 
current to reflect subject status at any time point during the course of the study. 
While entering the data, the investigator/delegate may be instantly alerted to data queries 
by validated programmed checks. Additional data review (including medical review) will 
be performed by sponsor personnel on an ongoing basis to look for discrepancies and 
unexpected patterns in data and to monitor the study. If discrepant data are detected or 
clarification is required, a query specifying the problem or question will be issued and 
visible to the investigator/delegate via the eCRF. All electronic queries visible in the 
system either require data correction (when applicable) and a response from the 
investigator/delegate to clarify the queried data directly in the eCRF, or simply a data 
correction in the eCRF. The investigator/delegate must, on request, supply the sponsor with 
any required background data from the study documentation or clinical records. This is 
particularly important when errors in data transcription are suspected. In the case of health 


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authority queries, it is also necessary to have access to the complete study records, provided 
that subject confidentiality is protected. 
This process will continue until database closure. 
Laboratory samples will be processed through the central laboratory and the results will be 
electronically sent to the sponsor. 
NT-proBNP samples will be processed through the central laboratory and the results will 
be sent to the sponsor electronically.  
Data collected by the vendors of the ePRO and actigraphy device, the imaging vendor and 
the IRT vendor are owned by Actelion Pharmaceuticals Ltd. The data will be sent to the 
sponsor electronically.  
AEs and procedures are coded according to the latest MedDRA used by the sponsor. 
After the database has been declared complete and accurate, the database will be closed. 
Any changes to the database after that time may only be made as described in the sponsor’s 
appropriate QS documents. After database closure, the investigator will receive the eCRFs 
of the subjects of his/her site (including all data changes made) on electronic media. 
12 PROCEDURES AND GOOD CLINICAL PRACTICE  
12.1 Ethics and Good Clinical Practice 
Sponsor personnel and the investigators will ensure that the study is conducted in full 
compliance with ICH-GCP guidelines, the principles of the Declaration of Helsinki, and 
with the laws and regulations of the country in which the study is conducted. 
12.2 Independent Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document(s) provided to the 
subject (such as the ICF) to an IEC/IRB. Approval from the committee/board must be 
obtained before starting the study, and must be documented in a dated letter to the 
investigator, clearly identifying the study, the documents reviewed and the date of 
approval. 
Modifications made to the protocol or the ICF after receipt of the approval must also be 
submitted as amendments by the investigator to the IEC/IRB, in accordance with local 
procedures and regulations [see Section 12.6]. 
A list of members participating in the IEC/IRB meetings must be provided, including the 
names, qualifications and functions of these members. If that is not possible, the attempts 


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made to obtain this information along with an explanation as to why it cannot be obtained 
or disclosed must be documented in the study documentation.  
If a member of the study personnel was present during an IEC/IRB meeting, it must be 
clear that this person did not vote. 
12.3 Informed consent 
It is the responsibility of the investigator/delegate to obtain informed consent, according to 
ICH-GCP and Declaration of Helsinki guidelines and local regulations, from each 
individual participating in this study and/or their legally designated representative. The 
investigator/delegate must explain to subjects 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 subject populations and of individual subjects, as well as to the methods used 
to give the information. Adequate time shall be given for the subject and/or their legally 
designated representative to consider his/her decision to participate in the study, and it shall 
be verified that the subject has understood the information (eg, by asking the subject to 
explain what is going to happen). 
Two study-specific ICFs will be provided: one for the hemodynamic cohort (approximately 
the first 90 randomized subjects) and one for the non-hemodynamic cohort. The ICFs will 
be provided in the country local language(s). 
Site personnel (according to local regulations) authorized to participate in the consent 
process and/or to obtain consent from the subject and/or their legally designated 
representative will be listed on the Delegation of Authority form supplied by the sponsor. 
A study physician must always be involved in the consent process. 
The subject and/or legally designated representative and authorized site personnel listed on 
the Delegation of Authority form supplied by the sponsor must sign, personally date and 
time (if the first study-mandated procedure is to be performed on the same day informed 
consent is obtained) the ICF before any study-related procedures (ie, any procedures 
required by the protocol) begin.  
A copy of the signed and dated ICF is given to the subject and/or their legally designated 
representative; the original is filed in the site documentation. The informed consent process 
must be fully documented in the subject’s medical records. This must include at a minimum 
the study reference, the subject number, the date and, if applicable, time when the subject 
was first introduced to the study, the date and, if applicable, time of consent, who 
participated in the consent discussion, who consented the subject, and any additional 
person present during the consent process (eg, subject’s family member[s]), and the 


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information that a copy of the signed ICF was given to the subject / their legally designated 
representative. 
If the site intends to recruit subjects who are considered as vulnerable (eg, subject cannot 
read or write, does not speak or understand the ICF language), additional measures must 
be implemented in order to ensure subject’s rights are respected and the consent obtained 
is legally valid. The sponsor, the regulatory authorities (if applicable), and the IEC/IRB 
must be informed prior to the recruitment. The consent process (eg, involvement of an 
impartial witness) must be fully described, submitted to, and approved by the IEC/IRB, 
according to procedures and before subjects are recruited. 
Subjects who are rescreened are required to sign a new ICF. By signing the ICF, the subject 
or legally designated representative is authorizing the collection of information about his 
or her survival status [see Section 7.2.3.9]. 
12.4 Indemnification, compensation and refund of expenses to subjects and 
investigators 
The sponsor provides insurance in order to indemnify (with both legal and financial 
coverage) the investigator/site against claims arising from the study, except for claims that 
arise from malpractice and/or negligence. 
The indemnification of the subject in the event of study-related injuries will comply with 
applicable regulations. 
Study subjects will be reimbursed for the study-related expenses (eg, travel costs, meals, 
hotel) and may be offered financial compensation for their participation in the study only 
to the extent permitted by applicable local regulations. 
12.5 Protocol adherence/compliance 
The investigator must conduct the study in compliance with the IEC/IRB and/or the 
regulatory authority-approved version of the protocol and must not implement any 
deviation/change from the protocol, except when deviation is necessary to eliminate an 
immediate hazard to the subject. 
If a protocol deviation occurs, the investigator/delegate will inform the sponsor or its 
representative in a timely manner. The investigator/delegate must document and explain 
any deviation from the approved protocol. Deviations considered to be a violation of 
ICH-GCP must be reported to the IEC/IRB and regulatory authorities according to the 
sponsor or (overruling) local requirements. 


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All important protocol deviations will be reported in the CSR. IECs/IRBs will be provided 
with listings of protocol deviations as per local requirements. 
12.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. An 
amended protocol must be submitted to the IEC/IRB and regulatory authorities, according 
to their requirements. 
12.7 Essential documents and retention of documents 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all 
CRF and all source documents that support the data collected from each participant, as well 
as all study documents as specified in ICH/GCP Section 8, Essential Documents for the 
Conduct of a Clinical Trial, and all study documents as specified by the applicable 
regulatory requirement(s). The investigator/institution will take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents must be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These 
documents will be retained for a longer period if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be 
retained. 
If the investigator cannot guarantee this archiving requirement at the site for any or all of 
the documents, special arrangements, respecting the data confidentiality, must be made 
between the investigator and the sponsor to store these documents outside the site, so that 
they can be retrieved in case of a regulatory inspection. No study document should be 
destroyed without prior written approval from the sponsor. Should the investigator wish to 
assign the study records to another party, or move them to another location, the sponsor 
must be notified in advance. 
If the site is using an electronic/computerized system to store subject medical records, it 
can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 or 
equivalent standard) and if the SM has been provided personal and restricted access to 
study subjects only, to verify consistency between electronic source data and the eCRF 
during monitoring visits. 
If the site is using an electronic/computerized system to store subject medical records but 
it could not be confirmed that the system is validated or if the SM could not be provided 


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access to the system, the site is requested to print the complete set of source data needed 
for verification by the SM. The printouts must be numbered, stapled together with a 
coversheet, signed and dated by the investigator/delegate to confirm that these certified 
copies are exact copies with 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 
subject’s medical records or with the subject’s eCRF. 
In order to verify that the process the site uses to prepare certified copies is reliable, the 
SM must be able to observe this process and confirm that the comparison of the source 
documents and the certified copy did not reveal inconsistencies. The SM does not need to 
verify this process for all data of all subjects, but at least for some of them (eg, first subject; 
regular check during the study of critical data like inclusion/exclusion criteria, endpoints 
for some subjects), as per the sponsor’s instructions. If it were not possible for the SM to 
observe this process, it would not be possible to rely on the site’s certified copies and 
therefore the site cannot be selected for the clinical study. 
12.8 Monitoring 
Prior to study start, a site initiation visit (SIV) will be performed after the required essential 
study documents are approved by the sponsor. Essential documents must be provided to 
the sponsor before shipment of study treatment to the study site. 
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 subjects. 
Following the SIV, a copy of the completed initiation visit report and follow-up letter will 
be provided to the PI and filed in the ISF. 
During the study, the SM will remotely contact and visit the site regularly and must be 
permitted, on request, to have access to study facilities and all source documents needed to 
verify adherence to the protocol and the completeness, consistency and accuracy of the 
data being entered in the CRFs and other protocol-related documents. The sponsor’s 
monitoring standards require full verification that informed consent has been provided, 
verification of adherence to the inclusion/exclusion criteria, documentation of SAEs and 
the recording of the main efficacy, safety and tolerability endpoints. Additional checks of 
the consistency of the source data with the CRFs will be performed according to the 
study-specific monitoring guidelines. The frequency of the monitoring visits will be based 
on subject recruitment rate and critical data collection times. 


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The PI must ensure that the eCRF is completed after a subject’s visit (site visit or telephone 
call), and that all requested subject files (eg, ICFs, medical notes/charts, other 
documentation verifying the activities conducted for the study) are available for review by 
the SM. The required site personnel must be available during monitoring visits and allow 
adequate time to meet with the SM to discuss study-related issues. 
The investigator agrees to cooperate with the SM(s) to ensure that any issues detected in 
the course of these monitoring visits are resolved. If the subject is hospitalized or dies in a 
hospital other than the study site, the investigator is responsible for contacting that hospital 
in order to document the SAE, in accordance with local regulations. 
A close-out visit will be performed for any initiated site when there are no more active 
subjects and all follow-up issues have been resolved. If a site does not enroll any subjects, 
the close-out visit may be performed prior to study database closure at the discretion of the 
sponsor. 
12.9 Investigator Site File 
Each site will be provided with an ISF prior to the SIV. It will contain all the essential 
documents that are required to be up-to-date and filed at site as per ICH-GCP section 8. 
The ISF will include a table of contents listing the essential documents. All study-related 
documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the SM regarding the filing of the study 
documents outside the ISF. It should be clearly documented where each document is filed. 
This note-to-file should be present in the specific tab of the document in the ISF. 
The ISF must be stored in a secure and access-restricted area during and after the study. It 
must be kept by the site for as long as needed to comply with any applicable rules and 
regulations, ICH-GCP, as well as instructions from the sponsor. If the site needs to transfer 
the ISF to another location and/or if the site facility can no longer store the ISF, the PI must 
immediately inform the sponsor. 
If the PI will change, or if the site will relocate, the SM must be notified as soon as possible. 
12.10 Audit 
Representatives of the sponsor’s clinical quality assurance department may visit the study 
site at any time during or after completion of the study to conduct an audit of the study in 
compliance with regulatory guidelines and company policy. These audits will require 
access to all study records, including source documents, for inspection. Participant privacy 
must, however, be respected. The investigator and study site personnel are responsible for 


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being present and available for consultation during routinely scheduled study site audit 
visits conducted by the sponsor or its designees. 
12.11 Inspections 
Similar auditing procedures may also be conducted by agents of any regulatory body, either 
as part of a national GCP compliance program or to review the results of this study in 
support of a regulatory submission. The investigator should immediately notify the sponsor 
if he or she has been contacted by a regulatory agency concerning an upcoming inspection. 
Health authorities and/or IECs/IRBs may also conduct an inspection of this study (during 
the study or after its completion) at the site. 
Should an inspection be announced by a health authority and/or IEC/IRB, the investigator 
must immediately inform the sponsor (usually via the SM) that such a request has been 
made. 
The investigator and site personnel must cooperate with inspector(s) and allow access to 
all study documentation (eg, subject records) and study facilities. 
12.12 Reporting of study results and publication 
All information, including but not limited to information regarding selexipag or the 
sponsor’s operations (eg, patent application, formulas, manufacturing processes, basic 
scientific data, prior clinical data, formulation information) supplied by the sponsor to the 
investigator and not previously published, generated as a result of this study, are considered 
confidential and remain the sole property of the sponsor. The investigator agrees to 
maintain this information in confidence and use this information only to accomplish this 
study and will not use it for other purposes without the sponsor’s prior written consent. 
The investigator understands that the information developed in the study will be used by 
the sponsor in connection with the continued development of selexipag, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to 
provide the sponsor with all data obtained in the study. 
The results of the study will be reported in a CSR generated by the sponsor and will contain 
data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters 
of the study will be used to determine a coordinating investigator for the study. Results of 
exploratory analyses performed after the CSR has been issued will be reported in a separate 
report and will not require a revision of the CSR.  


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Study participant identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from 
copyright protection (except any publication by the investigator as provided for below) 
shall be the property of the sponsor as author and owner of copyright in such work. 
Consistent with Good Publication Practices and International Committee of Medical 
Journal Editors (ICMJE) guidelines, the sponsor shall have the right to publish such 
primary (multicenter) data and information without approval from the investigator. The 
investigator has the right to publish study site-specific data after the primary data are 
published. If an investigator wishes to publish information from the study, a copy of the 
manuscript must be provided to the sponsor for review at least 60 days before submission 
for publication or presentation. Expedited reviews will be arranged for abstracts, poster 
presentations, or other materials. If requested by the sponsor in writing, the investigator 
will withhold such publication for up to an additional 60 days to allow for filing of a patent 
application. In the event that issues arise regarding scientific integrity or regulatory 
compliance, the sponsor will review these issues with the investigator. The sponsor will 
not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and sub-study approaches, secondary results 
generally should not be published before the primary endpoints of a study have been 
published. Similarly, investigators will recognize the integrity of a multicenter study by 
not submitting for publication data derived from the individual study site until the 
combined results from the completed study have been submitted for publication, within 18 
months after the study end date, or the sponsor confirms there will be no multicenter study 
publication. Authorship of publications resulting from this study will be based on the 
guidelines on authorship, such as those described in the ICMJE Recommendations for the 
Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which 
state that the named authors must have made a significant contribution to the conception 
or design of the work; or the acquisition, analysis, or interpretation of the data for the work; 
and drafted the work or revised it critically for important intellectual content; and given 
final approval of the version to be published; and agreed 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. 
Registration of clinical studies and disclosure of results 
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law. The disclosure of the final study results will be performed after the end-
of-study in order to ensure the statistical analyses are relevant.  


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13 REFERENCES 
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sequentially rejective multiple test procedures. Stat Med. 2009;28(4):586-604. 
[Borg 1998] Borg G. Borg’s Perceived Exertion and Pain Scales. IL:HK Champaign; 1998. 
[Child-Pugh 2012] Child-Pugh. In: Vincent JL., Hall J.B. (eds) Encyclopedia of Intensive 
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https://doi.org/10.1007/978-3-642-00418-6_3060 [accessed 28 Sep 2020]. 
[Dartevelle 2004] Dartevelle P, Fadel E, Mussot S et al. Chronic thromboembolic 
pulmonary hypertension. Eur Respir J. 2004 ;23(4):637-648. 
[Divers 2017] Divers C, Platt D, Wang E, Lin J, Lingohr-smith M, Mathai SC. A Review 
of Clinical Trial Endpoints of Patients with Pulmonary Arterial Hypertension and 
Chronic Thromboembolic Pulmonary Hypertension and How They Relate to Patient 
Outcomes in the United States. J Manag Care Spec Pharm. 2017;23(1):92-104. 


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[EMEA 2008] CHMP Guideline on the clinical investigations of medical products for the 
treatment 
of 
pulmonary 
arterial 
hypertension. 
(Ref. 
EMEA/CHMP/EWP/356954/2008). 
Available 
at: 
http://www.ema.europa.eu/ 
docs/en_GB/document_library/Scientific_guideline/2009/12/WC500016686.pdf 
[accessed 25 Jul 2018].  
[FDA 2003] Guidance for Industry, Pharmacokinetics in Patients with Impaired Hepatic 
Function: Study Design, Data Analysis, and Impact on Dosing and Labeling. 
May 2003. 
Available 
at : 
https://www.fda.gov/downloads/drugs/ 
guidancecomplianceregulatoryinformation/guidances/ucm072123.pdf [accessed 24 
Aug 2020]. 
[Galiè 2016] Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the 
diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2016;37(1):67-119.  
[Ghofrani 2013] Ghofrani HA, D’Armini AM, Grimminger F, et al. Riociguat for the 
treatment of chronic thromboembolic pulmonary hypertension. N Engl J 
Med. 2013;369(4):319-329. 
[Ghofrani 2017] Ghofrani HA, Simonneau G, D’Armini AM, et al. Macitentan for the 
treatment of inoperable chronic thromboembolic pulmonary hypertension 
(MERIT-1): results from the multicentre, phase 2, randomised, double-blind, 
placebo-controlled study. Lancet Respir Med. 2017;5(10):785-794.  
[Gopalan 2016] Gopalan D, Blanchard D, Auger WR. Diagnostic evaluation of chronic 
thromboembolic pulmonary hypertension. Ann Am Thorac Soc. 2016;13 Suppl 
3:S222-39. 
[Holm 1979] Holm S. A simple sequentially rejective multiple test procedure. Scand J 
Statist. 1979;6:65–70.  
[Hoeper 2009] Hoeper MM, Barberà JA, Channick RN, et al. Diagnosis, assessment, and 
treatment of non-pulmonary arterial hypertension pulmonary hypertension. J Am 
Coll Cardiol. 2009;54(1 Suppl):S85-96.  
[Holland 2014] Holland AE, Spruit MA, Troosters T, et al. An official European 
Respiratory Society / American Thoracic Society technical standard field walking 
tests in chronic respiratory disease. Eur Respir J 2014;44(6):1428-1446. 
[Humbert 2010] 
Humbert 
M. 
Pulmonary 
arterial 
hypertension 
and 
chronic 
thromboembolic pulmonary hypertension: pathophysiology. Eur Respir Rev. 
2010;19(115):59-63. 


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[Hwang 1990] Hwang IK, Shih WJ, DeCani JS. Group sequential designs using a family 
of type I error probability spending functions. Stat Med. 1990;9(12):1439-1445. 
[Janssen 2013] Janssen MF, Pickard AS, Golicki D, et al.: Measurement properties of the 
EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country 
study. Qual Life Res. 2013;22(7):1717-1727. 
[Jenkins 2013] Jenkins DP, Madani M, Mayer E et al. Surgical treatment of chronic 
thromboembolic pulmonary hypertension. Eur Respir J. 2013;41(3):735-42.  
[Lan 1983] Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. 
Biometrika. 1983;70:659-663 
[McCollister 2016] McCollister D, Shaffer S, Badesch BD at al. Development of the 
Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT®) 
questionnaire: a new patient-reported outcome instrument for PAH. Resp Res. 
2016;17:72. 
[Pepke-Zaba 2011] Pepke-Zaba J, Delcroix M, Lang I, et al. Chronic thromboembolic 
pulmonary hypertension (CTEPH): results from an international prospective registry. 
Circulation. 2011;124(18):1973-1981. 
[Preston 2018] Preston IR, Channick RN, Chin K et al. Temporary treatment interruptions 
with oral selexipag in pulmonary arterial hypertension: Insights from the 
Prostacyclin (PGI2) Receptor Agonist in Pulmonary Arterial Hypertension 
(GRIPHON) study. J Heart Lung Transplant. 2018;37(3):401-408. 
[Reilly 1993] Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a 
Work Productivity and Activity Impairment Instrument. PharmacoEconomics. 
1993;4(5):353-365. 
[Regitz-Zagrosek 2011] Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, et al. ESC 
Guidelines on the management of cardiovascular diseases during pregnancy: the 
Task Force on the Management of Cardiovascular Diseases during Pregnancy of the 
European Society of Cardiology (ESC). Eur Heart J. 2011;32(24):3147-3197.  
[Rosenkranz 2015] Rosenkranz S, Preston I. Right heart catheterisation: best practice and 
pitfalls in pulmonary hypertension. Eur Resp Rev. 2015;24(138):642-652. 
[Saouti 2009] Saouti N, de Man F, Westerhof N, et al. Predictors of mortality in inoperable 
chronic thromboembolic pulmonary hypertension. Respir Med. 2009;103(7):1013-
1019. 


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[Selexipag IB] Investigator’s Brochure. Selexipag, ACT-293987, IP receptor agonist. 
Edition 15. Actelion Pharmaceuticals Ltd, February 2020. 
[Sitbon 2015] Sitbon O, Channick R, Chin KM, et al. Selexipag for the Treatment of 
Pulmonary Arterial Hypertension. N Engl J Med. 2015;373(26):2522-2533. 
[Zigmond 1983] Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. 
Acta psychiatry. Scand. 1983;67(6):361-370. 
 


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14 APPENDICES 
14.1 Appendix 1 
Actelion heart catheterization guidance 
For the subjects in the hemodynamic cohort hemodynamic evaluations are to be carried out 
according to this guidance for those conditions and hemodynamic parameters that are 
described below. Further hemodynamic evaluations will be carried out according to the 
catheterization laboratory’s local practice.  
14.1.1 Heart Catheterization procedures 
14.1.1.1 Conditions 
Participants will undergo RHC/LHC at the study site (or other institution in case no suitable 
catheterization laboratory is available at the study site) in an appropriate care setting (eg, 
catheterization laboratory or medical procedures unit). If the assessment is performed at an 
external catheterization laboratory, the Primary Investigator is responsible to provide this 
guidance document to the external institution and to ensure that the catherization lab is 
sufficiently qualified.  
Whenever possible, it is recommended that baseline and any post-baseline RHC/LHC are 
performed by the same operator, according to the same standards and procedures and in 
the same catheterization laboratory to ensure data consistency.  
Where historical RHC/LHC is used for baseline measurements, then this guidance 
requirements for zeroing [Section 14.1.1.2] and heart catheterization measurement 
[Section 14.1.2] must have been followed and documented in the source notes. Otherwise 
a new RHC/LHC assessment will have to be performed for baseline measurements. 
14.1.1.2 ‘Zeroing’ 
‘Zeroing’ must be done prior to any RHC/LHC measurements. The participant needs to be 
in a supine position and the pressure transducer is to be set to zero level at the mid-thoracic 
line.  
This must be documented in the heart catherization worksheet. 
14.1.1.3 Oxygen  
If the participant requires supplemental oxygen during baseline RHC/LHC, oxygen should 
also be given during the follow-up RHC/LHC, if needed. 


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14.1.2 Heart catheterization measurements 
14.1.2.1 Right Heart Catheterization measurements 
14.1.2.1.1 Pulmonary Artery pressure (PAP) 
The participant will be asked to breath normally during the procedure. The operator will 
assess the appropriate systolic PAP (sPAP) and diastolic PAP (dPAP) readings based on 
the respiratory cycle and the pressure tracings. 
The sPAP and dPAP must be measured with two measurements documented in the source 
notes that are assessed by the operator as the most representative and reliable. 
If more than two values are recorded, all values must be documented on the source notes.  
14.1.2.1.2 Pulmonary artery wedge pressure (PAWP) 
The participant will be asked to breath normally during the procedure. The operator will 
assess the appropriate PAWP reading based on the respiratory cycle and the pressure 
tracing. 
If multiple measurements are performed, all PAWP values must be documented in the heart 
catherization worksheet.  
The operator must identify the most accurate PAWP on the heart catherization worksheet, 
based on their decision of which waveform to use. 
14.1.2.1.3 Cardiac Output  
The same method for CO measurement must be used for both the baseline and any post-
baseline RHC to ensure consistency. 
If thermodilution method is used: 
• The CO must be measured with at least three measurements documented in the heart 
catherization worksheet.  
• The three measurements must be within 10% of each other, ie, the lowest of the 3 CO 
values must not be lower than 10% of the middle value AND the highest value must 
not be higher than 10% of the middle value. 
• If the three values are not within 10% of each other (as per above), additional 
measurements can be performed until 3 measurements are obtained that are within 10% 
of each other. 


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• If more than three measurements are taken, the largest and/or smallest outlying values 
in the opinion of the operator should be discarded until at least three values are within 
10% of each other.  
• If more than three values are recorded, all values must be documented in the heart 
catherization worksheet.  
If Fick method (indirect or direct) is used, 
• Only one value is required and must be documented in the heart catherization 
worksheet.  
• If multiple values are performed, all CO values must be documented in the heart 
catherization worksheet. In addition, the operator must identify the most representative 
and reliable CO value.  
14.1.2.2 Left Heart Catheterization measurement 
14.1.2.2.1 Left ventricular end diastolic pressure (LVEDP) 
Left ventricular end diastolic pressure (LVEDP) is to be recorded only when PAWP is not 
available or not reliable. 
The participant will be asked to breath normally during the procedure. The operator will 
assess the appropriate LVEDP reading based on the respiratory cycle and the pressure 
tracing. 
If multiple measurements are performed, all LVEDP values must be documented in the 
heart catherization worksheet.  
The operator must identify the most representative and reliable LVEDP value on the heart 
catherization worksheet. 
14.1.2.3 Other measurements 
mRAP, dSAP, sSAP and SVO2 are measured as per local practice. 
Cardiac index (CI) and total peripheral resistance (TPR) are to be calculated as per local 
practice. 


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14.1.3 Documentation 
14.1.3.1 Tracings 
All relevant tracings are to be recorded and saved/ printed for each pressure measurement 
and filed as the participants’ source notes (electronic or paper). 
14.1.3.2 Heart catheterization worksheet 
It is mandatory to use the study heart catheterization worksheet to capture documentation 
of each RHC with/without LHC assessments newly performed for the purpose of the study 
and report relevant data in the eCRF, as indicated.  
It is not mandatory to use the study heart catheterization worksheet for historical RHC/LHC 
assessments. 
 
 




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14.3 Appendix 3 
Actelion 6MWT guidance 
This document stipulates the criteria under which study-required 6MWTs will be carried 
out in Clinical Protocol. 
These criteria are, in part, derived from the recommendations included in the ATS 
Guidelines issued in 2002 and the ERS/ ATS Technical Standard published in 2014 
[ATS Guidelines 2002, Holland 2014]. As opposed to the comprehensive published 
manuscripts, this guidance has been shortened and accustomed for use in a clinical study 
in which a variety of different assessments may need to be performed at a given visit. In 
addition, dyspnea will be assessed using the BDI scale [Appendix 4] / Borg CR10 Scale® 
[Borg 1998] [Appendix 5].  
14.3.1 Instructions 
14.3.1.1 General 
The 6-minute walk test (6MWT) must be performed indoors, along a long, flat, straight, 
enclosed corridor (or similar location) with a hard surface that can be blocked for traffic 
during the conduct of the test. The track length for the 6MWT must be free of obstacles. 
The use of treadmill and a continuous course, eg, a circuit, is not allowed.  
The ideal track length used for the 6MWT is 30 meters (If the track is shorter, it must be 
no shorter than 20 meters in length. The track must be marked at regular intervals to 
facilitate measurement of the distance walked (markings every 3 meters are 
recommended). The turnaround points must be marked with a cone. A starting line, which 
marks the beginning and the end of each lap (one lap is twice the length of the track used 
at the site), needs to be marked on the floor.  
Local safety practice regarding medical emergencies and contraindications for 6MWT 
must be followed at each participating site.  
The person administering the 6MWT (tester) needs to stand near the starting line during 
the 6MWT and must not walk with the participant, and not get distracted during the conduct 
of this 6MWT (eg, by talking to someone).  
Rest periods are allowed if the participant can no longer continue. If the participant needs 
to rest, he/she may pause, lean against the wall and continue walking whenever he/she feels 
able. The timer must continue to run even if the participant stops to rest. The 6MWT can 
be stopped at any moment as due to medical emergencies or safety issues such as chest 
pain, intolerable dyspnea, leg cramps, staggering, diaphoresis, and pale or ashen 
appearance. 


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The 6MWT is a non-encouraged test. An even tone of voice must be used when using the 
standard phrases. No other instructions or words of encouragement are given during the 
test, other than the pre-scripted phrases (see Section 14.3.3.1). Eye contact and body 
language signaling the participant to speed up must be avoided during the test.   
Whenever possible, for an individual participant, repeat 6MWTs must be conducted in the 
same corridor and by the same tester, and preferably at about the same time of the day (ie, 
within +/- 2 hours of the baseline test) to minimize variability. 
If a participant is oxygen dependent, the use of a portable device is allowed. The oxygen 
flow rate must remain constant from 30 minutes prior to each 6MWT, until the completion 
of all protocol-mandated assessments after the 6MWT. Additionally, the way oxygen is 
delivered (delivery device, application route, way of carrying the delivery device) must be 
the same for all 6MWTs, unless a change is required for documented medical reasons. 
14.3.1.2 Training tests 
For participants who have not previously performed a 6MWT, a training 6MWT must be 
performed before the first protocol-mandated 6MWT is performed.  
Data from the training 6MWT are not collected in the CRF but must be documented in the 
source data. 
14.3.1.3 Timing 
Only two 6MWTs can be performed on the same day. The interval between two 6MWTs 
on the same day must be at least 2 hours.  
14.3.2 Test requirements 
14.3.2.1 Participant 
• The participant must wear comfortable clothing and appropriate walking shoes.  
• The participant must not have exercised vigorously within 2 hours of beginning the 
test.  
• It is recommended that the participant rests for at least 15 minutes before the test starts. 
• If the participant is used to take bronchodilators, he/she must take them at least 10 to 
30 min before the test.  
• Walking aids (eg, cane) and walkers are not allowed.  
14.3.2.2 Equipment to perform the test 
• Countdown timer 


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• Mechanical lap counter 
• Two cones to mark the turnaround points  
• A chair that can be easily moved along the track  
• 6MWT Worksheet 
• BDI scale [Appendix 4]/Borg category-ratio (CR) 10 Scale® [Appendix 5] 
14.3.3 Performing the 6MWT 
14.3.3.1 Instructions to the participant during the 6MWT 
The tester uses the following exact dialogue with the participant: 
“The objective of this test is to walk as far as possible in 6 minutes. You will walk back 
and forth in this hallway. Six minutes is a long time to walk, so you will be exerting 
yourself. You will probably get out of breath or become exhausted. You are permitted 
to slow down, to stop, and to rest as necessary. You may lean against the wall while 
resting, but resume walking as soon as you are able.  
You will be walking back and forth around the cones. You should pivot briskly around 
the cones and continue back the other way without hesitation. Now I’m going to show 
you. Please watch the way I turn without hesitation”.  
(The tester demonstrates the walking and pivots around a cone briskly).  
“Are you ready to do that? I am going to use this counter to keep track of the number 
of laps you complete. I will click it each time you turn around at this starting line. 
Remember the object is to walk AS FAR AS POSSIBLE in 6 minutes, but don’t run or 
jog.”  
After these instructions are given to the participant, the tester says:  
“Start now, or whenever you are ready”  
As soon as the participant starts to walk, the tester starts the timer and writes down start 
time. The tester reminds the participant of the elapsed time by saying:  
After the first minute: “You are doing well. You have 5 minutes to go”. 
When the timer shows 4 minutes remaining: “Keep up the good work. You have 4 
minutes to go.” 
When the timer shows 3 minutes remaining: “You are doing well. You are halfway 
done.” 


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When the timer shows 2 minutes remaining: “Keep up the good work. You have 2 
minutes to go.” 
When the timer shows only 1 minute remaining: “You are doing well. You have only 1 
minute to go.” 
If the participant stops walking during the test and needs a rest, the tester says: 
“You can lean against the wall if you would like; then continue walking whenever you 
feel able.” 
The tester will not stop the timer. If the participant stops before the 6 minutes are up and 
refuses to continue (or the tester decides that they should not continue), the tester wheels 
the chair over for the patient to sit on, discontinue the walk, and note on the worksheet the 
distance, the time stopped, and the reason for stopping prematurely. 
When the timer is 15 seconds from completion, the tester says:  
“In a moment I’m going to tell you to stop. When I do, just stop right where you are 
and I will come to you”.  
When the timer alarm rings the tester says:  
“Stop!” 
14.3.3.2 Assessments after the 6MWT 
The tester walks over to the participant, marks the spot where the participant stopped, 
records the total distance walked in the 6MWT worksheet and congratulates the participant 
on good effort. 
The tester shows the BDI scale [Appendix 4]/Borg category-ratio (CR) 10 Scale® 
[Appendix 5] to the participant and asks the participant:  
“Please grade your dyspnea using this scale”. 
14.3.4 6MWT worksheet 
It is mandatory to use the 6MWT worksheet to capture documentation of each 6MWT 
newly performed for the purpose of the study and report relevant data in the eCRF, as 
indicated.  
It is not mandatory to use the study 6MWT worksheet for historical 6MWTs. 


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14.4 Appendix 4 
Borg dyspnea index (BDI) scale 
As soon as possible following the walk test, the subject is asked to rate his/her dyspnea 
using the following BDI scale. The tester will use the following dialogue: 
“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.” 
 
0 
NOTHING AT ALL 
0.5 
VERY, VERY SLIGHT (just noticeable) 
1 
VERY SLIGHT 
2 
SLIGHT (light) 
3 
MODERATE 
4 
SOMEWHAT SEVERE 
5 
SEVERE (heavy) 
6 
 
7 
VERY SEVERE 
8 
 
9 
 
10 
VERY, VERY SEVERE (maximal) 
 
 
 


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14.5 Appendix 5 
Borg CR10 scale® 
14.5.1 Instructions 
The Borg CR10 Scale® will be explained in detail to the participants at Screening before 
starting the first 6MWT (questionnaires and instructions will be provided in local 
language).  
The tester will provide the following instruction to the participant: 
“Use this rating scale to report how strong your perception of dyspnea. First look at the 
verbal expressions. Start with them and then the numbers. Of these ten (10) or “Extremely 
strong”, “Maximal” is a very important intensity level. This is the most intense perception 
or feeling you have ever had. 
If your experience or feeling is “Very weak”, you should say “1”, if it is “Moderate”, say 
“3”. Note that “Moderate” is “3” and thus weaker than “Medium”, “Mean” or “Middle”. If 
the experience is “Strong” or “Heavy” (it feels “Difficult”) say “5”. Note that “Strong” is 
about half of “Maximal”. If your feeling is “Very strong”, choose a number from 6 to 8. If 
your perception or feeling is stronger than “10”, - “Extremely strong”, “Maximal”–you can 
use a larger number, eg 12 or still higher (that’s why “Absolute maximum” is marked with 
a dot “•”).  
It’s very important that you report what you actually experience or feel, not what you think 
you should report. Be as spontaneous and honest as possible and try to avoid under- or 
overestimating. Look at the verbal descriptors and then choose a number. 
When rating dyspnea give a number that corresponds to how hard and strenuous you 
perceive your breathing to be7. The perception of dyspnea is mainly the feeling that one 
cannot breathe well enough. 
0 - “Nothing at all”, means that you don’t feel any shortness of breath.  
1 - “Very weak” means a very light shortness of breath. 
3 - “Moderate” is somewhat but not especially hard. You are somewhat shorter of 
breath.  
5 - “Strong”. Breathing is getting difficult. The effort to breathe is about half as 
intense as “Maximal”.  
 
7 The instructions for rating dyspnea have been customized by the Sponsor based on the instructions for rating exertion. 
These modifications have not been validated by Borg Perception AB. 


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7 - “Very strong” is quite strenuous. You can still breathe, but breathing is getting 
very difficult. 
10 - “Extremely strong–Maximal” is the greatest shortness of breath you have ever 
experienced in your life. 
“•” - Is “Absolute maximum” for example “12” or even more. 
Any questions?” 


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14.5.2 Borg CR10 Scale® 
 
 


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14.6 Appendix 6 
WHO function classification of Pulmonary Hypertension 
Class I 
Patients with pulmonary hypertension but without resulting limitation of physical 
activity. Ordinary physical activity does not cause undue dyspnea or fatigue, 
chest pain or near syncope. 
Class II 
Patients with pulmonary hypertension resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity causes undue 
dyspnea or fatigue, chest pain or near syncope. 
Class III 
Patients with pulmonary hypertension resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes undue 
dyspnea or fatigue, chest pain or near syncope. 
Class IV 
Patients with pulmonary hypertension with inability to carry out any physical 
activity without symptoms. These patients manifest signs of right heart failure. 
Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by 
any physical activity. 
 
 


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14.7 Appendix 7 
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. 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 160/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
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 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 161/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
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 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 162/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
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 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 163/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
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 up hill? 
☐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 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 164/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
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 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 165/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
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 
 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 166/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
14.8 Appendix 8 
EQ-5D-5L 
Under each heading, please tick the ONE box that best describes your health TODAY 
 
MOBILITY 
 
I have no problems in walking about 
☐ 
I have slight problems in walking about 
☐ 
I have moderate problems in walking about 
☐ 
I have severe problems in walking about 
☐ 
I am unable to walk about 
☐ 
 
SELF-CARE  
 
I have no problems washing or dressing myself 
☐ 
I have slight problems washing or dressing myself 
☐ 
I have moderate problems washing or dressing myself 
☐ 
I have severe problems washing or dressing myself 
☐ 
I am unable to wash or dress myself 
☐ 
 
USUAL ACTIVITIES (eg, work, study, housework, family or leisure activities) 
 
I have no problems doing my usual activities 
☐ 
I have slight problems doing my usual activities 
☐ 
I have moderate problems doing my usual activities 
☐ 
I have severe problems doing my usual activities 
☐ 
I am unable to do my usual activities 
☐ 
 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
☐ 
I have slight pain or discomfort 
☐ 
I have moderate pain or discomfort 
☐ 
I have severe pain or discomfort 
☐ 
I have extreme pain or discomfort 
☐ 
 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
☐ 
I am slightly anxious or depressed 
☐ 
I am moderately anxious or depressed 
☐ 
I am severely anxious or depressed 
☐ 
I am extremely anxious or depressed 
☐ 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 167/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
 
 
 
 
 
• 
We would like to know how good or bad your health is 
TODAY. 
• 
This scale is numbered from 0 to 100. 
• 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• 
Mark an X on the scale to indicate how your health is 
TODAY. 
• 
Now, please write the number you marked on the scale in 
the box below.  
 
 
YOUR HEALTH TODAY = 
 
 
 
 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 168/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
14.9 Appendix 9 
Work Productivity and Activity Impairment 
Questionnaire: General Health (WPAI©: GH) V2.0 
The following questions ask about the effect of your health problems on your ability to 
work and perform regular activities. By health problems we mean any physical or 
emotional problem or symptom. Please fill in the blanks or circle a number, as indicated. 
1. Are you currently employed (working for pay)?  
____NO 
__YES  
 
If NO, check “NO” and skip to question 6. 
The next questions are about the past seven days, not including today. 
2. During the past seven days, how many hours did you miss from work because of 
your health problems? Include hours you missed on sick days, times you went in 
late, left early, etc., because of your health problems. Do not include time you 
missed to participate in this study. 
 
 
_____HOURS 
3. During the past seven days, how many hours did you miss from work because of 
any other reason, such as vacation, holidays, time off to participate in this study? 
 
_____HOURS 
4. During the past seven days, how many hours did you actually work? 
 
_____HOURS (If “0”, skip to question 6.) 
 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 169/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
5. During the past seven days, how much did your health problems affect your 
productivity while you were working? 
 
Think about days you were limited in the amount or kind of work you could do, 
days you accomplished less than you would like, or days you could not do your 
work as carefully as usual. If health problems affected your work only a little, 
choose a low number. Choose a high number if health problems affected your work 
a great deal.  
Consider only how much health problems affected 
productivity while you were working. 
Health problems 
had no effect on 
my work 
 
 
 
 
 
 
 
 
 
 
 
Health problems 
completely 
prevented me from 
working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
 
6. During the past seven days, how much did your health problems affect your ability 
to do your regular daily activities, other than work at a job?  
 
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc. Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like. If health problems affected your activities only a little, 
choose a low number. Choose a high number if health problems affected your 
activities a great deal.  
Consider only how much health problems affected your ability 
to do your regular daily activities, other than work at a job. 
Health problems 
had no effect on my 
daily activities 
 
 
 
 
 
 
 
 
 
 
 
Health problems 
completely 
prevented me from 
doing my daily 
activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 170/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
14.10 Appendix 10 Child-Pugh classification 
The Child-Pugh classification will be used to assess the severity of the liver disease 
according to the following table [FDA 2003]: 
Table 11 
Child-Pugh Classification 
 
Score 
 
1 
2 
3 
Total bilirubin (mg/dL) 
<2.0 
2.0-3.0 
>3.0 
Serum albumin (g/dL) 
>3.5 
2.8-3.5 
<2.8 
Ascites 
Absent 
Slight 
Moderate 
Hepatic encephalopathy* 
Grade 0 
Grade 1-2 
Grade 3-4 
Prothrombin time (seconds prolonged) 
<4 
4-6 
>6 
or 
 
 
 
INR [Child-Pugh 2012] 
<1.7 
1.7 – 2.2 
>2.2 
INR = International normalized ratio 
*Hepatic encephalopathy scoring will be based on the following criteria: 
• Grade 0: normal consciousness, personality, neurological examination, and electroencephalogram. 
• Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, five cycles per second waves. 
• Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves. 
• Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves. 
• Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2–3 cycles per second delta activity. 
• 
Class A: Score 5-6 
• 
Class B: Score 7-9 
• 
Class C: Score 10-15 
 
 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 171/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
14.11 Appendix 11 Protocol amendment history 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC) and the previous two amendments 
have been included in this appendix. 
Amendment 2 [(16 April 2020)] 
Overall Rationale for the Amendment: 
Time to clinical worsening (TTCW) has been identified as an important clinical endpoint in 
addition to improvement in exercise capacity (6-minute walk distance [6MWD]) [Divers 2017], 
and has been accepted by health authorities as an endpoint. Therefore, a study powered for TTCW 
would provide additional clinical data to support clinical treatment decisions in chronic 
thromboembolic pulmonary hypertension (CTEPH). The sponsor has revised the study design to 
power the study for the additional clinical endpoint, TTCW. Consequently, elements of the study 
design, key secondary endpoints, sample size, testing hierarchy and analysis timepoints have been 
amended to ensure the evaluation of 6MWD and TTCW endpoints. These design changes will be 
used for efficacy confirmation based on 6MWD and TTCW endpoints.  
In addition, this amendment implements the sponsor’s standardized guidelines for the assessment 
of heart catheterization (HC), 6-minute walk test (6MWT) and Borg dyspnea index (BDI), and 
addition of the Borg category-ratio 10 (Borg CR10) Scale® and a Clinical Event Committee (CEC) 
to the study.  
Section Number 
and Name 
Description of Change 
Brief Rationale 
Title Page 
PROTOCOL SYNOPSIS 
AC-065B302; 
3.1. Study Design; 
3.2. Study Design 
Rationale; 
3.4.2. Independent Data 
Monitoring Committee; 
5.1.5. Blinding; 
5.1.10. Premature 
Discontinuation of Study 
Treatment; 
7. Visit Schedule and 
Study Assessments; 
8.1. Study Completion as 
per Protocol; 
 
Changes made to study periods and 
visit schedule. 
 
 
To power the study for the TTCW 
endpoint, the duration of 
observation of subjects on double-
blind (DB) treatment was 
prolonged. 
The open-label period was 
shortened to the time required until 
the DB period results become 
available. 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 172/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Section Number 
and Name 
Description of Change 
Brief Rationale 
PROTOCOL SYNOPSIS 
AC-065B302; 
3.1.1.2 Treatment period  
Figure 1 Study design; 
3.1.2 Study duration  
Table 4 
Open-label 
treatment period: visit and 
assessment schedule  
Changes made to the OL treatment 
extension period and visit schedule.  
On-site visits every 26 weeks were 
added for subjects who were 
transitioned to the OL treatment 
extension period before 
implementation of the AC-065B302 
protocol amendment 2. This is to 
ensure follow-up of these subjects 
until the availability of the double-
blind period results. 
PROTOCOL SYNOPSIS 
AC-065B302; 
2.2. Secondary 
Objectives; 
3.2.2. Rationale for the 
Duration of the Study; 
10.3.1. Overall testing 
Strategy; 
10.3.3. Analysis of 
Secondary Efficacy 
Variable(s); 
10.4. Interim Analyses; 
10.6. Sample Size; 
10.6.3. Time to Clinical 
Worsening 
 
Place TTCW as a key secondary 
endpoint with the other key 
secondary endpoint, 6MWD. The 
testing hierarchy is modified 
accordingly. The sample size is 
increased, and the DB treatment 
period is modified with variable 
follow-up.  
 
TTCW is an important clinical 
endpoint, justified as a key 
secondary endpoint. With variable 
follow-up in the DB treatment 
period, the chance of observing 
clinical worsening events has 
increased. 
 
10.1.4.3. TTCW Per-
protocol analysis set; 
10.1.7. Usage of the 
Analysis Sets; 
Table 6 
Analysis sets 
and their usage at each 
analysis time point; 
Added Per-protocol set for TTCW. 
TTCW is a key secondary endpoint. 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 173/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Section Number 
and Name 
Description of Change 
Brief Rationale 
PROTOCOL SYNOPSIS 
AC-065B302; 
3.1. Study Design; 
5.1.5. Blinding; 
5.1.6.1. Timing of Study 
Analyses; 
10.1.7. Use of the 
Analyses Sets; 
10.3.1. Overall testing 
Strategy; 
10.3.3. Analysis of 
Secondary Efficacy 
Variable(s); 
10.4. Interim Analyses; 
10.5. Double-blind and 
Open-label Analyses; 
10.6. Sample Size 
 
Change in analysis time points. 
As the sample size is increased and 
the DB treatment period is 
prolonged, one additional interim 
analysis time point is considered 
appropriate.  
PROTOCOL SYNOPSIS 
AC-065B302; 
4.1. Subject population 
description; 
4.3. Inclusion criteria 
 
The lower limit of age for inclusion 
in the study was clarified as being 
18 or the legal age of consent in the 
jurisdiction in which the study is 
taking place. 
Amended for clarity at the request 
of Ethics committee. 
PROTOCOL SYNOPSIS 
AC-065B302; 
4.3. Inclusion criteria  
 
For the non-hemodynamic cohort, 
the pulmonary vascular resistance 
(PVR) threshold for inclusion will 
be ≥300 dyn.sec/cm5 or ≥3.75 
Wood units. 
The non-hemodynamic cohort will 
not contribute to the primary 
endpoint of change in PVR at Week 
20. For this reason, the amended 
PVR is deemed more appropriate as 
an inclusion criterion for this 
cohort. 
PROTOCOL SYNOPSIS 
AC-065B302; 
3.1. Study Design; 
5.1.4. Treatment 
Assignment; 
10.3.5. Subgroup 
Analyses 
 
The stratification factor of CTEPH 
population was redefined to 
inoperable (with or without balloon 
pulmonary angioplasty [BPA]) 
versus persistent/recurrent after 
pulmonary endarterectomy (PEA) 
(including PEA followed by BPA). 
It is anticipated that the use of BPA 
as an intervention may increase over 
the course of the study. It would be 
appropriate to have both inoperable 
and persistent/recurrent CTEPH 
sub-populations balanced in the two 
treatment arms. 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 174/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Section Number 
and Name 
Description of Change 
Brief Rationale 
7.1. General Information 
Table 5; 
Assessments for subjects entering 
the post-treatment observation 
period (PTOP) are changed. 
Subjects who discontinue from DB 
study treatment before the end-of-
double-blind period should continue 
with all visits and assessments up to 
the PTOP-End-of-Study (EOS) to 
comply with the intent-to-treat 
principle. 
 
3.2.2. Rationale for the 
Duration of the Study; 
3.2.3. Rationale for the 
Post-treatment 
Observation Period; 
5.1.10. Premature 
Discontinuation of Study 
Treatment; 
7.1. General Information 
7.2.3.9. Survival Follow-
up 
 
Long-term survival information will 
be collected for subjects who 
prematurely discontinue DB study 
treatment and do not agree to 
continue to perform the visits and 
assessments until the PTOP-EOS 
visit. 
Mortality analysis can be biased due 
to informative censoring by 
competing risks. To reduce such 
bias, long-term survival data would 
be relevant to collect on subjects 
who have prematurely discontinued 
the DB study treatment. 
3.4.3. Adjudication 
Committees 
 
Clarification that the adjudication 
committee’s (AC) role is to confirm 
CTEPH diagnosis, 
persistence/recurrence of pulmonary 
hypertension (PH) (when 
applicable) and inoperability. 
 
Clarification of the role of the ACs. 
PROTOCOL SYNOPSIS 
AC-065B302; 
3.4.4. Clinical Event 
Committee; 
6.1.2. Secondary Efficacy 
Endpoints; 
10.3.3. Analysis of 
Secondary Efficacy 
Variables 
 
Addition of a clinical event 
committee (CEC). 
The CEC will ensure an 
independent adjudication of clinical 
worsening events. 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 175/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Section Number 
and Name 
Description of Change 
Brief Rationale 
PROTOCOL SYNOPSIS 
AC-065B302; 
4.1.1. Adjudication 
procedure; 
4.3. Inclusion Criteria; 
7.1. General Information; 
7.2.3.1. Right Heart 
Catheterization (and Left 
Heart Catheterization, if 
Needed) 
 
The time window for baseline 
hemodynamic data in case of 
rescreening was extended. 
 
This timeframe was deemed 
appropriate by the Central 
Adjudication Committee (CAC) to 
maintain robust baseline 
hemodynamic data while avoiding 
repeating the HC procedure within a 
short time frame for subjects who 
are rescreened. 
PROTOCOL SYNOPSIS 
AC-065B302; 
3.1.1.4. Post-treatment 
Observation Period; 
5.1.2. Study Treatment 
Administration; 
5.1.3. Study Treatment 
Up-titration; 
5.1.9. Study Treatment 
Dose Adjustments and 
Interruptions 
 
Introduction of once daily dosing 
frequency for subjects with 
moderate hepatic impairment 
(Child-Pugh B). 
To align with selexipag product 
information. 
PROTOCOL SYNOPSIS 
AC-065B302; 
4.4.3. Exclusion Criteria 
related to Selexipag Use; 
5.1.11.2. Hepatic 
Impairment 
 
Clarification provided for exclusion 
criterion #12. 
Exclusion criterion #12 was 
clarified for consistency in the 
selexipag development program to 
indicate that Child-Pugh scoring is 
only required in patients with 
hepatic impairment and does not 
apply to patients with no hepatic 
impairment. 
PROTOCOL SYNOPSIS 
AC-065B302; 
4.4.3. Exclusion Criteria 
related to Selexipag Use; 
5.1.3. Study Treatment 
Up-titration; 
5.1.9. Study Treatment 
Dose Adjustments and 
Interruptions 
 
Caution when administering strong 
inhibitors of UGT1A3 and UGT2B7 
and moderate inducer of CYP2C8 
added.  
Included for completeness as per 
Ethics Committees request. 
7.1. General Information; 
 
Removal of patient experience 
survey. 
The survey will not be conducted 
due to logistical challenges. 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 176/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Section Number 
and Name 
Description of Change 
Brief Rationale 
PROTOCOL SYNOPSIS 
AC-065B302; 
6.1.2. Secondary Efficacy 
Endpoints; 
6.1.3. Other Efficacy 
Endpoints; 
10.2.2. Secondary 
Efficacy Variable(s); 
10.2.3. Other Efficacy 
Variable(s); 
10.3.3. Analysis of 
Secondary Efficacy 
Variable(s) 
 
Specify the changes from baseline 
to Week 26 in the two symptoms 
domains of PAH-SYMPACT® as 
secondary endpoint and from 
baseline to Week 39 in all four 
domains as exploratory endpoint. 
Analysis strategy alignment with 
other ongoing sponsor’s selexipag 
studies. 
PROTOCOL SYNOPSIS 
AC-065B302; 
3.1. Study Design; 
5.1.6.1. Timing of Study 
Analyses; 
10.1.7. Use of the 
Analyses Sets; 
10.3.1. Overall testing 
Strategy; 
10.3.3. Analysis of 
Secondary Efficacy 
Variable(s); 
10.4. Interim Analyses; 
10.5. Double-blind and 
Open-label Analyses; 
10.6. Sample Size 
 
Changes in the decision flow 
throughout the conduct of the study. 
 
 
 
6MWD endpoint was removed from 
the interim analysis time point 1. 
 
The new flow takes into account 
new analysis time points and 
depends on results of PVR, 6MWD 
and TTCW. 
 
To allow the collection of sufficient 
data for TTCW and other endpoints 
at later time points. 
 
PROTOCOL SYNOPSIS 
AC-065B302; 
2.2 Secondary objectives; 
3.2.2. Rationale for the 
Duration of the Study; 
6.1.2. Secondary Efficacy 
Endpoints; 
10.3.3. Analysis of 
Secondary Efficacy 
Variable(s) 
 
Changed rate of death or 
hospitalizations related to PH 
worsening up to Week 52 to 
all-cause death or hospitalizations 
related to PH worsening, and added 
log-rank test as the main analysis. 
The log-rank test is for time to 
all-cause death or hospitalizations 
related to PH worsening. This is 
clinically relevant. 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 177/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Section Number 
and Name 
Description of Change 
Brief Rationale 
PROTOCOL SYNOPSIS 
AC-065B302; 
3.1. Study Design; 
3.2.2. Rationale for the 
Duration of the Study; 
3.3. Site Personnel and 
Roles; 
3.4.3. Adjudication 
Committees; 
4.1.1. Adjudication 
Procedure; 
4.3. Inclusion Criteria; 
4.4. Exclusion Criteria; 
5.2.3. Auxiliary 
Medicinal Products; 
5.2.5. Forbidden 
Concomitant Therapy; 
7.1.1. 
Screening/rescreening; 
7.1.2. Unscheduled Visits; 
7.2.2. Assessment for 
Diagnosis of CTEPH and 
Judgment of 
Inoperability; 
7.2.3. Efficacy 
Assessments; 
10.3.2. Analysis of 
Primary Efficacy 
Variable(s); 
14.1. Actelion Heart 
Catheterization Guidance 
 
Clarifying HC in the study and 
update the guidelines for HC. 
To implement the sponsor’s 
standardized guidelines for the 
assessment of HC. 
14.3. Actelion 6MWT 
Guidance 
 
Actelion 6MWT guidance updated. 
To implement the sponsor’s 
standardized guidelines for the 
assessment of 6MWD. 
 
14.4. Borg Dyspnea Index 
(BDI) Scale 
 
Borg Dyspnea Index (BDI) scale 
updated. 
To implement the standardized 
guidelines for the assessment of 
BDI. 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 178/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Section Number 
and Name 
Description of Change 
Brief Rationale 
PROTOCOL SYNOPSIS 
AC-065B302; 
7.2.3.3. Post-6MWT 
dyspnea; 
14.5. Borg CR10 Scale® 
 
Borg CR10 Scale® added. 
To implement the standardized 
guidelines for the assessment of 
Borg CR10® Scale. 
7.1.2. Unscheduled Visits; 
7.2. Study assessments 
 
Mandatory unscheduled visits added 
in case of World Health 
Organization (WHO) functional 
class (FC) increase or 6MWD 
decrease from baseline. 
Confirmation of clinical 
deterioration is needed for 
confirmation of clinical worsening. 
 
6.1.3. Other Efficacy 
Endpoints; 
7.2.3.5. Daily Life 
Physical Activity 
(DLPA); 
10.2.3. Other Efficacy 
Variables 
 
Changes in parameters of daily life 
physical activity (DLPA) 
 
 
Based on the experience in the 
TRACE study and health authority 
interaction. 
 
 
4.5.2. Acceptable 
Methods of Contraception 
Updated acceptable methods of 
contraception for hormonal 
contraceptive initiated during the 
study. 
 
To be consistent with the Janssen 
protocol template and to ensure that 
there is a constant contraception 
method for the enrolled subjects 
while in the study. 
 
Throughout the protocol 
 
Inconsistencies within the protocol 
and with Janssen processes 
addressed. 
To be consistent with the Janssen 
protocol template and style guide. 
 
Throughout the protocol 
Minor grammatical, formatting, or 
spelling changes were made. 
Minor errors were noted. 
 
 
Amendment 1 (09 January 2019) 
Overall Rationale for the Amendment:   
The sponsor has revised several inclusion criteria with the aim of ensuring the recruitment of 
subjects who could potentially benefit from medical therapy (only technically non-operable 
subjects assessed based on imaging review for all CTEPH subpopulation) and with substantially 
impaired pulmonary vascular function (PVR ≥400 dyn.sec/cm5 or ≥5 Wood units). In addition, 
statistical changes have been made following interactions with health authorities. 
 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 179/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Section Number 
and Name 
Description of Change 
Brief Rationale 
Synopsis  
4.3. Inclusion 
Criteria 
To change the inclusion criteria for the study 
population to subjects with CTEPH who are 
diagnosed as inoperable (ie, technically non-
operable) or with persistent/recurrent 
pulmonary hypertension (PH). Subjects with 
inoperability defined as technically operable 
with non-acceptable surgical risk/benefit ratio 
will not be included in this study. In addition, 
the study population will be limited to subjects 
with pulmonary vascular resistance at rest 
≥400 dyn.sec/cm5 or ≥5 Wood units.  
To ensure the recruitment of 
subjects with substantially 
impaired pulmonary vascular 
function. 
4.3. Inclusion 
Criteria 
Clarification of inclusion criterion #4.  
To avoid any ambiguity 
regarding the degree of 
symptoms that needs to be 
demonstrated, the term 
‘symptomatic’ has been 
removed. 
10.3.1 Overall 
testing strategy 
10.4 Interim 
analysis 
The Pocock-type error spending function is 
replaced by the Hwang, Shih and DeCani’s 
error spending function with parameter γ=−4. 
Remaining secondary endpoints will be tested 
using an O’Brien and Fleming’s error 
spending function. 
To implement a more 
conservative interim type I error 
spending strategy for 6-minute 
walk distance. 
Table 1  
4.3 Inclusion 
criteria 
7.2.2 Assessments 
for diagnosis of 
CTEPH and 
judgment of 
inoperability 
To change the data required for eligibility 
review by the adjudication committees (ACs). 
At least one post-surgery imaging and the 
historical surgery and intervention report will 
be submitted to the ACs for both post-
pulmonary endarterectomy (PEA) and post-
balloon pulmonary angioplasty (BPA) 
subjects.  
To allow exclusion of subjects 
with persistent/recurrent PH due 
to proximal disease. 
3.1.1.4 Post-
treatment 
observation period  
Table 5 
The sequence and naming of PTOP visits have 
been amended. 
To allow collection of Week 52 
data in the PTOP in case of DB 
study treatment discontinuation 
after Week 48. 
Table 5 
The rules for adverse events (AE)/ serious 
adverse event (SAE) reporting and follow-up 
have been clarified. 
To collect all AEs and SAEs in 
the PTOP period. 
Throughout the 
protocol 
The description of the patient population has 
been clarified. 
To allow designation of PEA as 
surgical treatment and BPA as 
interventional treatment. 
5.1.3 Study 
treatment up-
titration  
The use of moderate cytochrome P-450 (CYP) 
2C8 inhibitors (eg, clopidogrel, deferasirox, 
teriflunomide) is now permitted. 
Following new data from a 
Phase 1 study (AC-065-117; 
Selexipag IB), the use of 
moderate CYP2C8 inhibitors is 


Selexipag / ACT-293987 
Chronic Thromboembolic Pulmonary 
Hypertension 
Protocol AC-065B302, SELECT 
Amendment 3, Version 4 
29 September 2020, page 180/180 
 
EudraCT 2018-002823-41 
Doc No D-20.234 
 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Section Number 
and Name 
Description of Change 
Brief Rationale 
5.1.3.1 Double-
blind study 
treatment up-
titration  
5.1.9 Study 
treatment dose 
adjustments and 
interruptions 
permitted but requires the 
selexipag dosing frequency to 
be once daily. The dose will be 
taken in the morning to allow 
post-dose efficacy assessments. 
Dosing frequency must be 
changed to twice daily when co-
administration of the moderate 
CYP2C8 inhibitor is stopped. 
5.2.5 Forbidden 
concomitant 
therapy 
The timing regarding the permitted use of 
prostacyclin or analogs has been clarified. 
To allow rescue therapy with 
prostacyclin or analogs 
immediately after study 
treatment interruption. 
7.2.3.5 Daily life 
physical activity 
(DLPA)  
7.2.6.1 PAH-
SYMPACT™ 
questionnaire 
Conditions of use of contract research 
organization (CROs) devices (actigraphy and 
hand-held mobile device for PAH-
SYMPACT®) have been clarified. 
To align with the selected 
devices for the study that 
require different set-up methods 
and offer different data upload 
options. 
6.1.3 Other efficacy 
endpoints  
Table 3  
7.2 Study 
assessments  
7.2.3.8 Clinician 
reported outcomes  
10.2.3 Other 
efficacy variables  
Additional exploratory endpoints have been 
introduced. 
This is to prospectively assess 
the impact of selexipag versus 
placebo on risk stratification, on 
Clinician Global Impression of 
Severity and Clinician Global 
Impression of Change. 
6.1.3 Other efficacy 
endpoints 
10.2.3 Other 
efficacy variables 
The change from baseline in PAH-
SYMPACT® scores will be assessed at Week 
39 instead of Week 52 in the exploratory 
endpoints.  
PAH-SYMPACT® scores are 
assessed for 7 days after the last 
visit; therefore, they cannot be 
assessed beyond Week 52, as 
the open-label study treatment 
starts in the evening of Week 
52. 
Appendix 8 
The Hospital Anxiety and Depression Scale 
(HADS) questionnaire has been removed. 
A license for use is not 
available. 
Throughout the 
protocol 
Minor grammatical, formatting, or spelling 
changes were made. 
Minor errors were noted. 
 
 


CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
1 
Status: Final, Date: 16 June 2020 
Actelion Pharmaceuticals Ltd 
Janssen Research & Development* 
Clinical Protocol 
COVID-19 Appendix 
Protocol Title 
A multicenter, randomized, double-blind, placebo-controlled, parallel-group, group-
sequential, adaptive, Phase 3 study with open-label extension period to assess the efficacy 
and safety of selexipag as an add-on to standard of care therapy in subjects with inoperable 
or persistent/recurrent after surgical and/or interventional treatment Chronic 
Thromboembolic Pulmonary Hypertension. 
 SELECT: SELExipag in inoperable or persistent/recurrent Chronic Thromboembolic 
pulmonary hypertension 
Protocol AC-065B302; Phase 3 
 JNJ-67896049 / ACT-293987  Selexipag 
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Actelion Pharmaceuticals Ltd ; Janssen Biotech, Inc.; Janssen
Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica
NV; Janssen Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC,.
The term “sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration 
Investigational New Drug (IND) regulations (21 CFR Part 312). 
EudraCT NUMBER: 2018-002823-41 
Status: 
Approved  
Date: 
16 June 2020 
Prepared by: Actelion Pharmaceuticals Ltd, a division of Janssen Research & Development 
EDMS number: 
D-20.207 
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL 
GCP Compliance:  This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements.  
Confidentiality Statement 
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or otherwise. 
NCT03689244


COVID-19 Appendix  
 
JNJ-67896049 / ACT-293987 selexipag  
Clinical Protocol AC-065B302  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
2 
Status: Final, Date: 16 June 2020 
COVID-19 APPENDIX 
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC 
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by subjects and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks.  
In alignment with recent health authority guidance, the sponsor is providing options for study 
related subject management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgement of the 
investigator to protect the health and well-being of subjects and site staff. If, at any time, a subject’s 
safety is considered to be at risk, study treatment will be discontinued, and study follow-up will 
be conducted. 
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, subjects will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Subjects will also be questioned regarding general 
health status to fulfill any physical examination requirement.  
Every effort should be made to adhere to protocol-specified assessments for subjects on study 
treatment, including follow up. Modifications to protocol-required assessments may be permitted 
via COVID-19 Appendix after consultation with the subject, investigator, and the sponsor. Missed 
assessments/visits will be captured in the clinical trial management system for protocol deviations. 
Discontinuations of study treatments and withdrawal from the study should be documented with 
the prefix “COVID-19-related” in the case report form (CRF). 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance. 
If a subject has tested positive for COVID 19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study treatment and follow-up. Modifications made 
to the study conduct as a result of the COVID-19 pandemic will be summarized in the clinical 
study report. 
 
 


COVID-19 Appendix  
 
JNJ-67896049 / ACT-293987 selexipag  
Clinical Protocol AC-065B302  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
3 
Status: Final, Date: 16 June 2020 
GUIDANCE SPECIFIC TO THIS PROTOCOL 
• 
Related to Protocol Section 5.1.7.3 Study treatment dispensing 
− For subjects unable to visit the clinic/hospital, direct-to-patient (DTP) shipment of study 
drugs may be implemented, where allowed per local regulations and if requested by the 
treating study physician. Where DTP shipments are deemed necessary, the process should 
be coordinated between the site and sponsor staff following the “COVID-19 DTP Guidance 
Document”. 
• 
Related to Protocol Section 7.2.6 Patient reported outcomes 
− The PAH-SYMPACT® questionnaire will be assessed for the seven consecutive days 
following the remote/virtual visit when an on-site visit is not possible. 
− The EQ-5D-5L and the WPAI©: GH scores will be collected via a remote/virtual visit and 
entered on an electronic device by the site staff when an on-site visit is not possible. 
• 
Related to Protocol Section 12.3 Informed consent 
− Consenting and re-consenting of subjects will be performed as applicable for the measures 
taken (including remote consenting by phone or video consultation) and according to local 
guidance for informed consent as applicable.  
 
 



SAP_003.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 11 July 2022
Actelion Pharmaceuticals Ltd*
(a Janssen Pharmaceutical Company of Johnson & Johnson)
Statistical Analysis Plan
A multicenter, randomized, double-blind, placebo-controlled, parallel-group, group 
sequential, adaptive, Phase 3 study with open-label extension period to assess the efficacy 
and safety of selexipag as an add-on to standard of care therapy in subjects with inoperable 
or persistent/recurrent after surgical and/or interventional treatment Chronic 
Thromboembolic Pulmonary Hypertension
SELECT: SELExipag in inoperable or persistent/recurrent Chronic Thromboembolic 
pulmonary hypertension
Protocol AC-065B302; Phase 3
JNJ-67896049 (selexipag)
*Actelion Pharmaceuticals Ltd (“Actelion”) is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Actelion studies may vary, such as, but not
limited to Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; or Janssen Research &
Development, LLC. The term “sponsor” is used throughout this document to represent these various legal entities; the
sponsor is identified on the Contact Information page that accompanies the protocol
Status:
Approved
Date:
11 July 2022
Prepared by:
Actelion Pharmaceuticals Ltd, Janssen Research & Development, a division of 
Janssen Pharmaceutical NV
Document No.: EDMS-RIM-521486, 3.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or otherwise.
NCT03689244


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065B302
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 11 July 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 5
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Objectives and Endpoints ................................................................................................................ 6
1.2.
Study Design.................................................................................................................................... 7
1.2.1.
Study Periods ............................................................................................................................... 8
1.2.2.
Study Duration ............................................................................................................................ 10
1.2.3.
Study Visits and Assessment Schedule .....................................................................................11
1.2.4.
Analysis Time Points .................................................................................................................. 18
1.2.5.
Randomization and Blinding....................................................................................................... 20
1.2.5.1.
Method of Treatment Assignment and Randomization ........................................................... 20
1.2.5.1.1.
Randomization ..................................................................................................................... 20
1.2.5.1.2.
Stratification.......................................................................................................................... 20
1.2.5.2.
Blinding and Unblinding........................................................................................................... 21
1.2.5.2.1.
Blinding................................................................................................................................. 21
1.2.5.2.2.
Unblinding ............................................................................................................................ 21
1.2.5.2.2.1.
Unblinding for IDMC meetings .......................................................................................... 21
1.2.5.2.2.2.
Unblinding for the first analysis time point (final analysis of PVR).................................... 21
1.2.5.2.2.3.
Unblinding for the final analysis ........................................................................................ 21
1.2.5.2.2.4.
Other unblindings.............................................................................................................. 22
2.
STATISTICAL HYPOTHESES.......................................................................................................... 22
2.1.
Hypotheses for the Primary Endpoint ............................................................................................ 22
2.2.
Hypotheses for Secondary Endpoints............................................................................................ 22
3.
SAMPLE SIZE DETERMINATION....................................................................................................22
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS.....................................................................23
5.
STATISTICAL ANALYSES............................................................................................................... 24
5.1.
General Considerations ................................................................................................................. 24
5.1.1.
Overall Testing Strategy ............................................................................................................. 24
5.1.2.
Visit and Analysis Time Windows............................................................................................... 26
5.1.3.
Study Day and Relative Day....................................................................................................... 28
5.1.4.
Baseline and Endpoint................................................................................................................ 28
5.1.5.
Study Periods ............................................................................................................................. 28
5.1.6.
Study Completion ....................................................................................................................... 29
5.1.7.
Imputation Rules for Missing Adverse Event Date/Time of Onset .............................................29
5.1.7.1.
Treatment-emergent AEs ........................................................................................................ 29
5.1.7.2.
Imputation Rules...................................................................................................................... 29
5.2.
Subject Dispositions....................................................................................................................... 30
5.3.
Primary Endpoint Analysis ............................................................................................................. 31
5.3.1.
Definition of Endpoint.................................................................................................................. 31
5.3.2.
Estimand..................................................................................................................................... 32
5.3.3.
Analysis Methods........................................................................................................................ 33
5.3.3.1.
Statistical Model ...................................................................................................................... 33
5.3.3.2.
Handling of Missing Data......................................................................................................... 33
5.3.3.2.1.
Main imputation approach.................................................................................................... 33
5.3.3.2.2.
Alternative imputation approach........................................................................................... 34
5.3.3.3.
Main, Sensitivity and Supplementary Analyses....................................................................... 36
5.3.3.3.1.
Main analysis........................................................................................................................ 36
5.3.3.3.2.
Sensitivity analyses.............................................................................................................. 37
5.3.3.3.3.
Supplementary analyses...................................................................................................... 37


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065B302
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved, Date: 11 July 2022
5.3.3.4.
Subgroup Analyses ................................................................................................................. 38
5.4.
Secondary Endpoint(s) Analysis .................................................................................................... 38
5.4.1.
6MWD at Week 26 (key secondary endpoint)............................................................................38
5.4.1.1.
Definition of Endpoint .............................................................................................................. 38
5.4.1.2.
Estimand.................................................................................................................................. 38
5.4.1.3.
Analysis Methods .................................................................................................................... 39
5.4.1.3.1.
Statistical model ................................................................................................................... 39
5.4.1.3.2.
Handling of missing data...................................................................................................... 39
5.4.1.3.2.1.
Main imputation approach................................................................................................. 39
5.4.1.3.3.
Main, sensitivity and supplementary analyses..................................................................... 40
5.4.1.3.3.1.
Main analysis .................................................................................................................... 40
5.4.2.
TTCW (key secondary endpoint)................................................................................................ 40
5.4.2.1.
Definition of Endpoint .............................................................................................................. 40
5.4.2.2.
Estimand.................................................................................................................................. 41
5.4.2.3.
Analysis Methods .................................................................................................................... 42
5.4.2.3.1.
Statistical model ................................................................................................................... 42
5.4.2.3.2.
Handling of missing data...................................................................................................... 42
5.4.2.3.3.
Main, sensitivity and supplementary analyses..................................................................... 42
5.4.2.3.3.1.
Main analysis .................................................................................................................... 42
5.4.2.3.3.2.
Sensitivity analyses........................................................................................................... 42
5.4.3.
Supportive Secondary Endpoint(s)............................................................................................. 42
5.4.3.1.
Change from baseline to Week 26 in BDI/Borg CR10®........................................................... 43
5.4.3.1.1.
Definition .............................................................................................................................. 43
5.4.3.1.2.
Analysis Methods ................................................................................................................. 43
5.5.
Exploratory Endpoint(s) Analysis ................................................................................................... 44
5.5.1.
Change from baseline up to EOS, by visit, in BDI/Borg CR10® collected immediately at 
the end of each individual 6MWT ...............................................................................................44
5.5.1.1.
Definition.................................................................................................................................. 44
5.5.1.2.
Analysis Methods .................................................................................................................... 44
5.5.2.
Change from baseline up to EOS, by visit, in exercise capacity, as measured by the 
6MWD......................................................................................................................................... 44
5.5.2.1.
Definition.................................................................................................................................. 44
5.5.2.2.
Analysis Methods .................................................................................................................... 44
5.5.3.
Change from baseline to Week 20 in other hemodynamic parameters (cardiac output 
[CO], cardiac index [CI] and mean right atrial pressure [mRAP]) measured at rest................... 45
5.5.3.1.
Definition.................................................................................................................................. 45
5.5.3.2.
Analysis Methods .................................................................................................................... 46
5.6.
Safety Analyses ............................................................................................................................. 46
5.6.1.
Extent of Exposure ..................................................................................................................... 46
5.6.1.1.
Exposure Duration................................................................................................................... 46
5.6.1.2.
iMTD ........................................................................................................................................ 47
5.6.1.3.
Others...................................................................................................................................... 47
5.6.2.
Adverse Events........................................................................................................................... 48
5.6.2.1.
Adverse Events of Special Interest (AESI)..............................................................................49
5.6.2.2.
Deaths ..................................................................................................................................... 50
5.6.2.3.
Subgroup Analyses ................................................................................................................. 51
5.6.3.
Additional Safety Assessments .................................................................................................. 51
5.6.3.1.
Clinical Laboratory Tests......................................................................................................... 51
5.6.3.2.
Vital Signs and Physical Examination Findings....................................................................... 53
5.6.3.3.
Electrocardiogram ................................................................................................................... 54
5.6.3.4.
Other Safety Parameters......................................................................................................... 54
5.6.3.4.1.
Procedures........................................................................................................................... 54
5.7.
Other Analyses............................................................................................................................... 55
5.7.1.
Definition of Subgroups .............................................................................................................. 55
5.8.
Interim Analyses............................................................................................................................. 56
5.8.1.
Independent Data Monitoring Committee (IDMC) or Other Review Board ................................ 56
5.8.1.1.
Independent Data Monitoring Committee................................................................................56
5.8.1.1.1.
Outputs for IDMC meetings.................................................................................................. 56


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065B302
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved, Date: 11 July 2022
5.8.1.2.
Other Review Boards .............................................................................................................. 57
5.8.1.2.1.
Steering committee .............................................................................................................. 57
5.8.1.2.2.
Adjudication committees ...................................................................................................... 57
5.8.1.2.3.
Clinical Event Committee..................................................................................................... 57
6.
SUPPORTING DOCUMENTATION ..................................................................................................58
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 58
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 61
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 64
6.4.
Appendix 4 Protocol Deviations ..................................................................................................... 66
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................84
6.6.
Appendix 6 Medical History ........................................................................................................... 85
6.7.
Appendix 7 Intervention Compliance ............................................................................................. 86
6.8.
Appendix 8 Adverse Events of Special Interest.............................................................................87
6.9.
Appendix 9 Medications of Special Interest................................................................................... 88
6.10.
Appendix 10 Marked Abnormal Laboratory Values ....................................................................... 89
6.11.
Appendix 11: COVID-19................................................................................................................. 90
7.
REFERENCES................................................................................................................................... 92


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VERSION HISTORY
Table 1:
SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
27 September 2021
Not Applicable
Initial release
2
26 October 2021
1. Updates in Section 5.3:
! 5.3.3.2.1: Main Imputation
Approach
“All observed PVR values will be used to 
derive the imputed values.” updated to 
“Observed PVR values (excluding those 
PVR values beyond the analysis time 
window) will be used to derive the imputed 
values.”
! 5.3.3.3.1: Main Analysis
Addition of “PVR values beyond the 
analysis time window will also be imputed 
using the rules defined in Section 5.3.3.2.1, 
for subjects who are alive and do not have a 
post baseline value.”
! 5.3.3.3.3: Supplementary Analysis 2
Updated from “A further analysis will be 
conducted using observed data only ie, with 
no imputation, on the HES, to assess the 
impact of delayed/missing RHC 
assessments (assumed to be mainly due to 
COVID-19) on the analysis of PVR at 
Week 20.” to “A further analysis will be 
conducted using observed data only 
(including the delayed PVR values beyond 
the analysis time window) ie, with no 
imputation, on the HES, to assess the 
impact of delayed/missing RHC 
assessments (assumed to be mainly due to 
COVID-19) on the analysis of PVR at 
Week 20.”
2. Update to footnote in Table 19.
Clarification on handling 
of specific subgroup 
analyses.
3
11 July 2022
Abbreviated CSR: reduction/change in 
scope.
Early termination of the 
study. 


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the planned analyses for the abbreviated clinical 
study report (CSR) of study AC-065B302. Plans for the analysis and reporting of the double-blind 
(DB) and open-label (OL) periods will be presented.
On 13 December 2021, the results of the planned interim analysis (IA) on the primary endpoint, 
pulmonary vascular resistance (PVR) versus placebo at Week 20, were presented to the 
Independent Data Monitoring Committee (IDMC) by the independent Statistical Support Group 
(SSG). This planned IA did not demonstrate efficacy on the primary endpoint; hence the IDMC 
recommended to stop the study for futility (see IDMC Charter Section 7 for details). Based upon 
the recommendation from the IDMC, the sponsor decided to discontinue the study on 14 December 
2021; this was communicated to sites on 15 December 2021.
Following the decision to prematurely terminate the study it was decided that an abbreviated CSR 
would be produced to summarize key efficacy and safety data only. Such analyses are described 
in this SAP. The study team remains blinded to the results of the IA conducted by the SSG, until 
database lock occurs for the abbreviated CSR planned analyses. A separate SAP or SAP(s) (not 
described here) will be developed for all other analyses.
This SAP is referring to the documents listed in Table 2 and contains definitions of analysis sets, 
key derived variables, and statistical methods for the analysis of efficacy and safety for the 
AC-065B302 SELECT study.
Table 2:
Study Documents
Document
Date, Version
Study Protocol Amendment 3 [EDMS-RIM-265242, 2.0]
29 September 2020, Final Version 4
IDMC Charter [EDMS-RIM-348405, 1.0]
23 February 2021, Final Version 4.0
The SAP for the SSG and open session of IDMC regular data review meetings is provided in a 
separate document. A further IDMC SAP for closed sessions is written and maintained by the SSG
(see IDMC Charter Section 8 for details).
Titles, mock-ups, and programming instructions for all statistical output (tables, listings, and 
figures) are provided in a separate data presentation specifications (DPS 1) document.
Source data for the analyses are provided as Statistical Analysis Software (SAS®) data sets 
according to Clinical Data Interchange Standards Consortium Study Data Tabulation Model 
(SDTM). All descriptive or formal statistical analyses will be performed using SAS®
(Version 9.4), unless otherwise specified.
1.1.
Objectives and Endpoints
Section 2 and Section 6 of the study protocol outline the objectives and endpoints of the study, 
respectively.


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Changes to protocol planned analyses are described in see Section 6.2 Appendix 2. 
1.2.
Study Design
This is a prospective, multi-center, randomized, DB, placebo-controlled, add-on to standard of 
care, parallel-group, group sequential, adaptive Phase 3 study with an OL extension period
(Figure 1). 
Up to 280 subjects will be randomized in a 1:1 ratio to receive either selexipag or placebo during 
the DB period. Subjects completing the DB period will enter the OL extension period and will 
receive selexipag (see protocol Section 5.1.3.2 for OL treatment initiation).
Subjects will be recruited in two sequential cohorts. Approximately the first 90 randomized 
subjects will constitute the hemodynamic cohort and, in addition to the overall study assessments, 
will undergo a right heart catheterization (RHC) (and left heart catheterization ∀LHC#, if needed) 
at Week 20 (see protocol Section 7.2.3.1.2). The remaining subjects will constitute the non-
hemodynamic cohort, who do not require a post-baseline hemodynamic assessment. Both cohorts 
are combined for the evaluation of secondary (and exploratory) efficacy endpoints, which do not 
require a post-baseline hemodynamic assessment. 
Treatment allocation will be stratified by (see Section 1.2.5.1.2):
!
Treatment with PH-specific therapies (ie, endothelin receptor antagonists [ERAs], and/or 
phosphodiesterase type 5 [PDE-5] inhibitors or soluble guanylate cyclase [sGC] stimulators 
[riociguat]: one versus two versus naive [naive capped at 40%]) and
!
CTEPH population: inoperable (with or without BPA) versus persistent-recurrent after PEA 
(including PEA followed by BPA). 


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Figure 1:
Study design
bid = twice daily; BPA = balloon pulmonary angioplasty; DB = double-blind, EDBT = End-of-Double-Blind-Treatment; 
EOLT = End-of-Open-Label-Treatment; EOS = End-of-Study; FU = follow-up, OL = open-label; PH = pulmonary hypertension; 
PTOP = post-treatment observation period, SFU = safety follow-up; V = visit; W = week. 
(1) End-of-double-blind period announcement: when the overall target number of clinical worsening events has been 
reached, or earlier following recommendation of the IDMC or sponsor’s decision.
(2) EDBT visit to occur within 4 weeks of End-of-double-blind period announcement [see (1)].
(3) DB period results to be released approx. 6 months after last EDBT/PTOP-EOS visit.
(4) Variable duration of OL treatment extension period for individual subjects depending on time randomization, with visits 
every 26 weeks ONLY FOR SUBJECTS WHO WERE TRANSITIONED TO THE OL TREATMENT EXTENSION PERIOD 
BEFORE IMPLEMENTATION OF THE AC-065B302 PROTOCOL AMENDMENT 2.
(5)
EOLT visit to occur any time within 26 weeks of the DB period results release [see (3)].
(6) PTOP-EOS visit to occur within 4 weeks of End-of-double-blind period announcement [see (1)].
(7) For subjects with moderate hepatic impairment (Child-Pugh B) or who are concomitantly taking a moderate CYP2C8 
inhibitor (eg, clopidogrel, deferasirox, teriflunomide), the dosing frequency of study treatment is once daily (qd), which must 
be taken in the morning ∀see protocol Section 5.1.9#.
At the time of the decision to terminate the study, a total of 128 subjects had been randomized, of 
whom 91 subjects were randomized in the hemodynamic cohort.
1.2.1.
Study Periods
In both hemodynamic and non-hemodynamic cohorts, the study comprises the following periods: 
screening period, treatment periods, follow-up period, and post-treatment observation period (see 
Figure 1).


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Screening period: Lasts at least 14 days and up to 60 days; starts with the signature of the 
Informed Consent Form (ICF) and ends with the subject’s randomization at Visit 2, Day 1.
The two treatment periods are: 
!
Double-blind treatment period: Starts with the administration of the first dose of DB study
treatment in the evening of the day of randomization (Visit 2) (except in case of once daily
[qd] dosing, where the subjects must take the study treatment in the morning) and with a
titration phase of up to 12 weeks (see Figure 2). It ends on the day of the last dose of DB study
treatment with the EDBT visit. The EDBT visit will occur shortly (within 4 weeks) after the
announcement of end-of-double-blind period, for all subjects who have not discontinued study
treatment prematurely. The end-of-double-blind period will be announced by the sponsor
when the overall target number of clinical worsening events has been reached, or earlier
following the recommendation of the IDMC or sponsor’s decision (see protocol Section 8.3).
!
Open-label treatment period: For subjects who have completed the DB treatment period,
the OL treatment extension period will last at least until the DB period results release and up
to a maximum of 26 weeks after the DB period results release or upon sponsor’s decision for
early termination. It starts with the first dose of the OL study treatment in the evening of the
day of the last dose of DB study treatment, ie, the EDBT visit (except in case of qd dosing,
where the subjects must take the study treatment in the morning). All subjects will have a
titration phase of up to 12 weeks. It ends with the End-of-Open-Label-Treatment (EOLT) visit
that occurs any time within 26 weeks of the DB period results release or upon sponsor’s
decision for early termination.
Follow-up period: Starts on the day after the last dose of OL study treatment and ends 30−35 days 
thereafter with the safety follow-up (SFU) telephone call.
Post-treatment observation period (PTOP): Subjects who prematurely discontinue the DB 
treatment period will enter the PTOP and will continue to perform the visits and assessments as 
scheduled until the PTOP-EOS visit, provided the subject’s consent for this limited participation 
in the study has not been withdrawn.
Up to the point of the decision to prematurely terminate the study, there were 15 subjects who had 
transitioned to the OL treatment period, under study protocol amendment 1, version 2. Subjects
who were randomized from study protocol amendment 2, version 3 onwards or transitioned to 
protocol amendment 2, version 3, during DB treatment, remained in the DB treatment period or 
PTOP.


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Figure 2:
Titration phase
bid = twice daily; D = day; iMTD = individual maximum tolerated dose; V = visit; W = week. 
= weekly telephone calls. 
* 
For subjects with moderate hepatic impairment (Child-Pugh B) or who are concomitantly taking a moderate CYP2C8 
inhibitor (eg, clopidogrel, deferasirox, teriflunomide), the dosing frequency of the study treatment is once daily (qd), which 
must be taken in the morning ∀see protocol Section 5.1.9#.
If the dose regimen is not well tolerated or symptoms cannot be fully managed with symptomatic treatment, the duration of 
the titration step can be prolonged to two weeks (see protocol Section 5.1.3).
1.2.2.
Study Duration
The study starts with the first act of recruitment (ie, first ICF signed) and ends with the last 
telephone call or visit of the last subject.
The subjects will be treated in the DB treatment period for a variable duration depending on each 
subject’s individual date of randomization. The actual duration depends on actual accrual rate and 
clinical worsening event rate (see protocol Section 10.6.3) as well as recommendations of the 
IDMC ∃see protocol Section 10.4% and sponsor’s decision (see protocol Section 8.3). Following 
the decision to prematurely terminate the study, the actual duration is determined by the date that 
decision was communicated to sites, plus the time for each randomized subject’s EDBT visit and 
subsequent SFU phone call. 
Subjects who complete the DB treatment period will enter the OL treatment extension period, 
which lasts at least until the release of results from the DB treatment period and up to a maximum 
of 26 weeks after the DB period results release, or upon sponsor’s decision for early termination. 
Subjects who were transitioned to the OL treatment extension period before implementation of the 
AC-065B302 Protocol amendment 2: Those subjects transitioned to the OL treatment extension 
period after 52 weeks of DB treatment will be treated in the OL treatment period for a variable 
duration depending on each subject’s individual date of randomization. They will remain in the 


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OL treatment extension period until EOLT occurring anytime within 26 weeks of the DB period 
results release ∃see Figure 1 and Table 4%& or upon sponsor’s decision for early termination.
Subjects who prematurely discontinue the DB study treatment will enter a PTOP and cannot enter 
the OL treatment extension period (see protocol Section 3.1.1.4). 
For an individual subject, the EOS visit is defined as the last telephone call/visit performed in the 
study ∃see protocol Section 8.1%. 
1.2.3.
Study Visits and Assessment Schedule
Visit and assessment schedules are presented in Table 3 for the DB treatment period, Table 4 for 
the OL treatment period, and Table 5 for the PTOP (protocol Tables 3, 4 and 5, respectively). 


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Table 3:
Double-blind treatment period: visit and assessment schedule
PERIODS
Name
SCREENING
DOUBLE-BLIND TREATMENT
Duration
At least 14 
days and up to 
60 days
VISITS
Number
1
2
Titration 
phase
3
4
5
6
7
TC every 
26 weeks10
Visit every 
26 weeks10
EDBT
U1, 2, 3, etc.
Name
Screening/ 
Rescreening
Randomi
zation
Week 12 Week 20 Week 26 Week 39 Week 52
Week 65, 
91, 117, etc.
Week 78, 
104, 130, etc
Announced11 or 
for premature 
EDBT within 
7 days after last 
DB dose
Unscheduled 
visit1
Time
Day −60 to Day 
−14
Day 1
Weekly 
from Week 
1 to Week 
11 (± 3 days)
Day 85
(∋7
days)
Day 141
(∋7
days)
Day 183
(∋7
days)
Day 274
(∋7
days)
Day 365
(∋7
days)
Day 456, 
638, 820 etc. 
(∋7 days)
Day 547, 
729, 911, 
etc.
(∋7 days)
Any time
Informed consent
X
Eligibility
X
X
Medical history/Demographics
X
Previous/concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
W
Physical examination*
X
X
X
X
X
X
X
X
X
W
Height
X
Vital signs (BP, HR), Weight
X
X
X
X
X
X
X
X
X
W
Local 12-lead ECG
X
X
X
(X)
RHC (and LHC, if needed)
X2
X3,4
(X)
V/Q scan, PA, CTPA, MRA5
X
Hematology and clinical 
chemistry**
X
X6
X
X
X
X
X
X
X
(X)
Serum pregnancy test**
X
(X)
Urine pregnancy test*
X
monthly (±7 days)
(X)
6MWT/BDI or Borg CR10®
X
X
Post-dose 6MWT/BDI or Borg 
CR10®3
X
X
X
X
X
X
X
W
WHO FC
X
X
X
X
X
X
X
X
X
W
Actigraphy**
X
Every day, 24 hours per day
PAH-SYMPACT®**, 7
X
X
X
X
X
X
EQ-5D-5L, WPAI©: GH**
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
CGI-C
X
X
X
X
X
X
X
NT-proBNP**
X
X
X
X
X
X
X
X
X
(X)
Dose titration
8
iMTD
DB Study treatment 
dispensing/return
–
X
X
X
X
X
X
X
X
SAEs/AEs9
X
X
X
X
X
X
X
X
X
X
X
W


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6MWT = 6-minute walk test; AE = adverse event; BDI = Borg dyspnea index; Borg CR10® = Borg category-ratio 10 Scale®; BP = blood pressure; BPA = balloon 
pulmonary angioplasty; CGI-C = Clinician Global Impression of Change; CGI-S = Clinician Global Impression of Severity; CT = computed tomography; 
CTPA = computed tomography pulmonary angiogram; DB = double-blind; ECG = electrocardiogram; eCRF = electronic Case Report Form; EDBT = End-of-
Double-Blind-Treatment; EOS = end of study; EQ-5D-5L = Euro Quality of Life-5Dimension-5-Level; FC = functional class; HR = heart rate; IDMC = Independent 
data management committee; iMTD = individual maximum tolerated dose; LHC = left heart catheterization; MRA = magnetic resonance angiography; NT-
proBNP = N-terminal pro b-type natriuretic peptide; PA = pulmonary angiography; PAH-SYMPACT® = Pulmonary arterial hypertension symptoms and impact 
questionnaire; PEA = pulmonary endarterectomy; RHC = right heart catheterization; SAE = serious adverse event; V/Q scan = ventilation/perfusion scan; WHO = 
World Health Organization; WPAI©: GH = Work Productivity and Activity Impairment Questionnaire: General Health. 
= telephone call.
1
Unscheduled visits may be performed at any time during the DB treatment period. Assessments (marked with an ‘(X)’ or ‘W’) are performed at the discretion of the
investigator.
If the unscheduled visit is performed due to increase from baseline in WHO FC, deterioration from baseline by at least 15% in exercise capacity, as measured by the 
6MWD, suspicion of clinical worsening (as defined in protocol Section 7.1.2), any change in dose, initiation of PH-specific therapies, or up-titration of DB study 
treatment beyond Week 12, the mandatory
assessments to be performed are marked with a ‘W’. If an RHC (and LHC, if needed) is done at an unscheduled visit, this information must be collected in the eCRF.
2
RHC (and LHC, if needed) must have been performed at least 90 days after full anticoagulation and at least 90 days after last surgical (PEA) or interventional (BPA) 
treatment for subjects with persistent/recurrent CTEPH.
For the hemodynamic cohort, a historical RHC (and LHC, if needed) is allowed, provided it was performed within 30 days prior to Screening*, at least 90 days after 
last change in PH-specific therapies (ie, change in dose or initiation of new class of drugs) and as per guidance in protocol Appendix 1. 
For the non-hemodynamic cohort, historical RHC (and LHC, if needed) is allowed, provided it was performed within 6 months prior to Screening*. 
If no historical results are available, RHC (and LHC, if needed) must be performed during the Screening period (as per guidance in protocol Appendix 1 for the 
hemodynamic cohort).
*
In case of rescreening in the hemodynamic cohort within 6 months of the first Screening Visit, the first screening RHC (and LHC if needed) can be used, provided 
there have been no changes in PH-specific therapy(ies) since the first Screening Visit. In case of rescreening in the non-hemodynamic cohort within 6 months of the 
first Screening Visit, the first screening RHC (and LHC if needed) can be used.
3
Assessment to be performed within 2–5 hours post-dose.
4
Only for subjects in the hemodynamic cohort and must be done after the post-dose 6MWT.
5
Performed in the 14-month period prior to randomization and after last surgical (PEA) and/or interventional (BPA) treatment for subjects with persistent/recurrent 
CTEPH (protocol Section 7.2.2). If no historical results are available, the assessments must be performed during the Screening period.
6
If the results of the screening blood samples from the central laboratory are not available in time for randomization of the subject, an additional blood sample may be 
drawn to verify eligibility based on a local laboratory test.
7
PAH-SYMPACT® questionnaire to be completed for the seven consecutive days following the visit at site (ie, starting the day following the visit day) for the 
symptom part, and on the seventh day of the symptoms diary data collection period, together with the symptom part (ie, in the evening) for the impact part. 
8 
Scheduled telephone calls as per up-titration scheme (protocol Section 5.1.3.1).
9
All AEs and SAEs that occur after signing the Informed Consent Form and until the EOS, as defined in protocol Section 8.1, must be reported (see also protocol 
Section 9).
10 After Week 52, the phone and on-site visits will be alternating every 13 weeks (~3 months).
11. The EDBT visit occurs within 4 weeks after the end-of-double-blind period announcement, ie, within 4 weeks of reaching the overall target number of clinical 
worsening events, or earlier following recommendation of the IDMC, or sponsor’s decision.
* Assessment not collected in eCRF. 
** Transferred electronically by an external service provider.


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Table 4:
Open-label treatment period: visit and assessment schedule
PERIODS
Name
TRANSITION
OPEN-LABEL TREATMENT
SAFETY
FOLLOW-UP
Duration
At least until the DB period results release or
up to a maximum of 26 weeks after the DB period results release
30 days
VISITS1
Number
EDBT
Titration
phase
OL 1
OL 2
Visits every 26 
weeks7
EOLT
Safety follow-up
(Telephone call)
Name
OL-Week 12
OL-Week 26
OL-Week 52, 78, 
104, etc
Time
Announced6
Weekly 
from OL-
Week 1 to 
OL-Week 
11
(± 3 days)
Day 85 after 
EDBT 
(∋7 days)
Day 183 after 
EDBT
(∋7 days)
Day 365, 547, 729 
after EDBT, etc 
(∋7 days)
Any time within 26 weeks of 
the DB period results release 
or for premature EOLT 
within 7 days after last OL 
dose
30 (+ 5) days after last 
OL dose
Previous/concomitant therapy
X
X
X
X
X
X
Physical examination*
X
X
X
X
Vital signs (BP, HR), Weight
X
X
X
X
Hematology and clinical chemistry**
X
X
X
X
Urine pregnancy test*
monthly (±7 days)
Post-dose 6MWT/BDI or Borg 
CR10®2
X
X
X
WHO FC
X
X
X
Dose titration
3
iMTD
OL Study treatment 
dispensing/return
X4
X
X
X
X
SAEs/AEs5
X
X
X
X
X
X
6MWT = 6-minute walk test; AE = adverse event; BDI = Borg dyspnea index; Borg CR10® = Borg category-ratio 10 Scale®; BP = blood pressure; CGI-C = 
Clinician Global Impression of Change; CGI-S = Clinician Global Impression of Severity; DB = double blind; eCRF = electronic Case Report Form; EDBT = End-
of-Double-Blind-Treatment; EOLT = End-of-Open-Label-Treatment; EOS = end of study; EQ-5D-5L = Euro Quality of life-5-Dimension-5-Level; FC = functional 
class; HR = heart rate; IDMC = Independent data management committee; iMTD = individual maximum tolerated dose; LHC = left heart catheterization; NT-pro 
BNP = N-terminal pro b-type natriuretic peptide; OL = open label; PAH-SYMPACT® = Pulmonary arterial hypertension symptoms and impact questionnaire; 
PTOP-SFU = Post-treatment observation period-Safety follow-up; RHC = right heart catheterization; SAE = serious adverse event; WHO = World Health 
Organization. 
= telephone call
1
Unscheduled visits may be performed at any time during the OL treatment period. Assessments are performed at the discretion of the investigator. If any RHC (and 
LHC, if needed) is done at an unscheduled visit, this must be collected in the eCRF.
2
Assessment to be performed within 2–5 hours post-dose.
3
Scheduled telephone calls as per up-titration scheme (see protocol Section 5.1.3.2).
4
First OL dose to be taken on the evening of the EDBT visit or in the morning of the day after EDBT visit in case of qd regimen. (see protocol Section 5.1.3.2).
5
All AEs and SAEs that occur after first dose of OL study treatment and up to 30 days after study treatment discontinuation must be reported (see also protocol 
Section 9).


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6
The EDBT visit occurs within 4 weeks after the end-of-double-blind period announcement ie within 4 weeks of reaching the overall target number of clinical 
worsening events, or earlier following recommendation of the IDMC, or sponsor’s decision.
7
ONLY for subjects who were transitioned to the OL treatment extension period before implementation of the AC-065B302 protocol AMENDMENT 2.
* Assessment not collected in eCRF. 
** Transferred electronically by an external service provider.


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Table 5:
PTOP: visit and assessment schedule
PERIODS
Name
DOUBLE-BLIND PERIOD - OFF-TREATMENT1
(after premature discontinuation of double-blind study treatment)
SURVIVAL 
FOLLOW-UP
VISITS
Number
TC every 
26 weeks8
Visit every 
26 weeks8
PTOP-EOS
SFU 1, 2, 3, etc
Name
PTOP-SFU2
(telephone 
call)
PTOP-
Week 12
PTOP-
Week 20
PTOP-
Week 26
PTOP-
Week 39
PTOP-
Week 52
PTOP-
Week 65, 
91, 117, etc
PTOP-
Week 78, 
104, 130, 
etc
Announced5  Survival Follow-
up
Time
30 (+5 days) 
after last DB 
dose
Day 85
(∋7 days)
Day 141
(∋7 days)
Day 183
(∋7 days)
Day 274
(∋7 days)
Day 365
(∋7 days)
Day 456, 
638, 820 
etc. 
(∋7 days)
Day 547, 
729, 911, 
etc.
(∋7 days)
Yearly after study 
discontinuation
until death or 
announcement6
Previous/concomitant therapy
X
X
X
X
X
X
X
X
X
Physical examination*
X
X
X
X
X
X
X
Vital signs (BP, HR), Weight
X
X
X
X
X
X
X
Local 12-lead ECG
X
X
Hematology and clinical chemistry**
X
X
X
X
X
X
X
6MWT/BDI or Borg CR10®
X
X
X
X
X
X
X
WHO FC
X
X
X
X
X
X
X
Actigraphy**
Every day, 24 hours per day
PAH-SYMPACT®**, 3
X
X
X
X
EQ-5D-5L, WPAI©: GH**
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
CGI-C
X
X
X
X
X
X
X
NT-proBNP**
X
X
X
X
X
X
X
SAEs/AEs4
X
X
X
X
X
X
X
X
X
Survival
X7
6MWT = 6-minute walk test; AE = adverse event; BDI = Borg dyspnea index; Borg CR10® = Borg category-ratio 10 Scale®, PTOP = Post-Treatment Observation 
Period; FC = functional class; SAE = serious adverse event; SFU = safety follow-up; WHO = World Health Organization. 
1 
Depending on the time point of premature double-blind treatment discontinuation, the sequence and/or the applicability of visits may change. If one of the site visits 
falls within the time window of the premature EDBT visit ∀as defined in protocol Section 5.1.1.10#, only the assessments of the premature EDBT are to be 
performed.
2
If the PTOP-SFU falls within the time window of any of the other PTOP visits, then the PTOP-SFU is combined with the corresponding PTOP site visit. In this 
case, the PTOP-SFU assessments are to be done in addition to the assessments of the respective visit. 
3
PAH-SYMPACT® questionnaire to be completed for the seven consecutive days following the visit at site (ie, starting the day following the visit day) for the 
symptom part, and on the seventh day of the symptoms diary data collection period, together with the symptom part (ie, in the evening) for the impact part.
4
All AEs and SAEs that occur after signing the Informed Consent Form and until the EOS, as defined in protocol Section 8.1, must be reported (see also protocol 
Section 9).


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5
The PTOP-EOS visit occurs within 4 weeks after the end-of-double-blind period announcement, ie, within 4 weeks of reaching the overall target number of clinical 
worsening events, or earlier following recommendation of the IDMC, or sponsor’s decision.
6
The end of the survival follow-up period for alive subjects will be announced and corresponds to the end-of-double-blind period announcement ie, within 4 weeks of 
reaching the overall target number of clinical worsening events, or earlier following recommendation of the IDMC, or sponsor’s decision.
7
Only for subjects who prematurely discontinue from DB study treatment and who disagree to continue to perform visits and assessments until the end of the PTOP, 
survival information will be collected yearly ∀see protocol Section 7.2.3.9#.
8
After Week 52, the phone and on-site visits will be alternating every 13 weeks (~3 months).
*
Assessment not collected in electronic Case Report Form. 
** Transferred electronically by an external service provider.


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Following the decision to terminate the study, the sites were instructed to proceed as follows:
Visits Required 
Subjects in Screening
!
Contact the subject and screen fail subject in IWRS 
Subjects on DB Treatment
!
Complete EDBT visit within 4 weeks (no later than 12-Jan-
2022)*
!
30-35 days after the EDBT, complete SFU (telephone call) 
Subjects on OL Treatment 
!
Complete EOLT visit within 4 weeks (no later than 12-Jan-
2022)*
!
30-35 days after the EOLT, complete SFU (telephone call)
Subjects in PTOP
!
Complete PTOP-EOS visit within 4 weeks (no later than 12-
Jan-2022)
!
If the subject has not already completed the PTOP-SFU, this 
must be completed 30-35 days after last dose 
Subjects currently in SFU
!
Complete SFU visit (telephone call) as per protocol (30-35
days after last dose)
Subjects in survival follow-up
!
Contact subject within 4 weeks (no later than 12-Jan-2022) 
and discontinue subject from the study**
* Study treatment should be stopped at the EDBT/EOLT visit. If subject discontinued treatment prior to the EDBT/EOLT visit, 
subject should return for their EDBT/EOLT visit within 7 days of discontinuation of treatment.
** Delays in EOT visits due to: Holidays (Christmas and New Year) between announcement and requested EOT date; COVID-19 
situation at sites where some site staff not returning until mid Jan2022; Post-Trial Access (PTA) requests for individual 
patients seeing clinical benefit of selexipag (PTA requests following premature termination due to futility were unexpected 
and had to be handled on a country-by-country basis).
1.2.4.
Analysis Time Points
The database was to be locked, and the data extracted and analyzed at five planned analysis time 
points during the study (Figure 3):


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Figure 3:
Study Analyses
6MWD = 6-minute walk distance; CRO = Contract Research Organization; EDBT = End-of-Double-Blind-
Treatment; FSFV = First subject first visit; LHC = Left heart catheterization; LSLV = Last subject last visit; 
PTOP-EOS = Post-treatment observation period end-of-study; PVR = pulmonary vascular resistance; RHC = 
Right heart catheterization; SM = Site manager; TTCW = Time to clinical worsening; W = week.
The diagram is not to scale.
The first analysis time point was when approximately 90 randomized subjects (= subjects who 
participated in the hemodynamic cohort) had completed the Week 20 RHC (and LHC, if needed) 
or prematurely discontinued from the study. The final analysis of the primary endpoint (PVR) was
performed by the independent SSG for the IDMC. The details of decision rules and actions to be 
taken following this analysis are presented in the IDMC Charter Section 7.
Due to early termination of the study, analysis time points 2 and 3 are no longer applicable and 
analysis time points 4 and 5 are combined and constitute the final analysis reporting of the study, 
when all randomized subjects up to the point of early termination have performed their EOS visit,
conducted by the sponsor, according to this abbreviated CSR SAP. The primary endpoint analyses, 
as conducted at analysis time point 1 by the SSG, will also be performed by the sponsor, as part of 
this SAP.


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1.2.5.
Randomization and Blinding
1.2.5.1.
Method of Treatment Assignment and Randomization
1.2.5.1.1.
Randomization
After the ICF has been signed, the investigator/delegate contacts the Interactive Response 
Technology (IRT) system at Visit 1 (Screening Visit) to obtain a subject number.
In case of rescreening, the subject number attributed at the time of first screening will be used for 
the rescreened subject.
At Visit 2 (Randomization Visit), after having verified that the subject meets all inclusion criteria 
(including confirmation of CTEPH and inoperability by the corresponding adjudication committee 
(AC) [country-specific adjudication committee (CSAC) or central adjudication committee 
(CAC)]) and none of the exclusion criteria, the investigator/delegate contacts the IRT system to 
randomize the subject. The IRT assigns a unique randomization number to the subject and assigns 
the treatment kit number, which matches the treatment arm assigned by the randomization list to 
the randomization number. The randomization list is generated by an independent Contract 
Research Organization (CRO), Almac Clinical Technologies, using SAS® version 9.4.
1.2.5.1.2.
Stratification
Treatment allocation will be stratified by:
!
Treatment with PH-specific therapies (ie, ERAs, PDE-5 inhibitors, sGC stimulators 
[riociguat]; one versus two versus naïve [naïve capped at 40%]), and 
!
CTEPH population; inoperable [with or without BPA] versus persistent-recurrent after 
PEA [including PEA followed by BPA])
PH-specific therapies currently considered are as follows:
Category
Subcategory
Ingredient names
Antihypertensives for pulmonary 
arterial hypertension
ERAs
ambrisentan, bosentan, sitaxentan, macitentan 
PDE-5 Inhibitors
avanafil, lodenafil, sildenafil, tadalafil, udenafil,
vardenafil
sGC stimulator
riociguat 
Prostanoids*
epoprostenol, treprostinil, iloprost, beraprost  
*Note as per protocol - Exclusion criteria 3: Treatment with prostacyclin (epoprostenol), prostacyclin analogs (ie, 
treprostinil, iloprost, beraprost) or prostacyclin receptor agonists (ie, selexipag/Uptravi®) within 90 days prior to 
randomization (Visit 2), except those given at vasodilator testing during RHC.
Categories are identified by searching the coded WHODRUG preferred terms for occurrence of any of the 
ingredient names. eg, 'sildenafil' and 'sildenafil citrate' will both be assigned to PDE-5 inhibitors. The searching 
methods will be adopted according to the dictionary format in the SDTM. 
Avanafil, lodenafil, udenafil and vardenafil are only approved for treatment of erectile dysfunction but are 
included if the investigator indicates “Underlying study disease (CTEPH)” on the eCRF.
Source: https://www.whocc.no/atc_ddd_index/
If applicable, the list of PH-specific therapies will be updated prior to each planned analysis in the 
respective SAP amendment.


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1.2.5.2.
Blinding and Unblinding
1.2.5.2.1.
Blinding
The first treatment period of this study up to EDBT will be performed in a DB fashion. The 
investigator and study personnel, the subjects, the site managers (SM), sponsor personnel and CRO 
personnel involved in the conduct of the study will remain blinded to the study treatment until the 
fourth analysis time point, ie, until all randomized subjects have completed EDBT/PTOP-EOS 
Visit or prematurely discontinued from the study, and when the DB database is locked and the data 
extract is performed, or when the study is terminated prematurely.
Until the time of sponsor unblinding (see Section 1.2.5.2.2), the randomization list is kept strictly 
confidential and accessible only to authorized persons (ie, an independent SSG and Secure Data 
Office [SDO]), 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.
1.2.5.2.2.
Unblinding
1.2.5.2.2.1.
Unblinding for IDMC meetings
An independent SSG not otherwise involved in the design, conduct and analysis of the study will 
have access to the randomization codes in order to prepare unblinded reports for review by the 
IDMC (see IDMC Charter). The randomization codes will be made available to the independent 
SSG in accordance with the sponsor’s Quality System (QS) documents.
1.2.5.2.2.2.
Unblinding for the first analysis time point (final analysis of 
PVR)
Full randomization information of all subjects randomized so far were made available to the 
independent SSG for the final analysis of PVR. In accordance with the IDMC Charter, the IDMC 
will review the unblinded results and provide a recommendation on continuation or premature 
study termination (see IDMC Charter Section 7).
Following the decision to prematurely terminate the study, the study team remains blinded to the 
results of the IA conducted by the SSG, until database lock occurs for the abbreviated CSR planned 
analyses, which combines analysis time points 4 and 5 as described above in Section 1.2.4.
1.2.5.2.2.3.
Unblinding for the final analysis
Full randomization information will be made available to the sponsor clinical trial team (CTT) for 
data analysis only after all randomized subjects have completed the DB treatment period, or the 
PTOP or prematurely discontinued from the study, and when the DB part of the database is locked 
and the data extract is performed, in accordance with current standard operating procedures. 
Following each subject’s completion of the DB treatment period they will enter the OL extension 
period. In order to preserve the blind of each individual subject until the DB part of the database 
is locked, all subjects will be up-titrated with OL selexipag (see protocol Section 5.1.3.2).


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1.2.5.2.2.4.
Other unblindings
Sponsor personnel responsible for clinical study supply distribution will need to be unblinded at a 
supply level to ensure adequate supply of study treatment. These persons will be clearly identified 
with their unblinding documented in the Trial Master File (TMF).
For the other unblindings, ie, unblinding for suspected unexpected serious adverse reactions and 
emergency procedure for unblinding, please refer to protocol Section 5.1.6.5 and Section 5.1.6.6, 
respectively.
2.
STATISTICAL HYPOTHESES
2.1.
Hypotheses for the Primary Endpoint
The hypotheses for the primary endpoint PVR at Week 20 are formulated in terms of geometric 
mean of PVR pre-post (Baseline-Week 20) percent in subjects treated with selexipag (GMselexipag) 
versus placebo (GMplacebo):
H0: GMselexipag = GMplacebo
HA: GMselexipag ≠ GMplacebo
2.2.
Hypotheses for Secondary Endpoints
Secondary Endpoints
Hypotheses
Change from baseline in 6MWD to Week 26 (key 
secondary endpoint).
The hypotheses are formulated in terms of mean 6MWD pre-
post (Baseline-Week 26) change in subjects treated with 
selexipag (μselexipag) versus placebo (μplacebo):
H0: μselexipag = μplacebo
HA: μselexipag ≠ μplacebo
TTCW (key secondary endpoint)
The null hypothesis is that there is no difference between 
selexipag (Sselexipag(t)) and placebo (Splacebo(t)) for the 
distribution of time to the first CHMP-defined clinical 
worsening event. The alternative hypothesis is that there is 
a difference:
H0: Sselexipag(t) = Splacebo(t)
HA: Sselexipag(t) ≠ Splacebo(t)
Change from baseline to Week 26 in BDI/Borg 
CR10®
The null hypothesis is that there is no difference between 
selexipag and placebo in the mean pre-post (Baseline-Week 
26) change. 
3.
SAMPLE SIZE DETERMINATION
Full details regarding sample size determination for the study are provided in the protocol Section
10.6.
The study consists of two cohorts: approximately the first 90 subjects randomized will form the 
hemodynamic cohort, targeting the primary endpoint of PVR at Week 20. The remaining subjects 
will be randomized to enrich information on all secondary endpoints. If subject enrollment is not 


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terminated for futility or efficacy at analysis time point 1 or 2, the total sample size will be 280 
subjects.
At the time of the decision to terminate the study, a total of 128 subjects had been randomized, of 
whom 91 subjects were randomized in the hemodynamic cohort.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
An overview of analysis sets is provided in Table 6.
Table 6:
Overview of Analysis Sets
Analysis Sets
Description
Screened Analysis Set (SCR)
Includes all subjects who are screened and have a subject identification 
number.
The screen failure subjects are those who are not randomized via the 
interactive voice recognition system, eg, not eligible or withdrawal of
consent.
Full Analysis Set (FAS)
Includes all subjects assigned to a study treatment. In order to adhere to 
the intention-to-treat principle as much as possible: 
!
Subjects are evaluated according to the study treatment they
have been assigned to (which may be different from the study
treatment they have received); and
!
All available data are included.
Hemodynamic Set (HES)
The HES is a subset of subjects in the FAS and comprises all randomized 
subjects in the hemodynamic cohort. In order to adhere to the intention-
to-treat principle as much as possible:
!
Subjects are evaluated according to the study treatment they
have been assigned to (which may be different from the study
treatment they have received); and
!
All available data are included.
Efficacy Evaluable Set (EES) for Week 
26 efficacy endpoints
The EES is a subset of subjects in the FAS and includes all subjects 
who have reached their Week 26 visit (according to the analysis time 
window for the specific Week 26 efficacy endpoint) or have 
discontinued earlier (for any reason except Sponsor decision = Study 
Termination).
An EES is defined for:
!
6MWD: From Day 2 to Day 273 (see Table 8)
!
Other efficacy endpoints: From Day 2 to Day 229 (see Table 8)
Per-protocol Analysis Set (PPS)
The PPS includes a subset of subjects in the FAS who were in 
compliance with the protocol.
The PPS comprises all subjects who received study treatment and who 
complied with the protocol sufficiently to be likely to exhibit the 
treatment effects. Criteria for sufficient compliance include exposure to 
study treatment, availability of measurements and absence of major
protocol deviations that have an impact on the treatment effect. 
A PPS is defined for:
!
PVR Per-protocol Analysis Set (PPS): Includes all subjects in
the HES who do not have major protocol deviations that have
an impact on treatment effect in PVR.


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The full list of criteria for sufficient compliance and the full list of 
protocol deviation codes for exclusion from the PPS are detailed in 
Section 6.4 Appendix 4.
Safety Analysis Set (SAF)
Includes all subjects who received at least one dose of study treatment. 
Subjects are evaluated according to the study treatment they have 
received (which may be different from the study treatment they have 
been randomized to):
!
If a subject has taken at least one dose of selexipag, she/he is 
assigned to the selexipag treatment group.
!
If a subject has taken only placebo, she/he is assigned to the 
placebo treatment group.
Table 7 defines all analysis sets and their specific usage at all analysis time points. For 
decision-making at analysis time point 1, PVR was evaluated on the HES. Week 26 efficacy 
endpoints will be evaluated on the EES. All other efficacy analyses will be evaluated on the FAS, 
unless otherwise specified. Safety endpoints will be evaluated on the SAF.
Table 7:
Analyses sets and their usage at each analysis time-point
Analysis 
Time point
Analysis 
Analysis Set
FAS
HES
PPS
EES**
SAF
1
Final PVR
X
X
1
Exposure and safety
X
1
Others*
X
X
EOS
Final 6MWD
X
X
EOS
Final TTCW
X
EOS
Final hemodynamic 
parameters other than PVR
X
EOS
Final DB 
X
X
X
EOS
Final OL
X
X
*
Demographic and baseline characteristics, medial history, previous and concomitant medications, efficacy endpoints other 
than PVR, 6MWD and TTCW.
** For Week 26 efficacy endpoints.
The “X” indicates the analysis sets to be used for the main analyses for the respective endpoints and time points.
6MWD = 6-minute walk distance; DB = double-blind; EES = Efficacy Evaluable Set (EES) for Week 26 efficacy endpoints; 
FAS = Full analysis set; HES = Hemodynamic set; OL = open-label; PPS = Per-protocol analysis set; 
PPS = PVR Per-protocol analysis set; SAF = Safety analysis set; TTCW = Time to clinical worsening.
5.
STATISTICAL ANALYSES
5.1.
General Considerations
5.1.1.
Overall Testing Strategy
The primary and secondary efficacy endpoints were to be tested in a specified hierarchy (Figure 4)
and at multiple time points (see Section 1.2.4). 


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Figure 4:
Testing strategy for primary and secondary endpoints (2-sided type I error rate, α = 5%)
6MWD = 6-minute walk distance; BDI = Borg dyspnea index; Borg CR10®= Borg category-ratio 10 Scale®; CHMP = Committee 
for Medicinal Products for Human Use; PAH-SYMPACT®= Pulmonary Arterial Hypertension Symptoms and Impact®; PH = 
pulmonary hypertension; PVR = pulmonary vascular resistance; TTCW = Time to clinical worsening; WHO FC = World Health 
Organization functional class.
The primary endpoint analysis as described in Section 5.3, was performed at analysis time point
1, when approximately 90 randomized subjects (= subjects who participated in the hemodynamic 
cohort) had completed the Week 20 RHC (and LHC, if needed) or prematurely discontinued from 
the study. This analysis constitutes the first and final analysis of the PVR endpoint and was tested 
on the HES at 2-sided alpha of 5%. Failure to meet success on the primary endpoint led to 
termination of the study for futility, as no remaining alpha is available to formally test secondary 
endpoints.
Following the decision to prematurely terminate the study due to futility at analysis time point 1, 
the pre-planned testing hierarchy is no longer applicable, and all efficacy analyses other than PVR 
are exploratory. Further, early termination of the study has a significant impact on the amount of 
data available for the analysis of key secondary, supportive, and exploratory endpoints (eg, number 
of subjects reaching the Week 26 endpoint, low number of CW events), which may result in limited 
interpretation of some of the analyses.


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Key and supportive secondary efficacy variables and their analyses are described in Section 5.4, 
as well as important exploratory efficacy variables as described in Section 5.5 and safety analyses 
as described in Section 5.6, using analysis sets as specified in Table 7. 
5.1.2.
Visit and Analysis Time Windows
As subjects do not always adhere to the protocol visit schedule, the following rules are applied to 
assign actual visits (including unscheduled visit results) to analysis visits. Listed below are the 
visit and analysis time windows and the target days for each visit. The reference day is Study Day 
1 for the DB period or the first OL dose for the OL period. Each assessment will be assigned to 
one corresponding visit label and analysis time window. If a subject has two or more actual visits 
in a given visit window, the visit closest to the target day will be used as the analysis visit for that 
visit window. The other additional visit(s) will not be used in the table summaries or analyses 
unless otherwise specified (for example, they can be used for determination of clinically important 
endpoints). If two visit assessments are equidistant from the target day within a visit window, the 
later visit assessment is used. For endpoints evaluated at specific time points, assessments at 
different visits may be used. 
All assignments will be made in chronological order. Once a visit date is assigned to a visit 
window, it will no longer be eligible to be used for a later time point except for the endpoint. 
Table 8 presents scheduled visits with the corresponding visit labels, target study days and analysis 
time windows for efficacy and safety data parameters.
Table 8:
Visit and Analysis Time Windows
Parameter
Analysis
Period
Scheduled 
Visit 
Number
Time Interval 
(label on output)
Analysis Time 
Window6) (Day)
Target 
Time 
Point 
(Day)5)
Efficacy* RHC
Screening
1
Screening
< 1
-60 to -14
DB
  44)  
(DB-W20)
Endpoint at W20
2 to 1891)
141
Efficacy* 6MWD
Screening
1
Screening
< 1
-60 to -14
DB
2
Baseline
<=1
1
DB
3
Week 12
2 to 113
85
DB
4
Week 20
114 to 162
141
DB
5
Week 26
163 to 229
183
DB
6
Week 39
230 to 320
274
DB
7
Week 52
321 to 456
365
DB
  87)
Week 78
457 to 638
547
DB
9
Week 104
639 to 820
729
DB
10
Week 130
821 to 1002
911
DB
11
Week 156
1003 to 1184
1093
etc
etc
etc
etc
DB
Endpoint at W26
2 to 2731)
183
DB
DB-Endpoint
2 to end of DB 
Efficacy parameters*2)
(excl. RHC and 
6MWD)
Screening
1
Screening
< 1
-60 to -14
DB
2
Baseline
<=1
1
DB
3
Week 12
2 to 113
85
DB
4
Week 20
114 to 162
141


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Table 8:
Visit and Analysis Time Windows
Parameter
Analysis
Period
Scheduled 
Visit 
Number
Time Interval 
(label on output)
Analysis Time 
Window6) (Day)
Target 
Time 
Point 
(Day)5)
DB
5
Week 26
163 to 229
183
DB
6
Week 39
230 to 320
274
DB
7
Week 52
321 to 456
365
DB
  87)
Week 78
457 to 638
547
DB
9
Week 104
639 to 820
729
DB
10
Week 130
821 to 1002
911
DB
11
Week 156
1003 to 1184
1093
etc
etc
etc
etc
DB
Endpoint at W26
2 to 2291)
183
DB
DB-Endpoint
2 to end of DB 
Safety parameters*3)
Screening
1
Screening
< 1
-60 to -14
DB
2
Baseline
<=1
1
DB
3
Week 12
2 to 113
85
DB
4
Week 20
114 to 162
141
DB
5
Week 26
163 to 229
183
6
Week 39
230 to 320
274
DB
7
Week 52
321 to 456
365
DB
  87)
Week 78
457 to 638
547
DB
9
Week 104
639 to 820
729
DB
10
Week 130
821 to 1002
911
DB
11
Week 156
1003 to 1184
1093
etc
etc
etc
etc
Re-Baseline in OL**
OL
  1027)
OL-Baseline
<= [1]
[1]
OL
103
OL-Week 12
[2] to [134]
[85]
OL
105
OL-Week 26
[135] to [274]
[183]
OL
  1078)
OL-Week 52
[275] to [456]
[365]
OL
108
OL-Week 78
[457] to [638]
[547]
OL
109
OL-Week 104
[639] to end of 
OL
[729]
etc
etc
etc
etc
OL
OL-Endpoint
[2] to end of OL 
6MWD = 6-minute walk distance; DB = Double blind; OL = Open label; RHC = Right heart catheterization
*
Time Interval and Target Time Point are relative to Visit 2 (Study Day 1)
** Target Time Point and Analysis Time Window specified in [xx] are relative to the start date of OL; first OL dose to be taken 
on the evening of the EDBT visit or in the morning of the day after EDBT visit in case of qd regimen (see protocol Table 4).
1) 
Missing data will be imputed. 
2)
Efficacy parameters: TTCW, BDI/Borg CR10®. 
3) 
Safety parameters: Vital Signs, Weight, laboratory tests.
4)
Only for subjects in the hemodynamic cohort. 
5)
Target time point as defined in the protocol visit and assessment schedules.
6)
Analysis time windows are wider than the assessment schedules specified in protocol. The analysis time windows will be 
applied to all collected data including scheduled, unscheduled and PTOP visits. PTOP flag will be included in the ADaM. 
7)
Scheduled Visit Number = After Week 52, phone and on-site visits will be alternating every 13 weeks (~3 months).
8)
ONLY FOR SUBJECTS WHO WERE TRANSITIONED TO THE OL TREATMENT EXTENSION PERIOD BEFORE 
IMPLEMENTATION OF THE AC-065B302 PROTOCOL AMENDMENT 2.
Note: “Endpoint at Week XX” is the value used for the analysis endpoints, as applicable.


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5.1.3.
Study Day and Relative Day
Visit 2 is the date of randomization and usually also the date of the first study treatment 
administration. In general, in the DB period, for baseline characteristics, as well as efficacy 
endpoints the Study Day 1 or Day 1 refers to date of randomization; while for medical history, 
previous and concomitant medications exposure and safety endpoints the Study Day 1 or Day 1 
refers to date of the first study treatment administration. If the date of randomization and the date 
of the first study treatment administration are different, the study day would not be the same for 
all endpoints. 
For the OL period, Study Day 1 or Day 1 refers to date of the first study treatment administration 
in the OL treatment period.
All assessments at all visits will be assigned a study day relative to the respective Study Day 1.
Study day for an event/assessment on or after the respective Study Day 1 (≥date of Study Day 1) 
is calculated as: 
Event/assessment date - (date of Study Day 1) + 1. 
Study day for an event/assessment prior to the respective Study Day 1 (< Study Day 1 date) is 
calculated as: 
Event/assessment date - (date of Study Day 1). 
There is no 'Day 0'.
5.1.4.
Baseline and Endpoint
In the DB period, baseline is defined as the last observation prior to or at the randomization date 
for baseline characteristics, as well as for all efficacy endpoints; while for medical history, previous 
and concomitant medications, exposure, and safety endpoints baseline is defined as the last 
observation prior to the date of the first study treatment administration. OL-baseline is relative to 
the start date of the first study treatment administration in the OL treatment period.
Endpoint is defined as the available post-baseline result that is closest to the protocol defined target 
time point(s) within the respective analysis time-window(s) (see Section 5.1.2). Unscheduled visit 
results are included in this definition and will be considered as the endpoint value if the 
unscheduled visit result is the post-baseline result that is closest to the protocol defined target time 
point(s) within the respective analysis time-window(s). 
For the primary and key secondary endpoints, if there is no post-baseline result available within 
the respective analysis time-window, the imputation rules will be applied according to
Section 5.3.3.2 and Sections 5.4.1.3.2 and 5.4.2.3.2, respectively. 
5.1.5.
Study Periods
An overview of the study periods is provided in Section 1.2.1 and Table 3, Table 4 and Table 5.


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5.1.6.
Study Completion
As per protocol Section 8.1, subjects who perform the EOS telephone call/visit are considered as 
study completers: 
!
For subjects who complete their study treatment up to the EOLT visit, the EOS visit 
corresponds to the safety telephone call which occurs 30–35 days after the last OL dose.
!
For subjects who prematurely discontinue the DB study treatment, the EOS visit corresponds 
to the last visit in the PTOP period, ie, the PTOP-EOS visit. It occurs within 4 weeks after the 
end-of-double-blind period announcement, ie, within 4 weeks of reaching the overall target 
number of clinical worsening events (protocol Section 10.6.3), or earlier following 
recommendation of the IDMC (protocol Section 10.4) and sponsor’s decision (protocol 
Section 8.3). 
!
For subjects who prematurely discontinue the OL study treatment, the EOS visit corresponds 
to the safety telephone call (ie, 30–35 days after last OL dose).
Subjects who prematurely withdraw from the study, per protocol Section 8.2, are not considered 
as study completers:
!
For subjects who prematurely withdraw from the study, the EOS date is defined as the date of 
either death, last unsuccessful follow-up contact attempt, consent withdrawal, physician 
decision or sponsor decision, depending on the reason for study discontinuation.
5.1.7.
Imputation Rules for Missing Adverse Event Date/Time of Onset
5.1.7.1.
Treatment-emergent AEs
AEs with completely missing onset dates will be considered as treatment-emergent (avoiding 
under reporting of treatment-emergent AEs). AEs with partially missing onset dates will also be 
included as treatment-emergent when the month (if it exists) and the year occur on or later than 
the month and year of the initial study treatment date.
5.1.7.2.
Imputation Rules
The date value is split into day, month, and year parts as outlined below:
Day
Month
Year
Partial AE Start Date
Not used 
(missing and will be imputed) 
MON
YYYY
Treatment Start Date (TRTSDT)
Not used
TRTM
TRTY
Completely missing start dates will not be imputed. Partial AE start dates are imputed with 
reference to the treatment start date (TRTSDT) as outlined in the matrix of start year (YYYY) vs 
start month (MON) below.


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The Italic bold font indicates the imputed values.
MON MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY MISSING
Do not impute
Do not impute
Do not impute
Do not impute
YYYY < TRTY
(D) = 31DECYYYY
Before Treatment 
Start 
(C) = 01MONYYYY
Before Treatment 
Start 
(C) = 01MONYYYY
Before Treatment 
Start
(C) = 01MONYYYY
Before Treatment 
Start
YYYY = TRTY
(B) = min(TRTSDT, 
AE resolution)
Uncertain
(C) = 01MONYYYY
Before Treatment 
Start
(B) = min(TRTSDT, 
AE resolution)
Uncertain
(A) = 01MONYYYY
After Treatment 
Start
YYYY > TRTY
(E) = 01JANYYYY
After Treatment 
Start
(A) = 01MONYYYY
After Treatment 
Start
(A) = 01MONYYYY
After Treatment 
Start
(A) = 01MONYYYY
After Treatment 
Start
The following table is the legend to the matrix above.
Relationship
Before Treatment Start 
Partial date indicates AE start date prior to Treatment Start Date 
After Treatment Start 
Partial date indicates AE start date after Treatment Start Date
Uncertain
Partial date insufficient to determine the sequence of AE start date 
and Treatment Start Date
Imputation Calculation
(A) After Treatment Start 
01MONYYYY 
(The closest date to the treatment start date for imputation)  
(B) Uncertain
min(TRTSDT, AE resolution)
(AE happed just after the treatment start)  
(C) Before Treatment Start
01MONYYYY
(Start-month point will be used for imputation)  
(D) Before Treatment Start
31DECYYYY
(End-year point will be used for imputation)  
(E) After Treatment Start
01JANYYYY
(The closest date to the treatment start date for imputation)  
Note: Imputation rules for concomitant medications follow the same approach as for AEs.
5.2.
Subject Dispositions
The number of subjects screened and the number of screen failures, as well as the reason for screen 
failures will be summarized overall. If a subject is rescreened, they will be counted only once in 
the SCR. If a subject was rescreened and screen failed for a second time, they will be counted only 
once as a screen failure and only the later reason for screen failure will be considered. If a subject 
was rescreened and subsequently randomized, they will not be considered as a screen failure. The 
number of subjects rescreened, and the number of subjects rescreened and not randomized will be
summarized in the screen failure disposition table.
The number and percentage of subjects in the following disposition categories will be summarized
throughout the study by treatment group and overall:
!
Subjects randomized
!
Subjects receiving study treatment in DB period


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!
Subjects completed the EDBT
!
Subjects who prematurely discontinued DB treatment 
(
Reasons for discontinuation of DB study treatment
(
Subjects discontinued before Week 20
(
Subjects discontinued before Week 26
!
Subjects who entered PTOP
!
Subjects completed the PTOP
!
Subjects who started selexipag treatment in the OL treatment period
!
Subjects who completed the End-of-Open-Label-treatment (EOLT) 
!
Subjects who prematurely discontinued OL study treatment before EOLT
(
Reasons for discontinuation of OL study treatment
!
Study completion
(
Study completers (as defined in Section 5.1.6 and protocol Section 8.1).
(
Reasons for premature withdrawal from study
Listings of subjects will be provided for the following categories:
!
Subjects’ randomization information
!
Subjects who were mis-stratified (PH-specific therapies and CTEPH population) in the IRT 
system.
!
Subjects who were randomized yet did not receive DB study treatment
!
Subjects who started DB study treatment after but not on day of randomization
!
Subjects who received wrong study treatment to their randomized assignment
!
Subjects who prematurely discontinued (DB and OL) treatment, including flags for the 
following:
(
Subjects who prematurely discontinued DB treatment before Week 20
(
Subjects who prematurely discontinued DB treatment before Week 26
!
Subjects who entered PTOP
!
Subjects who were unblinded by investigator during the DB study period
5.3.
Primary Endpoint Analysis
The primary endpoint, primary estimand and the primary analyses methods are described below 
in Sections 5.3.1, 5.3.2 and 5.3.3, respectively. Sections 5.3.3.3.2, 5.3.3.3.3 and 5.3.3.4 provide a 
summary of sensitivity, supplementary and subgroup analyses which are planned to support the 
primary efficacy endpoint.
5.3.1.
Definition of Endpoint
The primary efficacy endpoint of this study is the PVR at Week 20, assessed at rest, within 2–5 
hours post-dose, expressed as percent of baseline PVR.
The Week 20 value is the one identified for the Week 20 analysis time window (see Table 8).


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At each assessment, PVR (dyn.sec/cm5) is derived as follows:
 = 80 ×  −

,
where mPAP is mean pulmonary artery pressure measured in mmHg, PAWP is pulmonary artery 
wedge pressure measured in mmHg, and CO is cardiac output measured in L/min. Following the 
Actelion Heart Catheterization Guidance (see protocol Appendix 1), left ventricular end diastolic 
pressure (LVEDP) is to be recorded when PAWP is not available or not reliable. In this case, 
LVEDP will replace PAWP in the calculation of PVR. The results from the sponsor derived PVR 
(in dyn.sec/cm5) in the analysis dataset are used for analysis. Smaller PVR values indicate better 
condition. 
The primary endpoint PVR at Week 20 is expressed as percent of the baseline value, ie:
 -  =    20
   !" × 100 (%)
5.3.2.
Estimand
Primary trial objective:
To evaluate the effect of selexipag versus placebo on PVR at Week 20 in subjects with inoperable 
CTEPH (ie, technically non operable) and persistent/recurrent CTEPH after surgical (pulmonary 
endarterectomy [PEA]) and/or interventional (balloon pulmonary angioplasty [BPA]) treatment.
Estimand scientific question of interest:
What is the effect on percent change from baseline to Week 20 in PVR, when subjects diagnosed 
with CTEPH, as defined by the study eligibility criteria, are assigned to selexipag versus placebo?
Estimand
A. Treatment:
!
Experimental: Selexipag
!
Control: Placebo
B. Population: Subjects with inoperable CTEPH or persistent/recurrent CTEPH after surgical
(PEA) and/or interventional (BPA) treatment in the HES.
C. Variable: PVR at Week 20, expressed as percent of the baseline value, ie, the PVR pre-post 
percent defined above. For subjects who die without a Week-20 PVR assessment, the PVR 
pre-post percent will be imputed as defined in Section 5.3.3.2.1.
D. Summary measure (Population-level summary): difference in means of natural logarithm 
transformed PVR pre-post percent between selexipag and placebo, or equivalently ratio of 
geometric means of PVR pre-post percent between selexipag and placebo, ie,
'! ( -  !  (!))
'! ( -  !  )


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The main estimator of the treatment effect will be evaluated using an ANCOVA model for natural 
logarithm transformed PVR pre-post percent with treatment group, stratification factors and 
natural logarithm transformed baseline PVR value as covariates.
E. Intercurrent events (IE) and their corresponding strategies: IEs and their corresponding
strategies are summarized in Table 9 below.
Table 9:
Intercurrent Events and Corresponding Strategies for the Main Estimand of PVR
Intercurrent Events
Strategy for Addressing Intercurrent Events and Its Description
Premature discontinuation of 
DB treatment for any reason
Treatment policy strategy: The occurrence of the IE is considered irrelevant in 
defining the treatment effect of interest ie, the value of the variable of interest is 
used regardless of whether or not the IE occurs (to reflect intention-to-treat (ITT) 
principle). Data for the variable of interest will still be collected after the IE (in 
PTOP).
Receiving additional therapy
(see protocol 
Section 5.1.11.4 and 5.2.5)
Death
Composite variable strategy: The IE is considered in itself to be informative 
about the subject’s outcome and is therefore incorporated into the definition of 
the variable.
Deaths occurring prior to the Week 20 assessment will be addressed by imputing 
the Week 20 PVR value, using the rules defined in Section 5.3.3.2.1.
5.3.3.
Analysis Methods
5.3.3.1.
Statistical Model
Hypotheses and statistical model:
The hypotheses for the primary endpoint PVR at Week 20 are described in Section 2.1.
An ANCOVA model will be applied on the loge-transformed PVR pre-post percent. Model
covariates will include randomized treatment, stratification factors (PH-specific therapies and 
CTEPH population [see Section 1.2.5.1.2]) and the loge-transformed baseline PVR value. The 
residuals of the loge-transformed pre-post percent values are assumed to follow a normal 
distribution.
Improvement in PVR by selexipag over placebo is indicated by a small (< 1) ratio of the geometric 
mean (GMselexipag/GMplacebo). 
5.3.3.2.
Handling of Missing Data
5.3.3.2.1.
Main imputation approach
Imputation methods for PVR will be specific to the reason for missing data.
The baseline reference value for PVR is based on the last right heart catheterization (RHC) (and 
LHC, if needed) performed prior to randomization (see protocol Section 7.2.3.1.1). 
If PVR cannot be calculated due to missing PAWP and LVEDP, the following conventions will 
be applied for the calculation at a visit at which both mPAP and CO are assessed:


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1.
If PAWP and LVEDP are missing both at baseline and post-baseline, the missing PAWP is 
imputed using the median of all values observed at the respective time point in all subjects 
from the same randomized treatment group.
2.
If PAWP and LVEDP are missing either at baseline or at post-baseline, the available PAWP 
for the subject is used as a substitute for the missing PAWP.
In the case of a missing PVR value at Week 20, the last available post-baseline value obtained 
before the Week 20 analysis time window is carried forward. It is assumed that this will mainly 
occur in subjects who have an unscheduled RHC performed at the time of a PH-related disease 
progression prior to the Week 20 analysis time window. This imputation will be performed except 
in the following cases:
!
If a subject dies without a Week 20 value, then the missing pre-post percent value is imputed 
with the largest pre-post percent value at Week 20 amongst all subjects in the same treatment 
group and analysis set (as in Zeng 2012 and Ghofrani 2017). The resulting imputed Week 20 
PVR is the product of this imputed pre-post percent value and the respective baseline PVR 
value. Subjects who die before the Week 20 assessment are likely to have experienced 
considerable deterioration prior to death. This imputation approach assigns the worst observed 
value in the same treatment group to such subjects; hence presenting the potentially worst-case
scenario.
!
If the subject is alive and does not have a post-baseline value, then the missing pre-post percent 
value is imputed with the 50th percentile of the pre-post percent values from all subjects in the 
same treatment group and analysis set (as in Ghofrani 2017). The resulting imputed Week 20 
PVR is the product of this imputed pre-post percent value and the respective baseline PVR 
value. Subjects who are still alive at Week 20 are likely to be in relatively good condition. 
This imputation approach assigns the median value in the same treatment group to such 
subjects; hence presenting a neutral scenario.
Observed PVR values (excluding those PVR values beyond the analysis time window) will be 
used to derive the imputed values.
5.3.3.2.2.
Alternative imputation approach
As an alternative approach for missing values, multiple imputation will be applied 
(Carpenter 2008, O’Kelly 2014), under the assumption of missing at random, with slight 
modification based on the reason for missingness. 
The randomly imputed value for a missing loge-transformed PVR pre-post percent value (due to 
missing at baseline or at Week 20) will be generated from a normal distribution with a mean value 
that depends on the reason for missingness, and a variance estimated from the complete cases 
within the subject’s treatment group and analysis set.
Reasons for missing information are derived from collected data in the electronic Case Report 
Form (eCRF) and are expected to be justified by a change in outcome (such as WHO FC, AE, 
etc.). For each missing pre-post percent value, the reason for missingness is categorized to 
worsening, no change or improvement. The criteria for the categorization and the corresponding 
means and standard deviations (SD) for the normal distributions to generate imputed values of 
loge-transformed PVR pre-post percent are summarized in Table 10 below.


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Table 10:
Categorization of missing data and the corresponding means and standard deviations for the 
normal distributions to generate imputed loge-transformed pre-post percent values of PVR
Category
Criterion
Meana for imputation
SDa,b for imputation
Worsening
If subject has:
A worsening in WHO FC
(increase from baseline) is 
reported at or before the time 
point of missing data, or 
Any treatment-emergent SAE 
occurrence, or
Study treatment or study is 
prematurely discontinued with 
the main reason given as lack of 
efficacy, treatment failure, 
tolerability or efficacy related.
The upper quartile of 
the loge-transformed
pre-post percent values
One quarter of the 
difference between 
the maximum and the 
median of the 
observed 
loge-transformed pre-
post percent values
Improvement
If subject has:
No above-mentioned SAEs or 
premature discontinuation, and 
An improvement in WHO FC
(decrease from baseline) is 
reported at or before the time 
point of missing data.
The lower quartile of 
the loge-transformed
pre-post percent values
One quarter of the 
difference between 
the minimum and the 
median of the 
observed 
loge-transformed pre-
post percent values
No change
All other cases with missing 
data.
The median of the 
loge-transformed pre-
post percent values
The SD of observed 
loge-transformed pre-
post percent values 
per treatment group 
and analysis set
SD = standard deviation.
a
Mean and standard deviation for a normal distribution, determined based on complete cases in the respective 
treatment group and analysis set.
b
The standard deviation to be used to generate imputed pre-post percent values is designed to create an 
appropriate distribution of imputed values around the upper quartile, the median and the lower quartile for the 
worsening, no change and improvement categories, respectively.
With the respective means and SDs, missing loge-transformed pre-post percent values will be 
imputed randomly from normal distributions to create a total of 100 analysis sets with complete 
data. ANCOVA models as described in Section 5.3.3.1 will be applied to each of these 100 analysis 
sets. Results will be aggregated following Rubin’s rule, ie, the final estimate is the mean of per-
imputation point estimates and the final variance is the sum of the average within-imputation 
variance and 1.01 times the between-imputation variance (Rubin 1987). On final point and 
variance estimates, 95% CL will be determined before back-transformation.


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In summary, the randomly imputed value of loge-transformed pre-post percent for a subject will 
be generated from:
!
normal distributions based on complete cases for each treatment arm 
!
Mean/SD adjusted for reasons for missingness 
Step 1: Derive the quartiles, maximum and minimum within treatment group from the non-missing 
values of the loge-transformed PVR pre-post percent change from baseline to Week 20.
Step 2: Impute the missing data by drawing a value from a normal distribution with a Mean and 
SD depending on the subject categorization in Table 10.
Step 3: Repeat step 2, 100 times
Step 4: Estimate treatment difference using ANCOVA analysis with stratification factors 
(PH-specific therapies and CTEPH population) and the loge-transformed baseline PVR value as 
covariates and treatment as factor in the model for each of the imputed datasets generated in step 
3.
Step 5: Use the SAS MIANALYZE procedure to estimate the combined treatment difference and 
standard error from the estimates obtained in step 4.
5.3.3.3.
Main, Sensitivity and Supplementary Analyses
5.3.3.3.1.
Main analysis
For the main estimand defined in Section 5.3.2, the main analysis refers to the final analysis of 
PVR at Week 20 with observed or imputed values (using the main imputation approach in 
Section 5.3.3.2.1), tested on the HES (pre-planned with approximately 90 subjects) at a full 2-sided 
significance level of 5% using the ANCOVA model (see Section 5.3.3.1). Missing PVR 
assessments at baseline or at Week 20 will be imputed specific to the reason for missing data and 
death occurring prior to the Week 20 visit will be addressed by imputing the Week 20 PVR value,
using the rules defined in Section 5.3.3.2.1. PVR values beyond the analysis time window will 
also be imputed using the rules defined in Section 5.3.3.2.1, for subjects who are alive and do not 
have a post-baseline value.  
From the ANCOVA model, PVR pre-post percent will be summarized by treatment group using 
covariate-adjusted geometric means and corresponding 2-sided 95% CL. The between-group ratio 
of geometric means with corresponding 2-sided 95% CL and p-value will be displayed as the 
placebo-corrected treatment effect. 
For each treatment group, the arithmetic mean and 95% CL of the natural logarithm of the pre-post 
percent will be inversely transformed using the exponential function and multiplied by 100 to 
provide the geometric mean of the pre-post percent and the corresponding 95% CL, expressed as 
a percent. 


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Absolute values at baseline and at Week 20 as well as absolute pre-post changes from baseline to 
Week 20 in PVR will also be summarized using descriptive statistics. 
A listing of observed and imputed values and changes from baseline to Week 20 for PVR will be
provided for the HES by treatment group. Observed data after EDBT (PTOP) and imputed data 
will be flagged.
A listing of hemodynamic parameters (as per Table 16) will also be provided on the FAS (HES 
subjects will be flagged).
5.3.3.3.2.
Sensitivity analyses
For the main estimand defined in Section 5.3.2, the following sensitivity analyses will be 
performed to assess the robustness of the main analysis results. All these analyses will be 
performed on the HES. Given the descriptive nature of these analyses, no adjustments for 
multiplicity testing will be considered
1.
An analysis using the alternative imputation approach (Section 5.3.3.2.2) to assess the
imputation assumptions of the main statistical analysis for PVR at Week 20.
2.
An analysis of PVR at Week 20 using the main imputation approach for missing data
(Section 5.3.3.2.1) but including all observed post-baseline PVR values ie, no imputation for
values beyond the analysis time window, to assess the impact of delayed RHC assessments
(assumed to be mainly due to COVID-19).
3.
The median treatment effect using the Hodges-Lehmann estimate and the corresponding 95%
asymptotic (Moses) CL will be derived and displayed, to assess relaxation of the assumption
for the main ANCOVA model (Section 5.3.3.3.1).
4.
An analysis following the main analysis approach in Section 5.3.3.3.1 but where the
ANCOVA model covariates will include randomized treatment, stratification factors (PH-
specific therapies and CTEPH population as per the eCRF (rather than the IRT stratification
factors) and the loge-transformed baseline PVR value.
5.3.3.3.3.
Supplementary analyses
In support of the main estimand, two supplementary estimands using subsets of the HES will be 
evaluated as described below. Given the descriptive nature of these analyses, no adjustments for 
multiplicity testing will be considered. 
1.
An analysis of PVR at Week 20 using the main imputation approach (Section 5.3.3.2.1) will
be conducted in the subset of the HES meeting the PPS criteria to assess the robustness of the
results of the main statistical analysis against protocol deviations leading to exclusion from
the PPS.
2.
A further analysis will be conducted using observed data only (including the delayed PVR
values beyond the analysis time window) ie, with no imputation, on the HES, to assess the
impact of delayed/missing RHC assessments (assumed to be mainly due to COVID-19) on
the analysis of PVR at Week 20.


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5.3.3.4.
Subgroup Analyses
In order to assess the consistency of the treatment effect across different subject subgroups for the 
primary efficacy variable, subgroup analyses will be performed according to the demographic and 
baseline disease characteristics at randomization as defined in Table 14 on the HES. No 
multiplicity adjustment will be introduced; the subgroup analyses are descriptive in nature.
Subgroup analyses will be conducted according to the ANCOVA method for the main analysis as 
described in Section 5.3.3.3.1.
The treatment effect within subgroups will primarily be displayed with their corresponding 95% 
CLs and presented in a forest plot. The forest plot will also include as a reference the ‘overall’
treatment effect based on the main analysis (as described in Section 5.3.3.3.1).
Subjects with undetermined subgroup information due to missingness will not be included in the 
subgroup analyses.
5.4.
Secondary Endpoint(s) Analysis
Following the decision to prematurely terminate the study due to futility at analysis time point 1, 
all efficacy analyses other than PVR are exploratory and therefore the presented p-values for each 
secondary endpoint will be for exploratory purposes only. For each secondary endpoint, a 2-sided 
95% CL for treatment effect will also be presented. 
Details of the key secondary efficacy endpoints of 6MWD at Week 26 and TTCW are provided in 
Section 5.4.1 and 5.4.2 and for the supportive secondary efficacy endpoint BDI/Borg CR10® in 
Section 5.4.3.
5.4.1.
6MWD at Week 26 (key secondary endpoint)
5.4.1.1.
Definition of Endpoint
6MWD at Week 26 is defined as the change from baseline to Week 26 in 6MWD (in meters): 
6MWD pre-post change (m) = 6MWD (m) at Week 26 − 6MWD (m) at baseline.
The baseline reference value (baseline) for the 6MWD is the distance obtained from the last 6-
minute walk test (6MWT) performed prior to or at randomization. The Week 26 value is the one 
identified for the Week 26 analysis time window (see Table 8).
The longer 6MWD values indicate better condition.
5.4.1.2.
Estimand
The main estimand defining the treatment effect for the 6MWD at Week 26 endpoint has the 
following attributes:
A. Treatment:
!
Experimental: Selexipag


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!
Control: Placebo
B. Population: Subjects with inoperable CTEPH or persistent/recurrent CTEPH after surgical
(PEA) and/or interventional (BPA) treatment in the Efficacy Evaluable Set (EES).
C. Variable: 6MWD at Week 26, expressed as change from baseline value. For subjects who die 
without a Week-26 6MWD assessment, the Week-26 6MWD will be imputed as defined in 
Section 5.4.1.3.2.1.
D. Summary measure (Population-level summary): The main estimator of the treatment effect 
will be evaluated using descriptive statistics.
E. Intercurrent events (IE) and their corresponding strategies: IEs and their corresponding 
strategies are summarized in Table 11 below.
Table 11:
Intercurrent Events and Corresponding Strategies for the Main Estimand of 6MWD
Intercurrent Events
Strategy for Addressing Intercurrent Events and Its Description
Premature discontinuation of 
DB treatment for any reason
Treatment policy strategy: The occurrence of the IE is considered irrelevant in 
defining the treatment effect of interest ie, the value of the variable of interest is 
used regardless of whether or not the IE occurs (to reflect intention-to-treat (ITT) 
principle). Data for the variable of interest will still be collected after the IE (in 
PTOP).
Receiving additional therapy
Death
Composite variable strategy: The IE is considered in itself to be informative 
about the subject’s outcome and is therefore incorporated into the definition of 
the variable.
For subjects who died without any visit performed in the Week 26 analysis time 
window, 0m is imputed for the 6MWD at Week 26 assessment, as defined in 
Section 5.4.1.3.2.1.
5.4.1.3.
Analysis Methods
5.4.1.3.1.
Statistical model
Hypotheses and statistical model:
The hypotheses for the key secondary endpoint 6MWD at Week 26 are described in Section 2.2.
6MWD values at baseline and at Week 26 as well as pre-post changes from baseline to Week 26
will be summarized using descriptive statistics, on the EES.
5.4.1.3.2.
Handling of missing data
5.4.1.3.2.1.
Main imputation approach
Missing values of 6MWD at Week 26 will be imputed as follows: 
!
Rule 1: For subjects unable to walk at Week 26, a 0 is imputed for 6MWD at Week 26. This 
includes: 
(
Subjects who died without any visit performed in the Week 26 analysis time window 


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(
Subjects for whom the Week 26 Visit corresponds to a scheduled (or unscheduled) visit 
and who were unable to walk due to clinical worsening (ie, the reason is entered in the 
eCRF as ‘Clinical worsening (PH-related)’)
!
Rule 2 (if Rule 1 does not apply): The second-lowest observed 6MWD value at Week 26 in 
the same analysis set, according to treatment group, is imputed.
5.4.1.3.3.
Main, sensitivity and supplementary analyses
5.4.1.3.3.1.
Main analysis
For the main estimand defined in Section 5.4.1.2, the above-mentioned summary using descriptive 
statistics will be presented. Missing 6MWD assessments at Week 26 will be imputed using the 
rules defined in Section 5.4.1.3.2.1.
A listing of observed and imputed values and changes from baseline to Week 26 for 6MWD will
also be provided by treatment group, on the EES. Observed data after EDBT (PTOP) and imputed 
data will be flagged.
Further descriptive analyses of 6MWD over time, on the FAS, are outlined in Section 5.5.2.
5.4.2.
TTCW (key secondary endpoint)
5.4.2.1.
Definition of Endpoint
The other key secondary efficacy endpoint is TTCW, where clinical worsening is defined (adapted 
from the CHMP definition [EMEA 2008]) as at least one of the following components, confirmed 
by the CEC:
!
All-cause death
!
Non-planned PH-related hospitalization
!
PH-related deterioration identified by at least one of the following:
(
Increase from baseline in WHO FC*;
(
Deterioration from baseline by at least 15% in exercise capacity, as measured by the 
6MWD*;
(
New or worsening of signs or symptoms of right heart failure, defined as a reported AE 
with one of the following preferred terms: “CTEPH”, “pulmonary hypertension”, “right 
ventricular failure”, “right ventricular dysfunction” and “acute right ventricular failure”.
*Confirmed by a second measurement performed on a different day within 14 days.
The CEC confirms which component corresponds to the onset of clinical worsening, selecting only 
one component from the highest level ie, All-cause death, Non-planned PH-related hospitalization,
or PH-related deterioration. In the case of PH-related deterioration, multiple sub-components can 
be selected if they have the same onset date and should this be the case, then the conditions are 
ordered hierarchically as follows (decrease of severity from 1 to 3; where the most severe 
component will be taken as the onset of clinical worsening):


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1.
New or worsening of signs or symptoms of right heart failure
2.
Increase from baseline in WHO FC
3.
Deterioration from baseline by at least 15% in exercise capacity
The CEC adjudicate clinical worsening events from DB and PTOP periods only (as per CEC 
charter).
5.4.2.2.
Estimand
The main estimand defining the treatment effect for the TTCW endpoint has the following 
attributes:
A. Treatment:
!
Experimental: Selexipag
!
Control: Placebo
B. Population: Subjects with inoperable CTEPH or persistent/recurrent CTEPH after surgical
(PEA) and/or interventional (BPA) treatment in the FAS.
C. Variable: TTCW will be calculated from date of randomization to the date of onset of the first 
CEC confirmed (applicable for DB summaries only) component event (Section 5.4.2.1). For 
subjects who have not experienced an event by the respective cut-off date, their time will be 
right censored at the earliest date of the following: EDBT visit, the last PTOP visit or last 
contact. Longer times to clinical worsening indicate better condition.
D. Summary measure (Population-level summary): HR of selexipag versus placebo.
E. Intercurrent events (IE) and their corresponding strategies: IEs and their corresponding 
strategies are summarized in Table 12 below.
Table 12:
Intercurrent Events and Corresponding Strategies for the Main Estimand of TTCW
Intercurrent Events
Strategy for Addressing Intercurrent Events and Its Description
Premature discontinuation of DB 
treatment for any reason
Treatment policy strategy: The occurrence of the IE is considered irrelevant 
in defining the treatment effect of interest ie, the value of the variable of 
interest is used regardless of whether or not the IE occurs (to reflect intention-
to-treat (ITT) principle). Data for the variable will still be collected after the 
IE (in PTOP).
Receiving additional therapy
Hospitalization not related to PH
!
All-cause death
!
Non-planned PH-related 
hospitalization
!
PH-related deterioration 
(Section 5.4.2.1)
Composite variable strategy: An IE is considered in itself to be informative 
about the subject’s outcome and is therefore incorporated into the definition 
of the variable.
Value of the variable at the time of IE component:
TTCW = *   t(IE component), if IE component occurs           
Censored, if IE component does not occur


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5.4.2.3.
Analysis Methods
5.4.2.3.1.
Statistical model
Hypotheses and statistical model:
The hypotheses for the key secondary endpoint TTCW are described in Section 2.2.
Kaplan-Meier estimates for the survival functions will be provided. The HR will be estimated 
using a Cox model, including treatment group and all stratification factors as covariates.
Improvement by selexipag over placebo is indicated by a small (<1) HR, ie, (hazard with 
selexipag)/(hazard with placebo).
5.4.2.3.2.
Handling of missing data
For subjects who have not experienced any event by the respective analysis cut-off date, their time 
will be right censored at the earliest date of the following: EDBT visit, the last PTOP visit or last 
contact.
5.4.2.3.3.
Main, sensitivity and supplementary analyses
5.4.2.3.3.1.
Main analysis
The frequency of each component event will be presented by treatment group and separately for 
the DB and OL treatment periods.
TTCW will be summarized for the DB and OL treatment periods, where Kaplan-Meier estimates 
for the survival functions will be provided together with 2-sided 95% CL. The HR and the 
corresponding 2-sided 95% CL in the DB treatment period will be estimated using a Cox model, 
including treatment group and all stratification factors as covariates. Kaplan-Meier plots will also 
be provided for the DB treatment period only.
Listings will be provided including a description of clinical worsening events with flags to indicate 
CEC confirmation status, occurrence of any events during the PTOP and censored times. 
5.4.2.3.3.2.
Sensitivity analyses
For the main estimand defined in Section 5.4.2.2, the following sensitivity analysis will be 
performed to assess the robustness of the main analysis results. 
An analysis following the main analysis approach in Section 5.4.2.3.3.1 but where the 
stratification factors (PH-specific therapies and CTEPH population) will be utilized as per the 
eCRF, rather than the IRT stratification factors.
5.4.3.
Supportive Secondary Endpoint(s)
The hypothesis for the supportive secondary endpoint is described in Section 2.2.


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5.4.3.1.
Change from baseline to Week 26 in BDI/Borg CR10®
Dyspnea is assessed by two scales in this study: the BDI scale or the Borg CR10® scale (protocol 
Appendix 4 and Appendix 5, respectively], at time points indicated in the study visits and 
assessment schedules in Table 3, Table 4 and Table 5, immediately after stopping the 6MWT.
If a subject started the study using the BDI scale, then that scale will be used for the duration of 
their participation in the study. This also applies for the Borg CR10® scale.
The scales are used to rate the strength of the subject’s perception on dyspnea and exertion. The 
numeric points on the scale are anchored by (categorical) verbal expressions. Responses can range 
from 0 to 10 for the BDI scale and from 0 to beyond a score of 10 for the Borg CR10® scale.
The lower BDI/Borg CR10® values indicate better condition.
5.4.3.1.1.
Definition
Absolute pre-post change from baseline to Week 26 in BDI/Borg CR10® is defined as:
BDI/Borg CR10® pre-post change = BDI/Borg CR10® at Week 26 − BDI/Borg CR10® at 
baseline.
Improvement by selexipag over placebo is indicated by a negative (<0) difference in the mean pre-
post change, ie, (mean pre-post change with selexipag) ( (mean pre-post change with placebo).
5.4.3.1.2.
Analysis Methods
The null hypothesis is that there is no difference between selexipag and placebo in the mean pre-
post change. 
The BDI/Borg CR10® pre-post changes will be analyzed by means of an ANCOVA model 
including treatment, baseline index value and stratification factors as covariates. Least squares 
estimates for each treatment group will be displayed with means and 95% CLs.
BDI/Borg CR10® values at baseline and at Week 26 as well as pre-post changes from baseline to 
Week 26 will also be summarized using descriptive statistics, on the EES.
A listing of observed values and changes from baseline to Week 26 for BDI/Borg CR10® will also
be provided by treatment group, on the EES.
Further descriptive analyses of BDI/Borg CR10® over time, on the FAS, are outlined in 
Section 5.5.1.
Handling of missing data
In case of missing data, no imputation will be performed and only observed data will be 
summarized.   


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5.5.
Exploratory Endpoint(s) Analysis
Unless otherwise indicated, all exploratory efficacy analyses will be performed on the FAS. Given 
the exploratory nature of these analyses, no adjustment for multiplicity will be done.
5.5.1.
Change from baseline up to EOS, by visit, in BDI/Borg CR10®
collected immediately at the end of each individual 6MWT
Dyspnea is assessed by either the BDI scale or the Borg CR10® scale, as described in 
Section 5.4.3.1.
Analyses for change from baseline up to EOS (including OL), by visit, will be presented.
5.5.1.1.
Definition
Absolute pre-post change from baseline to each post-baseline visit in BDI/Borg CR10® is defined 
as:
BDI/Borg CR10® pre-post change = BDI/Borg CR10® at a post-baseline visit − BDI/Borg 
CR10® at baseline.
5.5.1.2.
Analysis Methods
Absolute values at baseline and at each visit, as well as absolute changes from baseline, by visit
and separately for the DB and OL treatment periods, will be summarized by treatment group on 
the FAS using descriptive statistics.
Handling of missing data
In case of missing data, no imputation will be performed and only observed data will be 
summarized.
5.5.2.
Change from baseline up to EOS, by visit, in exercise capacity, as 
measured by the 6MWD
Analyses for change from baseline up to EOS (including OL), by visit, will be presented.
5.5.2.1.
Definition
Similar to the key secondary endpoint analysis described in Section 5.4.1 except for the variable 
which uses data up to EOS:
Variable: 6MWD up to end of EOS, expressed as change from baseline value.
5.5.2.2.
Analysis Methods
Absolute values at baseline and at each regular collection timepoint up to EOS, as well as absolute 
changes from baseline up to EOS, for each regular collection timepoint and separately for the DB 
and OL treatment periods, will be summarized by treatment group on the FAS using descriptive 
statistics.


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A listing of observed values for 6MWD over time will be provided for the FAS. PTOP type data 
will be flagged.
Handling of missing data
In case of missing data, no imputation will be performed and only observed data will be 
summarized.    
5.5.3.
Change from baseline to Week 20 in other hemodynamic parameters 
(cardiac output [CO], cardiac index [CI] and mean right atrial pressure 
[mRAP]) measured at rest
5.5.3.1.
Definition
Hemodynamic parameters are collected in the study, based on RHC results and RHC methodology 
as described in Section 7.2.3.1 of the protocol and in the sponsor heart catheterization guidance in 
Appendix 1 of the protocol.
Table 13 provides a list of all hemodynamic parameters of interest, their source and derivation 
rules (if applicable). Whenever duplicate/triplicate measurements are collected, the relevant 
mean/most accurate assessment, as appropriate, should be used for the derivations described in 
Table 13.
Table 13:
Overview of hemodynamic parameters 
Hemodynamic Parameter
Source
Derivation
Pulmonary artery wedge pressure (PAWP)
eCRF
As collected
Left ventricular end diastolic pressure (LVEDP)
eCRF
As collected, if available
Systolic pulmonary artery pressure (sPAP)
eCRF
As collected (2 measurements and their 
average calculated by the eCRF)
Diastolic pulmonary artery pressure (dPAP)
eCRF
As collected (2 measurements and their 
average calculated by the eCRF)
Mean pulmonary artery pressure (mPAP)
eCRF
As collected (calculated by the eCRF)
Thermodilution Cardiac output (CO) 
eCRF
As collected (3 measurements and their 
average calculated by the eCRF)
Fick Cardiac output (CO) 
eCRF
As collected (3 measurements and their 
average calculated by the eCRF)
Heart Rate
eCRF
As collected
Mean right atrial pressure (mRAP)
eCRF
As collected
Mixed venous oxygen saturation (SvO2)
eCRF
As collected
Systolic Systemic Arterial Pressure (s-SAP)
eCRF
As collected
Diastolic Systemic Arterial Pressure (d-SAP)
eCRF
As collected
Pulmonary Vascular Resistance (PVR) Wood Units
eCRF
As collected (calculated by the eCRF)
Pulmonary Vascular Resistance (PVR) dyn.sec/cm5
eCRF
As collected (conversion by the eCRF)
Cardiac index (CI)
eCRF
As collected (calculated by the eCRF)
Total pulmonary resistance (TPR) 
eCRF
As collected (calculated by the eCRF)


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The variables which will be used for this exploratory analysis are change from baseline to Week 
20 in the following hemodynamic parameters:
!
CO 
!
CI
!
mRAP
5.5.3.2.
Analysis Methods
Absolute values at baseline and at Week 20 as well as absolute changes from baseline to Week 20 
will be summarized by treatment on the HES using descriptive statistics.
Handling of missing data
In case of missing data, no imputation will be performed and only observed data will be 
summarized.   
5.6.
Safety Analyses
All safety analyses will be based on the SAF according to actual treatment received, unless 
otherwise specified.
Summaries will be performed separately for the DB and OL treatment periods, where applicable.
For all continuous safety variables, descriptive statistics by treatment group will include the N, 
mean, SD, median, and range [minimum, maximum]. Categorical variables will be summarized 
by treatment group using frequency counts and percentages.
5.6.1.
Extent of Exposure
5.6.1.1.
Exposure Duration
The number and percentage of subjects who receive study treatment will be summarized separately 
for the DB and OL treatment periods. 
Study treatment duration in days is defined as (date of last dose of study treatment – date of first 
dose of study treatment) +1.
Descriptive statistics for study treatment duration will be presented. Subject-years of exposure is
calculated as days of exposure/365.25. Subject-months of exposure is calculated as days of 
exposure/30.4.
Duration of exposure will be summarized with number and percentage in the following duration 
categories (where applicable): <1 month, 1 - <3 months, 3 - <6 months, 6 - <12 months, 12 - <24 
months, 24 - <36 months, ≥36 months. 
Cumulative exposure will be summarized with number and percentage in the following duration 
categories (where applicable): ≥1 month, ≥3 months, ≥6 months, ≥12 months, ≥24 months, ≥36
months.


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5.6.1.2.
iMTD
The individual maximum tolerated dose (iMTD) will be expressed for twice daily (bid) dosing 
frequency. 
!
If once daily (qd) dosing frequency is applied, it will be grouped together with the bid dose as 
the iMTD only when moderate CYP2C8 inhibitors are co-administered or for subjects with 
moderate hepatic impairment (Child-Pugh B): eg, 200 μg bid and 200 μg qd will be grouped 
together as an iMTD of 200 μg bid.
!
For subjects with no co-administration of moderate CYP2C8 inhibitor or no moderate hepatic 
impairment (Child-Pugh B), dose X μg qd will be considered as equivalent to X/2 μg bid.
The iMTD of each treatment period (DB or OL) will be defined by the following rules as per the 
selexipag standard: 
!
Subjects who entered the study defined maintenance period (= who completed the study 
titration period):
(
The iMTD is defined as the last bid/qd dose at the end of titration period, ie, the dose 
administered on study day 85 after the first dose of treatment in the DB treatment period 
or on study day 85 after the first dose of treatment in the OL period. 
!
Subjects who did not enter the study defined maintenance period (= who discontinued the 
study treatment during the study titration period):
(
The iMTD is defined as the latest bid/qd dose that was not ended for the following 
reasons: "Dose reduced due to an AE", "Dose reduced not due to an AE", "Temporarily 
interrupted due to an AE", "Temporarily interrupted not due to an AE" or "Premature 
discontinuation". 
(
If the latest bid/qd dose is 200 μg and was ended for "Dose reduced due to an AE", "Dose 
reduced not due to an AE", "Temporarily interrupted due to an AE", "Temporarily 
interrupted not due to an AE" or "Premature discontinuation", then the iMTD is defined 
as zero. 
The bid/qd iMTD for each treatment period will be summarized with descriptive statistics, the 
number and percentage of subjects in each iMTD dose level and in each iMTD dose category: Low 
(200-400 μg bid), Medium (600, 800 and 1000 μg bid) and High (1200, 1400 and 1600 μg bid).
For subjects who discontinued during the up-titration period, then iMTD = 0 since iMTD was not 
determined in those subjects, then their 0 dose will be included in the < 200 mcg bid category.
5.6.1.3.
Others
For each study treatment period, the mode dose for a subject is defined as the dose that was 
administered for the longest duration, irrespective of interruptions, for that subject within the 
respective treatment period. In case of in a tie, the highest dose will be taken as the mode dose.
For each study treatment period, the weighted average dose for a subject is defined as the average 
of daily bid dose intensity for that subject within the respective treatment period. The exposure 
SDTM dataset will have records of all dose levels administered. If the end date of bid dose level 


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X and the start date of bid dose level Y are the same, it will be assumed that the subject took dose 
X in the morning and dose Y in the evening. In this case, the daily bid dose intensity on that day 
is calculated as (X + Y)/2. If a subject took qd dose level Z, the daily bid dose intensity will be 
calculated as Z/2. 
The mode doses and the weighted average doses of all subjects will be summarized with 
descriptive statistics for the titration period in DB (up to and including study day 84), the 
maintenance period in DB (start on study day 85), the entire DB treatment period, the titration 
period in OL (up to and including study day 84 after treatment initiation in the OL period ), the 
maintenance period in OL (start on study day 85 after treatment initiation in OL period), and the 
entire OL treatment period.
Study treatment administration will also be listed.
5.6.2.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). 
AEs will be summarized separately for the DB and OL treatment periods and defined as follows:
!
DB: Any AE occurring at or after the initial administration of study treatment through the day 
of last dose in the double-blind treatment period plus 3 days (EDBT +3 days) and prior to start 
of OL study treatment (as subjects transition without interruption to the OL period) is 
considered to be treatment-emergent. For subjects who transition to the OL treatment period
and have their first OL dose (evening dose) on the same day as their EDBT dose (morning 
dose), then their event(s) are assigned to the DB treatment period.
!
OL: Any AE occurring after the initial administration of study treatment in the OL treatment 
period through the day of last dose in the OL treatment period plus 3 days is considered to be 
treatment-emergent. For subjects who transition to the OL treatment period, any AE from Day 
2 of the OL treatment period is assigned to OL (regardless of the +3 days from EDBT).
If the event occurs on the day of the initial administration of study treatment, and either event time 
or time of administration (morning or evening) are missing, then the event will be assumed to be 
treatment-emergent. If the event date is recorded as partial or completely missing, then the event 
will be considered to be treatment-emergent unless it is known to be prior to the first administration 
of study treatment based on partial onset date or resolution date.
For each AE, the number and percentage of subjects who experience at least 1 occurrence of the 
given event will be summarized by treatment group, by system organ class (SOC) and preferred 
term (PT) in descending order of frequency in the selexipag treatment group.
Summary tables will be provided, for DB and OL treatment periods, for:
!
overall summary tables of treatment-emergent AEs
!
treatment-emergent AEs
!
treatment-emergent serious AEs (SAEs)


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!
treatment-emergent AEs leading to permanent discontinuation of study treatment
!
treatment-emergent AEs by severity
!
treatment-emergent AEs related to study treatment
!
treatment-emergent SAEs related to study treatment
!
treatment-emergent AEs leading to hospitalization
!
treatment-emergent AEs leading to dose interruption/dose modification of study treatment.
!
treatment-emergent AEs with fatal outcome
!
all SAEs up to 30 days after study treatment discontinuation
!
all SAEs up to EOS (defined as in protocol Section 8.1)
In addition to the summary tables, listings will be provided, for DB and OL treatment periods, for 
subjects who had:
!
treatment-emergent AEs
!
treatment-emergent SAEs
!
treatment-emergent AEs leading to permanent discontinuation of study treatment
!
treatment-emergent AEs with fatal outcome
5.6.2.1.
Adverse Events of Special Interest (AESI) 
Incidence of treatment-emergent AESI, for DB and OL treatment periods, will also be summarized
by treatment group, by AESI category and PT (in descending order of frequency in AESI category, 
in the selexipag treatment group). See Section 6.8 Appendix 8 for the list of categories of AESI.
In addition, each treatment-emergent AESI category will be summarized by preferred terms (PTs) 
and treatment group and will include:
!
Number and % of subjects with at least one AESI
–
Relative risk with 95% CI for selexipag vs. placebo 
!
Number and % of subjects with at least one AESI leading to permanent discontinuation of 
study treatment
!
Number and % of subjects with at least one serious AESI
!
Number and % of subjects with at least one related AESI
!
Number and % of subjects with at least one fatal AESI
!
Number and % of subjects with at least one event within the worst severity category where
the following hierarchical order is considered to determine worst severity: Severe, Moderate, 
Mild, Missing  
!
For recurrent events: 


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–
Cumulative number of recurrent AESIs (note: this includes the total number of events as 
subjects may have multiple PTs under an AESI category, and multiple events in a given 
PT)
–
Average annualized event rate (AER) 
where AER (per 100-SY) = 2
34546789:; <45=;> ?@ >;A4>>;<8 ;:;<8B
CD 8>;785;<8 ;EF?B4>;
× 100G
–
Subject Years (SY) of treatment exposure (calculated as indicated in Section 5.6.1.1) and 
is further based on first dose of study treatment up to EDBT +3days / EOLT +3days, as 
applicable
–
Outcome for cumulative number of recurrent AESIs 
o
Number and % of fatal events
o
Number and % of not recovered/not resolved events
o
Number and % of events that recovered/resolved with sequelae
o
Number and % of recovered/resolved events
o
Number and % of events with unknown outcome
In addition to the AESI summary tables, listings by treatment group and AESI category will also 
be provided for DB and OL treatment periods. Further listings for other AESI categories, for the 
DB and OL treatment periods, will also be provided.
5.6.2.2.
Deaths
Deaths will be summarized by treatment group and separately for the DB and for the overall study 
period.
Summary tables will be provided for:
!
all deaths in the DB period up to EDBT + 30 days (up to start of the OL period)
!
all deaths up to EOS (defined as in protocol Section 8.1)
Frequencies for the following parameters will be included in the summary tables:
!
Number of subjects who died
!
Cause of death
!
Relationship to study treatment (yes/no)
The summary will be based on the Death Information eCRF page, and relationship to the study 
treatment will be mapped through the corresponding AE, if available.
A listing of subjects who died will be provided including the study day of death in relation to Study 
Day 1 and days off treatment.


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5.6.2.3.
Subgroup Analyses
The following treatment-emergent AEs in the DB treatment period will also be summarized for 
specific subgroups as defined below:
!
treatment-emergent AEs  
!
treatment-emergent SAEs
by
!
Gender (Male vs. Female)
!
Age (18-64 years vs. 65-74 years vs. ≥75 years)
Subgroup analyses will not be conducted for the OL treatment period (only 15 subjects entered the 
OL treatment period).
5.6.3.
Additional Safety Assessments 
5.6.3.1.
Clinical Laboratory Tests
All laboratory data will be reported in International System (SI) units [except for eGFR, where the 
conventional unit will be used, as per Section 6.10 Appendix 10 (mL/min/1.73m2)]. All laboratory 
data provided by central laboratory will be considered regardless of whether they correspond to 
scheduled (per protocol) or unscheduled visits. Local laboratory data (scheduled or unscheduled)
will be included in listings and used only to find marked abnormalities. If a value below limit of 
quantification (LOQ) is recorded, the LOQ value itself will be used in the summaries instead. It 
will be clearly noted in the listings if a value is below LOQ.
List of parameters:
Clinical Chemistry
Hematology
Alanine aminotransferase (ALT)
Basophils
Alkaline phosphatase
Basophils/Leukocytes (fraction of 1)
Aspartate aminotransferase (AST)
Eosinophils
Bilirubin
Eosinophils/Leukocytes (fraction of 1)
Creatinine
Erythrocytes Mean Corpuscular Volume
Direct Bilirubin
Erythrocytes
Glomerular Filtration rate Adj for BSA
Hematocrit
Potassium
Hemoglobin
Sodium
Leukocytes
Thyrotropin [Thyroid Stimulating Hormone (TSH)]
Lymphocytes
Thyroxine (T4)
Lymphocytes/Leukocytes (fraction of 1)
Thyroxine, Free (FT4)
Monocytes
Triiodothyronine (T3)
Monocytes/Leukocytes (fraction of 1)
Triiodothyronine, Free (FT3)
Neutrophils, Segmented
Neutrophils, Segmented/Leukocytes (fraction of 1)
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Descriptive statistics will be presented for all chemistry and hematology laboratory tests at 
scheduled time points by treatment group, and separately for the DB and OL treatment periods.
Change from baseline to each scheduled post-baseline visit will also be summarized. 
Marked abnormalities in laboratory data are defined in Section 6.10 Appendix 10 (notable 
values/changes from baseline for thyroid parameters of interest are provided below).
Marked abnormalities will be summarized by treatment group, separately for chemistry and 
hematology laboratory parameters and separately for the DB and OL treatment periods, defined as 
follows:
!
DB: Any abnormality occurring at or after the initial administration of study treatment through 
the day of last dose in the double-blind treatment period plus 3 days (EDBT +3 days) and 
prior to the start of OL study treatment (as subjects transition without interruption to the OL
period) is considered to be treatment-emergent.
!
OL: Any abnormality occurring after the initial administration of study treatment in the OL 
treatment period through the day of last dose in the OL treatment period plus 3 days is 
considered to be treatment-emergent.
If the abnormality occurs on the day of the initial administration of study treatment, and either the 
laboratory collection time or time of study treatment administration are missing, then the 
abnormality will be assumed to be treatment-emergent. If the date of the abnormality is recorded 
as partial or completely missing, then the abnormality will be considered to be treatment-emergent 
unless it is known to be prior to the first administration of study treatment based on partial onset 
date or resolution date. If the abnormality was present at baseline, then any post-baseline 
abnormality will be considered to be treatment-emergent only if the post-baseline abnormality is 
in a category worse than at baseline.
In case the abnormality is defined based on the lower or upper limit of the normal reference range
(eg, Alanine aminotransferase) and the corresponding lower or upper limit is not available, the 
abnormality will not be derived. 
In case the marked abnormality is defined as an increase from the baseline (eg, Hemoglobin), 
comparison of the central laboratory baseline value with the local laboratory post-baseline value 
to assess the marked abnormality is allowed. 
The number and percentage of subjects with treatment-emergent marked abnormal values will be 
presented for each chemistry and hematology laboratory parameter for which marked 
abnormalities are defined, by treatment group, and separately for the DB and OL treatment periods.
In addition to the summary tables, chemistry and hematology laboratory data will be listed,
together with a derived marked abnormality flag. Separate listings of marked abnormality
chemistry and hematology laboratory values will also be provided.


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The following summaries will also be provided for thyroid parameters of interest:
The number and percentage of subjects with clinically notable TSH change from baseline (as 
defined below) by treatment group, and separately for the DB and OL treatment periods.
!
TSH ≤0.1 mIU/L
!
TSH >0.1 mIU/L and <0.45 mIU/L
!
TSH ≥5.33 mIU/L and < 10 mIU/L
!
TSH ≥10 mIU/L
5.6.3.2.
Vital Signs and Physical Examination Findings
Vital signs will be summarized at scheduled time points, by treatment group and separately for the 
DB and OL treatment periods.
Continuous vital sign parameters including weight, pulse, blood pressure (systolic and diastolic)
and body mass index (BMI) at each assessment time point as well as the change from baseline to 
each post-baseline assessment visit will be summarized with descriptive statistics. BMI will be 
calculated as weight (kg)/(height (m))2, at each time point that body weight is measured. The height 
measurement collected at screening will be used in the calculation.
Notable vital signs will be summarized by treatment group and separately for the DB and OL 
treatment periods, defined as follows:
!
DB: Any abnormality occurring at or after the initial administration of study treatment through 
the day of last dose in the double-blind treatment period plus 3 days (EDBT +3 days) and 
prior to the start of OL study treatment (as subjects transition without interruption to the OL
period) is considered to be treatment-emergent.
!
OL: Any abnormality occurring  after the initial administration of study treatment in the OL 
treatment period through the day of last dose in the OL treatment period plus 3 days is 
considered to be treatment-emergent.
Incidence of treatment-emergent notable vital signs, as defined below will be summarized for 
subjects who had at least 1 post-baseline assessment for that vital sign.
!
Systolic blood pressure (SBP) <90 mmHg (baseline status is not considered)
!
Decrease of >40 mmHg in SBP from baseline
!
Diastolic blood pressure (DBP) <50 mmHg (baseline status is not considered)
!
Decrease of >20 mmHg in DBP from baseline
!
All above four notable criteria fulfilled: SBP <90 mmHg and with >40 mmHg decrease from 
baseline and DBP <50 mmHg and with >20 mmHg decrease from baseline
!
Pulse <50 bpm or Pulse >120 bpm (baseline status is not considered)
!
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In addition, the following table summary will be provided, separately for the DB and OL treatment 
periods, at each visit for:
!
Weight: the incidence of increases/decreases from baseline >15% will be summarized by a 
frequency distribution.
!
BMI:  categorized as Underweight: BMI < 18.5 kg/m2, Normal: 18.5 kg/m2 ) BMI < 25 kg/m2, 
Overweight: 25 kg/m2 ) BMI < 30 kg/m2, Obese: BMI ∗30 kg/m2. The frequency and 
percentage of subjects in each category will be presented.
A listing of subjects with treatment-emergent clinically notable vital signs will be presented, 
separately for the DB and OL treatment periods. A listing of all vital sign measurements will also 
be provided, with clinically notable vital signs flagged.
Physical examination assessments are not collected in the eCRF. The date of the physical 
examination is collected in the eCRF and clinically relevant findings (other than those related to 
CTEPH) that are present prior to signing of informed consent should be recorded on the Medical 
History eCRF page. Physical examination findings made after signing of informed consent, which 
meet the definition of an AE (see protocol Section 9.1.1), should be recorded on the AE page of 
the eCRF.
5.6.3.3.
Electrocardiogram
A standard 12-lead electrocardiogram (ECG) is performed at timepoints indicated in the schedule 
of assessment as shown in Table 3 during the DB treatment period and Table 5 during the PTOP, 
with an overall interpretation of “Normal”, “Abnormal” or “Not evaluable” being captured on the 
ECG Test Results eCRF.
The ECG is interpreted locally and stored at the site. 
Clinically relevant ECG findings that are present prior to the initiation of study treatment should 
be documented in the Medical History section of the eCRF. Clinically relevant ECG findings found 
after the study treatment initiation that were not present at Screening or that worsened during the 
study should be reported as an AE (see protocol Section 9.1.1) as appropriate.
Descriptive statistics (n, %) will be presented at scheduled time points, by treatment group.
Shift from baseline to each scheduled post-baseline visit will be summarized with the number and 
percentage of subjects in the combination of baseline vs. post-baseline categories, by treatment 
group.  
A listing of abnormal ECG results will also be provided, including unscheduled visit data.
5.6.3.4.
Other Safety Parameters
5.6.3.4.1.
Procedures
Therapeutic or diagnostic procedures are collected on the imaging and the heart catheterization 
eCRFs and the procedure eCRF. BPA and PEA are procedures of specific interest as reported on 


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the medical history eCRF and are identified by preferred terms that code to BPA (eg, “angioplasty” 
and “arterial angioplasty”) and PEA (eg, “endarterectomy” and “pulmonary endarterectomy”).
The number and percentage of subjects who underwent any therapeutic or diagnostic procedure, 
and for which indication (per protocol, medical history, trial indication (CTEPH), prophylaxis, 
other, AE), as well as procedures of interest (related to BPA and PEA), will be presented separately
for DB and OL treatment periods, including baseline and post-baseline summaries (as applicable).
A listing of all procedures will also be provided, including if the procedure was elective (yes/no).
5.7.
Other Analyses
5.7.1.
Definition of Subgroups
Table 14 summarizes the subgroups which will be used in this study.
Table 14:
Definition of Subgroups
Subgroup
Category
Stratification factor 1: PH-specific 
therapies (as per IRT) $
!
One
!
Two
!
Naïve
Stratification factor 2: CTEPH population
(as per IRT) $
!
Inoperable (with or without BPA)
!
Persistent-recurrent after PEA (including PEA followed by BPA)
CTEPH sub-population *
!
Inclusion criteria 3a: Inoperable CTEPH
!
Inclusion criteria 3b: CTEPH after BPA
!
Inclusion criteria 3c: CTEPH after PEA or PEA followed by 
BPA

CTEPH after PEA

CTEPH after PEA followed by BPA
Gender
!
Male
!
Female
Age Group
!
18-64 years
!
65-74 years
!
≥75 years
Race
!
Black or African American
!
American Indian or Alaska Native
!
Native Hawaiian or Other Pacific Islander
!
Asian
!
White
!
Other
!
Not reported
Geographic region 1
!
North America
!
Western Europe/Australia
!
Eastern Europe
!
Asia
!
Latin America
Geographic region 2
!
US 
!
Non-US
WHO FC at baseline
!
I
!
II
!
III
!
IV


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Table 14:
Definition of Subgroups
Subgroup
Category
Dose group (iMTD)
!
Low (200–400 μg bid)
!
Medium (600, 800 and 1000 μg bid)
!
High (1200, 1400 and 1600 μg bid)
NT-proBNP 1 **
!
Low (<300 ng/L)
!
Medium (300 to 1400 ng/L)
!
High (>1400 ng/L)
NT-proBNP 2 ***
!
Low
!
Medium
!
High
*
As captured on the CTEPH sub-population eCRF.
**
Based on 2015 European Society of Cardiology/European Respiratory Society guidelines cutoffs.
*** Based on NT-proBNP baseline tertiles.
$
Analysis model will not include the subgrouping variable as a covariate.
5.8.
Interim Analyses
The database was to be locked, and the data extracted and analyzed at five time points during the 
study (see details in Section 1.2.4, Figure 3 and IDMC Charter). 
Due to early termination of the study due to futility at analysis time point 1, analysis time points 
2 and 3 are no longer applicable and analysis time points 4 and 5 are combined and constitute the 
final analysis reporting of the study, when all randomized subjects up to the point of early 
termination have performed their EOS visit, conducted by the sponsor, according to this SAP.
5.8.1.
Independent Data Monitoring Committee (IDMC) or Other Review 
Board
5.8.1.1.
Independent Data Monitoring Committee
An IDMC has overall responsibility for safeguarding the interests of subjects by monitoring 
unblinded safety and efficacy data obtained during the study and for reviewing the results of the 
interim analyses, thereby ensuring that the study is conducted in accordance with the highest 
scientific and ethical standards. 
The IDMC is tasked to organize and conduct the interim analyses with the assistance of the 
independent SSG. The IDMC will make appropriate recommendations based on statistical 
analyses summaries provided by the SSG team, based on the IDMC SAP for closed session, 
prepared in accordance with the IDMC Charter.
All communication between the IDMC and the sponsor will be directed through a Sponsor 
Committee, as defined in the IDMC Charter, which includes senior medical and statistical 
members. The Sponsor Committee will make decisions based on the recommendations from the 
IDMC.
5.8.1.1.1.
Outputs for IDMC meetings
For periodic data reviews and the pre-planned IAs at analysis time points 1, 2 and 3, summary 
tables will be created by the independent SSG, according to the IDMC SAP for closed session, 


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prepared by the SSG, using SAS® (SAS Institute Inc.) and R (R Core Team (2012) and based on 
the blinded SDTM and Analysis Data Models (ADaMs) provided by the sponsor. Summaries will 
be created for the data available at the time of the IDMC data cut-off. The summary tables in the 
IDMC data package will be displayed by treatment arm with masked treatment code label. The 
assignment of codes to the study treatment will not be provided in the report but will be provided 
separately and will be consistent throughout the study. 
A separate data package will be created by the sponsor, for the open session, only presenting data 
for the overall pooled subject population (not by treatment group). The details of analyses and list 
of outputs and mock layouts are described in an IDMC specific SAP for SSG and Open Session 
of IDMC. 
5.8.1.2.
Other Review Boards 
5.8.1.2.1.
Steering committee
A Steering Committee (SC) has been appointed by the sponsor to contribute to the design of the 
protocol, oversee the conduct of the study, evaluate the results and support publications. The 
committee is governed by a dedicated SC Charter.
5.8.1.2.2.
Adjudication committees
The study population includes subjects with CTEPH who are diagnosed as inoperable (ie, 
technically non-operable) or with persistent/recurrent CTEPH after surgical (PEA) and/or 
interventional (BPA) treatment. In accordance with the European Society of Cardiology and the 
European Respiratory Society Guidelines for the diagnosis and treatment of PH (Galiè 2016), an 
operability assessment for CTEPH subjects should be performed by a multidisciplinary CTEPH 
team.
Therefore, in addition to the CTEPH diagnosis, the inoperability,
and the 
persistence/recurrence of PH of CTEPH subjects considered eligible for study inclusion by the 
investigational sites will be confirmed by a multidisciplinary CTEPH team. For this purpose, two 
sets of independent adjudication committees (ACs) are established:
!
Country-specific Adjudication Committees (CSACs) and
!
Central Adjudication Committee (CAC) for countries without a CSAC.
The composition and operation of these committees is described in the ACs’ Charter.
5.8.1.2.3.
Clinical Event Committee
A Clinical Event Committee (CEC) has been appointed by the sponsor to adjudicate, in a blinded 
fashion, components of the clinical worsening events. Full details for this procedure, as well as 
the composition and operation of the CEC, are described in the CEC Charter.


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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
6MWD
6-minute walk distance
6MWT
6-minute walk test
AC
Adjudication Committee
AE
adverse event
AESI
adverse events of special interest
ANCOVA
analysis of covariance
ATC
anatomic and therapeutic class
bid
twice daily
BDI
Borg dyspnea index
BMI
body mass index
Borg CR10®
Borg category-ratio 10 Scale®
BPA
balloon pulmonary angioplasty
bpm
beats per minute
BSA
body surface area
CAC
Central Adjudication Committee
CEC
Clinical Events Committee
CGI-C
Clinician Global Impression of Change
CGI-S
Clinician Global Impression of Severity
CHMP
Committee for Medicinal Products for Human Use (European Union)
CI
cardiac index
CL
confidence limit(s)
CMH
Cochran-Mantel-Haenszel
CO
cardiac output
CRO
Contract Research Organization
CSAC
Country-specific Adjudication Committee
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CTEPH
chronic thromboembolic pulmonary hypertension
CTT
Clinical Trial Team
CV
coefficient of variation
CW
clinical worsening
DB 
DBP
DLPA
dPAP
d-SAP
double-blind
diastolic blood pressure
daily life physical activity
Diastolic pulmonary arterial pressure
Diastolic systemic arterial pressure
DPS
data presentation specifications
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDBT
EES
End-of-Double-Blind-Treatment
Efficacy Evaluable Set
EOLT
End-of-Open-Label-Treatment
EOS
End-of-Study
EOT
End-of-Treatment
ERA
endothelin receptor antagonist
EQ-5D-5L©
Euro Quality of life-5-Dimension-5-Level
FAS
FC
Full Analysis Set
Functional Class
FDA
FSFV
Food and Drug Administration
First subject first visit
FT3
Triiodothyronine, Free
FT4
Thyroxine, Free
FU
follow-up
HES
Hemodynamic Set


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HR
hazard ratio
IA
ICF
interim analysis
Informed Consent Form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IE
inter-current event
IF
iMTD
information fraction
individual maximum tolerated dose
IQ
IRT
Interquartile
Interactive Response Technology
LHC
left heart catheterization
LLOQ
lower limit of quantification
LOCF
LSLV
LVEDP
LWYY
last observation carried forward
Last subject last visit
left ventricular end diastolic pressure
Lin-Wei-Yang-Ying 
MedDRA
Medical Dictionary for Regulatory Activities
mPAP
mRAP
MVPA
mean pulmonary arterial pressure
mean right atrial pressure
moderate to vigorous physical activity
NT-proBNP
N-terminal pro b-type natriuretic peptide
OL
open-label
PAH
pulmonary arterial hypertension
PAH-SYMPACT®
PAWP
PDE-5
PEA
PAH Symptoms and Impact® questionnaire 
pulmonary artery wedge pressure
phosphodiesterase type 5
pulmonary endarterectomy
PH
pulmonary hypertension
PPS
PVR Per-Protocol Analysis Set
PRO
patient-reported outcome(s) 
PT
PTA
PTOP
PTOP EOS
PVR
qd
preferred term
Post-Trial Access
post-treatment observation period
post-treatment observation period end-of-study
pulmonary vascular resistance 
once daily
RHC
RR
right heart catheterization
rate ratio
SAE
serious adverse event
SAP
statistical analysis plan
SAF
SAS®
SBP
Safety Analysis Set
Statistical Analysis Software
systolic blood pressure
SD
SDTM
SIS
standard deviation
Study Data Tabulation Model
Selexipag-Initiated Set
SFU
sGC
SL
SM
safety follow-up
soluble guanylate cyclase
significance level
Site manager
SMQs
Standardized MedDRA Query
SOC
sPAP
s-SAP
system organ class
Systolic pulmonary artery pressure
Systolic systemic arterial pressure
SSG
SvO2
Statistical Support Group
Mixed venous oxygen saturation
T3
Triiodothyronine
T4
Thyroxine


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TEAE
TPR
treatment-emergent adverse event
total pulmonary resistance
TSH
Thyroid Stimulating Hormone (Thyrotropin)
TTCW
time to clinical worsening
ULN
WASO
WCC
upper limit of normal 
wake after sleep onset
WorldCare Clinical
WHO
World Health Organization
WHO-DD
WPAI©: GH
World Health Organization Drug Dictionary
Work Productivity and Activity Impairment: General Health


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6.2.
Appendix 2 Changes to Protocol-Planned Analyses
Following the decision to prematurely terminate the study due to futility at analysis time point 1, 
it was decided that an abbreviated CSR would be produced to summarize key efficacy and safety 
data only. Such analyses are described in this SAP. The study team will remain blinded to the 
results of the IA conducted by the SSG, until database lock occurs for the abbreviated CSR planned 
analyses. 
For the abbreviated CSR, some endpoints (and analyses) have been removed or adapted compared 
to the protocol planned analyses, to better evaluate the data that is available for them at the time 
of early termination of the study. Endpoints to be considered for the abbreviated CSR are primary 
and key secondary endpoints (and associated supportive and exploratory endpoints) and a full 
complement of safety. 
All efficacy analyses other than PVR are exploratory. A summary is provided below:
!
Primary Endpoint
(
PVR
o
No change in protocol specified analysis approach. Sensitivity and supplementary 
analyses will also be conducted, as per Section 5.3.
!
Key Secondary Endpoints
(
Change from baseline in 6MWD to Week 26 
o
ANCOVA analysis approach will not be conducted. Descriptive analyses will be 
performed (as per Section 5.4.1).
(
TTCW
o
Low number of events at the time of early termination: log rank test will not be 
performed; descriptive analyses only (as per Section 5.4.2).
!
Supportive Secondary Endpoints
(
Change from baseline to Week 26 in BDI/Borg CR10®
o
No change in protocol specified analysis approach (as per Section 5.4.3).
!
Exploratory Endpoints
(
Change from baseline up to EOS, by visit, in BDI/Borg CR10® collected immediately at 
the end of each individual 6MWT
o
Descriptive analysis will be performed (as per Section 5.5.1).
(
Change from baseline up to EOS, by visit, in exercise capacity, as measured by the 
6MWD
o
Descriptive analysis will be performed (as per Section 5.5.2).
(
Change from baseline to Week 20 in other hemodynamic parameters (cardiac output 
[CO], cardiac index [CI] and mean right atrial pressure [mRAP]) measured at rest
o
Descriptive analysis will be performed (as per Section 5.5.3).


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Secondary endpoints which will no longer be included in the abbreviated CSR:
!
Improvement in WHO FC at Week 26
!
Change from baseline to Week 26 in PAH-SYMPACT® cardiopulmonary symptoms domain 
and cardiovascular symptoms domain
!
Change from baseline to Week 26 in NT-proBNP
!
All-cause death or hospitalizations related to PH worsening (confirmed by the CEC)
Exploratory endpoints which will no longer be included in the abbreviated CSR:
!
Changes in 6MWD, WHO FC and NT-proBNP from baseline to all regular collection 
timepoints up to the EDBT period.
(
Note: 6MWD is already included, by definition, in the above exploratory endpoint 
“Change from baseline up to EOS, by visit, in exercise capacity, as measured by the 
6MWD.”
!
Rate of hospitalizations up to end of double-blind period
!
Mean number of hospital days for all-cause hospitalization
!
Mean number of hospital days related to PH worsening
!
Improvement in WHO FC from baseline up to EOS, by visit
!
Change from baseline to Week 26 in actigraphy-assessed daily life physical activity (DLPA)
!
Change from baseline up to Week 39, by visit, in PAH-SYMPACT® scores (including 
cardiopulmonary symptoms domain, cardiovascular symptoms domain, physical impacts 
domain, and cognitive/emotional impacts domain)
!
Change from baseline up to Week 52, by visit, in EQ-5D-5L
!
Change from baseline up to Week 52, by visit, in WPAI©: GH scores
!
Change from baseline to all regular collection timepoints up to end of double-blind period in 
the CGI-S scores and in the CGI-C scores
!
Change from baseline to Week 20 in the number of low-risk criteria, defined as WHO FC I or 
II, 6MWD ≥440 m, NT-proBNP <300 ng/L and CI ≥2.5 L/min/m2 (Galiè 2016)
Updates and clarifications have also been included as follows:
!
The primary efficacy endpoint and key secondary efficacy endpoints have been described in 
terms of estimands.
!
Analysis Sets: 
(
Efficacy Evaluable Set(s) have been defined for the Week 26 efficacy endpoints
o
The EES is a subset of subjects in the FAS and includes all subjects who have reached 
their Week 26 visit (according to the analysis time window for the specific Week 26 
efficacy endpoint) or have discontinued earlier (for any reason except Sponsor 
decision = Study Termination). An EES is defined for:


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+
6MWD: From Day 2 to Day 273 (see Table 8)
+
Other efficacy endpoints: From Day 2 to Day 229 (see Table 8)
(
PVR Per-protocol Analysis Set (PPS1) renamed to PPS since only one per-protocol 
analysis set now required. 6MWD Per-protocol Analysis Set (PPS2) and TTCW Per-
protocol Analysis Set (PPS3) have been removed since per-protocol analyses are no 
longer applicable for those key secondary endpoints (descriptive analyses only).
(
The Selexipag Initiated Set (SIS) has been removed since there is no need for this specific 
analysis set. Safety summaries are based on the SAF. As per protocol, all subjects in the 
OL treatment period received selexipag.
!
Table 7: Analyses sets and their usage at each analysis time-point
(
Updated in line with corresponding updates in analysis sets and early termination of the 
study.
!
Details regarding interim analysis and DB and OL analyses (Section 10.4 and 10.5 of the 
protocol) have been updated in line with early termination of the study
(
Due to early termination of the study for futility at analysis time point 1, analysis time 
points 2 and 3 are no longer applicable and analysis time points 4 and 5 are combined and 
constitute the final analysis reporting of the study, conducted by the sponsor, according 
to this SAP.
(
Efficacy and safety summaries will be presented at each analysis time point and 
performed separately for the DB and OL treatment periods, as applicable.
!
Additional subgroups of interest (compared to those listed in protocol Section 10.3.5)
(
CTEPH sub-population (now collected directly on eCRF).
(
Age Group
(
WHO FC at baseline
(
NT-proBNP


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6.3.
Appendix 3 Demographics and Baseline Characteristics
The number of subjects in each analysis set will be summarized by treatment group and overall. A 
by subject listing of subjects included in each analysis set will also be provided. In addition, the 
distribution of subjects by region, country/territory, and site ID will be presented.
Table 15 presents a list of the demographic variables that will be summarized by treatment group 
and overall, for the FAS (and HES at analysis time point 1; as described in Table 7). Demographics 
will also be summarized by region using the FAS.
By-subject listings of demographic data will also be provided based on the FAS (HES subjects 
will be flagged).
Separate summaries will be produced for the DB and OL treatment periods, where the OL 
summary will include summaries of those variables that are collected again after baseline or those 
that will be derived e.g., Age at start of OL, BMI at start of OL. At entry of OL, the only new 
information collected is weight (BMI can be derived), age will be derived from the age collected 
at screening to the start of OL; the rest are unchanged and correspond to the DB output.
Table 15:
Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum]).
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2)
Categorical Variables:
Age (18-64 years, 65-74 years, ≥75 years)
Frequency distribution with the 
number and percentage of subjects
in each category.
Sex (male, female)
Racea (American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or Other Pacific Islander, White, Other, Not 
applicable, Multiple)
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown)
Region (North America, Western Europe/Australia, Eastern Europe, Asia, 
Latin America)
BMI (underweight: <18.5 kg/m2, normal: 18.5 to <25 kg/m2, overweight: 25 
kg/m2 to <30 kg/m2, obese: ∗30 kg/m2)
a If multiple race categories are indicated, the Race is recorded as 'Multiple'.
Table 16 presents a list of the baseline PH characteristics variables that will be summarized by 
treatment group and overall, for the FAS (and HES at analysis time point 1; as described in Table 
7). By subject listings of baseline data will also be provided based on the FAS (HES subjects will 
be flagged). 
Separate summaries will be produced for the DB and OL treatment periods, where the OL 
summary will include summaries of those variables that are collected again after baseline or those 
that will be re-calculated e.g., Time from CTEPH diagnosis; the rest are unchanged and correspond 
to the DB output.


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Table 16:
Baseline pulmonary hypertension characteristics variables
Continuous Variables:
Summary Type
Time since initial CTEPH diagnosis (years) 
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum]).
Hemodynamic parameters
! Heart rate (bpm)
! PVR (Wood units, calculated eCRF)
! PVR (dyn.sec/cm5, conversion eCRF)
! PVR (dyn.sec/cm5, derived)
! mRAP (mmHg)
! PAWP (mmHg)*
! LVEDP (mmHg)*
! sPAP (mmHg)
! dPAP (mmHg)
! mPAP (mmHg)
! Cardiac Output (L/min)
! Mixed Venous Oxygen Saturation (%)
! s-SAP (mmHg)
! d-SAP (mmHg)
! Cardiac Index (L/min/m2)
! Total Pulmonary Resistance (dyn.sec/cm5)
6MWD (meters)
NT-pro BNP (ng/L)
Number of BPA performed
Categorical Variables:
CTEPH population (Inoperable, Persistent-Recurrent) (collected in IRT)
Frequency distribution with the 
number and percentage of subjects
in each category.
CTEPH sub-population (collected in eCRF): 
! Inclusion criterion 3a: inoperable CTEPH
! Inclusion criterion 3b: CTEPH after BPA
! Inclusion criterion 3c: CTEPH after PEA or PEA followed by BPA
! CTEPH after PEA
! CTEPH after PEA followed by BPA
PH-specific therapy at baseline
! One, two or naive (collected in IRT)
! "ERAs Only", "PDE-5i Only", "sGC Only", "ERAs + PDE-5i", 
"ERAs + sGC", naïve (none of them) (collected in eCRF)
WHO FC (I, II, III, IV)
Borg Dyspnea Index (BDI)
Borg CR10 Score
6MWD = 6-minute walk distance; bpm = beats per minute; CTEPH = Chronic thromboembolic pulmonary hypertension; dPAP = 
Diastolic pulmonary arterial pressure; d-SAP = Diastolic systemic arterial pressure; ERA = Endothelin receptor antagonist; FC = 
Functional class; IRT = Interactive response technology; LVEDP = Left ventricular end diastolic pressure; mPAP = Mean 
pulmonary arterial pressure; mRAP = Mean right atrial pressure; NT-proBNP = N-terminal pro b-type natriuretic peptide; PAWP 
= Pulmonary artery wedge pressure; PDE-5 = Phosphodiesterase type-5; PH = Pulmonary hypertension; PVR = Pulmonary 
vascular resistance; sGC = Soluble guanylate cyclase; sPAP = Systolic pulmonary arterial pressure; s-SAP = Systolic systemic
arterial pressure; WHO = World Health Organization.
*Following the Actelion Heart Catheterization Guidance (see protocol Appendix 1), LVEDP is to be recorded when PAWP is not
available or not reliable.


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6.4.
Appendix 4 Protocol Deviations
In general, major protocol deviations may have the potential to impact subjects’ rights, safety or 
well-being, or the integrity and/or result of the clinical study.
Subjects with major protocol deviations will be identified during the conduct of the study in an 
ongoing manner using a comprehensive list of criteria (documented on the Major Protocol 
Deviation Criteria Form) as indicated in the Cross-Pharma TV-SOP-04282: Identification and 
Management of Clinical Trial Issues and Protocol Deviations for the definition of major protocol 
deviations.
Prior to each analysis time point all deviations will be closed, final and locked in the clinical trial 
management system and subjects with major protocol deviations will be summarized by the 
following categories/codes (DVDECOD).
!
Entered but did not satisfy criteria (subject randomized but did not satisfy the 
inclusion/exclusion selection criteria)
!
Received a disallowed concomitant treatment (subject took a forbidden concomitant 
medication)
!
Received wrong treatment or incorrect dose (subject received wrong study treatment or 
incorrect dose)
!
Developed withdrawal criteria but not withdrawn (subject developed withdrawal criteria 
during the study but was not withdrawn)
!
Other (as per the full list on the study specific Major Protocol Deviation Criteria Form):
The specific major protocol deviations that will lead to exclusion from PPS are summarized in 
Table 17.
The number and percentage of subjects with major protocol deviations will be summarized using 
the FAS (and HES at analysis time point 1) and the impact on the primary endpoint will be assessed 
based on PPS. Subjects in PPS will be analyzed according to the assigned study treatment. Listings
will also be provided for subjects with major protocol deviations in the FAS and subjects with 
major protocol deviations leading to exclusion from PPS in the HES.
Protocol Deviations resulting from COVID-19 impact are described in Section 6.11, Appendix 11.


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Table 17:
Major Protocol Deviations Leading to Exclusion from PPS
Sequence 
No. 
Description 
Protocol Deviation Description (DVTERM)
PD Criterion
Protocol Deviation Coded 
Term (DVDECOD)
Exclude from PPS
INCLUSION CRITERIA
1
Subject must have signed and dated the ICF.
Inclusion criterion 1 not met: Subject 
didn't <specify: sign and/or date> the 
ICF..
Inclusion Criterion 1 not met
Entered but did not 
satisfy criteria
Yes
2
Subjects must be ≥18 (or the legal age of consent 
in the jurisdiction in which the study is taking 
place) and ≤ 85 years old at Screening (Visit 1). 
Inclusion criterion 2 not met: Subject 
was <specify age> years old.
Inclusion Criterion 2 not met
Entered but did not 
satisfy criteria
Yes
3
Subject must have eligibility confirmed by the AC 
(CSAC or CAC) prior to randomization.
Inclusion criterion 3 not met: Eligibility 
was not confirmed by the AC (CSAC or 
CAC) prior to randomization.
Inclusion Criterion 3 related 
to AC not met
Entered but did not 
satisfy criteria
Yes
4
Baseline RHC (and LHC, if needed) criteria:
–
performed at least 90 days after start of full 
anticoagulation 
–
performed at least 90 days after last 
surgery/treatment (for subject with 
persistent/recurrent CTEPH after BPA or 
PEA ∀including PEA followed by BPA#)
–
CO measured with a minimum of 3 
consecutive measurements that should not 
differ by > 10% when the thermodilution 
method is used and with 1 measurement 
when the Fick method is used. 
Inclusion criterion 3 related to baseline 
RHC/LHC conditions not met: <specify 
which criteria not met from the 
description list>
Inclusion Criterion 3 related 
to baseline RHC/LHC 
conditions not met - Protocol 
Version 1 and 2
Entered but did not 
satisfy criteria
Yes
5
Historical RHC (and LHC, if needed) criteria for 
the hemodynamic cohort:
(
performed within 30 days prior to 
(re)screening
(
performed at least 90 days after last change 
in PH-specific therapies (i.e., change in dose 
or initiation of new class of drugs) 
Inclusion criterion 3 related to historical 
baseline RHC/LHC conditions not met
for the hemodynamic cohort: <specify 
which criteria not met from the 
description list>
Inclusion Criterion 3 related 
to baseline RHC/LHC 
conditions not met ‒ 
hemodynamic cohort -
Protocol Version 1 and 2
Entered but did not 
satisfy criteria
Yes
6
Historical RHC (and LHC, if needed) criteria for 
the hemodynamic cohort:
(
performed within 30 days prior to screening*
(
performed at least 90 days after last change 
in PH-specific therapies (i.e., change in dose 
or initiation of new class of drugs) 
*in case of rescreening within 6 months of the first 
Screening Visit, the first screening RHC (and LHC 
if needed) can be used, provided there have been 
no changes in PH-specific therapy(ies) since the 
first Screening Visit.
Inclusion criterion 3 related to historical 
baseline RHC/LHC conditions not met
for the hemodynamic cohort: <specify 
which criteria not met from the 
description list>
Inclusion Criterion 3 related 
to baseline RHC/LHC 
conditions not met ‒ 
hemodynamic cohort - From 
Protocol Version 3 onwards
Entered but did not 
satisfy criteria
Yes
7
Historical RHC (and LHC, if needed) criteria for 
the non-hemodynamic cohort:
Inclusion criterion 3 related to historical 
baseline RHC/LHC conditions not met
Inclusion Criterion 3 related 
to baseline RHC/LHC 
Entered but did not 
satisfy criteria
N/A


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Table 17:
Major Protocol Deviations Leading to Exclusion from PPS
Sequence 
No. 
Description 
Protocol Deviation Description (DVTERM)
PD Criterion
Protocol Deviation Coded 
Term (DVDECOD)
Exclude from PPS
(
performed within 6 months prior to 
(re)screening.
for the non-hemodynamic cohort: 
historical RHC not performed within 6 
months prior to (re)screening
conditions not met ‒ non-
hemodynamic cohort -
Protocol Version 1 and 2
8
Historical RHC criteria for the non-hemodynamic 
cohort:
performed within 6 months prior to screening*.
* In case of rescreening within 6 months of the 
first Screening Visit, the first screening RHC (and 
LHC if needed) can be used.
Inclusion criterion 3 related to historical 
baseline RHC conditions not met for 
the non-hemodynamic cohort: historical 
RHC not performed within 6 months 
prior to (re)screening
Inclusion Criterion 3 related 
to baseline RHC/LHC 
conditions not met ‒ non-
hemodynamic cohort - From 
Protocol Version 3 onwards
Entered but did not 
satisfy criteria
N/A
9
For the hemodynamic cohort, historical HC for 
eligibility: The HC guidance requirements for 
zeroing and heart catheterization measurement 
must have been followed and documented in the 
source notes if a historical HC is used. Otherwise, 
a new HC assessment will have to be performed 
for baseline measurements.
Subject was randomized based on a 
historic HC which was not conducted 
as per HC guidelines and no new HC 
was performed during screening: 
<specify>
Historic HC not performed as 
per HC guidelines and no 
new HC performed during 
screening.
Entered but did not 
satisfy criteria
Yes
10
Baseline RHC (and LHC, if needed) criteria:
–
PVR at rest ≥ 300 dyn.sec/cm5 or ≥ 3.75 WU
–
mPAP ≥ 25 mmHg, 
–
Pulmonary arterial wedge pressure (PAWP) 
≤ 15 mmHg or, if not available or unreliable, 
a left ventricular end diastolic pressure 
(LVEDP) ≤ 15 mmHg.
Inclusion criterion 3 related to baseline 
RHC/LHC data not met: <specify which 
criteria not met from the description 
list>
Inclusion Criterion 3 related 
to baseline RHC/LHC data 
not met - Protocol Version 1 
and non-hemodynamic 
Version 3 onwards
Entered but did not 
satisfy criteria
Yes
11
Baseline RHC (and LHC, if needed) criteria:
–
PVR at rest ≥ 400 dyn.sec/cm5 or ≥ 5 WU
–
mPAP ≥ 25 mmHg,
–
Pulmonary arterial wedge pressure (PAWP) 
≤ 15 mmHg or, if not available or unreliable, 
a left ventricular end diastolic pressure 
(LVEDP) ≤ 15 mmHg.
Inclusion criterion 3 related to baseline 
RHC/LHC data not met: <specify which 
criteria not met from the description 
list>
Inclusion Criterion 3 related 
to baseline RHC/LHC data 
not met ‒ from Protocol 
Version 2 and hemodynamic 
Version 3 onwards
Entered but did not 
satisfy criteria
Yes
12
For the hemodynamic cohort, zeroing as per HC 
guideline must be done prior to the HC 
measurement.
Zeroing was not done according to the 
HC guidelines at screening: <specify>
Zeroing was not done before 
HC measurements at 
screening.
Entered but did not 
satisfy criteria
Yes
13
For the hemodynamic cohort, for sPAP and dPAP 
the 2 most representative and reliable 
measurements must be documented in the source 
notes.
sPAP and/or dPAP not documented 
with 2 representative and reliable 
measurements at screening: <specify 
which parameter was not measured 
and documented as per guidance sPAP 
and/or dPAP>
sPAP and/or dPAP not 
measured or documented as 
per HC guidance at 
screening.
Entered but did not 
satisfy criteria
Yes
14
For the hemodynamic cohort, for the HC, if 
thermodilution method is used to measure CO, 
the CO must be measured with at least 3 
Thermodilution CO at screening not 
measured at least 3 times: <specify 
deviation>
Thermodilution CO at 
screening not measured at 
least 3 times.
Entered but did not 
satisfy criteria
Yes


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Table 17:
Major Protocol Deviations Leading to Exclusion from PPS
Sequence 
No. 
Description 
Protocol Deviation Description (DVTERM)
PD Criterion
Protocol Deviation Coded 
Term (DVDECOD)
Exclude from PPS
measurements documented in the heart 
catherization worksheet.
15
For the hemodynamic cohort, for the HC, if 
thermodilution method is used to measure CO, 3 
measurements must be within 10% of each other, 
i.e., the lowest of the 3 CO values must not be 
lower than 10% of the middle value AND the 
highest value must not be higher than 10% of the 
middle value.
Thermodilution CO values at screening: 
the upper and/or lower values are more 
than 10% +/- of the middle value: 
<specify and list the CO values>
Thermodilution CO the upper 
and/or lower values are more 
than 10% +/- of the middle 
value at screening.
Entered but did not 
satisfy criteria
Yes
16
HC is to be performed at screening.
HC is missing at screening: <specify> 
HC missing at screening.
Entered but did not 
satisfy criteria
Yes
17
For the hemodynamic cohort CO must be 
measured at screening.
Missing CO at screening <specify>
Missing CO at screening.
Entered but did not 
satisfy criteria
Yes
18
For the hemodynamic cohort, sPAP must be 
measured at screening.
Missing sPAP at screening: <specify>
Missing sPAP at screening.
Entered but did not 
satisfy criteria
Yes
19
For the hemodynamic cohort, dPAP must be 
measured at screening.
Missing dPAP at screening. <specify>
Missing dPAP at screening.
Entered but did not 
satisfy criteria
Yes
20
For the hemodynamic cohort, PAWP or LVEDP, if 
PAWP is missing or not reliable must be available 
at screening.
Missing or not reliable PAWP and 
missing LVEDP at screening: <specify>
Missing or not reliable PAWP 
and LVEDP not available at 
screening.
Entered but did not 
satisfy criteria
Yes
21
Subjects 
must 
have 
available 
imaging 
assessments performed in the 14-month period 
prior to randomization (Visit 2) or during screening 
as follows:
–
Subject with Inoperable CTEPH must have at 
least two imaging assessments 
–
Subject with Persistent/Recurrent CTEPH 
after BPA must have at least one imaging 
assessment
Inclusion criterion 3 related to baseline 
imaging not met: <specify which criteria 
not met from the description list>
Inclusion Criterion 3 related 
to baseline imaging not met ‒ 
Protocol Version 1
Entered but did not 
satisfy criteria
N/A
22
Subjects 
must 
have 
available 
imaging 
assessments performed in the 14-month period 
prior to randomization (Visit 2) or during screening 
as follows:
–
Subject with Inoperable CTEPH must have at 
least two imaging assessments 
–
Subject with Persistent/Recurrent CTEPH 
after BPA must have at least one imaging 
assessment performed after last 
interventional (BPA) treatment
–
Subject with Persistent/Recurrent CTEPH 
after PEA (including PEA followed by BPA) 
Inclusion criterion 3 related to baseline 
imaging not met: <specify which criteria 
not met from the description list>
Inclusion Criterion 3 related 
to baseline imaging not met ‒ 
from Protocol Version 2 
onwards
Entered but did not 
satisfy criteria
N/A


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Table 17:
Major Protocol Deviations Leading to Exclusion from PPS
Sequence 
No. 
Description 
Protocol Deviation Description (DVTERM)
PD Criterion
Protocol Deviation Coded 
Term (DVDECOD)
Exclude from PPS
must have at least one imaging assessment 
performed after last surgical (PEA) or 
interventional (BPA) treatment.
23
Subject must have PH in WHO FC I-IV
Inclusion criterion 4 not met: WHO FC 
not assessed at (re)screening
Inclusion Criterion 4 not met
Entered but did not 
satisfy criteria
N/A
24
Subject must be able to perform the 6MWT with a
minimum distance of 100 m and a maximum 
distance of 450 m at (re)screening visit (Visit 1).
Inclusion criterion 5 not met: 6MWD at 
(re)screening was <specify 6MWD at 
(re)screening> or <not available>.
Inclusion Criterion 5 not met
Entered but did not 
satisfy criteria
N/A
25
6MWT is to be performed at screening
6MWT not done at screening: 
<specify>
6MWT not done at screening.
Entered but did not 
satisfy criteria
N/A
26
For the 6MWT all the following requirements 
related to the subject must be followed:
- wear comfortable clothing
-  wear appropriate shoes
- must not have exercised vigorously within 2 
hours before the 6MWT
The 6MWT requirements related to the 
subject at screening were not followed: 
<specify deviation>
The 6MWT guidance related 
to the subject were not 
followed at screening.
Entered but did not 
satisfy criteria
N/A
27
If the subject is used to take bronchodilators, 
he/she must take them at least 10 to 30 minutes 
before the 6MWT.
Bronchodilators were not taken 10 to 
30 minutes before the 6MWT at 
screening: <specify>
Bronchodilators not taken as 
per 6MWT guidance at 
screening.
Entered but did not 
satisfy criteria
N/A
28
Walking aids (e.g., cane) and walkers are not 
allowed.
Forbidden walking aid was used during 
the 6MWT at screening: <specify>
Used forbidden walking aid 
during the 6MWT at 
screening.
Entered but did not 
satisfy criteria
N/A
29
The interval between two 6MWTs on the same 
day must be at least 2 hours.
There was less than 2 hours between 2 
6MWTs performed at randomization: 
<specify>
Less than 2 hours between 
two 6MWTs at randomization.
Entered but did not 
satisfy criteria
N/A
30
Only two 6MWTs can be performed on the same 
day.
More than two 6MWT were performed 
at screening: <add description of the 
actual deviation>
More than 2 tests done 
screening.
Entered but did not 
satisfy criteria
N/A
31
The 6MWT must be performed indoors, along a 
long, flat, straight, enclosed corridor (or similar 
location) with a hard surface that can be blocked 
for traffic during the conduct of the test. The track 
must be marked at regular intervals. The 
turnaround points must be marked with a cone. A 
starting line, which marks the beginning and end 
of each lap needs to be marked on the floor. The 
use of treadmill and a continuous course, e.g., a 
circuit, is not allowed.
Corridor not compliant with 6MWT 
guidance requirements at screening: 
<add description of actual deviation>
Corridor does not meet 
6MWT guidance 
requirements at screening. 
Entered but did not 
satisfy criteria
N/A


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Table 17:
Major Protocol Deviations Leading to Exclusion from PPS
Sequence 
No. 
Description 
Protocol Deviation Description (DVTERM)
PD Criterion
Protocol Deviation Coded 
Term (DVDECOD)
Exclude from PPS
32
The corridor must not be shorter than 20 m in 
length.
6MWT at screening was done in a 
corridor with track length shorter than 
20 m: <add description of actual 
deviation>
Corridor length not as per 
6MWT guidance at 
screening.
Entered but did not 
satisfy criteria
N/A
33
If a subject is oxygen dependent, the use of a 
portable device is allowed. The oxygen flow rate 
must remain constant from 30 minutes prior to 
each 6MWT, until the completion of all protocol-
mandated assessments after the 6MWT. The way 
oxygen is delivered (delivery device, application 
route, way of carrying the delivery device) must be 
the same for all 6MWTs, unless a change is 
required for documented medical reasons.
Requirements for oxygen 
supplementation not followed at 
screening: <add description of actual 
deviation>
Requirements for oxygen 
supplementation not followed 
at screening. 
Entered but did not 
satisfy criteria
N/A
34
A woman of childbearing potential must:
Have a negative serum pregnancy test at 
(re)screening and a negative urine pregnancy test
at randomization.
Inclusion criterion 6a not met: subject 
had <a positive serum pregnancy test 
at (re)screening> and/or <a positive 
urine pregnancy test at randomization>.
Inclusion Criterion 6a not met
Entered but did not 
satisfy criteria
N/A
35
A woman of childbearing potential must:
–
Agree to undertake monthly urine pregnancy 
tests during the study and up to at least 30 
days after study treatment discontinuation.
Inclusion criterion 6b not met: subject 
doesn't agree to undertake monthly 
urine pregnancy tests during the study 
and up to at least 30 days after study 
treatment discontinuation.
Inclusion Criterion 6b not met
Entered but did not 
satisfy criteria
N/A
36
A woman of childbearing potential must:
–
Agree to use one of the methods of birth 
control described in protocol Section 4.5.2
from (re)screening up to at least 30 days 
after study treatment discontinuation.
Inclusion criterion 6c not met: the 
subject doesn't agree to use one of the 
methods of birth control described in 
protocol Section 4.5.2 from 
(re)screening up to at least 30 days 
after study treatment discontinuation.
Inclusion Criterion 6c not met
Entered but did not 
satisfy criteria
N/A
37
At re-screening, 6MWT, physical examination, 
vital signs, local 12-lead ECG and central 
laboratory assessments must be repeated.
At re-screening, the following 
assessments were not repeated: 
<specify assessment>.
Assessments not repeated at 
re-screening.
Entered but did not 
satisfy criteria
N/A
EXCLUSION CRITERIA RELATED TO THE DISEASE
38
Planned BPA within 26 weeks after randomization
is forbidden.
Exclusion criterion 1 met: BPA is 
planned for the subject within the first 
26 weeks after randomization.
Exclusion criterion 1 met
Entered but did not 
satisfy criteria
Yes
39
Change in dose or initiation of new PH-specific 
therapy within 90 days prior to the baseline RHC 
(and LHC, if needed) qualifying for enrollment for 
the hemodynamic cohort and within 90 days prior 
Exclusion criterion 2 met: subject had a 
change in dose or initiation of new PH-
specific therapy 
Exclusion criterion 2 met
Entered but did not 
satisfy criteria
Yes


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Table 17:
Major Protocol Deviations Leading to Exclusion from PPS
Sequence 
No. 
Description 
Protocol Deviation Description (DVTERM)
PD Criterion
Protocol Deviation Coded 
Term (DVDECOD)
Exclude from PPS
to randomization (Visit 2) for the non-
hemodynamic cohort is forbidden. 
40
Treatment with prostacyclin (epoprostenol), 
prostacyclin analogs (i.e., treprostinil, iloprost, 
beraprost) or prostacyclin receptor agonists (i.e., 
selexipag/Uptravi®) within 90 days prior to 
randomization (Visit 2) is forbidden, except those 
given at vasodilator testing during RHC.
Exclusion criterion 3 met: subject was 
treated with prostacyclin 
(epoprostenol), prostacyclin analogs 
(i.e., treprostinil, iloprost, beraprost) or 
prostacyclin receptor agonists (i.e. 
selexipag/Uptravi®) within 90 days prior 
to randomization (Visit 2).
Exclusion criterion 3 met
Entered but did not 
satisfy criteria
Yes
41
Change in dose or initiation of new diuretics 
and/or calcium channel blockers within 1 week 
prior to baseline RHC (and LHC, if needed) is 
forbidden.
Exclusion criterion 4 met: subject had a 
change in dose or initiation of new 
diuretics and/or calcium channel 
blockers within 1 week prior to baseline 
RHC/LHC. 
Exclusion criterion 4 met
Entered but did not 
satisfy criteria
Yes
EXCLUSION CRITERIA RELATED TO COMORBIDITIES
42
Severe coronary heart disease or unstable angina 
as assessed by the investigator is forbidden.
Exclusion criterion 5 met: subject has 
severe coronary heart disease or 
unstable angina.
Exclusion criterion 5 met
Entered but did not 
satisfy criteria
N/A
43
Myocardial infarction within the last 6 months prior 
to (re)screening is forbidden.
Exclusion criterion 6 met: subject had 
myocardial infarction within the last 6 
months prior to (re)screening.
Exclusion criterion 6 met -
Protocol Version 1 and 2
Entered but did not 
satisfy criteria
N/A
44
Myocardial infarction within the last 6 months prior 
to or during (re)screening is forbidden.
Exclusion criterion 6 met: subject had 
myocardial infarction within the last 6 
months prior to or during (re)screening.
Exclusion criterion 6 met -
From protocol Version 3 
onwards
Entered but did not 
satisfy criteria
N/A
45
Decompensated cardiac failure if not under close 
supervision is forbidden.
Exclusion criterion 7 met: subject has 
decompensated cardiac failure without
close supervision.
Exclusion criterion 7 met
Entered but did not 
satisfy criteria
N/A
46
Severe arrhythmias as assessed by the 
investigator is forbidden. 
Exclusion criterion 8 met: subject has 
severe arrhythmias as assessed by the 
investigator.
Exclusion criterion 8 met
Entered but did not 
satisfy criteria
N/A
47
Cerebrovascular events (e.g., transient ischemic 
attack, stroke) within the last 3 months prior to 
(re)screening is forbidden.
Exclusion criterion 9 met: subject had 
cerebrovascular events (e.g., transient 
ischemic attack, stroke) within the last 3 
months prior to (re)screening.
Exclusion criterion 9 met -
Protocol Version 1 and 2
Entered but did not 
satisfy criteria
N/A
48
Cerebrovascular events (e.g., transient ischemic 
attack, stroke) within the last 3 months prior to or 
during (re)screening is forbidden.
Exclusion criterion 9 met: subject had 
cerebrovascular events (e.g., transient 
ischemic attack, stroke) within the last 3 
months prior to or during (re)screening.
Exclusion criterion 9 met -
From protocol Version 3 
onwards
Entered but did not 
satisfy criteria
N/A


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73
Status: Approved, Date: 11 July 2022
Table 17:
Major Protocol Deviations Leading to Exclusion from PPS
Sequence 
No. 
Description 
Protocol Deviation Description (DVTERM)
PD Criterion
Protocol Deviation Coded 
Term (DVDECOD)
Exclude from PPS
49
Congenital or acquired valvular defects with 
clinically relevant myocardial function disorders 
not related to PH is forbidden. 
Exclusion criterion 10 met: subject has 
congenital or acquired valvular defects 
with clinically relevant myocardial 
function disorders not related to PH
Exclusion criterion 10 met
Entered but did not 
satisfy criteria
Yes
50
Known or suspicion of pulmonary veno-occlusive 
disease (PVOD) is forbidden.
Exclusion criterion 11 met: subjects has 
known or suspected PVOD.
Exclusion criterion 11 met
Entered but did not 
satisfy criteria
Yes
EXCLUSION CRITERIA RELATED TO SELEXIPAG USE
51
Known and documented severe hepatic 
impairment is forbidden. 
Exclusion criterion 12 met: subject has 
known and documented severe hepatic 
impairment.
Exclusion criterion 12 met
Entered but did not 
satisfy criteria
Yes
52
Severe renal failure (estimated glomerular 
filtration rate < 30 mL/min/1.73 m2 or serum 
creatinine > 2.5 mg/dL or 221 μmol/L) at 
(re)screening is forbidden. 
Exclusion criterion 13 met: subject has 
severe renal failure (estimated 
glomerular filtration rate < 30 
mL/min/1.73 m2 or serum creatinine > 
2.5 mg/dL or 221 μmol/L) at 
(re)screening.
Exclusion criterion 13 met
Entered but did not 
satisfy criteria
N/A
53
Known or suspected uncontrolled thyroid disease 
as per investigator judgment is forbidden 
Exclusion criterion 14 met: subject has 
known or suspected uncontrolled 
thyroid disease as per investigator 
judgment.
Exclusion criterion 14 met
Entered but did not 
satisfy criteria
N/A
54
Being pregnant, planning to become pregnant or 
lactating is forbidden. 
Exclusion criterion 15 met: subject is 
pregnant, planning to be become 
pregnant or lactating.
Exclusion criterion 15 met
Entered but did not 
satisfy criteria
N/A
55
Treatment with strong and moderate inhibitors of 
cytochrome P-450 2C8 (CYP2C8; e.g., 
gemfibrozil, clopidogrel, deferasirox, 
teriflunomide) within 14 days prior to 
randomization is forbidden. 
Exclusion criterion 16 met: subject was 
treated with strong and moderate 
inhibitors of cytochrome P-450 2C8 
(CYP2C8; e.g., gemfibrozil, clopidogrel, 
deferasirox, teriflunomide) within 14 
days prior to randomization.
Exclusion criterion 16 met –
Protocol Version 1
Entered but did not 
satisfy criteria
Yes
56
Treatment with strong inhibitors of cytochrome P-
450 2C8 (CYP2C8; e.g., gemfibrozil) within 14 
days prior to randomization is forbidden. 
Exclusion criterion 16 met: subject was 
treated with strong inhibitors of 
cytochrome P-450 2C8 (CYP2C8; e.g., 
gemfibrozil) within 14 days prior to 
randomization.
Exclusion criterion 16 met –
Protocol Version 2 
Entered but did not 
satisfy criteria
Yes
57
Treatment with strong inhibitors of cytochrome P-
450 2C8 (CYP2C8; e.g., gemfibrozil) or moderate 
inducers of CYP2C8 (e.g., rifampicin) within 14 
days prior to randomization is forbidden. 
Exclusion criterion 16 met: subject was 
treated with strong inhibitors of 
cytochrome P-450 2C8 (CYP2C8; e.g., 
gemfibrozil) or moderate inducers of 
CYP2C8 (e.g., rifampicin) within 14 
days prior to randomization.
Exclusion criterion 16 met –
from Protocol Version 3 
onwards
Entered but did not 
satisfy criteria
Yes


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065B302
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74
Status: Approved, Date: 11 July 2022
Table 17:
Major Protocol Deviations Leading to Exclusion from PPS
Sequence 
No. 
Description 
Protocol Deviation Description (DVTERM)
PD Criterion
Protocol Deviation Coded 
Term (DVDECOD)
Exclude from PPS
58
SBP < 90 mmHg at (re)screening (Visit 1) or at 
randomization (Visit 2) is forbidden. 
Exclusion criterion 17 met: subject had 
SBP < 90 mmHg at (re)screening (Visit 
1) or at randomization (Visit 2).
Exclusion criterion 17 met
Entered but did not 
satisfy criteria
N/A
59
Known hypersensitivity to selexipag or drugs of 
the same class, or any of their excipients is 
forbidden. 
Exclusion criterion 18 met: subjects has 
known hypersensitivity to selexipag or 
drugs of the same class, or any of their
excipients.
Exclusion criterion 18 met
Entered but did not 
satisfy criteria
Yes
GENERAL EXCLUSION CRITERIA
60
Planned or current treatment with another 
investigational treatment up to 3 months prior to 
randomization is forbidden. 
Exclusion criterion 19 met: subjects has 
planned or current treatment with 
another investigational treatment up to 
3 months prior to randomization.
Exclusion criterion 19 met
Entered but did not 
satisfy criteria
Yes
61
Any co-morbid condition that may influence the 
ability to perform a reliable and reproducible 
6MWT, including use of walking aids (cane, 
walker, etc.) is forbidden. 
Exclusion criterion 20 met: subject has 
any co-morbid condition that may 
influence the ability to perform a 
reliable and reproducible 6MWT, 
including use of walking aids (cane, 
walker, etc.).
Exclusion criterion 20 met
Entered but did not 
satisfy criteria
N/A
62
Any known factor or disease that might interfere 
with treatment compliance, study conduct, or 
interpretation of the results, such as drug or 
alcohol dependence or psychiatric disease is 
forbidden. 
Exclusion criterion 21 met: subject has 
any known factor or disease that might 
interfere with treatment compliance, 
study conduct, or interpretation of the 
results, such as drug or alcohol 
dependence or psychiatric disease.
Exclusion criterion 21 met: 
known interfering factor or 
disease
Entered but did not 
satisfy criteria
N/A
63
Known concomitant life-threatening disease with a 
life expectancy < 12 months is forbidden. 
Exclusion criterion 22 met: subject has 
a known concomitant life-threatening 
disease with a life expectancy < 12 
months.
Exclusion criterion 22 met: 
known life-threatening 
disease
Entered but did not 
satisfy criteria
N/A
CONCOMITANT MEDICATION
64
Change in dose or initiation of new PH-specific 
therapies (i.e., ERA, PDE-5 inhibitor, sGC 
stimulator) is forbidden from randomization and up 
to Week 26 (Visit 5).
Change in PH-specific therapies: 
<specify treatment>.
Change in PH-specific 
therapies 
Received a disallowed 
concomitant treatment
Yes
65
Treatment with prostacyclin (epoprostenol), 
prostacyclin analogs (i.e., treprostinil, iloprost, 
beraprost) or prostacyclin receptor agonists (i.e., 
selexipag/Uptravi) is forbidden from randomization 
(Visit 2) and up to study treatment discontinuation.
Received prostanoids: <specify 
treatment>.
Received prostanoids 
Received a disallowed 
concomitant treatment
Yes


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065B302
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75
Status: Approved, Date: 11 July 2022
Table 17:
Major Protocol Deviations Leading to Exclusion from PPS
Sequence 
No. 
Description 
Protocol Deviation Description (DVTERM)
PD Criterion
Protocol Deviation Coded 
Term (DVDECOD)
Exclude from PPS
66
Treatment with strong CYP2C8 (e.g., gemfibrozil) 
is forbidden from randomization and up to 30 days 
after study treatment discontinuation.
Received strong and/or moderate 
inhibitors of CYP2C8: <specify 
treatment>.
Received strong and/or 
moderate inhibitors of 
CYP2C8 – from Protocol 
Version 2 onwards
Received a disallowed 
concomitant treatment
Yes
DOSAGE & ADMINISTRATION
67
Wrong medication kit received/dispensed in the 
double-blind study treatment period.
NOTE: 
This PD leads to exclusion only if, after 
unblinding, the received/dispensed bottle did not 
contain the planned/randomized study treatment.
If PD date is available (either date of first intake 
from an incorrect bottle or if this date is not 
available, use the date when the wrong bottle was 
dispensed), only exclude if occurred prior to the 
corresponding efficacy assessment date.
Received wrong medication kit during 
the double-blind study treatment period 
<enter number>.
Received wrong medication 
kit during the double-blind 
study treatment period.
Received wrong 
treatment or incorrect 
dose
Yes 
(see note)
68
The double-blind study treatment dose reached at 
Week 12 (Visit 3) must be kept stable at least until 
Week 26 (Visit 5) but can be adjusted for safety 
and tolerability reasons.
Double-blind study treatment not stable 
from Week 12 until Week 26 and was 
changed for reason other than subject’s 
safety and tolerability.
Double-blind study treatment 
not stable from Week 12 until 
Week 26 except for safety 
and tolerability reasons.
Received wrong 
treatment or incorrect 
dose
Yes
69
Overall compliance is expected to be between 
80% and 120%.
NOTE: 
During double-blind treatment only.
Overall study drug compliance below 
80% or above120%: <specify actual 
deviation>
Overall study compliance 
outside expected range.
Received wrong 
treatment or incorrect 
dose
Yes
(see note)
70
Study treatment was not administered as per 
protocol (e.g., starting dose, dosing frequency 
adjustment due to moderate hepatic impairment 
or concomitant treatment with moderate CYP2C8 
inhibitors, titration scheme, reinitiating after 
temporarily interruption and overdose defined as 
any single dose greater than 1600 μg or a total 
daily dose greater than 3200 μg. For subjects with 
moderate hepatic impairment or who are 
concomitantly taking moderate (a) CYP2C8 
inhibitor(s) the dosing frequency is once daily, and 
an overdose is defined by the intake of a dose 
greater than 1600 μg or a total daily dose greater 
than 1600 μg.)  
Study treatment was not administered 
as per protocol: <specify actual 
deviation>
Study treatment was not 
administered as per protocol.
Received wrong 
treatment or incorrect 
dose
Yes


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065B302
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
76
Status: Approved, Date: 11 July 2022
Table 17:
Major Protocol Deviations Leading to Exclusion from PPS
Sequence 
No. 
Description 
Protocol Deviation Description (DVTERM)
PD Criterion
Protocol Deviation Coded 
Term (DVDECOD)
Exclude from PPS
WITHDRAWAL CRITERIA
71
Study treatment must be discontinued if study 
treatment interruptions exceed 14 consecutive 
days.
Study treatment was not discontinued 
following a study treatment interruption 
for more than 14 days: <specify actual 
deviation> 
Study treatment not 
discontinued despite 
interruption of more than 14 
days.
Developed withdrawal 
criteria but not 
withdrawn
Yes
72
Study treatment must be permanently 
discontinued if a subject develops severe hepatic 
impairment.
Study treatment was not prematurely 
discontinued in subject with severe 
hepatic impairment. <specify actual 
deviation>
Study treatment not 
discontinued in subject with 
severe hepatic impairment.
Developed withdrawal 
criteria but not 
withdrawn
Yes
73
Study treatment must be discontinued if 
pulmonary veno-occlusive disease (PVOD) is 
confirmed. 
Study treatment was not prematurely 
discontinued in subject with confirmed 
PVOD. <specify actual deviation>
Study treatment not 
discontinued in subject with 
confirmed PVOD.
Developed withdrawal 
criteria but not 
withdrawn
Yes
74
Study treatment must be permanently 
discontinued if strong inhibitors of CYP2C8 
(e.g., gemfibrozil) treatments are started during 
the treatment period.
Study treatment was not prematurely 
discontinued in subject receiving 
concomitant strong inhibitors of 
CYP2C8: <specify treatment>.
Study treatment not 
withdrawn in subject who 
received strong inhibitors of 
CYP2C8.
Developed withdrawal 
criteria but not 
withdrawn
Yes
75
Study treatment must be permanently 
discontinued if any investigational treatments are 
started during the treatment period.
Study treatment was not prematurely 
discontinued in subject receiving an 
investigational treatment <specify 
treatment>.
Study treatment not 
withdrawn in subject who 
received an investigational 
treatment.
Developed withdrawal 
criteria but not 
withdrawn
Yes
76
Study treatment must be discontinued if a subject 
becomes pregnant.
Subject became pregnant and study 
treatment was not discontinued. 
<specify actual deviation>
Study treatment not 
discontinued in subject who 
became pregnant.
Developed withdrawal 
criteria but not 
withdrawn
N/A
77
Study treatment must be discontinued if the 
subject (or the participants legally acceptable 
representative) does not agree to continue with 
administration of study treatment. 
Study treatment was continued despite 
the participants (or the participants 
legally acceptable representative) 
request to prematurely discontinue 
study treatment <specify actual 
deviation>
Study treatment not 
discontinued despite request 
to prematurely discontinue 
study treatment.
Developed withdrawal 
criteria but not 
withdrawn
N/A
78
Study treatment must be discontinued if the 
investigator considers that for safety or tolerability 
reasons (e.g., AE), it is in the best interests of the 
subject to discontinue study treatment.
Study treatment was not prematurely 
discontinued although the investigator 
considered this to be in the best 
interest of the participant: <specify 
actual deviation>
Study treatment not 
discontinued due to safety or 
tolerability concerns.
Developed withdrawal 
criteria but not 
withdrawn
N/A
79
A subject will be withdrawn from the study due to 
Sponsor’s decision for any reason, including, but 
not limited to premature termination or suspension 
of the study
Sponsor decision to withdraw subject or 
terminate the study but subject was not 
withdrawn from study treatment within 
the time indicated by the sponsor: 
<specify>.
Study treatment not 
discontinued due to Sponsor 
decision.
Developed withdrawal 
criteria but not 
withdrawn
N/A
OTHER – STUDY PROCEDURES


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065B302
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
77
Status: Approved, Date: 11 July 2022
Table 17:
Major Protocol Deviations Leading to Exclusion from PPS
Sequence 
No. 
Description 
Protocol Deviation Description (DVTERM)
PD Criterion
Protocol Deviation Coded 
Term (DVDECOD)
Exclude from PPS
80
Study treatment must be approved for use before 
administration 
Participant received study treatment
which was not approved for use: 
<specify>
Administration of study 
treatment which was not 
approved for use
Other
Yes
81
Under normal circumstances, the investigator and 
study personnel, the subjects, sponsor personnel
directly involved in the conduct of the trial, and 
CRO personnel involved in the conduct of the 
study will remain blinded to the study treatment 
until the fourth analysis time point (see protocol 
Section 5.1.6).
Non-justified unblinding of treatment
group: <specify actual deviation and 
reason for unblinding>.
Non-justified unblinding.
Other
Yes
82
Informed consent process not followed (e.g., 
study-related activity performed prior to signing 
initial ICF(s); new study-related activity performed 
before the subject was re-consented, subject not 
re-consented)
Informed consent process not followed:
<specify actual deviation>
Informed consent process not 
followed.
Other
N/A
83
The Visit 4/Week 20 must be performed on Day 
141 ± 7 days (i.e., days 134-148) after 
randomization.
The Visit 4/Week 20 was performed 
outside the allowed time window.
Visit 4/Week 20 outside time 
window.
Other
Yes 
(only if beyond the 
analysis time 
window ie, 
beyond Week 
27/Day 189)
84
The Visit 4/Week 20 must be performed.
The Visit 4/Week 20 was not 
performed.
Visit 4/Week 20 not 
performed.
Other
Yes
85
The Visit 5/Week 26 must be performed on Day 
183 ± 7 days (i.e., days 176-190) after 
randomization.
The Visit 5/Week 26 was performed 
outside the allowed time window. 
Visit 5/Week 26 outside time 
window.
Other
N/A
86
The Visit 5/Week 26 must be performed.
The Visit 5/Week 26 was not 
performed.
Visit 5/Week 26 not 
performed.
Other
N/A
87
For the hemodynamic cohort, at the Week 20 the 
CO must be measured with a minimum of 3 
consecutive measurements that should not differ 
by > 10% when the thermodilution method is used 
and with 1 measurement when the Fick method is 
used. The mean value will be recorded in the 
electronic Case Report Form (eCRF).
At the Week 20 RHC CO was not 
measured as per Actelion RHC/LHC
guidelines.
Week 20 CO not as per study 
guidelines.
Other
Yes
88
For the hemodynamic cohort, zeroing as per HC 
guideline must be done prior to the HC 
measurement.
Zeroing was not done according to the 
HC guidelines at Visit 4/Week 20: 
<specify>
Zeroing was not done before 
HC measurements at Visit 
4/Week 20.
Other
Yes
89
For the hemodynamic cohort, for sPAP and dPAP 
the 2 most representative and reliable 
sPAP and/or dPAP not documented 
with 2 representative and reliable 
sPAP and/or dPAP not 
measured or documented as 
Other
Yes


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065B302
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
78
Status: Approved, Date: 11 July 2022
Table 17:
Major Protocol Deviations Leading to Exclusion from PPS
Sequence 
No. 
Description 
Protocol Deviation Description (DVTERM)
PD Criterion
Protocol Deviation Coded 
Term (DVDECOD)
Exclude from PPS
measurements must be documented in the source 
notes.
measurements at Visit 4/Week 20: 
<specify which parameter was not 
measured and documented as per 
guidance sPAP and/or dPAP>
per HC guidance at Visit 
4/Week 20.
90
For the hemodynamic cohort, the same method 
for CO measurement must be used for both the 
baseline and any post-baseline HC.
Postbaseline CO at Visit 4/Week 20
was not measured with the same 
method as at baseline: <specify>.
Postbaseline CO method at 
Visit 4/Week 20 is not the 
same as for baseline CO 
measurement. 
Other
Yes
91
For the hemodynamic cohort, for the HC, if 
thermodilution method is used to measure CO, 
the CO must be measured with at least 3 
measurements documented in the heart 
catherization worksheet.
Thermodilution CO at Visit 4/Week 20
not measured at least 3 times: <specify 
deviation>
Thermodilution CO at Visit 
4/Week 20 not measured at 
least 3 times.
Other
Yes
92
For the hemodynamic cohort, for the HC, if 
thermodilution method is used to measure CO, 3 
measurements must be within 10% of each other, 
i.e. the lowest of the 3 CO values must not be 
lower than 10% of the middle value AND the 
highest value must not be higher than 10% of the 
middle value.
Thermodilution CO values at Visit 
4/Week 20: the upper and/or lower 
values are more than 10% +/- of the 
middle value: <specify and list the CO 
values>
Thermodilution CO the upper 
and/or lower values are more 
than 10% +/- of the middle 
value at Visit 4/Week 20.
Other
Yes
93
For the hemodynamic cohort, HC is to be 
performed at Visit 4/Week 20.
HC is missing at Visit 4/Week 20: 
<specify> 
HC not done at Visit 4/Week 
20.
Other
Yes
94
For the hemodynamic cohort, HC is to be 
performed at Visit 4/Week 20; Day 141 ± 7 days 
(i.e., days 134-148) after randomization.
Visit 4 /Week 20 HC was performed 
outside the allowed time window
Visit 4/Week 20 HC outside 
time window.
Other
Yes 
(only if beyond the 
analysis time 
window ie, 
beyond Week 
27/Day 189)
95
For the hemodynamic cohort, CO must be 
measured at Visit 4/Week 20.
Missing CO at Visit 4/Week 20: 
<specify>
Missing CO at Visit 4/Week 
20.
Other
Yes
96
For the hemodynamic cohort, sPAP must be 
measured at Visit 4/Week 20.
Missing sPAP at Visit 4/Week 20:
<specify>
Missing sPAP at Visit 4/Week 
20.
Other
Yes
97
For the hemodynamic cohort, dPAP must be 
measured at Visit 4/Week 20.
Missing dPAP at Visit 4/Week 20: 
<specify>
Missing dPAP at Visit 4/Week 
20.
Other
Yes
98
For the hemodynamic cohort, PAWP or LVEDP, if 
PAWP is missing or not reliable must be available 
Visit 4/Week 20.
Missing or not reliable PAWP and 
missing LVEDP at Visit 4/Week 20: 
<specify>
Missing or not reliable PAWP 
and LVEDP not available at 
Visit 4/Week 20.
Other
Yes
99
For the hemodynamic cohort, the Week 20 RHC
(and LHC, if needed) must be performed within 2 
to 5 hours post dose.
The Week 20 RHC/LHC was performed 
outside the 2 to 5 hours post dose
window.
Week 20 RHC/LHC outside 2 
to 5 hours post dose window.
Other
Yes


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065B302
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
79
Status: Approved, Date: 11 July 2022
Table 17:
Major Protocol Deviations Leading to Exclusion from PPS
Sequence 
No. 
Description 
Protocol Deviation Description (DVTERM)
PD Criterion
Protocol Deviation Coded 
Term (DVDECOD)
Exclude from PPS
100
For the hemodynamic cohort, the Week 20 RHC
(and LHC, if needed) must be performed after the
post-dose 6MWT
The Week 20 RHC/LHC was performed 
before the post-dose 6MWT
Week 20 RHC/LHC 
performed before post-dose 
6MWT.
Other
N/A
101
6MWT is to be performed at randomization
6MWT not done at randomization: 
<specify>
6MWT not done at 
randomization.
Other
N/A
102
6MWT is to be performed at Visit5/Week 26.
6MWT not done at Visit 5/Week 26: 
<specify>
6MWT not done at 
Visit5/Week 26.
Other
N/A
103
At Week 26, the 6MWT must be performed within 
2 to 5 hours post dose.
At Week 26 the 6MWT was performed 
outside the post dose time window of 2 
to 5 hours post dose.
Week 26 6MWT outside time 
window.
Other
N/A
104
6MWT is to be performed at PTOP-Week 26 visit.
6MWT not done at PTOP-Week 26 
visit: <specify> 
6MWT not done at PTOP-
Week 26 visit.
Other
N/A
105
For the 6MWT all the following requirements 
related to the subject must be followed:
- wear comfortable clothing
- wear appropriate shoes
- must not have exercised vigorously within 2 
hours before the 6MWT
The 6MWT requirements related to the 
subject at randomization were not 
followed: <specify deviation>
The 6MWT guidance related 
to the subject were not 
followed at randomization.
Other
N/A
106
For the 6MWT all the following requirements 
related to the subject must be followed:
- wear comfortable clothing
- wear appropriate shoes
- must not have exercised vigorously within 2 
hours before the 6MWT
The 6MWT requirements related to the 
subject at Visit 5/Week 26 were not 
followed: <specify deviation>
The 6MWT guidance related 
to the subject were not 
followed at Visit 5/Week 26.
Other
N/A
107
For the 6MWT all the following requirements 
related to the subject must be followed:
- wear comfortable clothing
- wear appropriate shoes
- must not have exercised vigorously within 2 
hours before the 6MWT
The 6MWT requirements related to the 
subject at PTOP-Week 26 visit were 
not followed: <specify deviation>
The 6MWT guidance related 
to the subject were not 
followed at PTOP-Week 26 
visit.
Other
N/A
108
If the subject is used to take bronchodilators, 
he/she must take them at least 10 to 30 minutes 
before the 6MWT.
Bronchodilators were not taken 10 to 
30 minutes before the 6MWT at 
randomization: <specify>
Bronchodilators not taken as 
per 6MWT guidance at 
randomization.
Other
N/A
109
If the subject is used to take bronchodilators, 
he/she must take them at least 10 to 30 minutes 
before the 6MWT.
Bronchodilators were not taken 10 to 
30 minutes before the 6MWT at Visit 
5/Week 26: <specify>
Bronchodilators not taken as 
per 6MWT guidance at Visit 
5/Week 26.
Other
N/A


JNJ-67896049  (selexipag)
Statistical Analysis Plan AC-065B302
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
80
Status: Approved, Date: 11 July 2022
Table 17:
Major Protocol Deviations Leading to Exclusion from PPS
Sequence 
No. 
Description 
Protocol Deviation Description (DVTERM)
PD Criterion
Protocol Deviation Coded 
Term (DVDECOD)
Exclude from PPS
110
If the subject is used to take bronchodilators, 
he/she must take them at least 10 to 30 minutes 
before the 6MWT.
Bronchodilators were not taken 10 to 
30 minutes before the 6MWT at PTOP-
Week 26 visit: <specify>
Bronchodilators not taken as 
per 6MWT guidance at 
PTOP-Week 26 visit.
Other
N/A
111
Walking aids (e.g., cane) and walkers are not 
allowed.
Forbidden walking aid was used during 
the 6MWT at randomization: <specify>
Used forbidden walking aid 
during the 6MWT at 
randomization.
Other
N/A
112
Walking aids (e.g., cane) and walkers are not 
allowed.
Forbidden walking aid was used during 
the 6MWT at Visit 5/Week 26: 
<specify>
Used forbidden walking aid 
during the 6MWT at Visit 
5/Week 26.
Other
N/A
113
Walking aids (e.g., cane) and walkers are not 
allowed.
Forbidden walking aid was used during 
the 6MWT at PTOP-Week 26 visit: 
<specify>
Used forbidden walking aid 
during the 6MWT at PTOP-
Week 26 visit.
Other
N/A
114
The interval between two 6MWTs on the same 
day must be at least 2 hours.
There was less than 2 hours between 2 
6MWTs performed at randomization: 
<specify>
Less than 2 hours between 
two 6MWTs at randomization.
Other
N/A
115
The interval between two 6MWTs on the same 
day must be at least 2 hours.
There was less than 2 hours between 2 
6MWTs performed at Visit 5/Week 26: 
<specify>
Less than 2 hours between 
two 6MWTs at Visit 5/Week 
26.
Other
N/A
116
The interval between two 6MWTs on the same 
day must be at least 2 hours.
There was less than 2 hours between 2 
6MWTs performed at PTOP-Week 26 
visit: <specify>
Less than 2 hours between 
two 6MWTs at PTOP-Week 
26 visit.
Other
N/A
117
Only two 6MWTs can be performed on the same 
day.
More than two 6MWT were performed 
at randomization: <add description of 
the actual deviation>
More than 2 tests done 
randomization.
Other
N/A
118
Only two 6MWTs can be performed on the same 
day.
More than two 6MWT were performed 
at Visit 5/Week 26: <add description of 
the actual deviation>
More than 2 tests done Visit 
5/Week 26.
Other
N/A
119
Only two 6MWTs can be performed on the same 
day.
More than two 6MWT were performed 
at PTOP-Week 26 visit: <add 
description of the actual deviation>
More than 2 tests done 
PTOP-Week 26 visit.
Other
N/A
120
The 6MWT must be performed indoors, along a 
long, flat, straight, enclosed corridor (or similar 
location) with a hard surface that can be blocked 
for traffic during the conduct of the test. The track 
must be marked at regular intervals. The 
turnaround points must be marked with a cone. A 
starting line, which marks the beginning and end 
of each lap needs to be marked on the floor. The 
use of treadmill and a continuous course, e.g., a 
circuit, is not allowed.
Corridor not compliant with 6MWT 
guidance requirements at 
randomization: <add description of 
actual deviation>
Corridor does not meet 
6MWT guidance 
requirements at 
randomization. 
Other
N/A


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Table 17:
Major Protocol Deviations Leading to Exclusion from PPS
Sequence 
No. 
Description 
Protocol Deviation Description (DVTERM)
PD Criterion
Protocol Deviation Coded 
Term (DVDECOD)
Exclude from PPS
121
The 6MWT must be performed indoors, along a 
long, flat, straight, enclosed corridor (or similar 
location) with a hard surface that can be blocked 
for traffic during the conduct of the test. The track
must be marked at regular intervals. The 
turnaround points must be marked with a cone. A 
starting line, which marks the beginning and end 
of each lap needs to be marked on the floor. The 
use of treadmill and a continuous course, e.g., a 
circuit, is not allowed.
Corridor not compliant with 6MWT 
guidance requirements at Visit 5/Week 
26: <add description of actual 
deviation>
Corridor does not meet 
6MWT guidance 
requirements at Visit 5/Week 
26. 
Other
N/A
122
The 6MWT must be performed indoors, along a 
long, flat, straight, enclosed corridor (or similar 
location) with a hard surface that can be blocked 
for traffic during the conduct of the test. The track 
must be marked at regular intervals. The 
turnaround points must be marked with a cone. A 
starting line, which marks the beginning and end 
of each lap needs to be marked on the floor. The 
use of treadmill and a continuous course, e.g., a 
circuit, is not allowed.
Corridor not compliant with 6MWT 
guidance requirements at PTOP-Week 
26 visit: <add description of actual 
deviation>
Corridor does not meet 
6MWT guidance 
requirements at PTOP-Week 
26 visit. 
Other
N/A
123
The corridor must not be shorter than 20 m in 
length.
6MWT at randomization was done in a 
corridor with track length shorter than 
20 m: <add description of actual 
deviation>
Corridor length not as per 
6MWT guidance at 
randomization.
Other
N/A
124
The corridor must not be shorter than 20 m in 
length.
6MWT at Visit 5/Week 26 was done in 
a corridor with track length shorter than 
20 m: <add description of actual 
deviation>
Corridor length not as per 
6MWT guidance at Visit 
5/Week 26.
Other
N/A
125
The corridor must not be shorter than 20 m in 
length.
6MWT at PTOP-Week 26 visit was 
done in a corridor with track length 
shorter than 20 m: <add description of 
actual deviation>
Corridor length not as per 
6MWT guidance at PTOP-
Week 26 visit.
Other
N/A
126
For participants who have not previously 
performed a 6MWT, a training 6MWT must be 
performed before the first protocol-mandated 
6MWT is performed.
Missing training 6MWT before the first 
protocol mandated 6MWT: <add 
description of actual deviation> 
Missing training 6MWT 
before first protocol-
mandated 6MWT.
Other
N/A
127
If a subject is oxygen dependent, the use of a 
portable device is allowed. The oxygen flow rate 
must remain constant from 30 minutes prior to 
each 6MWT, until the completion of all protocol-
mandated assessments after the 6MWT. The way 
Requirements for oxygen 
supplementation not followed at 
randomization: <add description of 
actual deviation>
Requirements for oxygen 
supplementation not followed 
at randomization. 
Other
N/A


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Table 17:
Major Protocol Deviations Leading to Exclusion from PPS
Sequence 
No. 
Description 
Protocol Deviation Description (DVTERM)
PD Criterion
Protocol Deviation Coded 
Term (DVDECOD)
Exclude from PPS
oxygen is delivered (delivery device, application 
route, way of carrying the delivery device) must be 
the same for all 6MWTs, unless a change is 
required for documented medical reasons.
128
If a subject is oxygen dependent, the use of a 
portable device is allowed. The oxygen flow rate 
must remain constant from 30 minutes prior to 
each 6MWT, until the completion of all protocol-
mandated assessments after the 6MWT. The way 
oxygen is delivered (delivery device, application 
route, way of carrying the delivery device) must be 
the same for all 6MWTs, unless a change is 
required for documented medical reasons.
Requirements for oxygen 
supplementation not followed at Visit 
5/Week 26: <add description of actual 
deviation>
Requirements for oxygen 
supplementation not followed 
at Visit 5/Week 26. 
Other
N/A
129
If a subject is oxygen dependent, the use of a 
portable device is allowed. The oxygen flow rate 
must remain constant from 30 minutes prior to 
each 6MWT, until the completion of all protocol-
mandated assessments after the 6MWT. The way 
oxygen is delivered (delivery device, application 
route, way of carrying the delivery device) must be 
the same for all 6MWTs, unless a change is 
required for documented medical reasons.
Requirements for oxygen 
supplementation not followed at PTOP-
Week 26 visit: <add description of 
actual deviation>
Requirements for oxygen 
supplementation not followed 
at PTOP-Week 26 visit. 
Other
N/A
130
A woman of childbearing potential must practice 
an acceptable method of contraception while 
receiving study treatment and until 30 days after 
last dose of study treatment - see section 4.5.2 of 
the protocol.
Woman of childbearing potential not 
using an acceptable method of 
contraception: <specify actual 
deviation>.
Subject non-compliant with 
contraception method use
Other
N/A
131
For female of childbearing potential, after 
randomization, urine pregnancy tests will be 
performed monthly (±7 days) until 30 days after 
study treatment discontinuation.
Pregnancy test missed <specify 
month>.
Subject non-compliant with 
pregnancy test.
Other
N/A
132
A SAEs or pregnancy is to be reported within the 
24 hours’ time frame of the investigator’s 
knowledge of the event.
An SAE or pregnancy not reported or 
not reported in time: <specify>
SAE/pregnancy not reported 
or not reported in time.
Other
N/A
133
The Safety follow-up phone call must be 
performed 30-35 days after the last DB study 
treatment dose in case of premature 
discontinuation of DB study treatment.
The SFU call was <not performed 30-
35 days after the last DB study 
treatment dose> or <was not 
performed>.
PTOP1 Safety follow-up 
telephone call not performed 
as per protocol.
Other
N/A


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Table 17:
Major Protocol Deviations Leading to Exclusion from PPS
Sequence 
No. 
Description 
Protocol Deviation Description (DVTERM)
PD Criterion
Protocol Deviation Coded 
Term (DVDECOD)
Exclude from PPS
134
Safety follow-up phone call must be performed 
30-35 days after the last OL study treatment dose.
Safety follow-up phone call was <not 
performed 30-35 days after the last OL 
study treatment dose> or <was not 
performed>.
Visit 13 safety follow-up 
telephone call not performed 
as per protocol.
Other
N/A
135
PH-specific therapies stratification reported in IRT 
is different from the actual stratification reported in 
eCRF
Incorrect stratification based on PH-
specific therapies
Incorrect stratification based 
on PH-specific therapies
Other
Yes
136
CTEPH population stratification reported in IRT is 
different from the actual stratification reported in 
eCRF
Incorrect stratification based on CTEPH 
population
Incorrect stratification based 
on CTEPH population
Other
Yes
137
An unscheduled visit must be performed within 14 
days of the following occurring at an on-site visit: 
o Increase from baseline in WHO FC. 
Unscheduled on-site visit not performed 
following increase from baseline in 
WHO FC
Unscheduled on-site visit not 
performed following increase 
from baseline in WHO FC
Other
N/A
138
An unscheduled visit must be performed within 14 
days of the following occurring at an on-site visit: 
o Increase from baseline in WHO FC. 
Unscheduled on-site visit performed 
outside the 14 days’ time window 
following increase from baseline in 
WHO FC
Unscheduled on-site visit 
performed outside the 14 
days’ time window following 
increase from baseline in 
WHO FC
Other
N/A
139
An unscheduled visit must be performed within 14 
days of the following occurring at an on-site visit: 
o Deterioration from baseline by at least 15% in 
exercise capacity, as measured by the 6MWD.
Unscheduled on-site visit not performed 
following deterioration from baseline in 
6MWD
Unscheduled on-site visit not 
performed following 
deterioration from baseline in 
6MWD
Other
N/A
140
An unscheduled visit must be performed within 14 
days of the following occurring at an on-site visit: 
o Deterioration from baseline by at least 15% in 
exercise capacity, as measured by the 6MWD.
Unscheduled on-site visit performed 
outside the 14 days’ time window 
following deterioration from baseline in 
6MWD
Unscheduled on-site visit 
performed outside the 14 
days’ time window following 
deterioration from baseline in 
6MWD
Other
N/A


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6.5.
Appendix 5 Prior and Concomitant Medications
Prior and Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). 
Prior medications are defined as any therapy used and discontinued before the day of first dose 
(partial or complete) of study treatment. 
Concomitant medications are defined as any therapy used on or after the same day as the first dose 
of study treatment, including those that started before and continue on after the first dose of study 
treatment.
!
Concomitant medications at baseline are defined as any therapy used on the first dose of study 
treatment, including those that started before and continue on after the first dose of study 
treatment.  
!
Concomitant medications initiated during the study treatment period are defined as any 
therapy used on or after the first dose of study treatment.
Summaries of prior and concomitant medications will be presented by Anatomical Therapeutic 
Chemical (ATC) term and treatment group. 
The number and proportion of subjects who receive each prior/concomitant medication will be 
summarized as well as the number and proportion of subjects who receive at least 1 
prior/concomitant medication by treatment group and overall, for the FAS (and HES at analysis 
time point 1; as described in Table 7). In addition, concomitant medications of special interest will 
be presented; these include PH-specific therapies, anticoagulants/antithrombotics and oxygen
therapy (see Section 6.9 Appendix 9 for a list of medications in each category).
The following summary tables will be provided:
!
Prior medications
!
Concomitant medications at baseline
!
Concomitant medications initiated during the DB treatment period (any therapy initiated on 
or after the first dose of study treatment in the DB treatment period).
!
Concomitant medications of special interest at baseline (special interest therapies used on the 
day of the first dose of study treatment, including those that started before and continue on 
after the first dose of study treatment)
(
Concomitant PH-specific therapy at baseline, by medication subcategory and medication 
name 
(
Concomitant anticoagulants/anti-thrombotics at baseline, by medication subcategory and 
medication name    
(
Long term concomitant oxygen therapies present at baseline. 
!
Concomitant medications initiated during the OL treatment period (any therapy initiated on 
or after the first dose of study treatment in the OL treatment period)
Prior and concomitant medications will also be listed based on the FAS (HES subjects will be 
flagged).   


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6.6.
Appendix 6 Medical History
All relevant medical history/current medical conditions based on the investigator’s judgment 
(eg, chronic and ongoing acute conditions, serious past conditions) present before and/or at the 
time of signing informed consent are collected on the Medical History eCRF page.
The verbatim terms used in the eCRF reported by investigators to identify medical history events 
will be coded using the MedDRA. 
The number and percentage of subjects in each category will be summarized by treatment group 
and overall, for the FAS (and HES at analysis time point 1; as described in Table 7), by system 
organ class (SOC) and preferred term (PT), in descending order of frequency in the SOC and PT
in the selexipag treatment group.
By subject listings of medical history data will also be provided based on the FAS (HES subjects 
will be flagged).


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6.7.
Appendix 7 Intervention Compliance
Study treatment compliance is based on study treatment accountability collected on the Study Drug 
Dispensing & Accountability eCRF page and the Study Drug Compliance eCRF page:
!
Study drug compliance for the whole treatment period is calculated from the first dose of 
study treatment to EDBT (overall treatment compliance).
where, 
!
Compliance during the DB treatment period (irrespective of any temporary study treatment 
dose adjustments and/or interruptions) is calculated as follows:
 ! (%)
= (H I   J!J    K!! −H I   HJ    K!!)
 (J H I    JH!) ℎ MN  !J
(100
where,
for bid dosing frequency:
O(J H I    JH!) ℎ MN  !J
= [MN  J J (OMNQ) −MN   J (MR 1) + 1](2
for qd dosing frequency:
O(J H I    JH!) ℎ MN  !J
= [MN  J J (OMNQ) −MN   J (MR 1) + 1]
Compliance will be summarized descriptively (N, mean, SD, median, and range [minimum, 
maximum]) by study treatment group for the FAS and actual treatment group for the SAF, 
respectively, over the DB treatment period. 
The number and percentage of subjects who have at least 80% compliance through the DB
treatment period in the FAS and SAF will also be summarized by treatment group. 
Similar and separate summaries will be provided for the OL treatment period.
By subject listing of compliance data will also be provided on the SAF.


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6.8.
Appendix 8 Adverse Events of Special Interest
The following categories of AESI have been considered as either potential/identified important 
risks in selexipag RMP or represent otherwise an event of interest for this study. These have been 
reported in selexipag studies, based on the Standardized MedDRA Query (SMQs)/PTs in the 
current MedDRA version.
Any modifications of terms (according to the MedDRA SMQs/PTs) may occur based on later 
dictionary updates and/or external guidance and the latest definitions will be used at the time of 
analyses. 
Details will be provided in an AESI definition file (doc_aesi) that is saved at the selexipag 
compound level and version controlled in the Entimo Integrated Clinical Environment (or 
equivalent system). 
!
Anaemia
!
Bleeding events
!
Gastrointestinal disturbances denoting intestinal intussusception (manifested as ileus or 
obstruction)
!
Hyperthyroidism
!
Hypotension
!
Light-dependent non-melanoma skin malignancies
!
Major adverse cardiovascular events (MACE)
!
Medication errors
!
Ophthalmological effects associated to retinal vascular system
!
Pulmonary venoocclusive disease associated with pulmonary oedema
!
Renal function impairment / acute renal failure
!
Other topics:
(
Pregnancy
(
Prostacyclin associated reactions
(
COVID-19 infection


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6.9.
Appendix 9 Medications of Special Interest
Concomitant medications of special interest for PH-specific therapies (as per Section 1.2.5.1.2), 
and oxygen therapy, are tracked in an excel spreadsheet “med_of_interest.xls”, which is located 
in the AC-065B302 SELECT programming study area for each reporting effort. Reviews and 
updates to this spreadsheet will be performed if there are additional terms included in the data for 
these specific concomitant medications of special interest at the time of each reporting event and/or 
if there is a change/update to the WHO-DD at the time of each reporting event.
A separate spreadsheet (sdg_b3c3_september1_2021_126_antithrombotic_drugs.xslx), which is
provided by the coding specialist based on the current coding version,
tracks the 
anticoagulant/anti-thrombotic medications of special interest. 


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6.10.
Appendix 10 Marked Abnormal Laboratory Values
The following protocol defined marked laboratory abnormalities will be used. 
Hematology (SI units)
Laboratory test name
(CDISC Synonym[s])
LL
LLL
HH
HHH
Hemoglobin
< 100 g/L
< 80 g/L
> 20 g/L above
baseline
> 40 g/L above
baseline
Hematocrit; Erythrocyte
Volume fraction (EVF);
Packed Cell Volume (PCV)
(male)
< 0.32 L/L
< 0.20 L/L
> 0.60 L/L
> 0.65 L/L
Hematocrit; Erythrocyte
Volume fraction; Packed Cell
Volume (female)
< 0.28 L/L
< 0.20 L/L
> 0.55 L/L
> 0.65 L/L
Platelets
(assuming no platelet cluster)
< 75 × 109/L
< 50 × 109/L
> 600 × 109/L
> 999 × 109/L
Leukocytes; White Blood
Cells
< 3.0 × 109/L
< 2.0 × 109/L
> 20.0 × 109/L
> 100.0 × 109/L
Neutrophils (Abs)
< 1.5 × 109/L
< 1.0 × 109/L
NA
NA
Eosinophils (Abs)
NA
NA
> 5.0 × 109/L
NA
Lymphocytes (Abs)
< 0.8 × 109/L
< 0.5 × 109/L
> 4.0 × 109/L
> 20 × 109/L
CDISC=Clinical Data Interchange Standards Consortium; NA = not applicable; ULN = upper limit of normal. 
Greyed fields represent alert criteria for expedited notification to respective investigational site.
Blood chemistry (SI units)
Laboratory test name
(CDISC Synonym[s])
LL
LLL
HH
HHH
Alanine Aminotransferase
NA
NA
> 3 × ULN
> 5 × ULN*
Aspartate Aminotransferase
NA
NA
> 3 × ULN
> 5 × ULN*
Alkaline Phosphatase
NA
NA
> 2.5 × ULN
> 5 × ULN
Bilirubin; Total Bilirubin
NA
NA
> 2 × ULN
> 5 × ULN
Creatinine
NA
NA
> 1.5× ULN
> 3 × ULN
Sodium
NA
< 130 mmol/L
> 150 mmol/L
> 155 mmol/L
Potassium
< 3.2 mmol/L
< 3.0 mmol/L
> 5.5 mmol/L
> 6.0 mmol/L
Glomerular Filtration Rate
< 60 ml/min/
1.73 m2
< 30 ml/min/
1.73 m2
NA
NA
* Additional thresholds are to be reported, namely > 8 × ULN.
CDISC=Clinical Data Interchange Standards Consortium; NA = not applicable; ULN = upper limit of normal. 
Greyed fields represent alert criteria for expedited notification to respective investigational site.


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6.11.
Appendix 11: COVID-19
A COVID-19 Appendix is available for the AC-065B302 SELECT study, issued as a separate 
document to the protocol. This COVID-19 Appendix provides guidance on the conduct of the 
study during the COVID-19 pandemic; including guidance on what should be done in the event 
that subjects cannot attend scheduled visits due to the COVID-19 pandemic (with a focus on trying 
to collect mandated assessments as per protocol, as far as remains possible).
Statistical considerations to evaluate the impact of COVID-19 pandemic:
!
Perform sensitivity/descriptive analyses to assess the impact of COVID-19: 
–
As described in Section 5.3.3.3.2 and 5.3.3.3.3 for the primary endpoint.
–
As described below for other assessments.
Subject Disposition and Study Completion/Withdrawal:
The following summaries will be added to the disposition reporting described in Section 5.2, for 
those subjects who prematurely discontinued DB treatment or prematurely discontinued OL study 
treatment or prematurely discontinued the study due to:
!
Adverse event - COVID-19 related
!
Death - COVID-19 related
!
Other – COVID-19 related
Prior and Concomitant Therapies:
Subjects who received one or more concomitant medications for COVID-19 infection will be 
summarized.
A listing of concomitant medications for COVID-19 infection will also be provided.
Protocol Deviations:
In terms of handling safety and efficacy data, COVID-19 related protocol deviations are captured 
on the eCRF and their impact on study safety and efficacy outcomes will be evaluated. 
The number and percentage of subjects with major protocol deviations related to COVID-19 will 
be provided, added to the major protocol deviation summary table described in Section 6.4
Appendix 4.
Separate listings of subjects with major (and minor) protocol deviations related to COVID-19 will 
also be provided.
Adverse Events and Deaths:
The following will be added to the overall AE table summaries described in Section 5.6.2:


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!
COVID-19 associated AEs
!
COVID-19 associated SAEs
!
COVID-19 associated non-serious AEs
where, COVID-19 associated AEs are based on events that code to a COVID-19 MedDRA term.
The following listings will also be provided:
!
Listing of subjects with treatment-emergent COVID-19 associated AEs during the DB 
treatment period.
!
Listing of subjects with treatment-emergent COVID-19 associated AEs during the OL 
treatment period.
!
Listing of subjects who died due to COVID-19 infection.


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7.
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Birmingham, UK: National Institute for Health Research, Publication RM03/JH17/MK; 2008. Available at 
http://www.missingdata.org.uk.
[EMEA 2008] CHMP Guideline on the clinical investigations of medical products for the treatment of pulmonary 
arterial hypertension. (Ref. EMEA/CHMP/EWP/356954/2008). Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/12/WC500016686.pdf 
[accessed 25 Jul 2018].
[Galiè 2016] Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of 
pulmonary hypertension. Eur Heart J. 2016;37(1):67-119. 
[Ghofrani 2017] Ghofrani H-A, Simonneau G, D’Armini AM, et al. Macitentan for the treatment of inoperable 
chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicenter, phase 2, randomized, 
double-blind, placebo-controlled study. Lancet Respir Med. 2017;5:785-94.
[O’Kelly 2014] O’Kelly M, Ratitch B. Clinical trials with missing data: A guide for practitioners. Chichester, UK: 
Wiley & Sons; 2014.
[Rubin 1987] Rubin DB. Multiple imputation for nonresponse in surveys. New York, NY, USA: Wiley & Sons; 
1987.
[Zeng 2012] Zeng W-J, Xiong C-M, Zhao L, et al. Atorvastatin in pulmonary arterial hypertension (APATH) study. 
Eur Respir J. 2012; 40:67-74.