Clinical trial NCT03187678
Conditions: Pulmonary Arterial Hypertension
Keywords: switch intravenous selexipag
Sponsor: Actelion
Start date: 2017-12-04; Completion date: 2018-05-29
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The development of selexipag for intravenous administration will be useful to avoid treatment interruptions in patients with pulmonary arterial hypertension (PAH) already treated with selexipag administered orally as tablets (Uptravi®). The target population for intravenous selexipag includes those PAH patients who are hospitalized and are unable to swallow tablets of Uptravi.

The primary objective of this study is to assess whether it is safe for patients with PAH to temporarily change from selexipag tablets (Uptravi®) to selexipag given directly into a vein (intravenous selexipag), and then switching back to the initial oral dose of selexipag.

Detailed description:
After screening (Visit 1), each subject will participate in the following consecutive treatment periods: Period 1(treatment with oral selexipag at Visit 2/Day 1), Period 2 (treatment with intravenous selexipag at Visit 2/ Day 2 and Day 3), Period 3 (treatment with oral selexipag starting in the evening of Visit 2/Day 3 and ending 7 to 11 days later at Visit 3). Then a safety follow-up period is planned up to end of study visit (EOS), which occurs between Day 33 and Day 40.

Arms: arm 1: Subjects with stable pulmonary arterial hypertension (PAH) and currently treated with a stable oral dose of Uptravi will be switched to i.v. selexipag from Day 2 to Day 3 (2 infusions on Day 2 and 1 infusion on Day 3). Otherwise, they will continue with their current oral selexipag treatment throughout the study.
Interventions: intervention 1: i.v. selexipag intervention 2: oral selexipag (Uptravi)
Intervention descriptions: intervention 1: Selexipag for intravenous administration, twice daily as an infusion over 87 min. The dose is individualized for each subject to correspond to his/her current oral dose of Uptravi®. intervention 2: Uptravi is used as an auxiliary medicinal product, as part of the PAH standard treatment and administered according to the local prescribing information

Protocol documents:
Prot_000.pdf: 
TPL-000052_v11
Selexipag / ACT-293987 
Pulmonary Arterial Hypertension 
Protocol AC-065A309 
A multicenter, open-label, single-sequence cross-over study to assess safety, 
tolerability, and pharmacokinetics of intravenous selexipag in subjects with stable 
pulmonary arterial hypertension switching from an oral stable dose of selexipag 
Study Phase: 
3 
EudraCT Number: 
2016-004035-21 
Status and version: 
Final Version 1 
Date: 
27 January 2017 
Document type: 
Global protocol 
Actelion 
document 
number 
(Doc No.): 
D-17.055 
Confidentiality statement 
The information contained in this document, especially unpublished data, is the property of the sponsor of 
this study, Actelion Pharmaceuticals Ltd. It is therefore provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your personnel, and an independent ethics 
committee or institutional review board. It is understood that this information will not be disclosed to others 
without written authorization from Actelion Pharmaceuticals Ltd, except to the extent necessary to obtain 
informed consent from those persons to whom the study treatment may be administered. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 2/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
SPONSOR CONTACT DETAILS 
Sponsor 
Actelion Pharmaceuticals Ltd 
Gewerbestrasse 16 
CH-4123 Allschwil 
Switzerland 
 
 
Clinical Trial Physician 
Contact details of the Clinical Trial Physician can 
be found in the Investigator Site File 
Medical Emergency Hotline 
Toll phone number: [number] 
Site-specific toll telephone numbers and toll-free 
numbers for the Medical Emergency Hotline can 
be found in the Investigator Site File 
ACTELION CONTRIBUTORS TO THE PROTOCOL 
Clinical Trial Scientist 
, PhD 
Clinical Trial Scientist (Trainee) 
, PhD 
Clinical Trial Statistician 
, PhD 
Clinical Trial Physician 
, MD 
Junior Clinical Pharmacologist 
, PharmD 
Drug Safety Physician 
, MD 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 3/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION 
 
CENTRAL LABORATORY 
 
 
 
 
INTERACTIVE RESPONSE 
TECHNOLOGY 
 
 
 
CENTRAL ECG 
 
 
 
A list of site-specific contact details for Contract Research Organizations (CROs) can be 
found in the Investigator Site File. 
 
 
 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 4/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
SIGNATURE PAGE FOR ACTELION PHARMACEUTICALS LTD 
Hereinafter called Actelion 
 
Treatment name / number 
Selexipag / ACT-293987 
Indication 
Pulmonary arterial hypertension 
Protocol number, study title 
AC-065A309 
A multicenter, open-label, single-sequence cross-over study to assess safety, tolerability, 
and pharmacokinetics of intravenous selexipag in subjects with stable pulmonary arterial 
hypertension switching from an oral stable dose of selexipag. 
I approve the design of this study.  
 
 
Title 
Name 
Date 
 
Signature 
Clinical Trial 
Physician 
 
 
Clinical Trial 
Statistician 
 
 
 
 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 5/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
Selexipag / ACT-293987 
Indication 
Pulmonary arterial hypertension 
Protocol number, study title 
AC-065A309 
A multicenter, open-label, single-sequence cross-over study to assess safety, tolerability, 
and pharmacokinetics of intravenous selexipag in subjects with stable pulmonary arterial 
hypertension switching from an oral stable dose of selexipag. 
 
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). 
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 
Clinical Research Associate(s) (CRA[s]) and auditor(s), and agree to inspection by 
regulatory authorities or IEC/IRB representative(s). I will ensure that the study 
treatment(s) supplied by the sponsor is/are being used only as described in this protocol. I 
will ensure that all subjects 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 
herewith that the sponsor is allowed to enter and utilize my professional contact details 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 6/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
and function in an electronic database for internal purposes and for submission to health 
authorities worldwide. 
 
 
Country 
Site 
number 
Town 
Date 
 
Signature 
Principal 
Investigator 
 
 
 
 
 
 
 
 
 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 7/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
TABLE OF CONTENTS 
SPONSOR CONTACT DETAILS ......................................................................................2 
ACTELION CONTRIBUTORS TO THE PROTOCOL .....................................................2 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION ...................................3 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................12 
PROTOCOL SYNOPSIS AC-065A309 ............................................................................15 
PROTOCOL ......................................................................................................................21 
1 
BACKGROUND .........................................................................................................21 
1.1 
Pulmonary arterial hypertension ...................................................................21 
1.2 
Study treatment: intravenous selexipag ........................................................21 
 
Background information: selexipag ..................................................21 
1.2.1
 
Intravenous formulation ....................................................................22 
1.2.2
 
Summary of nonclinical data ............................................................22 
1.2.3
 
Summary of clinical data ..................................................................22 
1.2.4
1.3 
Purpose and rationale of the study ................................................................23 
 
Purpose of the study ..........................................................................23 
1.3.1
 
Rationale of the study .......................................................................23 
1.3.2
1.4 
Summary of known and potential risks and benefits ....................................23 
2 
STUDY OBJECTIVES ...............................................................................................24 
2.1 
Primary objective(s) .....................................................................................24 
2.2 
Other objectives ............................................................................................24 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................25 
3.1 
Study design .................................................................................................25 
 
Study periods ....................................................................................25 
3.1.1
 
Study duration ...................................................................................26 
3.1.2
3.2 
Study design rationale ..................................................................................27 
3.3 
Study committees .........................................................................................27 
4 
SUBJECT POPULATION ..........................................................................................27 
4.1 
Subject population description .....................................................................27 
4.2 
Rationale for the selection of the study population ......................................27 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 8/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
4.3 
Inclusion criteria ...........................................................................................28 
4.4 
Exclusion criteria ..........................................................................................28 
4.5 
Criteria for women of childbearing potential ...............................................29 
 
Definition of childbearing potential ..................................................29 
4.5.1
 
Acceptable methods of contraception ...............................................29 
4.5.2
5 
TREATMENTS ..........................................................................................................29 
5.1 
Study treatment .............................................................................................29 
 
Investigational treatment: description and rationale .........................29 
5.1.1
 
Study treatment preparation ..............................................................30 
5.1.2
 
Infusion solution samples .................................................................30 
5.1.3
5.1.3.1 
Procedures for sampling ..........................................................31 
5.1.3.2 
Shipping procedures ................................................................31 
5.1.3.3 
Bioanalysis ..............................................................................31 
 
Study treatment administration .........................................................31 
5.1.4
 
Treatment assignment .......................................................................31 
5.1.5
 
Blinding ............................................................................................32 
5.1.6
 
Study treatment supply .....................................................................32 
5.1.7
5.1.7.1 
Study treatment packaging and labeling .................................32 
5.1.7.2 
Study treatment distribution and storage .................................32 
5.1.7.3 
Study treatment dispensing .....................................................32 
5.1.7.4 
Study treatment return and destruction ...................................33 
 
Study treatment accountability and compliance with study 
5.1.8
treatment ...........................................................................................33 
5.1.8.1 
Study treatment accountability ................................................33 
5.1.8.2 
Study treatment compliance ....................................................33 
 
Study treatment dose adjustments and interruptions ........................33 
5.1.9
 
Premature discontinuation of study treatment ..................................34 
5.1.10
 
Study-specific criteria for premature discontinuation of study 
5.1.11
treatment ...........................................................................................35 
5.2 
Previous and concomitant therapy ................................................................35 
 
Definitions ........................................................................................35 
5.2.1
 
Reporting of previous/concomitant therapy / auxiliary 
5.2.2
medicinal products in the CRF .........................................................35 
 
Auxiliary medicinal products ............................................................36 
5.2.3
 
Allowed concomitant therapy ...........................................................36 
5.2.4
 
Forbidden concomitant therapy ........................................................36 
5.2.5
6 
STUDY ENDPOINTS ................................................................................................37 
6.1 
Efficacy endpoints ........................................................................................37 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 9/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
6.2 
Safety and tolerability endpoints ..................................................................37 
 
Definitions ........................................................................................37 
6.2.1
 
Main safety and tolerability endpoints ..............................................37 
6.2.2
 
Other safety and tolerability endpoints .............................................37 
6.2.3
6.3 
Pharmacokinetic endpoints ...........................................................................38 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS ................................................38 
7.1 
Study visits ...................................................................................................38 
 
Screening/re-screening ......................................................................38 
7.1.1
 
Unscheduled visits ............................................................................39 
7.1.2
7.2 
Study assessments .........................................................................................43 
 
Demographics / baseline characteristics ...........................................43 
7.2.1
 
Efficacy assessments .........................................................................44 
7.2.2
 
Safety assessments ............................................................................44 
7.2.3
7.2.3.1 
Physical examination ...............................................................44 
7.2.3.2 
Vital signs ................................................................................44 
7.2.3.3 
Weight and height ...................................................................45 
7.2.3.4 
ECG assessment ......................................................................45 
 
Laboratory assessments ....................................................................46 
7.2.4
7.2.4.1 
Type of laboratory ...................................................................46 
7.2.4.2 
Laboratory tests .......................................................................46 
 
Pharmacokinetic assessments ...........................................................47 
7.2.5
7.2.5.1 
Pharmacokinetic assessments ..................................................47 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL 
CARE ..........................................................................................................................48 
8.1 
Study completion ..........................................................................................48 
8.2 
Premature withdrawal from study ................................................................48 
8.3 
Premature termination or suspension of the study ........................................49 
8.4 
Medical care of subjects after study completion / withdrawal from 
study ..............................................................................................................50 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................50 
9.1 
Adverse events ..............................................................................................50 
 
Definition of adverse events .............................................................50 
9.1.1
 
Intensity of adverse events ................................................................51 
9.1.2
 
Relationship to study treatment ........................................................52 
9.1.3
 
Reporting of adverse events ..............................................................52 
9.1.4
 
Follow-up of adverse events .............................................................52 
9.1.5
9.2 
Serious adverse events ..................................................................................52 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 10/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
 
Definitions of serious adverse events ...............................................52 
9.2.1
 
Reporting of serious adverse events .................................................53 
9.2.2
 
Follow-up of serious adverse events .................................................53 
9.2.3
 
After the 30-day follow-up period ....................................................53 
9.2.4
 
Reporting procedures ........................................................................53 
9.2.5
9.3 
Pregnancy .....................................................................................................54 
 
Reporting of pregnancy ....................................................................54 
9.3.1
 
Follow-up of pregnancy ....................................................................55 
9.3.2
9.4 
Study safety monitoring ................................................................................55 
10 STATISTICAL METHODS .......................................................................................55 
10.1 
Analysis sets .................................................................................................55 
 
Screened Analysis Set .......................................................................55 
10.1.1
 
Full Analysis Set ...............................................................................55 
10.1.2
 
i.v. Safety Set ....................................................................................55 
10.1.3
 
Safety Set ..........................................................................................56 
10.1.4
 
Pharmacokinetic Analysis Set ..........................................................56 
10.1.5
 
Usage of the analysis sets .................................................................56 
10.1.6
10.2 
Variables .......................................................................................................57 
 
Primary efficacy variable(s) ..............................................................57 
10.2.1
 
Key secondary efficacy variables .....................................................57 
10.2.2
 
Safety variables .................................................................................57 
10.2.3
10.2.3.1 
Adverse events ........................................................................57 
10.2.3.2 
Laboratory data ........................................................................57 
10.2.3.3 
ECG .........................................................................................58 
 
Pharmacokinetic variables ................................................................58 
10.2.4
10.3 
Description of statistical analyses .................................................................58 
 
Overall testing strategy .....................................................................58 
10.3.1
 
Analysis of the primary efficacy variable(s) .....................................58 
10.3.2
 
Analysis of key secondary efficacy variable(s) ................................58 
10.3.3
 
Analysis of the safety variable(s) ......................................................59 
10.3.4
 
Analysis of PK variables ...................................................................59 
10.3.5
 
Analysis of other variables ...............................................................60 
10.3.6
10.4 
Interim analyses ............................................................................................61 
10.5 
Sample size ...................................................................................................61 
11 DATA HANDLING ....................................................................................................61 
11.1 
Data collection ..............................................................................................61 
11.2 
Maintenance of data confidentiality .............................................................62 
11.3 
Database management and quality control ...................................................62 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 11/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
12 PROCEDURES AND GOOD CLINICAL PRACTICE .............................................63 
12.1 
Ethics and Good Clinical Practice ................................................................63 
12.2 
Independent Ethics Committee / Institutional Review Board ......................63 
12.3 
Informed consent ..........................................................................................63 
12.4 
Indemnification, compensation and expenses to subjects and 
investigators ..................................................................................................64 
12.5 
Protocol adherence/compliance ....................................................................65 
12.6 
Protocol amendments ...................................................................................65 
12.7 
Essential documents and retention of documents .........................................65 
12.8 
Monitoring ....................................................................................................66 
12.9 
Investigator Site File .....................................................................................67 
12.10 
Audit .............................................................................................................68 
12.11 
Inspections ....................................................................................................68 
12.12 
Reporting of study results and publication ...................................................68 
13 REFERENCES ............................................................................................................70 
14 APPENDICES .............................................................................................................71 
 
LIST OF TABLES 
 
Table 1 
Correspondence of i.v. selexipag doses to Uptravi oral doses ........................30 
Table 2 
Visit and assessment schedule ........................................................................40 
Table 3 
Visit 2 vital signs and PK blood collection schedule ......................................42 
Table 4 
Reporting periods and corresponding analysis sets. .......................................56 
Table 5 
Thresholds for marked laboratory abnormalities ............................................72 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design ....................................................................................................26 
 
LIST OF APPENDICES 
 
Appendix 1 Marked laboratory abnormalities ....................................................................71 
 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 12/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
LIST OF ABBREVIATIONS AND ACRONYMS 
ACT-333679  
The active metabolite of selexipag 
AE  
Adverse event 
AUC  
Area under the plasma concentration-time curve 
AUC0-∞  
Area under the plasma concentration-time curve from 0 to infinity 
AUCτ, ss  
Area under the plasma concentration-time curve during a dose 
interval at steady state 
b.i.d.  
Twice a day 
BLQ  
Below the limit of quantification 
CI  
Confidence interval 
Cmax, ss  
Maximum plasma concentration at steady state 
CRA  
Clinical Research Associate 
CRF  
Case Report Form (paper or electronic) 
CRO  
Contract Research Organization 
CSR  
Clinical Study Report 
Ctrough, ss  
Trough plasma concentration at steady state 
CV  
Coefficients of variation of arithmetic mean 
CVb  
Inter-subject coefficient of variation 
CVln  
Coefficients of variation of geometric mean 
DBP  
Diastolic blood pressure 
ECG  
Electrocardiogram 
EOS  
End-of-Study 
ERA  
Endothelin receptor antagonist 
FC  
Functional Class 
GCP  
Good Clinical Practice 
GLP  
Good Laboratory Practice 
i.v.  
Intravenous 
IB  
Investigator’s Brochure 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 13/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
ICF  
Informed Consent Form 
ICH  
International Council for Harmonisation 
IEC  
Independent Ethics Committee 
IP receptor  
Prostacyclin receptor 
IRB  
Institutional Review Board 
IRT  
Interactive Response Technology 
ISF  
Investigator Site File 
LC-UV  
Liquid chromatography with UV detector 
LC-MS/MS  
Liquid chromatography coupled to tandem mass spectrometry 
LOQ  
Limit of quantification 
MedDRA  
Medical Dictionary for Regulatory Activities 
MLA  
Marked laboratory abnormality 
PAH  
Pulmonary arterial hypertension 
PDE-5  
Phosphodiesterase type-5 
PI  
Principal Investigator 
PK  
Pharmacokinetics 
PKS  
Pharmacokinetic Analysis Set 
PT  
Preferred Term 
QTc  
Corrected QT interval 
QTcB  
QT interval corrected using Bazett’s formula 
QTcF  
QT interval corrected using Fridericia’s formula 
RSI  
Reference safety information  
SAE  
Serious adverse event 
SAF  
Safety Set 
SAP  
Statistical Analysis Plan 
SBP  
Systolic blood pressure 
SD  
Standard deviation 
SE  
Standard error 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 14/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
sGC  
Soluble guanylate cyclase 
SIV  
Site initiation visit 
SmPC  
Summary of Product Characteristics 
SOC  
System Organ Class 
tmax, ss  
Time to reach maximum plasma concentration at steady state 
USPI  
United States Package Insert 
WHO  
World Health Organization 
 
 
 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 15/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
PROTOCOL SYNOPSIS AC-065A309 
TITLE 
A multicenter, open-label, single-sequence cross-over study to 
assess safety, tolerability, and pharmacokinetics of intravenous 
selexipag 
in 
subjects 
with 
stable 
pulmonary 
arterial 
hypertension switching from an oral stable dose of selexipag 
OBJECTIVES 
Primary objective(s) 
The primary objective of this study is to assess whether 
temporary switching from a stable oral dose of selexipag to an 
intravenous (i.v.) dose of selexipag providing comparable 
exposure to active metabolite ACT-333679 and switching back 
to the initial oral dose of selexipag is safe and well tolerated in 
subjects with stable pulmonary arterial hypertension (PAH). 
Other objectives 
Other objectives are described in Section 2.2.  
DESIGN 
This is a prospective, multi-center, open-label, single-sequence, 
cross-over, Phase 3 study. 
Subjects with stable PAH, currently treated with Uptravi® at a 
stable dose (i.e., unchanged dose for 28 days), will be enrolled. 
Subjects will be hospitalized during Period 1 (pre-treatment 
period) and Period 2 (treatment period). 
No interim analysis is planned. 
PERIODS 
Screening period: 
Up to 28 days; starts with the signing of the Informed Consent 
Form (ICF) and ends with first day (Visit 2, Day 1) of Period 1 
(Uptravi, pre-treatment period).  
Treatment and observation period: 
The treatment and observation period includes the following 
consecutive periods: 
• Period 1 (Uptravi, pre-treatment period, in-hospital): 1 day 
Starts with intake of the morning dose of Uptravi at Visit 2 
Day 1 and ends the following day, before initiation of the 
first infusion of i.v. selexipag. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 16/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
• Period 2 (i.v. selexipag, treatment period, in-hospital): 
36 hours (3 doses) 
Starts in the morning of Visit 2 on Day 2 with the start of 
the first infusion of i.v. selexipag and ends in the evening of 
Visit 2 on Day 3 before the evening administration of 
Uptravi. Note: oral administration of Uptravi is interrupted 
during the treatment period with i.v. selexipag. 
• Period 3 (Uptravi, post-treatment period): 7 to 11 days 
Starts in the evening of Visit 2 on Day 3 with the oral 
administration of Uptravi and ends 7 to 11 days later, at 
Visit 3. 
Safety Follow-up period: 
Starts at the end of Visit 3 and ends 30 to 37 days after the last 
administration of i.v. selexipag with the End-of-Study 
telephone call (Visit 4). 
PLANNED DURATION 
Approximately 9–12 months from first subject first visit to last 
subject last visit. 
SITE(S) 
/ COUNTRY(IES) 
10 sites in 2 countries (planned). 
SUBJECTS / GROUPS 
Approximately 20 subjects will be enrolled in order to obtain 
18 evaluable subjects. 
Two different groups of subjects will be enrolled based on their 
dose of Uptravi: 
• Group A: Subjects with a stable dose of Uptravi between 
200 and 1000 μg twice daily (b.i.d.; inclusive): at least 5 
and up to 8 subjects will be enrolled in this dose group. 
• Group B: Subjects with a stable dose of Uptravi between 
1200 and 1600 μg b.i.d. (inclusive): At least 12 and up to 
15 subjects will be enrolled in this dose group. 
INCLUSION CRITERIA 
1. Signed ICF prior to any study-mandated procedure. 
2. Male and female subjects at least 18 to 75 years inclusive. 
3. Subjects with PAH belonging to the Updated Clinical 
Classification Group 1 [Galiè 2016] 
4. Subjects who have been prescribed Uptravi in compliance 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 17/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
with local prescribing information (i.e., SmPC or USPI). 
5. Stable PAH defined as WHO Functional Class (FC) I–III at 
Visit 1 and Visit 2 and no change (i.e., introduction or 
dose change) in PAH-specific medication (i.e., ERA, 
PDE-5 inhibitor or sGC stimulator) and diuretics in the 
last 28 days prior to Visit 2. 
6. Subjects currently treated with Uptravi at a stable dose (i.e., 
unchanged dose) for at least 28 days before Visit 2. 
7. A woman of childbearing potential is eligible only if she 
has a negative urine pregnancy test at Visit 1 and at 
Visit 2. 
EXCLUSION CRITERIA 
1. Pregnant, planning to become pregnant or lactating. 
2. Known and documented moderate or severe hepatic 
impairment. 
3. Subjects having received gemfibrozil at any time since 
initiation of Uptravi. 
4. Treatment with any prostacyclin and prostacyclin analogs 
within 28 days prior to Visit 1.  
5. SBP < 90 mmHg at Visit 1 or at Visit 2. 
6. Known or suspected uncontrolled hyperthyroidism. 
7. Severe renal failure and ongoing or planned dialysis. 
8. 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. 
9. Known concomitant life-threatening disease with a life 
expectancy < 12 months. 
10. Treatment with another investigational treatment within 
3 months of Visit 1. 
STUDY TREATMENTS 
Investigational treatment 
The study treatment (i.v. selexipag) will be administered b.i.d. 
intravenously as an infusion over an 87 minute period [see 
Section 5.1.4]. The dose of i.v. selexipag will be individualized 
for each subject and will aim to reach an exposure to the active 
metabolite (area under the concentration-time curve [AUC] 
between two doses) comparable to the one obtained with 
subject’s current oral dose of Uptravi. 
Comparator and/or placebo 
Not applicable. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 18/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
AUXILIARY MEDICINAL 
PRODUCTS 
The study population consists of subjects who have been 
prescribed Uptravi (oral selexipag) as part of their standard 
PAH treatment (i.e., Uptravi must not have been prescribed 
solely for the purpose of the study). Subjects will keep using 
Uptravi during their participation in the study as prescribed by 
their physician and in compliance with the USPI/SmPC 
[Uptravi® SmPC; Uptravi® USPI] including the use of 
contraception for women of childbearing potential. Subject’s 
oral treatment with Uptravi will be temporarily interrupted for 
36 hours during the administration of study treatment (i.v. 
selexipag). 
ENDPOINTS 
Primary efficacy endpoint(s) 
Not applicable. 
Secondary efficacy endpoints 
Not applicable. 
Main safety and tolerability endpoints 
The main safety and tolerability endpoints will be analyzed 
over the Period 1, Period 2, and Period 3 combined. 
• Discontinuations due to prostacyclin-associated adverse 
events (AEs). 
• AEs and serious AEs (SAEs). 
• Prostacyclin-associated AEs. 
• AEs related to injection site reactions. 
• PAH-related AEs. 
Other endpoints 
Other endpoints are described in Section 6.2.3. 
PHARMACOKINETIC 
ENDPOINTS 
• The AUC during a dose interval at steady state (AUCτ, ss) of 
selexipag and its active metabolite, ACT-333679, at steady 
state after Uptravi (oral selexipag) in Period 1 and after i.v. 
selexipag administration in Period 2. 
• The maximum plasma concentration at steady state (Cmax, ss) 
of selexipag and its active metabolite, ACT-333679 after 
Uptravi (oral selexipag) in Period 1 and i.v. selexipag 
administration in Period 2. 
• The time to reach maximum plasma concentration at 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 19/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
steady-state (tmax, ss) of selexipag and its active metabolite, 
ACT-333679 after Uptravi (oral selexipag) in Period 1 and 
i.v. selexipag administration in Period 2. 
• Trough plasma concentration at steady state (Ctrough, ss) of 
selexipag and its active metabolite, ACT-333679after 
Uptravi (oral selexipag) in Period 1 and i.v. selexipag 
administration in Period 2. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 2. 
STATISTICAL 
METHODOLOGY 
Approximately 20 patients will be enrolled. In the GRIPHON 
Phase 3 pivotal study of selexipag, a proportion of 7.5% of 
patients on selexipag prematurely discontinued the study (i.e., 
without a morbidity/mortality event) due to prostacyclin-
associated AEs. It is expected that the proportion of 
discontinuations will not be higher than 10%. 
The statistical analysis will be mainly descriptive, i.e., no 
hypotheses will be formally tested. 
Four analysis sets are defined in this study:  
• Screened Analysis Set includes all subjects who are 
screened and have a subject identification number.  
• i.v. Safety Set comprises all subjects who received at least 
one dose of i.v. study treatment.  
• Safety Set (SAF) includes all enrolled (included in the 
study on Day 1) subjects who receive at least one dose of 
selexipag (oral or i.v.).  
• Pharmacokinetic Analysis Set (PKS) comprises all subjects 
included in the SAF who received the 3 doses of i.v. study 
treatment and who complied with the protocol sufficiently 
and did not deviate from the protocol in a way that might 
affect the PK outcome of the study.  
The study comprises 3 main periods for analysis: Period 1, 
Period 2, and Period 3 and follow-up. AEs and SAEs will be 
tabulated, for the Safety Set and i.v. Safety Set, overall across 
periods as well as by study period. The proportion of 
discontinuations due to prostacyclin-associated AEs will be 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 20/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
tabulated for the i.v. Safety Set and the SAF to address the 
primary objective. Due to the sample size, the proportion will 
be provided with a conservative 95% Clopper-Pearson 
confidence interval based on exact methods.  
All secondary safety endpoints will be listed and tabulated in 
Safety Set and i.v. Safety Set.  
Exposure will be summarized.  
ECG 
abnormalities 
and 
laboratory 
variables 
will 
be 
descriptively summarized, both longitudinally across the study 
periods as well as separately per period. Death will be 
summarized by cause, by period, and overall.  
The proportion of patients in each WHO FC (I , II , III and IV) 
will be tabulated at baseline and post-baseline, as well as the 
change in WHO FC at all assessed time points. Also the 
absence of worsening in WHO FC will be tabulated (i.e., 
patients that are either stable or improve). 
 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 21/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
 
PROTOCOL 
1 
BACKGROUND 
Uptravi® (oral selexipag), a non-prostanoid, selective, prostacyclin receptor (IP receptor) 
agonist has recently been approved for pulmonary arterial hypertension (PAH) based on 
the 
demonstrated 
efficacy 
in 
a 
time 
to 
morbidity/mortality 
event 
study 
(AC-065A302/GRIPHON) [Sitbon 2015]. 
For patients with PAH treated with Uptravi, for whom a temporary interruption of 
Uptravi is unavoidable, and continuous treatment with selexipag is required, an 
intravenous (i.v.) formulation of selexipag has been developed. 
1.1 Pulmonary arterial hypertension 
PAH is a chronic, progressive and eventually fatal disease. PAH is characterized by 
pulmonary arterial vasoconstriction, vascular remodeling, inflammation, and fibrosis, 
resulting in a progressive increase in pulmonary arterial pressure and pulmonary vascular 
resistance, 
ultimately 
leading 
to 
ventricular 
failure 
and 
death 
[Barst 2004, 
D’Alonzo 1991, Galiè 2009, McLaughlin 2004].  
The current management of PAH is based primarily on results from studies in adult 
patients, together with expert recommendations, such as those from the 5th World 
Symposium for PH, which were recently adopted by the European Society of Cardiology 
and European Respiratory Society [Galiè 2016]. It includes several treatment options, 
such as general measures (e.g., physical activity, infection prevention, birth control), 
supportive therapy (e.g., diuretics, oxygen, oral anticoagulants) and PAH-specific 
therapies. To date, there are several drugs targeting various therapeutic pathways 
approved for the treatment of PAH, including oral selexipag (Uptravi). 
Current recommendations support the use of a combination of therapies and oral 
selexipag (Uptravi) is included in the treatment guidelines as an add-on to other oral 
treatments targeting the other pathways [Galiè 2016]. 
1.2 Study treatment: intravenous selexipag 
 Background information: selexipag 
1.2.1
Selexipag is an IP receptor agonist. Enzymatic hydrolysis of selexipag by 
carboxylesterase 1 in the liver yields ACT-333679, the active metabolite, and major 
contributor to efficacy of selexipag in humans. ACT-333679 is approximately 37-fold 
more potent than selexipag in cellular systems, and is present at 3- to 4-fold higher levels 
than the parent drug at steady state in humans after oral selexipag administration. 
Selexipag and ACT-333679 induce an increase in intracellular cAMP concentrations 
upon stimulation of the IP receptor, leading to relaxation of vascular smooth muscle cells 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 22/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
and vasodilation of pulmonary arteries. The oral formulation of selexipag, under the 
brand name Uptravi, is approved for the treatment of patients with PAH. The i.v. 
formulation of selexipag tested in this study has been developed to be used in patients 
with PAH receiving Uptravi who would be temporarily unable to swallow tablets of 
Uptravi. 
Refer to the Investigator’s Brochure (IB) [Selexipag IB, Selexipag IB Amendment 1] for 
more detailed information.  
 Intravenous formulation 
1.2.2
An i.v. formulation of selexipag, in the form of a dry powder to be reconstituted with 
sterile 0.9% NaCl solution, was developed. The inactive ingredients of this formulation 
are the following: sodium hydroxide, glycine, phosphoric acid and polysorbate 20. 
 Summary of nonclinical data 
1.2.3
A comprehensive package of nonclinical in vivo and in vitro studies was performed that 
supported the approval of selexipag as oral treatment for PAH. Details of the nonclinical 
development of selexipag are described in the IB [Selexipag IB, Selexipag IB 
Amendment 1]. 
The local tolerance of i.v. selexipag at the concentration of 36 µg/mL (clinical 
formulation to achieve a dose of 1800 µg i.v. selexipag corresponding to plasma 
concentration obtained with 1600 µg of oral Uptravi) was tested following a single 
intravenous, paravenous or intramuscular administration to the New Zealand White 
rabbit. Clinical and injection site observations as well as body weight and food 
consumption were recorded daily for 4 days. Injection sites and surrounding tissues were 
examined histopathologically.  
There were no clinical findings. Neither macroscopic nor microscopic observations 
indicated an effect of selexipag (36 µg/mL) at the injection sites. 
 Summary of clinical data 
1.2.4
A comprehensive package of clinical studies was performed that supported the approval 
of selexipag as oral treatment for PAH. Details of the clinical development of selexipag 
oral formulation are described in the IB [Selexipag IB, Selexipag IB Amendment 1]. 
So far a different formulation of i.v. selexipag has been administered to 18 healthy male 
subjects in an absolute bioavailability study (AC-065-110) and has not been administered 
to subjects with PAH. 
In the study AC-065-110, the geometric mean (95% confidence interval [CI]) of the area 
under the plasma concentration versus time curve (AUC) from 0 to infinity (AUC0-∞) of 
selexipag and ACT-333679 were 11.16 h⋅ng/mL (9.30, 13.38) and 14.91 h⋅ng/mL (11.42, 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 23/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
19.47), respectively, following a single i.v. infusion of 200 μg selexipag in healthy 
subjects. In the same study, following a single oral dose of 400 μg selexipag, geometric 
mean (95% CI) AUC0-∞ values of selexipag and ACT-333679 were 11.04 h⋅ng/mL (8.19, 
14.87) and 37.97 h⋅ng/mL (30.18, 47.78), respectively. The exposure (AUC0-∞) to 
ACT-333679 was 1.34- and 3.44-fold higher than to selexipag after i.v. administration 
and oral administration, respectively. This difference in metabolite exposure is likely due 
to the first pass metabolism of oral selexipag [Selexipag IB, Selexipag IB Amendment 1]. 
Single doses of i.v. and oral selexipag were both well tolerated. The most frequently 
reported treatment-emergent adverse event (AE) was headache. All treatment-emergent 
AEs were of mild to moderate intensity. There were no serious adverse events (SAEs) 
and no AEs leading to discontinuation. No clinically significant treatment-emergent 
abnormality in clinical laboratory, vital signs, or ECG variables was observed. 
1.3 Purpose and rationale of the study 
 Purpose of the study 
1.3.1
This study aims to investigate whether i.v. selexipag, administered as a twice-daily 
(b.i.d.) infusion, is safe and well tolerated when subjects are temporarily switched from 
stable oral selexipag dose. This study will serve as the basis for regulatory filings for 
marketing authorization and will provide guidance to ensure a seamless switch from 
orally administered Uptravi to i.v. selexipag and return to Uptravi. 
 Rationale of the study 
1.3.2
The development of an i.v. formulation of selexipag in PAH is guided by the 
understanding that in such a chronic, progressive, and ultimately fatal disease, treatment 
interruptions are to be avoided. The target population for an i.v. formulation of selexipag 
includes those PAH patients who are hospitalized (acutely or electively) and are unable to 
swallow tablets of Uptravi. Therefore, administration of i.v. selexipag would be 
appropriate for these patients to maintain selexipag plasma levels and to achieve 
comparable drug exposure to their oral dose of Uptravi. In the GRIPHON study, 
9 selexipag-treated subjects were hospitalized and had their selexipag treatment 
temporarily interrupted for at least 3 days, indicating the usefulness of developing an i.v. 
formulation for selexipag. 
1.4 Summary of known and potential risks and benefits 
There is no direct individual benefit for the subject to participate in the study. 
Uptravi local prescribing information essentially constitutes the benefit-risk summary for 
selexipag [Uptravi® USPI, Uptravi® SmPC]. The short and long-term safety profile of 
oral selexipag (Uptravi) has been established in the GRIPHON study and is mainly 
characterized by inter-individual susceptibility towards prostacyclin-associated AEs 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 24/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
associated with the mode of action of selexipag. Such AEs typically occur during the 
phase of individualized dose titration. No new safety findings were observed after single 
administration of i.v. selexipag in healthy subjects. Hence, the safety profile of i.v. 
selexipag is expected to be identical to that of Uptravi. Moreover, the dose of i.v. 
selexipag that will be administered during the study will target the same exposure to 
selexipag’s active metabolite ACT-333679 as with their prescribed dose of Uptravi. 
Hence, the risks associated to study participation are expected to be limited to the ones 
associated with any i.v. administration of drugs and with the invasive study-specific 
procedures (i.e., repeated blood sampling for pharmacokinetic [PK] and safety 
assessments). 
The following measures are taken to minimize the risks for the subjects participating in 
the study: 
 Exclusion of subjects with unstable PAH condition or severe co-morbidities [see 
Section 4.4]. 
 In-patient hospitalization during pre-treatment and treatment periods (Period 1 and 2). 
 Close monitoring of the subjects throughout the study, including frequent monitoring 
of vital signs following initiation of i.v. selexipag infusion. 
It is the investigator’s responsibility to monitor the risk-benefit ratio of the study 
treatment administration, as well as the degree of distress caused by the study procedures 
on an individual subject level, and to discontinue the study treatment or the study if, on 
balance, he/she believes that continuation would be detrimental to the subjects’ 
well-being. 
2 
STUDY OBJECTIVES 
2.1 Primary objective(s) 
The primary objective of this study is to assess whether temporary switching from a 
stable oral dose of selexipag to an i.v. dose of selexipag providing comparable exposure 
to active metabolite ACT-333679 and switching back to the initial oral dose of selexipag 
is safe and well tolerated in subjects with stable PAH. 
2.2 Other objectives 
 To evaluate the safety and tolerability of selexipag during each study period. 
 To evaluate the PK of selexipag and its active metabolite, ACT-333679, at stable oral 
dose at steady state and after the switch from selexipag oral to selexipag i.v. in 
subjects with stable PAH. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 25/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
This is a prospective, multi-center, open-label, single-sequence, cross-over, Phase 3 
study. 
Approximately 20 subjects with stable PAH, currently treated with Uptravi at a stable 
dose (i.e., unchanged dose for at least 28 days), will be enrolled in order to obtain 18 
evaluable subjects. Two different groups of subjects will be enrolled based on their dose 
of Uptravi: 
• Group A: Subjects with a stable dose of Uptravi between 200 and 1000 μg b.i.d. 
(inclusive): at least 5 and up to 8 subjects will be enrolled in this dose group. 
• Group B: Subjects with a stable dose of Uptravi between 1200 and 1600 μg b.i.d. 
(inclusive): At least 12 and up to 15 subjects will be enrolled in this dose group. 
Subjects will be hospitalized during Period 1 and Period 2 [see Section 3.1.1]. 
The study will be conducted at approximately 10 sites in 2 countries. Subjects on a stable 
dose of Uptravi will be screened. 
No interim analysis is planned. 
 Study periods 
3.1.1
The study comprises the following consecutive periods: 
Screening period: 
Up to 28 days; starts with the signing of the Informed Consent Form (ICF) and ends with 
first day (Visit 2, Day 1) of Period 1 (Uptravi, pre-treatment period).  
Treatment and observation period: 
The treatment and observation period includes the following consecutive periods: 
• Period 1 (Uptravi, pre-treatment period, in-hospital): 1 day 
Starts with intake of the morning dose of Uptravi at Visit 2 Day 1 and ends the 
following day, before initiation of the first infusion of i.v. selexipag. 
• Period 2 (i.v. selexipag, treatment period, in-hospital): 36 hours (3 doses) 
Starts in the morning of Visit 2 on Day 2 with the start of the first infusion of i.v. 
selexipag and ends in the evening of Visit 2 on Day 3 before the evening 
administration of Uptravi. Note: oral administration of Uptravi is interrupted during 
the treatment period with i.v. selexipag. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 26/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
• Period 3 (Uptravi, post-treatment period): 7 to 11 days 
Starts in the evening of Visit 2 Day 3 with the oral administration of Uptravi and ends 
7 to 11 days later, at Visit 3. 
Safety Follow-up period: 
Starts at the end of Visit 3 and ends 30 to 37 days after the last administration of i.v. 
selexipag with the End-of-Study (EOS) telephone call (Visit 4). 
The visit schedule and protocol-mandated procedures will be performed according to the 
table of assessments [Table 2] and are described in Section 7. 
The overall study design is depicted in Figure 1. 
Figure 1 
Study design 
 
 
*  12-hour PK profile after the morning dose. 
** For convenience hospitalization may be extended to the night before Day 1 and to the night of Day 3. 
D = day; EOS = End-of-Study; IV1–IV3 = dose of i.v. selexipag; V = visit 
 
 Study duration 
3.1.2
The study starts with the first act of recruitment (i.e., signed ICF) and ends with the last 
EOS visit of the last subject. The duration of the study is expected to be approximately  
9–12 months. 
End-of-Study for a single subject is defined as the date of the EOS telephone call 
(Visit 4). If a subject withdraws consent, EOS is the date of consent withdrawal for this 
subject. If a subject is declared lost to follow-up [see also Section 8.2], EOS is the date of 
last successful contact for this subject. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 27/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
For an individual subject, the study is completed with the EOS telephone call. The 
duration of the study for an individual subject will be up to 68 days (including a 36-h 
treatment period with i.v. selexipag). 
3.2 Study design rationale 
This study has been designed to address the question whether subjects with PAH on oral 
selexipag can be safely switched to i.v. selexipag and vice-versa. The single-sequence 
3-period cross-over design has been chosen to mimic the intended clinical use of i.v. 
selexipag. The study plans to enroll approximately 20 subjects and will aim for at least 
10 subjects to be treated with an i.v. selexipag dose corresponding to the oral dose of 
1200–1600 μg b.i.d. 
Subjects with a minimum of 28 days stable (i.e., dose unchanged) Uptravi dose will be 
enrolled. Subjects will be hospitalized and switched from the Uptravi oral dose to the 
corresponding b.i.d. i.v. dose of selexipag for a treatment period of 36 hours (3 doses) 
which allows the steady state of selexipag to be reached again and is therefore considered 
sufficient to assess tolerability and evaluate PK.  
3.3 Study committees 
No committees will be involved in the design or conduct of the study. 
4 
SUBJECT POPULATION 
4.1 Subject population description 
This study will enroll male and female subjects diagnosed with Group 1 PAH 
[Galiè 2016], aged 18 to 75 years, who have been prescribed Uptravi (oral selexipag) as 
part of their standard treatment for PAH. Eligible subjects will be at a stable dose of 
Uptravi for at least 28 days prior to enrollment. 
Subjects will be in WHO Functional Class (FC) I, II or III. They may be treated 
concurrently with a stable dose of diuretics or other PAH-specific medications which are 
not agonists of the IP receptor (i.e., ERA, PDE-5 inhibitors or sGC stimulators). 
4.2 Rationale for the selection of the study population 
The study population includes patients with PAH who have been prescribed Uptravi in 
compliance with local prescribing information (i.e., Uptravi® SmPC or Uptravi® USPI) as 
part of their standard treatment for PAH. 
Stability of PAH-specific concomitant medications is an important pre-requisite to assess 
the safety and tolerability of the switch from Uptravi to i.v. selexipag. Therefore, patients 
who have been prescribed Uptravi and are currently treated at a stable dose are 
considered to represent an adequate study population to evaluate whether switching from 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 28/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
an oral dose of selexipag to a corresponding selexipag i.v. dose is well tolerated in 
subjects with stable PAH. 
Subjects under 18 years are excluded due to absence of clinical experience and approval 
of selexipag for the treatment of pediatric patients. Subjects with significant 
cardiovascular, hepatic, or renal medical conditions are excluded since they could 
potentially be at greater risk of complications due to these pre-existing comorbidities, 
which could interfere with evaluation of study assessments and interpretation of study 
results. 
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 criterion: 
1. Signed ICF prior to any study-mandated procedure. 
2. Male and female subjects at least 18 to 75 years inclusive. 
3. Subjects with PAH belonging to the Updated Clinical Classification Group 1 
[Galiè 2016] 
4. Subjects who have been prescribed Uptravi in compliance with local prescribing 
information (i.e., SmPC or USPI). 
5. Stable PAH defined as WHO FC I–III at Visit 1 and Visit 2 and no change (i.e., 
introduction or dose change) in PAH-specific medication (i.e., ERA, PDE-5 inhibitor 
or sGC stimulator) and diuretics in the last 28 days prior to Visit 2. 
6. Subjects currently treated with Uptravi at a stable dose (i.e., unchanged dose) for at 
least 28 days before Visit 2. 
7. A woman of childbearing potential is eligible only if she has a negative urine 
pregnancy test at Visit 1 and at Visit 2. 
4.4 Exclusion criteria 
Subjects must not fulfill any of the following exclusion criteria. It is not permitted to 
waive any criterion: 
1. Pregnant, planning to become pregnant or lactating. 
2. Known and documented moderate or severe hepatic impairment. 
3. Subjects having received gemfibrozil at any time since initiation of Uptravi. 
4. Treatment with any prostacyclin and prostacyclin analogs within 28 days prior to 
Visit 1.  
5. SBP < 90 mmHg at Visit 1 or at Visit 2. 
6. Known or suspected uncontrolled hyperthyroidism. 
7. Severe renal failure and ongoing or planned dialysis. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 29/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
8. 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. 
9. Known concomitant life-threatening disease with a life expectancy < 12 months. 
10. Treatment with another investigational treatment within 3 months of Visit 1. 
4.5 Criteria for women of childbearing potential 
 Definition of childbearing potential 
4.5.1
A woman is considered to be of childbearing potential unless she meets at least one of the 
following criteria: 
• Previous bilateral salpingectomy, bilateral salpingo-oophorectomy or hysterectomy, 
• Postmenopausal (defined as 12 consecutive months with no menses without an 
alternative medical cause [ICH M3 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 Case Report 
Form (CRF). 
 Acceptable methods of contraception 
4.5.2
Women of childbearing potential [see definition in Section 4.5.1] must continue 
following their local Uptravi® instructions (as indicated in USPI or SmPC, as applicable) 
with regard to use of methods of birth control from Screening (Visit 1) up to Visit 4. 
The methods of birth control used (including non-pharmacological methods) must be 
recorded in the CRF. 
5 
TREATMENTS 
5.1 Study treatment 
 Investigational treatment: description and rationale 
5.1.1
Selexipag for i.v. administration will be supplied as 10 mL vials containing 1800 µg of 
dry powder of selexipag for injectable solution reconstitution. 
The study treatment, i.v. selexipag, will be administered intravenously b.i.d. as an 
infusion over an 87-minute period [see Section 5.1.4]. The dose will be individualized for 
each subject and will correspond to subject’s current dose of orally administered Uptravi. 
Since selexipag’s active metabolite ACT-333679 is up to 37-fold more potent than 
selexipag as an agonist of the human IP receptor in vitro, the i.v. formulation was 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 30/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
developed with the aim of reaching an exposure equivalent to the active metabolite (AUC 
between two doses) comparable to the one obtained with the oral formulation. 
The correspondence between doses of Uptravi and i.v. selexipag doses were determined 
based on the results of the absolute bioavailability study (AC-065-110). The i.v. 
selexipag doses corresponding to the oral Uptravi doses are provided in Table 1. 
Table 1 
Correspondence of i.v. selexipag doses to Uptravi oral doses 
Uptravi oral dose 
(µg) 
Corresponding i.v. 
selexipag dose (µg) 
200 
225 
400 
450 
600 
675 
800 
900 
1000 
1125 
1200 
1350 
1400 
1575 
1600 
1800 
 
 Study treatment preparation 
5.1.2
Before administration, the i.v. solution of selexipag is to be reconstituted and diluted with 
NaCl 0.9%. 
Reconstitution 
and 
dilution 
of 
selexipag 
dry 
powder 
must 
be 
performed 
extemporaneously, followed by an immediate infusion. If necessary, the diluted solution 
can be kept in sterile conditions at 2–8 °C (35.6 °F and 46.4 °F) and be protected from 
light, for no longer than 4 hours before use. In such case, the solution is to be removed 
from the refrigerator approximately 15 minutes before use. 
Residual vial contents must not be used for subsequent infusions. 
The process for the preparation of the i.v. selexipag infusion solution is detailed in the 
Handling and Instruction for use of Investigational Medical Product Guidelines. 
 Infusion solution samples 
5.1.3
For all subjects, infusion solution samples will be collected before each i.v. infusion and 
may be used to accurately confirm the amount of drug administered to each subject. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 31/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
5.1.3.1 Procedures for sampling 
Per subject, 1 aliquot of 1 mL must be obtained from the infusion solution for each 
infusion (i.e., a total of 3 aliquots per subject). The infusion solution samples will be 
collected from the tubing prior to the start of the infusion. 
These aliquots must be kept in an amber vial and stored at (or below) −20 °C ± 5 °C  
(–4 °F ± 9 °F) in a freezer. To prevent degradation of selexipag in the infusion solution 
samples, exposure of the samples to light must be minimized. 
The actual date and clock time of collection of each infusion solution sample must be 
entered in the CRF. 
5.1.3.2 Shipping procedures 
The central laboratory will ensure subsequent shipment of the infusion solution samples 
to the Analytical laboratory (
). 
5.1.3.3 Bioanalysis 
The analysis of the selexipag concentration in the infusion solution samples will be 
performed using a validated liquid chromatography with UV detector (LC-UV) assay. 
Concentrations will be calculated by using an external reference standard. Quality control 
samples will be analyzed throughout the LC-UV assay. Their measured concentrations 
will be used to determine between-run and overall precision and accuracy of the analysis. 
 Study treatment administration 
5.1.4
The following infusion scheme is to be followed: 
• Start with an infusion rate of 20 mL/h (0.333 mL/min) for 15 min for the first 5 mL. 
• Increase infusion rate to 37.5 mL/h (0.625 mL/min) for 72 min for infusion of the 
remaining 45 mL. 
Note: A dedicated infusion line must be used for i.v. selexipag administration. No other 
drugs or solutions should be administered through this line. 
The following information will be collected in the CRF to document each i.v. selexipag 
administration: 
• Date of administration. 
• Concentration of the i.v. infusion solution. 
• For each infusion rate: clock time of start and end. 
 Treatment assignment 
5.1.5
Approximately 20 subjects will be enrolled to perform the switch from stable dose of 
Uptravi to the corresponding dose of i.v. selexipag. The central Interactive Response 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 32/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
Technology (IRT) system will control enrollment in each group (5 to 8 subjects in 
Group A: 200–1000 µg b.i.d., and 12 to 15 subjects in Group B: 1200–1600 µg b.i.d.).  
After verification that a subject meets all inclusion criteria and none of the exclusion 
criteria, the investigator/delegate contacts the IRT system at Visit 2 (Day 1, baseline). 
The IRT system will assign the treatment kit numbers. 
 Blinding 
5.1.6
Not applicable. 
 Study treatment supply 
5.1.7
Manufacture, 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 
Selexipag for i.v. administration is provided as a lyophilized sterile powder for solution 
for infusion, packaged in a 10 mL Type I clear borosilicate glass vial closed with a rubber 
stopper and a flip off cap. Each vial contains 1800 µg of selexipag and is packed in an 
individual box. 
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 (dry powder vials) must be kept in their box and stored in an 
appropriate, secure area and stored according to the conditions specified on the label 
between 2 °C and 8 °C (35.6 °F and 46.4 °F) and protected from light. 
5.1.7.3 Study treatment dispensing 
Intravenous selexipag will be administered to the subject by site personnel according to 
the study-treatment preparation and administration procedures described in this protocol 
[see Sections 5.1.2 and 5.1.4]. The protocol-mandated study treatment administration 
procedures may not be altered without prior written approval from Actelion. An accurate 
record of the date and amount of study treatment dispensed to each subject must be 
available for inspection at any time. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 33/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
5.1.7.4 Study treatment return and destruction 
The protocol-mandated study treatment return procedures may not be altered without 
prior written approval from Actelion. On an ongoing basis and/or on termination of the 
study, the Clinical Research Associate (CRA) will collect used and unused treatment kits, 
which will be sent to the warehouse, where Actelion personnel or a deputy will check 
treatment reconciliation. In certain circumstances, used and unused study treatment 
containers may be destroyed at the site once study treatment accountability is finalized 
and has been checked by Actelion personnel or the deputy, and written permission for 
destruction has been obtained from Actelion. 
 Study treatment accountability and compliance with study treatment 
5.1.8
5.1.8.1 Study treatment accountability 
The inventory of study treatment dispensed (i.e., study treatment accountability) must be 
performed by site personnel and is to be recorded on the study-treatment dispensing and 
accountability log and in the CRF, and checked by the CRA during site visits and at the 
end of the study. The study treatment accountability log in the CRF will include at least 
the following information for each study treatment unit (i.e., selexipag dry powder vial) 
dispensed: 
• Vial number 
• Date dispensed 
• Date returned 
All study treatment supplies, including partially used or empty dry powder vials must be 
retained at the site for review by the CRA. 
5.1.8.2 Study treatment compliance 
Study treatment compliance is a measure of how closely the protocol instructions for 
administering i.v. selexipag were adhered to. 
The compliance will be calculated as the percentage of the actual dose infused compared 
with the targeted dose to be infused. 
Over the entire treatment period, compliance is expected to be between 80% and 120% 
otherwise it will be considered to be a protocol deviation and reported as such. The 
investigator must document in the subject’s source notes the reasons for this protocol 
deviation. 
 Study treatment dose adjustments and interruptions 
5.1.9
The i.v. selexipag dose corresponding to subject’s stable Uptravi dose is expected to be 
fully infused each time and adjustment of i.v. selexipag dose is not allowed in this study. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 34/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
Missing any of the 3 scheduled i.v. selexipag infusions is not allowed. If one or more of 
the i.v. selexipag infusions is missed, re-introduction is not permitted and i.v. selexipag 
treatment must be permanently discontinued [see Section 5.1.10]. Uptravi may be 
reintroduced after stopping i.v. selexipag, at the next scheduled dosing time point, if 
deemed medically needed for the subject. 
 Premature discontinuation of study treatment 
5.1.10
A subject is considered as having prematurely discontinued study treatment if the third 
i.v. selexipag infusion was not initiated. 
The decision to prematurely discontinue i.v. selexipag treatment may be made by the 
subject, the investigator or Actelion personnel. The main reason and whether 
discontinuation of i.v. selexipag treatment is the decision of the subject (e.g., tolerability- 
or efficacy-related), the investigator (e.g., due to pre-specified i.v. selexipag treatment 
discontinuation criteria, an AE or lack of efficacy), or Actelion (e.g., study terminated) 
must be documented in the CRF. 
A subject has the right to discontinue i.v. selexipag treatment at any time, without any 
justification, by withdrawal from study treatment only or by withdrawal from any further 
participation in the study (i.e., premature withdrawal from the study [see Section 8.2]). 
Although a subject is not obliged to provide his/her reason for prematurely withdrawing 
from the treatment or the study, it is recommended that the investigator makes a 
reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights. 
The investigator must discontinue i.v. selexipag treatment for a given subject if, he/she 
believes that continued administration would be contrary to the best interests of the 
subject. 
Study-specific criteria for discontinuation of i.v. selexipag treatment are described in 
Section 5.1.11. 
A subject who prematurely discontinues i.v. selexipag treatment is to be discontinued 
from the study. For safety reasons, it is recommended to perform the assessments of 
Visit 3. The EOS telephone call (Visit 4) must be performed, provided that the subject’s 
consent for this limited participation in the study has not been withdrawn. The 
assessments that are to be performed at each visit are described in Table 2. 
A subject who prematurely discontinues i.v. selexipag 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 as 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. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 35/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
 Study-specific criteria for premature discontinuation of study treatment 
5.1.11
Premature discontinuation of i.v. selexipag treatment 
Treatment with i.v. selexipag must be stopped and its re-introduction is not to be 
considered in the following cases: 
• New signs and symptoms of right heart failure following the switch to i.v. selexipag, 
indicating an acute worsening of the underlying PAH.  
• Signs of pulmonary edema associated with confirmed diagnosis of pulmonary veno-
occlusive disease. 
• Symptomatic hypotension. 
• Any missed infusion of i.v. selexipag.  
• Need to initiate a forbidden medication (i.e., gemfibrozil, prostacyclin, prostacyclin 
analogs). 
5.2 Previous and concomitant therapy 
 Definitions 
5.2.1
A previous therapy is any treatment for which the end date is prior to signing the ICF. 
A therapy that is study-concomitant is any treatment that is ongoing or initiated after 
signing the ICF, or initiated up to 30 days after last i.v. selexipag infusion. 
A therapy that is study treatment-concomitant is any treatment that is either ongoing at 
the start of first i.v. selexipag infusion or is initiated between the start of first i.v. 
selexipag infusion and the end of the last i.v. selexipag infusion. 
An auxiliary medicinal product is a medicinal product used for the purpose of the clinical 
study but not as an investigational medicinal product (e.g., a mandatory background 
therapy or a medicinal product used for a study-mandated procedure). 
 Reporting of previous/concomitant therapy / auxiliary medicinal products in 
5.2.2
the CRF 
The use of all study-concomitant therapy (including Uptravi, contraceptives, OTC drugs, 
traditional and alternative medicines, e.g., plant-, animal-, or mineral-based medicines) 
will be recorded in the CRF. Previous therapies must be recorded in the CRF if 
discontinued less than 30 days prior to signing the ICF. The generic name, start/end dates 
of administration (as well as whether it was ongoing at start of treatment and/or EOS), 
route, dose, and indication will be recorded in the CRF. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 36/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
 Auxiliary medicinal products 
5.2.3
The study population consists of subjects who have been prescribed Uptravi as part of 
their standard PAH treatment (i.e., Uptravi must not have been prescribed solely for the 
purpose of the study). Subjects will keep using Uptravi during their participation in the 
study as prescribed by their physician (i.e., same b.i.d. dose) and in compliance with the 
USPI/SmPC [Uptravi® SmPC; Uptravi® USPI] including the use of contraception for 
women of childbearing potential. Uptravi will be temporarily interrupted for 36 hours 
during the administration of study treatment (i.v. selexipag). 
In addition to the standard information regarding concomitant medications, the following 
information regarding treatment with Uptravi will be recorded in the CRF: 
• Dose of Uptravi and clock time of intake in the evening before Visit 2. 
• Dose of Uptravi and clock time of intake in the morning and evening of Visit 2 
Day 1. 
• Dose of Uptravi and clock time of intake in the evening of Visit 2 Day 3. 
 Allowed concomitant therapy 
5.2.4
PAH-specific therapies (i.e., ERA, PDE-5 inhibitor or sGC stimulator) are allowed if 
subjects have been on a stable dose for at least 28 days prior to Visit 2.  
All other treatments considered necessary for the subject’s well-being or required for 
contraception purposes and not categorized as forbidden concomitant medications are 
allowed during the study. 
The dose of PAH medications (including diuretics) must be kept stable from Visit 1 
(screening) and up to last PK blood sample collection on Visit 2 Day 3. 
The dose of all other concomitant treatments should preferably be kept stable from 
Visit 1 (screening) and up to last PK blood sample collection on Visit 2 Day 3. 
 Forbidden concomitant therapy 
5.2.5
• Prostacyclin and prostacyclin analogs are forbidden from Visit 1 (screening) until 
Visit 3, inclusive, to avoid concomitant administration of medications that would 
compete with selexipag as they have a similar mechanism of action. 
• Concomitant administration of gemfibrozil affects the PK of selexipag and 
ACT-333679. Therefore it is prohibited from Visit 1 (screening) and up to EOS 
telephone call (Visit 4), inclusive. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 37/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
• Concomitant administration of any other investigational drug is prohibited from 
Visit 1 (screening) and up to EOS telephone call (Visit 4), inclusive, as it may 
interfere with assessment of safety and tolerability of i.v. selexipag. 
6 
STUDY ENDPOINTS 
6.1 Efficacy endpoints 
Not applicable. No efficacy endpoint for this safety and tolerability study. 
6.2 Safety and tolerability endpoints 
 Definitions 
6.2.1
Prostacyclin-associated AEs and PAH-related AEs will be defined by Preferred Term in 
the Statistical Analysis Plan (SAP). 
 Main safety and tolerability endpoints 
6.2.2
The main safety and tolerability endpoints will be analyzed over Period 1, Period 2, and 
Period 3 and follow-up period combined. 
• Discontinuations due to prostacyclin-associated AEs. 
• AEs and SAEs. 
• Prostacyclin-associated AEs. 
• AEs related to injection site reactions. 
• PAH-related AEs. 
 Other safety and tolerability endpoints 
6.2.3
The other safety and tolerability endpoints will be analyzed: 
• For each study period separately: Period 1; Period 2; Period 3 and follow-up period 
combined. 
• For Period 1 and Period 2 combined. 
• For Period 2 and Period 3 combined.  
The following endpoints will be analyzed: 
• Discontinuations due to prostacyclin-associated AEs. 
• Discontinuations due to any AEs. 
• AEs and SAEs. 
• Prostacyclin-associated AEs. 
• PAH-related AEs. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 38/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
• Change from baseline in vital signs (SBP, diastolic blood pressure [DBP], and pulse 
rate) and body weight. 
• ECG abnormalities. 
• Marked laboratory abnormalities (MLAs). 
• Change from baseline in WHO FC. 
6.3 Pharmacokinetic endpoints 
• The AUC during a dose interval at steady state (AUCτ, ss) of selexipag and its active 
metabolite, ACT-333679, after Uptravi (oral selexipag) in Period 1 and after i.v. 
selexipag administration in Period 2. 
• The maximum plasma concentration at steady state (Cmax, ss) of selexipag and its 
active metabolite, ACT-333679, after Uptravi (oral selexipag) in Period 1 and i.v. 
selexipag administration in Period 2. 
• The time to reach maximum plasma concentration at steady state (tmax, ss) of selexipag 
and its active metabolite, ACT-333679, after Uptravi (oral selexipag) in Period 1 and 
i.v. selexipag administration in Period 2. 
• Trough plasma concentration at steady state (Ctrough, ss) of selexipag and its active 
metabolite, ACT-333679, after Uptravi (oral selexipag) in Period 1 and i.v. selexipag 
administration in Period 2. 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS 
7.1 Study visits 
The study visits are listed in Table 2. For all visits, the subjects must be seen on the 
designated day or within the visit window defined in Table 2. A follow-up safety visit 
must be performed by telephone 30 to 37 days after administration of the last i.v. dose of 
study treatment. 
In the event of premature discontinuation of study treatment, it is recommended to 
perform the assessments of Visit 3. The EOS telephone call (Visit 4) must be performed, 
provided that the subject’s consent for this limited participation in the study has not been 
withdrawn. 
Subjects who prematurely discontinue study treatment for any reason will not be 
replaced. 
 Screening/re-screening 
7.1.1
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. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 39/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
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 is met will not be enrolled. 
It is permitted to re-screen subjects once, if the reason for non-eligibility was transient 
(e.g., abnormal laboratory test, insufficient wash-out period of a forbidden medication). 
All screening assessments do not need to be repeated at the time of re-screening if they 
were performed within 28 days. 
 Unscheduled visits 
7.1.2
Unscheduled visits may be performed at any time during the study. Depending on the 
reason for the unscheduled visit (e.g., AE), appropriate assessments will be performed 
based on the judgment of the investigator. Only the results from study-specific 
assessments [as listed in Section 7.2], will be recorded in the CRF. After an unscheduled 
visit, the regular scheduled study visits must continue according to the planned visit and 
assessment schedule. 
 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 40/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
 
Table 2 
Visit and assessment schedule 
PERIODS 
Name 
SCREENING 
TREATMENT AND OBSERVATION PERIOD 
FOLLOW-UP 
 
 
 
Period 1  
(Pre-treatment 
Period; Uptravi) 
Period 2  
(Treatment Period; i.v. selexipag)  
Period 3  
(Post-treatment 
Period; Uptravi) 
 
VISITS1 
Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 (Phone call)
 
Name 
Screening 
Baseline  
 
 
EOS 
 
Time 
Day –28 to Day –1 
Day 1 
Day 2 
IV-1 (AM)
Day 2 
IV-2 (PM)
Day 3 
IV-3 (AM)
Day 12 (± 2days) 
30 to 37 days after 
i.v. study treatment 
discontinuation 
Informed consent 
X 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
Demographics / Medical history 
X 
 
 
 
 
 
 
WHO FC 
X 
X 
 
 
X2
X 
 
Previous/concomitant therapy 
X 
X
X
X 
X
X
X
Physical examination 
X 
 
 
 
 
X 
 
Vital signs (BP, pulse rate) 
X 
X 
X5 
 
X5 
X 
 
Body weight and Height3 
X 
X 
 
 
X 
X 
 
Hospitalization4** 
 
 
 
 
Laboratory tests* 
X 
X6 
 
 
X 
X 
 
12-lead ECG* 
 
X 
X7 
X7 
X7 
X 
 
Urine pregnancy test** 
X 
X 
 
 
 
 
X 
PK sampling8 
 
X 
 
 
X 
 
 
Study treatment administration 
(i.v. selexipag) 
 
 
X 
X 
X 
 
 
Infusion solution sampling9 
 
 
X 
X 
X 
 
 
SAEs/AEs10 
X 
X
X
X 
X
X
X


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 41/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
AE = adverse event; BP = blood pressure; ECG = electrocardiogram; EOS = End-of-Study; FC = Functional Class; i.v. = intravenous; PK = pharmacokinetic; SAE = 
serious adverse event; WHO = World Health Organization. *Electronically transferred to sponsor. ** Assessment not collected in CRF 
 
1. Unscheduled visits may be performed at any time during the study. Assessments performed during unscheduled visits are at the discretion of the investigator. 
2. On Day 3, WHO FC is to be assessed at the end of the i.v. selexipag infusion. 
3. Height will be assessed at Visit 1 (screening) only. 
4. In-patient hospitalization of subjects is mandatory during Visit 2 (Period 1 and Period 2) (i.e., 2 overnight stays from Day 1 to Day 3). For convenience, the 
hospitalization may be extended to the night before Day 1 and to the night of Day 3. 
5. Vital signs (BP and pulse rate) will be assessed at 7 different time points as detailed in Table 3. 
6. If Visit 1 and Visit 2 Day 1 are performed within 7 days, laboratory tests do not have to be repeated at Visit 2 Day 1. 
7. ECG will be performed at pre-dose and within 30 minutes after stopping of infusion (i.v. selexipag). 
8. PK profile includes 7 blood samples. Timing of blood samples is detailed in Table 3 
9. Infusion solution samples will be taken from the tubing before each infusion [see Table 3]. 
10. All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after i.v. selexipag study treatment discontinuation must be reported. 
 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 42/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
Table 3 
Visit 2 vital signs and PK blood collection schedule 
 
Visit 2 (hospitalization) 
 
 
Period 1 (Uptravi, Pre-
treatment Period) 
Period 2 (Treatment Period; i.v. selexipag) 
Period 3 (Uptravi, 
Post-treatment 
Period) 
 
Day 1 
Day 2 
Day 3 
 
Time1 after 
morning dose 
0 
h 
1 
h 
2 
h 
4 
h 
6 
h 
8 
h 
12 
h 
0 
h 
25 
min 
87 
min 
4 
h 
6 
h 
8 
h 
12 
h 
0 h 
25 
min 
87 
min 
4 
h 
6 
h 
8 
h 
12 h 
 
Uptravi oral intake 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Infusion solution 
sample2 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
Selexipag i.v. 
infusion 
 
 
 
 
 
 
 
   X 
 
 
 
X5 
   X 
 
 
 
 
 
 
PK blood sample 
X3 
X 
X 
X 
X 
X 
X3 
 
 
 
 
 
 
 
X3 
X 
X4 
X 
X 
X 
X3 
 
 
Vital signs (pulse 
rate and BP) 
X 
 
 
 
 
 
 
X3 
X 
X4 
X 
X 
X 
X3 
X3 
X 
X4 
X 
X 
X 
X3 
 
 
BP = blood pressure; i.v. = intravenous; PK = pharmacokinetic. 
 
1 A time window of ± 5% is allowed for PK time points.  
2 Infusion solution sample will be taken from the tubing prior to selexipag infusion. 
3 Vital signs and PK blood sample must be assessed/taken before selexipag administration (oral or i.v.).  
4 Immediately before stopping the infusion.  
5 Evening i.v. selexipag infusion to be started 12 h ± 1 h after the start of the morning infusion. 
 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 43/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
 
7.2 Study assessments 
The study assessments are listed in Table 2 and Table 3. The assessments that are 
mandatory during a visit are marked with an ‘X’. 
All study assessments are performed by qualified study personnel (medical, nursing, or 
specialist technical personnel) and are recorded in the CRF, unless otherwise specified. 
Results for study-specific assessments performed during unscheduled visits will also be 
recorded in the CRF. The following order of assessments must be followed: 
• When blood pressure and PK blood sampling are to be assessed at the same time 
point, blood pressure measurements will be performed before PK sampling. 
If the Principal Investigator (PI) delegates any study procedure/assessment for a subject 
to an external facility, he/she must inform Actelion to whom these tasks are delegated. 
The set-up and oversight will be agreed upon with Actelion. The supervision of any 
external facilities remains the responsibility of the PI. 
Calibration certificates / evidence of maintenance for the below-listed equipment used to 
perform study assessments must be available prior to the screening of the first subject. 
Calibration certificates of other equipment must be available as per local requirements. 
Equipment for which calibration certificates / evidence of maintenance are needed: 
• Temperature measurement devices for selexipag dry powder vials storage area, 
plasma PK sample and infusion solution sample storage area. 
• ECG equipment. 
• Infusion pump. 
• Cooling centrifuge used for preparation of plasma PK samples. 
 Demographics / baseline characteristics 
7.2.1
Demographic and baseline characteristic data to be collected on all subjects include: age, 
sex, race, and ethnicity (if allowed in the country). Relevant medical history/current 
medical conditions (e.g., chronic and ongoing acute conditions, serious past conditions) 
present before signing the ICF will be recorded on the medical history CRF form. Where 
possible, diagnoses and not symptoms will be recorded. 
Medical history of special interest will be captured on the specific Medical History CRF 
form and includes: 
• Etiology of PAH. 
• Date of initial diagnosis. 
• Uptravi dose at screening. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 44/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
For subjects who failed screening, at least the following data will be recorded in the CRF 
if available: 
• Demographics. 
• Inclusion criteria not met and exclusion criteria met. 
• Medical history of special interest. 
• Central laboratory and ECG results will be transferred to the sponsor if available. 
• all AEs and SAEs. 
 Efficacy assessments 
7.2.2
Not applicable. 
 Safety assessments 
7.2.3
The definitions, reporting and follow-up of AEs, SAEs and pregnancies are described in 
Section 9. 
7.2.3.1 Physical examination 
Physical examination will be performed according to standard practice at site and guided 
by medical history and/or symptoms. 
Information for all physical examinations must be included in the source documentation 
at the study site. The observations will be reported according to body system in the CRF 
as either normal or abnormal. Any abnormality must be specified on the corresponding 
CRF form, describing the signs related to the abnormality (e.g., systolic murmur) and not 
the diagnosis (e.g., mitral valve insufficiency). Clinically relevant findings (other than 
those related to PAH) that are present prior to signing the ICF must be recorded on the 
Medical History CRF form. Physical examination findings made after signing the ICF 
which meet the definition of an AE [see Section 9.1.1] must be recorded on the AE form 
of the CRF. 
7.2.3.2 Vital signs 
Pulse rate, SBP, and DBP will always be measured in a supine position and will be 
recorded in the CRF. It is recommended to assess vital signs on the same arm throughout 
the study and to allow the subject to rest for at least 5 minutes prior to each measurement. 
During the i.v. selexipag treatment (Period 2), vital signs will be measured before start of 
the morning infusion of selexipag and 6 times after the start of infusion (time schedule of 
measurements is detailed in Table 3). On Day 3, vital signs will be measured on the arm 
where the line for PK sample collection is placed (opposite arm from infusion of 
selexipag) and vital signs are to be measured immediately prior to blood collection. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 45/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
7.2.3.3 Weight and height 
Body weight will be measured in indoor clothing but without shoes and recorded in the 
CRF. 
Height will be measured without shoes and recorded in the CRF. 
7.2.3.4 ECG assessment 
Standard 12-lead ECGs will be recorded with the subject in a fully rested supine position. 
Prior to the measurement it is recommended to allow the subject to rest for at least 
5 minutes. 
A central ECG laboratory [see central ECG manual for contact details] will be used for 
all protocol-mandated ECGs [Table 2], including re-tests due to ECG abnormalities and 
ECGs performed at unscheduled visits. 
Central ECG reports will be sent to the investigator. In the event of specific (pre-defined 
in the central ECG laboratory manual) ECG abnormalities, the central ECG laboratory 
will alert Actelion personnel and the concerned site personnel. 
All ECG reports must be reviewed, signed, and dated by the investigator or delegate 
within 10 working days of receipt and filed with the source documentation. The 
investigator/delegate must indicate on the ECG report whether abnormal values or 
findings are considered clinically relevant or not.  
Clinically relevant ECG findings that are known at the time of signing the ICF must be 
documented in the Medical History section of the CRF.  
Clinically relevant ECG abnormalities detected after signing the ICF must be reported as 
an AE or SAE as appropriate. 
The data records will be electronically transmitted to the central ECG laboratory for 
central reading. ECG data will be electronically transferred from the ECG laboratory 
database to Actelion. Details on ECG procedures (recording, transfer of data, and 
reporting) will be provided in the central ECG laboratory manual. 
The following variables will be evaluated: HR (bpm), PR (ms), QRS (ms), QT (ms), 
QTcB (ms), QTcF (ms) and any ECG findings. QTc (ms) will be calculated according to 
Bazett’s and Fridericia’s formulae (i.e., QTcB = QT/√(RR) and QTcF = QT/(RR)1/3).  


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 46/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
 Laboratory assessments 
7.2.4
7.2.4.1 Type of laboratory 
A central laboratory [see central laboratory manual for contact detail]) will be used for all 
protocol-mandated laboratory tests, including re-tests due to laboratory abnormalities and 
laboratory tests performed at unscheduled visits. 
Exceptional circumstances that will require recording of local laboratory results of the 
variables described in Section 7.2.4.2 (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 a central laboratory sample is lost or cannot be analyzed for whatever reason, the 
investigator will consider collecting an additional sample as soon as possible if deemed 
medically needed for repeat analysis. 
Central laboratory reports will be sent to the investigator. In the event of specific (pre-
defined) laboratory abnormalities, the central laboratory will alert Actelion personnel and 
the concerned site personnel. Alert flags that will trigger such notifications are displayed 
in Appendix 1. 
All laboratory reports must be reviewed, signed, and dated by the investigator or delegate 
within 10 working days of receipt and filed with the source documentation. The 
investigator/delegate must indicate on the laboratory report whether abnormal values are 
considered clinically relevant or not. Clinically relevant laboratory findings that are 
known at the time of signing of informed consent must be recorded on the Medical 
History form of the CRF. Any study-emergent clinically relevant laboratory 
abnormalities detected after signing of informed consent must be reported as an AE or 
SAE as appropriate, and must be followed until the value returns to within the normal 
range or is stable, or until the change is no longer clinically relevant. 
Details about the collection, sampling, storage, shipment procedures, and reporting of 
results and abnormal findings can be found in the laboratory manual. 
7.2.4.2 Laboratory tests 
Hematology 
• Hemoglobin (g/L) 
• Hematocrit (L/L) 
• Erythrocytes (1012/L) 
• Leukocytes with differential counts (109/L) 
• Platelets (109/L) 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 47/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
Clinical chemistry 
•
Alanine aminotransferase (U/L)
•
Aspartate aminotransferase (U/L)
•
Alkaline phosphatase (U/L)
•
Total and direct bilirubin (μmol/L)
•
Creatinine (μmol/L)
•
Sodium, potassium (mmol/L)
Pregnancy test 
Only for women of childbearing potential: 
•
Urine pregnancy test will be performed as standard assessment during this study.
•
If pregnancy is suspected during the study, a serum pregnancy test must be performed
immediately.
The results of the pregnancy tests will not be collected in the CRF. 
 Pharmacokinetic assessments 
7.2.5
7.2.5.1 Pharmacokinetic assessments 
PK blood samples will be collected for all subjects in order to establish a 12-hour PK profile 
at steady state for selexipag and ACT-333679 when subjects are at their stable dose of 
Uptravi and after the switch from Uptravi to i.v. selexipag. 
7.2.5.1.1 Timing for sampling 
For all subjects, a total of 14 blood samples will be drawn. 
PK blood samples will be collected as displayed in Table 3. 
On Day 1, plasma concentrations of selexipag and ACT-333679 will be measured at 
pre-dose (trough) and 1, 2, 4, 6, 8, and 12 hours after the morning dose of Uptravi. 
On Day 3, plasma concentrations of selexipag and ACT-333679 will be measured at 
pre-dose (trough) and 25 min, 87 min (i.e., immediately before stopping the infusion), 4, 
6, 8, and 12 hours after initiation of the morning i.v. infusion of selexipag. 
The allowed time window is ± 5% from the scheduled time point (refer to laboratory 
manual for conversion table between % and minutes). 
7.2.5.1.2 Procedures for sampling 
Detailed instructions for the collection, preparation, labeling, storage, and shipment of the 
plasma samples can be found in the laboratory manual provided to the investigator.  


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 48/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
Important points: 
•
Trough blood samples must be drawn before the morning dose of selexipag (oral or
i.v.) is administered.
•
12-hour PK blood samples must be drawn before the evening dose of Uptravi is
administered.
•
PK blood samples on Day 3 must be taken from the opposite arm of infusion of i.v.
selexipag, i.e., do not use the same arm for i.v. selexipag infusion and PK sampling.
•
To prevent degradation of selexipag and ACT-333679 in the PK samples, exposure of
the PK samples to light needs to be minimized.
The actual date and clock times of each PK blood sampling must be collected in the CRF. 
7.2.5.1.3 Bioanalysis 
The plasma concentrations of selexipag and ACT-333679 will be determined using a 
validated LC-MS/MS assay. The limit of quantification (LOQ) for both analytes in 
plasma is 0.01 ng/mL. Concentrations will be calculated by interpolation from a 
calibration curve. Quality control samples will be used to determine between-run and 
overall precision and accuracy of the analysis. No genetic analysis will be conducted. 
7.2.5.1.4 Shipping procedures 
The site staff will be responsible for the shipment of the plasma PK samples. Samples 
must be sent to the central laboratory (
), at time 
intervals as defined in the laboratory manual. The samples, together with the completed 
shipment forms, must be packed securely in polystyrene-insulated shipping containers 
containing enough dry ice to last for 48 h. The central laboratory will ensure subsequent 
shipment of the plasma PK samples to 
 Actelion. 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE 
8.1 Study completion 
A subject who received at least one dose of i.v. treatment and performed the follow-up 
period is considered to have completed the study. 
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 (i.e., withdrawal of consent), die, or are lost 
to follow-up. If a subject withdraws consent, no further data will be collected in the CRF 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 49/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
from the date of withdrawal onward. The investigator may withdraw a subject from the 
study (without regard to the subject’s consent) if, on balance, he/she believes that 
continued participation in the study would be contrary to the best interests of the subject. 
Withdrawal from the study may also result from a decision by Actelion for any reason, 
including premature termination or suspension of the study. 
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 (e.g., 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 CRF. The following methods must be used: at least three 
telephone calls must be placed to the last available telephone number and one registered 
letter must be sent by post to the last available home address. Additional methods may be 
acceptable if they are compliant with local rules/regulations (e.g., a visit by site personnel 
to the subject’s home), respecting the subject’s right to privacy. If the subject is still 
unreachable after all contact attempts listed above, he/she will be considered to be lost to 
follow-up. 
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 
Actelion personnel) must be recorded in the CRF, if known. 
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 
discuss follow-up medical care. Data obtained during this last appointment / telephone 
call will be recorded in the subjects’ medical records but it will not be collected in the 
CRF. 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 
Actelion reserves the right to terminate the study at any time globally or locally. 
Investigators can terminate the participation of their site in the study at any time. 
If the study is prematurely suspended or terminated, Actelion will promptly inform the 
investigators, the independent ethics committees / institutional review boards 
(IECs/IRBs), and health authorities, as appropriate, and provide the reasons for the 
suspension or termination. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 50/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
If the study is suspended or prematurely terminated for any reason, the investigator – in 
agreement with Actelion – must promptly inform all enrolled subjects and ensure their 
appropriate treatment and follow-up, as described in Section 8.4. Actelion may inform 
the investigator of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the subjects’ interests. 
In addition, if the investigator suspends or terminates the study without prior agreement 
from Actelion, the investigator must promptly inform Actelion personnel and the 
IEC/IRB, and provide both with a detailed written explanation of the termination or 
suspension. 
If the IEC/IRB suspends or terminates its approval / favorable opinion of the study, the 
investigator must promptly notify Actelion personnel and provide a detailed written 
explanation of the termination or suspension. 
8.4 Medical care of subjects after study completion / withdrawal from study 
After the subject’s study completion or premature withdrawal from the study, whichever 
applies, the investigator/delegate will explain to subjects what treatment(s) / medical care 
is necessary and available according to local regulations. Such care may include 
continuation of their prescribed Uptravi. 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
9.1 Adverse events 
 Definition of adverse events 
9.1.1
An AE is any untoward medical occurrence, i.e., any unfavorable and unintended sign, 
including an abnormal laboratory finding, symptom, or disease that occurs in a 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 i.v. selexipag; 
from start of first i.v. selexipag infusion until 30 days after end of last i.v. selexipag 
infusion (i.e., Period 2, and Period 3 and follow-up Period combined); 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. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 51/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
• Continuous persistent disease or symptoms present at study start that worsen 
following the signing of informed consent. 
• Abnormal assessments, e.g., change on physical examination, ECG findings, if they 
represent a clinically significant finding that was not present at study start or 
worsened during the course of the study. 
• Laboratory test abnormalities if they represent a clinically significant finding, 
symptomatic or not, which was not present at study start or worsened during the 
course of the study or led to dose reduction, interruption or permanent discontinuation 
of study treatment. 
Overdose, misuse, abuse of the study treatment (i.v. selexipag) and study treatment errors 
will be reported as an AE. 
Overdose is defined as any infused dose of selexipag greater than the dose corresponding 
to 1600 µg b.i.d. of Uptravi. 
Study treatment errors include medication error (e.g., any infused dose of selexipag 
greater than the individual corresponding prescribed dose of Uptravi) and administration 
errors (e.g., incorrect infusion rate). 
 Intensity of adverse events 
9.1.2
The intensity of clinical AEs is graded on a three-point scale – mild, moderate, severe – 
and is reported on specific AE form of the CRF. 
If an AE changes in intensity (i.e., worsening or improvement) during the course of the 
study, this will be reported in the CRF. 
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. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 52/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
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. 
 Relationship to study treatment 
9.1.3
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the study treatment, and reported as either related or 
unrelated. The determination of the likelihood that the study treatment caused the AE will 
be provided by the investigator. 
 Reporting of adverse events 
9.1.4
All AEs with an onset date after signing of informed consent and up to 30 days after 
study treatment discontinuation (i.e., EOS visit / telephone call) must be recorded on 
specific AE form of the CRF. 
Reporting of AE in CRF will include onset time. 
 Follow-up of adverse events 
9.1.5
AEs still ongoing more than 30 days after study treatment discontinuation must be 
followed up until they are no longer considered clinically relevant or until stabilization. 
The follow-up information obtained after the subject’s EOS visit / telephone call will not 
be collected by Actelion. 
9.2 Serious adverse events 
 Definitions of serious adverse events 
9.2.1
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 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 53/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
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 as SAEs: 
• Hospitalization for cosmetic elective surgery, or social and/or convenience reasons. 
• Hospitalization for pre-planned (i.e., planned prior to signing informed consent) 
surgery or standard monitoring of a pre-existing disease or medical condition that did 
not worsen, e.g., hospitalization for coronary angiography in a subject with stable 
angina pectoris. 
However, complications that occur during hospitalization are AEs or SAEs (e.g., if a 
complication prolongs hospitalization). 
 Reporting of serious adverse events 
9.2.2
All SAEs occurring after signing of informed consent up to 30 days after study treatment 
discontinuation must be reported on AE forms in the CRF and on an SAE form, 
regardless of the investigator-attributed causal relationship with study treatment (i.v. 
selexipag) or study-mandated procedures. 
An SAE is defined as related to protocol-mandated procedures if it appears to have a 
reasonable possibility of a causal relationship to either the study design or to 
protocol-mandated procedures. 
 Follow-up of serious adverse events 
9.2.3
SAEs still ongoing more than 30 days after study treatment discontinuation must be 
followed up until resolution or stabilization, or until the event outcome is provided. The 
follow-up information obtained after the subject’s EOS visit / telephone call must be 
reported to Actelion Global Drug Safety, but it is not recorded in the CRF. 
 After the 30-day follow-up period 
9.2.4
New SAEs occurring after the 30-day follow-up period must be reported to Actelion 
Global Drug Safety (contact details are provided on the SAE form) 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. 
 Reporting procedures 
9.2.5
All SAEs must be reported by the investigator to Actelion Global Drug Safety within 
24 hours of the investigator’s first knowledge of the event. 
All SAEs must be recorded on an SAE form, irrespective of the study treatment received 
by the subject, and whether or not this event is considered by the investigator to be 
related to study treatment. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 54/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
The SAE forms must be sent to Actelion Global Drug Safety (contact details are provided 
on the SAE form). The investigator must complete the SAE form in English, and must 
assess the event’s causal relationship to the study treatment. 
Any relevant information from source documents regarding the SAE, e.g., hospital notes 
or discharge summaries, etc., must be summarized on the SAE form. 
Follow-up information about a previously reported SAE must also be reported within 
24 hours of receiving it. Actelion Global Drug Safety 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 a reported serious adverse reaction is determined by Actelion in the 
reference safety information (RSI) section provided in the most recent version of the IB. 
Any SAE that is reported as related and assessed as unexpected against the RSI will be 
classified as a suspected unexpected serious adverse reaction (SUSAR) and reported by 
Actelion to concerned health authorities (including the EudraVigilance database if the 
study is conducted in Europe), IECs/IRBs and investigators. 
The following SAEs are commonly seen in subjects with underlying PAH disease and are 
therefore anticipated to occur in this subject population. These SAEs (unless fatal) do not 
require expedited reporting to health authorities, ECs/IRBs, and investigators: symptoms 
of PAH worsening/exacerbation/ progression, abdominal pain, anorexia, chest pain, 
cyanosis, diaphoresis, dizziness, pre-syncope, syncope, dyspnea, orthopnea, fatigue, 
hemoptysis, heart failure, hypoxia, palpitations, collapse, systemic arterial hypotension, 
and tachycardia. Like all other SAEs, these SAEs must be reported on a SAE form by the 
investigator to the Actelion drug safety department within 24 hours of the investigator’s 
first knowledge of the event, and be reported on the AE form of the CRF. 
9.3 Pregnancy 
If a woman becomes pregnant during the study, the investigator must counsel the subject 
and discuss the risks of continuing with the pregnancy and the possible effects on the 
fetus. 
 Reporting of pregnancy 
9.3.1
Any pregnancy occurring after study start (i.e., signing of informed consent) up 
to 30 days following study treatment discontinuation must be reported within 24 hours of 
the investigator’s knowledge of the event. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 55/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
Pregnancies must be reported on the Actelion Pregnancy form, which is faxed to Actelion 
Global Drug Safety [see contact details provided on the Pregnancy form], and on an AE 
form in the CRF. 
 Follow-up of pregnancy 
9.3.2
Any pregnancies must be followed-up to their conclusion and the outcome must be 
reported to Actelion Global Drug Safety. 
Any AE associated with the pregnancy occurring during the follow-up period after study 
treatment discontinuation must be reported on separate AE forms in the CRF. Any SAE 
occurring during the pregnancy must be reported on a SAE form as described in 
Section 9.2.1. 
9.4 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 Actelion Clinical Team (in charge of ensuring subjects’ safety as well as data 
quality). 
10 STATISTICAL METHODS 
All statistical analyses will be conducted by Actelion or by a designated Contract 
Research Organization (CRO) supervised by Actelion. 
A SAP will provide full details of the analyses, data displays, and algorithms to be used 
for data derivations. 
10.1 Analysis sets 
 Screened Analysis Set 
10.1.1
The Screened Analysis Set includes all subjects who are screened and have a subject 
identification number. 
 Full Analysis Set 
10.1.2
Not applicable. 
 i.v. Safety Set 
10.1.3
The i.v. Safety Set comprises all subjects who received at least one dose of i.v. study 
treatment. 
The i.v. Safety Set will be used to capture safety and tolerability for all subjects who had 
at least one dose of i.v. selexipag. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 56/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
All analyses for Periods 2 and 3 combined, and for Period 2 separately will be carried out 
on the i.v. Safety Set. 
 Safety Set 
10.1.4
The Safety Set (SAF) includes all enrolled (included in the study on Day 1) subjects who 
receive at least one dose of selexipag (oral or i.v.). 
 Pharmacokinetic Analysis Set 
10.1.5
The Pharmacokinetic Analysis Set (PKS) comprises all subjects included in the SAF who 
received the 3 doses of i.v. study treatment and who complied with the protocol 
sufficiently and did not deviate from the protocol in a way that might affect the PK 
outcome of the study. Criteria for sufficient compliance include exposure to treatment, 
availability of measurements, and absence of major protocol deviations that have an 
impact on the PK. The full list of criteria will be detailed in the SAP.  
 Usage of the analysis sets 
10.1.6
Subject disposition is described for the Screened Analysis Set. Demographics and 
baseline characteristics will be reported on the SAF. Safety analyses will be carried out 
on the SAF and on the i.v. Safety Set. PK analyses will be carried out on the PKS. 
Subject listings are based on the SAF or Screened Analysis Set as applicable. The 
following table describes the use of the analysis sets. 
Table 4 
Reporting periods and corresponding analysis sets. 
Reporting period(s)* 
Variables 
Analysis set 
Period 1 
Safety and tolerability 
SAF 
Period 2 
Safety and tolerability 
i.v. Safety Set 
Period 3 
Safety and tolerability 
i.v. Safety Set 
Period 1 and 2  
Safety and tolerability 
SAF 
Period 2 and 3  
Safety and tolerability 
i.v. Safety Set 
Period 1 and 2 and 3 
Safety and tolerability 
SAF 
Period 1 and 2 
Pharmacokinetic  
SAF, PKS 
Follow-up period will be reported together with Period 3. 
* If a subject does not take at least one dose of selexipag i.v. they will not be considered as having entered Period 2 
(or 3).  


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 57/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
10.2 Variables 
All analyses will be mainly descriptive in nature. 
 Primary efficacy variable(s) 
10.2.1
No primary efficacy endpoint is defined for this study. Tolerability endpoints address the 
main objective.  
 Key secondary efficacy variables 
10.2.2
Not applicable. 
 Safety variables 
10.2.3
The following variable will be derived from the safety endpoints: 
• Proportion of AEs  
• Proportion of prostacyclin-associated AEs 
• Proportion of AEs related to injection site reactions 
• Proportion of PAH-related AEs 
• Proportion of SAEs 
• Proportion of AEs leading to discontinuation 
• Proportion of discontinuations due to prostacyclin-associated AEs  
• Proportion of ECG abnormalities 
• Proportion of MLAs 
• Change in WHO FC. 
Other safety variables will be taken into account such as, e.g., changes in vital signs and 
body weight. 
10.2.3.1 Adverse events 
An AE is defined as any event that is recorded on the AE CRF module regardless of the 
onset date. The onset date will determine which events belong to each of the treatment 
periods (i.e., before/after intake of oral/i.v. selexipag). All events during the study will be 
listed and/or tabulated accordingly. In the event of partially missing dates/times, 
imputation will be carried out to link event and period using a conservative algorithm.  
10.2.3.2 Laboratory data 
Laboratory analyses are based on data received from the central laboratory. All 
transferred central laboratory data are taken into account regardless of whether they 
correspond to scheduled or unscheduled assessments. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 58/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
10.2.3.3 ECG 
ECG analyses are based on data received from the central ECG. All transferred central 
ECG data are taken into account regardless of whether they correspond to scheduled or 
unscheduled assessments. 
Baseline ECG refers to the latest ECG performed prior to the start of study treatment.  
All ECG values collected will be listed. Descriptive summary statistics of each variable 
(HR and the intervals PR, QRS, QT, QTcF and QTcB) by visit will be provided for 
observed values and absolute changes from baseline. 
 Pharmacokinetic variables 
10.2.4
Plasma PK parameters of selexipag and its active metabolite, ACT-333679, will be 
derived by non-compartmental analysis of the concentration-time profiles. The PK 
parameters will be calculated on the basis of the real blood sampling time points (in 
relation to the last selexipag intake during each period). 
The measured individual plasma concentrations of selexipag will be used to directly 
obtain Ctrough, ss, Cmax, ss, and tmax, ss. 
AUCτ, ss will be calculated according to the linear trapezoidal rule using the measured 
concentration-time values above the LOQ during one dosing interval at steady state. 
For mean value calculations, all values below the limit of quantification (BLQ) will be 
set to zero. If > 50% of the values at a given time point are BLQ, no mean value will be 
calculated. Mean concentration-time profiles will be generated using these criteria. 
Cmax, ss, Ctrough, ss, and AUCτ, ss, values are assumed to be log-normally distributed 
[Julious 2000]. 
10.3 Description of statistical analyses 
 Overall testing strategy 
10.3.1
The statistical analysis will be mainly descriptive, i.e., no hypotheses will be formally 
tested. CIs will be calculated at the 95% level for the main safety variables, per period 
(and combination of periods) and overall. CIs for PK variables will be calculated at the 
95% level for descriptive analysis. A level of 90% will be used for the ratio of geometric 
means of PK parameters to account for the limited sample size. 
 Analysis of the primary efficacy variable(s) 
10.3.2
Not applicable. 
 Analysis of key secondary efficacy variable(s) 
10.3.3
Not applicable.  


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 59/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
 Analysis of the safety variable(s) 
10.3.4
The study comprises 3 main periods for analysis, Period 1 (Uptravi, pre-treatment), 
Period 2 (i.v. selexipag; treatment period) and Period 3 (Uptravi; post-treatment).  
Tolerability and safety analyses will be carried out descriptively on the SAF and the i.v. 
Safety Set. AEs that occur prior to first intake of Uptravi on Day 1 as a result of 
study-mandated procedures will be analyzed descriptively in the Screened Analysis Set. 
All AEs and SAEs will be coded using MedDRA. 
The number and percentage of subjects experiencing AEs by period [as per Table 4] will 
be tabulated by MedDRA System Organ Class (SOC) and individual Preferred Term (PT) 
within each of the SOCs, in descending order of incidence of SOC, alphabetical order of 
PT, PT descending order of incidence and alphabetical order of PT for each period 
separately. AEs and SAEs will be tabulated, for the SAF and i.v. Safety Set overall across 
periods as well as by study period. The same summary applies to SAEs, AEs leading to 
premature discontinuation of study treatment and death. Furthermore, AEs and SAEs will 
be tabulated by severity and relationship to i.v. selexipag. 
The proportion of discontinuations due to prostacyclin-associated AEs and AEs leading 
to discontinuation will be tabulated for the SAF and i.v. Safety Set (as well as all other 
discontinuations, irrespective of reason). Due to the small sample size, estimates of the 
proportion will be provided with a conservative 95% Clopper-Pearson CI based on exact 
methods. 
Safety endpoints will be listed and tabulated in the SAF and i.v. Safety Set, overall and 
by study period [see Table 4 for details]. Treatment exposure will be summarized. 
Selexipag dose (oral and i.v.) will be summarized by visit, number of subjects and 
percentage. Shift tables between oral and i.v. dose will also be provided. 
ECG abnormalities and laboratory variables will be descriptively summarized, both 
longitudinally across the study periods as well as separately per period. Death will be 
summarized by cause, by period, and overall.  
All laboratory test assessments will be listed by subject, for all subjects in the SAF and 
will be tabulated on the SAF and i.v. Safety Set. Descriptive summary statistics by visit 
will be provided for observed values and absolute changes from baseline. 
 Analysis of PK variables 
10.3.5
For all PK analyses, the Pharmacokinetic Analysis Set will be employed. 
• Plasma concentrations of selexipag and ACT-333679 will be summarized per time 
point by dose and period using arithmetic mean, geometric mean, minimum, median, 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 60/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
maximum, standard deviation (SD), standard error (SE), and two-sided 95% CI of the 
means.  
• Ctrough, ss of selexipag and ACT-333679 will be listed by dose, period and subject, and 
will be summarized by dose and period using arithmetic mean, geometric mean, 
minimum, median, maximum, SD, SE, and coefficients of variation (CV, CVln) in %, 
and two-sided 95% CI of the means.  
• Cmax, ss, tmax, ss, and AUCτ, ss of selexipag and ACT-333679 will be listed by dose, 
period, and subject. 
• Cmax, ss, tmax, ss,* and AUCτ, ss, will be summarized by dose and period with arithmetic 
mean, geometric mean, minimum, median, maximum, SD, SE, CV% and CVln%, 
95% CI of the arithmetic and geometric means, and inter-subject coefficient of 
variation (CVb). (* For tmax, ss, the geometric mean, its 95% CI and CVln will not be 
calculated). 
• Differences in Cmax, ss and AUCτ, ss, of selexipag and ACT-333679 between periods 
will be explored after dose normalization and within each dose level by using the 
90% CI of the ratio of the geometric means of selexipag i.v. (test treatment) versus 
selexipag oral (reference treatment). The log-transformed values will be analyzed by 
mixed-effect models including treatment and period as fixed effects and subject as 
random effect. The ratios of geometric means and their 90% CI will be calculated 
from the corresponding back log-transformed contrasts of the mixed-effects models 
for Cmax, ss and AUCτ, ss of selexipag and ACT-333679 after oral or i.v. selexipag 
administration. 
• Differences for tmax, ss of ACT-333679 between periods will be explored within each 
dose level using the Wilcoxon signed rank test providing the median differences and 
their 90% CI. 
• Dose proportionality for AUCτ, ss, of selexipag and ACT-333679 after selexipag i.v. 
will be explored by the power model as described by [Gough 1995], (this analysis 
will only be done if there are at least 3 different doses in the study). 
• Cmax, ss and AUCτ, ss ratio of ACT-333679 / selexipag will be listed by dose, period, 
and subject and will be summarized by dose and period. 
 Analysis of other variables 
10.3.6
The proportion of subjects in each WHO FC (I, II, III and IV) will be tabulated at 
baseline and post-baseline, as well as the change in WHO FC at all assessed time points. 
Also the absence of worsening in WHO FC will be tabulated (i.e., subjects that are either 
stable or improved). A shift table approach may also be used. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 61/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
10.4 Interim analyses 
No interim analysis is planned for this study. 
10.5 Sample size 
Approximately 20 subjects will be enrolled to have at least 18 subjects in the i.v. Safety 
Set. In the GRIPHON Phase 3 pivotal study of selexipag, a proportion of 7.5% of 
subjects prematurely discontinued the study (i.e., without a morbidity/mortality event) 
due to prostacyclin-associated AEs across the titration and maintenance phases. It is 
expected that the proportion of early discontinuations during the entire study will not be 
higher than 10% (i.e., that approximately 18 subjects will enter the i.v. period). 
A sample size of 18 subjects in the i.v. Safety Set will assure, if the true rate of 
discontinuations due to prostacyclin-associated AEs (p0) is between 5% and 10%, that the 
half-width (ω) of the 95% CI will be below 35%. 
The precision achieved with a sample size of approximately 18 subjects in the i.v. Safety 
Set is considered adequate for this study (e.g., the upper bound of the CIs for the i.v. 
Safety Set excludes values above 35% and for the SAF above 32%).  
11 DATA HANDLING 
11.1 Data collection 
The investigator/delegate is responsible for ensuring the accuracy, completeness and 
timeliness of the data reported. All source documents must be completed in a neat, legible 
manner to ensure accurate interpretation of the data. Data reported in the CRF derived 
from source documents must be consistent with the source documents. 
CRF data will be captured via electronic data capture (using the Rave system provided by 
Medidata, 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 (i.e., confirm the accuracy 
of the data recorded) using an electronic signature (ref. to US 21 CFR Part 11). 
Subject screening and enrollment data will be completed for all subjects (i.e., eligible and 
non-eligible) through the IRT system and CRF. 
For each subject screened, regardless of study treatment initiation, a CRF 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 
noted on the CRF. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 62/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
11.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On CRFs or 
other documents (e.g., documents attached to SAE forms / Pregnancy forms) submitted to 
Actelion 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. The 
investigator/delegate must keep a subject identification code list at the site, showing the 
screening number, the subject’s name, date of birth, and address or any other locally 
accepted identifiers. Documents identifying the subjects (e.g., signed ICFs) must not be 
sent to Actelion, and must be kept in strict confidence by the investigator/delegate. 
11.3 Database management and quality control 
CRFs will be used for all subjects. The investigators will have access to the site CRF data 
until the database is closed. Thereafter, they will have read-only access. The CRF 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 will be instantly alerted to data queries 
by validated programmed checks. Additional data review will be performed by Actelion 
personnel on an ongoing basis to look for unexpected patterns in data and for study 
monitoring. If discrepant data are detected, a query specifying the problem and requesting 
clarification will be issued and visible to the investigator/delegate via the CRF. All 
electronic queries visible in the system either require a data correction (when applicable) 
and a response from the investigator/delegate to clarify the queried data directly in the 
CRF, or simply a data correction in the CRF. The investigator/delegate must, on request, 
supply Actelion with any required background data from the study documentation or 
clinical records. This is particularly important when errors in data transcription are 
suspected. In the case of health authority queries, it is also necessary to have access to the 
complete study records, provided that subject confidentiality is protected. 
This process will continue until database closure. 
Laboratory samples and ECG readings will be processed through a central vendor and the 
results will be electronically sent to Actelion. 
AEs are coded according to the latest version of MedDRA used by Actelion. 
After the database has been declared complete and accurate, the database will be closed. 
Any changes to the database after that time may only be made as described in the 
appropriate Actelion Quality System docs. After database closure, the investigator will 
receive the CRFs of the subjects of his/her site (including all data changes made) on 
electronic media or as a paper copy. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 63/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
12 PROCEDURES AND GOOD CLINICAL PRACTICE 
12.1 Ethics and Good Clinical Practice 
Actelion 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 
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. 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 legally designated representative to consider his or 
her decision to participate in the study and it shall be verified that the subject has 
understood the information (e.g., by asking the subject to explain what is going to 
happen). 
The ICF will be provided in the country’s local language(s). 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 64/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
Site personnel authorized to participate in the consent process and/or to obtain consent 
from the subject will be listed on the Delegation of Authority form supplied by Actelion. 
A study physician must always be involved in the consent process. 
The subject and authorized site personnel listed on the Delegation of Authority form 
supplied by Actelion must sign, personally date, and time (if the first study-mandated 
procedure is to be performed on the same day informed consent is obtained) the ICF 
before any study-related procedures (i.e., any procedures required by the protocol) begin. 
A copy of the signed and dated ICF is given to the subject; 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 (e.g., subject’s family member[s]), and the information that a copy of the 
signed ICF was given to the subject. 
If the site intends to recruit subjects who are considered vulnerable (e.g., subject cannot 
read or write, does not speak or understand the ICF language), additional measures must 
be implemented in order to ensure subject’s rights are respected and the consent obtained 
is legally valid. Actelion, the regulatory authorities (if applicable), and the IEC/IRB must 
be informed prior to the recruitment. The consent process (e.g., involvement of an 
impartial witness) must be fully described, submitted to, and approved by the IEC/IRB, 
according to procedures and before subjects are recruited. 
12.4 Indemnification, compensation and expenses to subjects and 
investigators 
Actelion provides insurance in order to indemnify (with both legal and financial 
coverage) the investigator/site against claims arising from the study, except for claims 
that arise from malpractice and/or negligence. 
The indemnification of the subject in the event of study-related injuries will comply with 
applicable regulations. 
There is no direct individual medical benefit for the subject to participate in the study. In 
addition to the refund for the study-related expenses (e.g., travel costs, meals, hotel…), 
the subject will be offered financial compensation for their participation to the study in 
compliance with applicable local regulations. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 65/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
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 Actelion or its 
representative in a timely manner. The investigator/delegate must document and explain 
any deviation from the approved protocol. Deviations considered to be a violation of 
ICH-GCP must be reported to the IEC/IRB and regulatory authorities according to 
Actelion or (overruling) local requirements. 
All protocol deviations will be reported in the Clinical Study Report (CSR). IECs/IRBs 
will be provided with listings of protocol deviations as per local requirements. 
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 
The investigator/delegate must maintain adequate records necessary for the 
reconstruction and evaluation of the study. A number of attributes are considered of 
universal importance to source data and the records that hold those data. These include 
that the data and records are accurate, legible, contemporaneous, original (or certified 
copy), attributable, complete, consistent, enduring, and available when needed. 
These records are to be classified into two different categories of documents: Investigator 
Site File (ISF) and subjects’ source documents. 
These records must be kept by the investigator for as long as is necessary to comply with 
Actelion’s requirements (i.e., as specified in the clinical study agreement), and national 
and/or international regulations, whichever would be the longest period. If the 
investigator cannot guarantee this archiving requirement at the site for any or all of the 
documents, special arrangements, respecting the data confidentiality, must be made 
between the investigator and Actelion to store these documents outside the site, so that 
they can be retrieved in case of a regulatory inspection. No study document should be 
destroyed without prior written approval from Actelion. Should the investigator wish to 
assign the study records to another party, or move them to another location, Actelion 
must be notified in advance. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 66/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
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 CRA has been provided personal and restricted access 
to study subjects only, to verify consistency between electronic source data and the CRF 
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 CRA could not be provided 
access to the system, the site is requested to print the complete set of source data needed 
for verification by the CRA. The print-outs must be numbered, stapled together with a 
coversheet, signed and dated by the investigator/delegate to confirm that these certified 
copies are exact copies having the same information as the original source data. The 
printouts will be considered as the official clinical study records and must be filed either 
with the subject’s medical records or with the subject’s CRF. 
In order to verify that the process the site uses to prepare certified copies is reliable, the 
CRA must be able to observe this process and confirm that the comparison of the source 
documents and the certified copy did not reveal inconsistencies. The CRA does not need 
to verify this process for all data of all subjects but at least for some of them (e.g., first 
subject; regular check during the study of critical data like inclusion/exclusion criteria, 
endpoints for some subjects) as per Actelion’s instructions. If it were not possible for the 
CRA to observe this process, it would not be possible to rely on the site’s certified copies 
and therefore the site cannot be selected for the clinical study. 
12.8 Monitoring 
Prior to study start, a site initiation visit (SIV) will be performed after the required 
essential study documents are approved by Actelion. The study treatment will be shipped 
to the site upon approval of the required essential documents. 
The PI must ensure that all site personnel involved in the study are present during the SIV 
and will dedicate enough time to it. Site Information Technology support should also be 
available during the SIV. 
The SIV must be completed before the site can start the screening of study 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 CRA will contact and visit the site regularly and must be permitted, 
on request, to have access to study facilities and all source documents needed to verify 
adherence to the protocol and the completeness, consistency, and accuracy of the data 
being entered in the CRFs and other protocol-related documents. Actelion monitoring 
standards require full verification that informed consent has been provided, verification 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 67/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
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. 
The PI must ensure that the CRF is completed after a subject’s visit (site visit or 
telephone call), and that all requested subject files (e.g., ICFs, medical notes/charts, other 
documentation verifying the activities conducted for the study) are available for review 
by the CRA. The required site personnel must be available during monitoring visits and 
allow adequate time to meet with the CRA to discuss study-related issues. 
The investigator agrees to cooperate with the CRA(s) to ensure that any issues detected in 
the course of these monitoring visits are resolved. If the 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 Actelion. 
12.9 Investigator Site File 
Each site will be provided with an Investigator Site File (ISF) prior to the SIV. It will 
contain all the essential documents that are required to be up-to-date and filed at site as 
per ICH-GCP section 8. 
The ISF will include a table of content listing the essential documents. All study-related 
documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the CRA regarding the filing of the study 
documents outside the ISF. It should be clearly documented where each document is 
filed. This note to file should be present in the specific tab of the document in the ISF. 
The ISF must be stored in a secure and access-restricted area during and after the study. It 
must be kept by the site for as long as needed to comply with any applicable rules and 
regulations, ICH-GCP, as well as instructions from Actelion. If the site needs to transfer 
the ISF to another location and/or if site facility can no longer store the ISF, the PI must 
immediately inform Actelion. 
If the PI will change, or if the site will relocate, the CRA must be notified as soon as 
possible. 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 68/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
12.10 Audit 
Actelion’s Global Quality Management representatives may audit the investigator site 
(during the study or after its completion). The purpose of this visit will be to determine 
the investigator’s adherence to ICH-GCP, the protocol, and applicable regulations; 
adherence to Actelion’s requirements (e.g., standard operating procedures [SOPs]) will 
also be verified. Prior to initiating this audit, the investigator will be contacted by 
Actelion to arrange a time for the audit. 
The investigator and site personnel must cooperate with the auditor(s) and allow access to 
all study documentation (e.g., subject records) and facilities. 
12.11 Inspections 
Health authorities and/or IEC/IRB may also conduct an inspection of this study (during 
the study or after its completion) at the site. 
Should an inspection be announced by a health authority and/or IEC/IRB, the investigator 
must immediately inform Actelion (usually via the CRA) that such a request has been 
made. 
The investigator and site personnel must cooperate with inspector(s) and allow access to 
all study documentation (e.g., subject records) and study facilities. 
12.12 Reporting of study results and publication 
Actelion will post the key elements of this protocol and the summary of results on 
Actelion’s Clinical Trial Register and within the required timelines on publically 
accessible databases (e.g., clinicaltrials.gov, EU database), as required by law and 
regulation. 
Study results will be documented in a CSR that will be signed by Actelion representatives 
and the Coordinating Investigator (or PI for single-center studies). 
In accordance with the Good Publication Practices and ethical practice, the results of the 
study will be submitted for publication in a peer-reviewed journal. Study results can be 
submitted for presentation at a congress before submission to a peer-reviewed journal. 
The Coordinating Investigator and the Steering Committee, if any, will have the 
opportunity to review the analysis of the data and to discuss the interpretation of the 
study results with Actelion personnel prior to submission to a peer-reviewed journal or 
presentation at a congress. 
Authorship will be determined in accordance with the International Committee of Journal 
Editors criteria, and be based on: 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 69/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
•
substantial contributions to the conception or design of the study, or the acquisition,
analysis, or interpretation of data; and
•
drafting of the publication or critical review for important intellectual content; and
•
providing final approval of the version to be published; and
•
agreement to be accountable for all aspects of the work in ensuring that questions
related to the accuracy or integrity of any part of the work are appropriately
investigated and resolved.
The list of authors of any publication of study results may include representatives of 
Actelion and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted 
to Actelion for review at least 30 days prior to submission for publication or presentation 
at a congress. Upon review, Actelion may provide comments, and may also request 
alterations and/or deletions for the sole purpose of protecting its confidential information 
and/or patent rights. Neither the institution nor the investigator should permit publication 
during such a review period. 
 
 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 70/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
13 REFERENCES 
[Barst 2004] Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential 
assessment of pulmonary arterial hypertension. JACC. 2004;43(12):40S-47S. 
[CTCAE 2010] Common Terminology Criteria for Adverse Events (CTCAE). Version 
4.03, June 2010. U.S. Department of health and human services. 
[D’Alonzo 1991] D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with 
primary pulmonary hypertension - results from a national prospective registry. Ann 
Intern Med. 1991;115:343-9. 
[Galiè 2009] Galiè N, Hoepper MM, Humbert M, et al. Guidelines for the diagnosis and 
treatment of pulmonary arterial hypertension. Eur Respir J. 2009;34:1219-63. 
[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. 
[Gough 1995] Gough K, Hutchinson M, Keene O, Byrom B, Ellis S, Lacey L, et al 
Assessment of dose proportionality: Report from the statisticians in The 
Pharmaceutical Industry/Pharmacokinetics UK joint working party. Drug 
Information Journal. 1995;29:1039–48. 
[Julious 2000] Julious SA, Debarnot CA. Why are pharmacokinetic data summarized by 
arithmetic means? J Biopharm Stat. 2000;10:55–71. 
[McLaughlin 2004] McLaughlin V, Presberg K, Doyle R, et al. Prognosis of pulmonary 
arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 
2004;126(1):78–92. 
[Selexipag IB] 
Investigator's 
Brochure 
for 
selexipag, 
version 
11. 
Actelion 
Pharmaceuticals Ltd, June 2016. 
[Selexipag IB Amendment 1] Investigator’s Brochure for selexipag, version 11 
amendment 1. Actelion Pharmaceuticals Ltd, December 2016. 
[Sitbon 2015] Sitbon O, Channick R, Chin KM, et al. Selexipag for the Treatment of 
Pulmonary Arterial Hypertension. N Engl J Med. 2015;373:2522-33. 
[Uptravi® SmPC] 
Uptravi® 
Summary 
of 
Product 
Characteristics. 
Actelion 
Pharmaceuticals Ltd. May 2016. 
[Uptravi® USPI] Uptravi® US Prescribing Information. Actelion Pharmaceuticals Ltd. 
December 2015. 
 


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 71/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
14 APPENDICES 
Appendix 1 
Marked laboratory abnormalities 
Laboratory values below or above the normal range will be graded at three levels (H, HH, 
HHH for values above normal range and L, LL, LLL for values below the normal range) 
where L stands for “low”, H for “high”. 
The term “marked abnormality” describes laboratory values, with grading of 
abnormalities at two levels: LL/HH and LLL/HHH. These thresholds have been defined 
by the sponsor for the purpose of standardized data analysis and reporting by the sponsor. 
The definitions of marked abnormal values are based mainly on the CTCAE grading 
system [CTCAE 2010] [see Table 5]. 
The marked abnormal values (i.e., LL, LLL, HH, HHH) will also be used as flags and 
alerts on the laboratory reports to the investigators, and Actelion: 
• Marked abnormality HH/LL: flag on laboratory report to investigators. 
• Extreme marked abnormality HHH/LLL: alert on laboratory report to investigators 
and subject to additional communication to investigator via telephone call and to 
Actelion via email. 
Thresholds for abnormality of level L or H are not provided in this appendix but will be 
provided in the central laboratory manual. Variables for which no threshold is defined in 
the table below may be defined in the central laboratory manual.  


Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A309 
Version 1 
27 January 2017, page 72/72 
Confidential 
EudraCT: 2016-004035-21 
Doc No D-17.055 
 
Table 5 
Thresholds for marked laboratory abnormalities 
Laboratory test name 
(SI unit) 
LL 
LLL 
HH 
HHH 
Hemoglobin (g/L) 
< 100 
< 80 
Increase of 
> 20 g/L above 
ULN or above 
baseline (if 
baseline > ULN) 
Increase of 
> 40 g/L above 
ULN or above 
baseline (if 
baseline > ULN) 
Hematocrit (L/L) 
< 0.28 (female) 
< 0.32 (male) 
< 0.20 
> 0.55 (female) 
> 0.60 (male) 
> 0.65 
Platelet count (109/L) 
< 75 
< 50 
> 600 
> 999 
Leukocytes (109/L) 
< 3.0 
< 2.0 
> 20.0 
> 100.0 
Neutrophils (109/L) 
< 1.5 
< 1.0 
NA 
NA 
Eosinophils (109/L) 
NA 
NA 
> 5.0 
NA 
Lymphocytes (109/L) 
< 0.8 
< 0.5 
> 4.0 
> 20 
ALT (U/L) 
NA 
NA 
> 3 × ULN 
> 5 × ULN 
AST (U/L) 
NA 
NA 
> 3 × ULN 
> 5 × ULN 
Alkaline phosphatase (U/L) 
NA 
NA 
> 2.5 × ULN 
> 5 × ULN 
Total bilirubin (μmol/L) 
NA 
NA 
> 2 × ULN 
> 5 × ULN 
Creatinine (μmol/L) 
NA 
NA 
> 1.5 × ULN 
> 3 × ULN 
Sodium (mmol/L) 
NA 
< 130 
> 150 
> 155 
Potassium (mmol/L) 
< 3.2 
< 3.0 
> 5.5 
> 6.0 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; NA = not applicable; SI = international system of 
units; ULN = upper limit of normal. 
 

SAP_001.pdf: 
TPL-000241 v02 
STATISTICAL ANALYSIS PLAN 
FOR CLINICAL STUDY REPORT 
AC-065A309 
A MULTICENTER, OPEN-LABEL, SINGLE-SEQUENCE 
CROSS-OVER STUDY TO ASSESS SAFETY, 
TOLERABILITY, AND PHARMACOKINETICS OF 
INTRAVENOUS SELEXIPAG IN SUBJECTS WITH 
STABLE PULMONARY ARTERIAL HYPERTENSION 
SWITCHING FROM AN ORAL STABLE DOSE OF 
SELEXIPAG 
Purpose of Analysis 
Clinical Study Report 
Investigational Drug 
Selexipag / ACT-293987 
Protocol Number 
AC-065A309 
Actelion Document Number 
D-18.239 
Document Status/Version Number 
Final 2.0  
Date 
2 July 2018 
Author 
 CRO Trial Statistician 
Reviewer 
 Clinical Science Program Head / 
Clinical Trial Physician 
Reviewer 
 Clinical Pharmacologist 
Reviewer 
 Medical Writer 
Reviewer 
 Medical Writer  
Reviewer 
 Clinical Trial Scientist 
Reviewer 
 Drug Safety Physician 
Reviewer 
 Senior Expert Statistician 
Confidential 
Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or 
otherwise disclosed without the consent of Actelion Pharmaceuticals Ltd. 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 2/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................6 
1 
INTRODUCTION .........................................................................................................8 
2 
STUDY DESIGN AND FLOW ....................................................................................8 
2.1 
Study design ...................................................................................................8 
2.2 
Study visit and assessment schedule ..............................................................9 
2.3 
Analysis periods .............................................................................................9 
2.4 
Randomization and blinding .........................................................................11 
2.5 
Sample Size ..................................................................................................11 
3 
OBJECTIVES .............................................................................................................11 
3.1 
Primary objective ..........................................................................................11 
3.2 
Other objectives ............................................................................................11 
4 
ANALYSIS SETS .......................................................................................................12 
4.1 
Definitions of analysis sets ...........................................................................12 
4.1.1 
Screened Analysis Set .......................................................................12 
4.1.2 
Full Analysis Set ...............................................................................12 
4.1.3 
Safety Analysis Set ...........................................................................12 
4.1.4 
i.v. Safety Analysis Set .....................................................................12 
4.1.5 
Pharmacokinetic Analysis Set ..........................................................12 
4.2 
Usage of the analysis sets .............................................................................14 
5 
STUDY SUBJECTS VARIABLES AND ANALYSES ............................................15 
5.1 
Subject disposition ........................................................................................15 
5.1.1 
Subject disposition and enrollment into analysis periods .................15 
5.1.2 
Screening failures .............................................................................15 
5.1.3 
Study completion/discontinuation ....................................................15 
5.1.4 
Study treatment completion/discontinuation ....................................16 
5.2 
Protocol deviations .......................................................................................16 
5.3 
Exclusion from analysis sets .........................................................................16 
5.4 
Subject characteristics ..................................................................................16 
5.4.1 
Demographics ...................................................................................16 
5.4.2 
Baseline disease characteristics ........................................................17 
5.4.3 
Other baseline characteristics ...........................................................17 
5.4.4 
Medical history .................................................................................17 
5.4.5 
Previous and concomitant therapies .................................................17 
5.5 
Study treatment exposure and compliance ...................................................19 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 3/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
5.5.1 
Exposure ...........................................................................................19 
5.5.2 
Compliance with study treatment .....................................................20 
6 
EFFICACY VARIABLES AND ANALYSES ...........................................................20 
7 
SAFETY VARIABLES ..............................................................................................20 
7.1 
Overview of safety analyses including subgroup analyses ..........................20 
7.1.1 
Overview of safety and tolerability endpoints ..................................20 
7.2 
Adverse events ..............................................................................................22 
7.2.1 
Variables ...........................................................................................22 
7.2.2 
Analysis ............................................................................................24 
7.3 
Deaths ...........................................................................................................26 
7.4 
Laboratory ....................................................................................................26 
7.4.1 
Measurements ...................................................................................26 
7.4.2 
Variables ...........................................................................................27 
7.4.3 
Analysis ............................................................................................27 
7.5 
Vital signs, physical findings, and other observations related to safety .......28 
7.5.1 
Vital signs .........................................................................................28 
7.5.2 
Physical findings ...............................................................................30 
7.5.3 
WHO functional class .......................................................................31 
7.6 
Electrocardiograph ........................................................................................31 
7.6.1 
Variables ...........................................................................................31 
7.6.2 
Variables ...........................................................................................32 
7.6.3 
Analysis ............................................................................................33 
7.7 
Subgroup analysis of safety variables ..........................................................34 
7.8 
Pharmacokinetic variables ............................................................................34 
7.8.1 
Measurements ...................................................................................34 
7.8.2 
Pharmacokinetic endpoints ...............................................................34 
7.8.3 
Pharmacokinetic variables ................................................................34 
7.8.4 
Analysis ............................................................................................35 
8 
GENERAL STATISTICAL METHODOLOGY ........................................................37 
8.1 
General rules for data presentations .............................................................37 
8.1.1 
Summary statistics of non-PK data ...................................................37 
8.1.2 
Summary statistics of PK data ..........................................................37 
8.2 
Statistical methods ........................................................................................38 
8.2.1 
Statistical methods for discrete data .................................................38 
8.2.2 
Statistical methods for continuous data ............................................38 
9 
INTERIM ANALYSIS ...............................................................................................41 
10 GENERAL DEFINITIONS AND DERIVATIONS ...................................................41 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 4/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
10.1 
Handling of screening and re-screening data ...............................................41 
10.2 
Analysis periods and visit windows .............................................................41 
10.2.1 
Study treatment start and end date ....................................................41 
10.2.2 
Study days .........................................................................................41 
10.2.3 
Baseline .............................................................................................41 
10.2.4 
Unscheduled visits and visit windows ..............................................41 
10.3 
Uptravi dosage subgroups ............................................................................42 
10.4 
Derived and computed variables for analysis datasets .................................42 
10.5 
Handling of missing/incomplete date and time fields ..................................42 
10.6 
Handling of missing infusion durations ........................................................43 
11 CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL .................................................................................................43 
11.1 
Changes to the analyses planned in the study protocol ................................43 
11.2 
Changes in the conduct of the study / data collection ..................................43 
11.3 
Clarifications concerning endpoint definitions and related variables or 
statistical methods .........................................................................................43 
11.3.1 
Treatment/period as factor in mixed model analysis ........................43 
11.3.2 
Additional analyses as compared to the study protocol ....................44 
12 LIST OF TABLES, LISTINGS AND FIGURES .......................................................44 
13 REFERENCES ............................................................................................................57 
14 APPENDICES .............................................................................................................58 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 5/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
LIST OF TABLES 
 
Table 1 
Study documents ..........................................................................................8 
Table 2 
Summary of analysis periods .....................................................................10 
Table 3 
Protocol deviations leading to an exclusion from the PKS ........................13 
Table 4 
Overview of the different analysis sets and their usage .............................14 
Table 5 
PAH-specific therapies ...............................................................................18 
Table 6 
Correspondence of i.v. selexipag dose compared to Uptravi oral 
doses ...........................................................................................................20 
Table 7 
Overview of safety and tolerability endpoints and populations in 
planned analysis periods .............................................................................21 
Table 8 
Overview of adverse event analyses ..........................................................25 
Table 9 
Schedule vital signs monitoring in Period 2...............................................29 
Table 10 
Marked abnormalities in blood pressure ....................................................30 
Table 11 
Pre-specified ECG findings categories ......................................................32 
Table 12 
QT prolongations in ECG parameters ........................................................33 
Table 13 
Analysis visit windows ...............................................................................42 
Table 14 
Thresholds for marked laboratory abnormalities .......................................65 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design and flow ................................................................................10 
 
 
LIST OF APPENDICES 
 
Appendix A Protocol synopsis ........................................................................................58 
Appendix B 
Visit and assessment schedule....................................................................63 
Appendix C 
Discussion and further considerations of the applied statistical 
methods ......................................................................................................65 
Appendix D Definitions of marked abnormalities and elevated liver function tests ......65 
Appendix E 
Mock layout ................................................................................................66 
Appendix F 
Document history .....................................................................................135 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 6/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
LIST OF ABBREVIATIONS AND ACRONYMS 
 
AE  
Adverse event 
ADaM  
Analysis data model 
ALT  
Alanine aminotransferase 
AP  
Alkaline phosphatase 
AST  
Aspartate aminotransferase 
ATC  
Anatomic Therapeutic Chemical 
AUCτ, ss  
Area under the plasma concentration-time curve during a dose 
interval at steady state 
b.i,d.  
Twice daily 
BLQ  
Below limit of quantification 
CDISC  
Clinical data interchange consortium 
CI  
Confidence interval 
Cmax, ss  
Maximum plasma concentration at steady state 
CSR  
Clinical study report 
Ctrough, ss  
Trough plasma concentration at steady state 
CV  
Coefficient of variation 
CVb  
Inter-subject coefficient of variation 
DBP  
Diastolic blood pressure 
ECG  
Electrocardiograph 
eCRF  
Electronic case report form 
EOS  
End-of-study 
EudraCT  
European Union Drug Regulating Authorities Clinical Trials 
IB  
Investigator’s Brochure 
i.v.  
Intravenous 
ivSAF  
intravenous Safety Analysis Set 
LOQ  
Limit of quantification 
MedDRA  
Medical Dictionary for Regulatory Activities 
MSE  
Mean squared error 
PAH  
Pulmonary arterial hypertension 
PDs  
Protocol deviations 
PK  
Pharmacokinetic 
PKS  
Pharmacokinetic Analysis Set 
PR  
Pulse rate 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 7/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
PT  
Preferred Term 
QTcB  
QT interval corrected using Bazett’s formula 
QTcF  
QT interval corrected using Fridericia’s formula 
RMP  
Risk Management Plan 
SAE  
Serious adverse event 
SAF  
Safety Analysis Set 
SAP  
Statistical analysis plan 
SAS®  
Statistical Analysis Software 
SBP  
Systolic blood pressure 
SCR  
Screened Analysis Set 
SD  
Standard deviation 
SDTM  
Study data tabulation model 
SE  
Standard error of the mean 
SOC  
System organ class 
tmax, ss  
Time to reach maximum plasma concentration at steady state 
WHO  
World Health Organization 
WHO FC  
WHO functional class 
WHODD  
WHO Drug Dictionary 
 
 




Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 9/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
• Group B: Subjects with a stable dose of Uptravi between 1200 and 1600 μg b.i.d. 
(inclusive); at least 12 and up to 15 subjects will be enrolled in this dose group. 
The study will be conducted at approximately 10 sites in 2 countries.  
2.2 Study visit and assessment schedule 
The study visit and assessment schedule is included in Appendix A. 
2.3 Analysis periods 
The study comprises five analysis periods: 
Screening period: This period starts with the signing of the Informed Consent Form and 
ends with the first day of Period 1 (Visit 2 Day 1). 
Period 1 (Uptravi, pre-treatment period, in-hospital): This period starts with intake of 
the morning dose of Uptravi at Visit 2 Day 1, and ends the following day before initiation 
of the first infusion of i.v. selexipag. 
Period 2 (i.v. selexipag, treatment period, in-hospital): This period starts in the 
morning of Visit 2 on Day 2 with the start of the first infusion of i.v. selexipag, and ends 
after approximately 36 hours in the evening of Visit 2 on Day 3 with the resuming of 
administration of Uptravi at the evening dose.  
Period 3 (Uptravi, post-treatment period): This period starts in the evening of Visit 2 
Day 3 with the first dose of resumed oral administration of Uptravi, and ends 7 to 11 days 
later at Visit 3. 
Safety follow-up period: This period starts at the end of Visit 3 and ends 30 to 37 days 
after the last administration of i.v. selexipag with the End-of-Study (EOS) telephone call 
(Visit 4). 
A summary of analysis periods is presented in Table 2: 




Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 11/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
2.4 Randomization and blinding 
Not applicable, as this is a single-sequence, open-label study. 
2.5 Sample Size 
No confirmatory statistical tests are planned in the study. 
Approximately 20 subjects will be enrolled to have at least 18 subjects in the i.v. Safety 
Set. In the GRIPHON Phase 3 pivotal study of selexipag, a proportion of 7.5% of 
subjects prematurely discontinued the study (i.e., without a morbidity/mortality event) 
due to prostacyclin-associated adverse events (AEs) across the titration and maintenance 
phases. It is expected that the proportion of early discontinuations during the entire study 
will not be higher than 10% (i.e., that approximately 18 subjects will enter the i.v. 
period). 
A sample size of 18 subjects in the i.v. Safety Analysis Set will ensure that, if the true 
rate of discontinuations due to prostacyclin-associated AEs is between 5% and 10%, the 
half-width of the 95% confidence interval (CI) will be below 35%. 
The precision achieved with a sample size of approximately 18 subjects in the i.v. Safety 
Set is considered adequate for this study (e.g., the upper boundary of the CI for the i.v. 
Safety Analysis Set excludes values above 35%, and for the Safety Analysis Set, above 
32%). 
3 
OBJECTIVES 
3.1 Primary objective 
The primary objective of this study is to assess whether temporary switching from a 
stable oral dose of selexipag to an i.v. dose of selexipag providing comparable exposure 
(e.g., area under the plasma concentration-time curve during a dose interval at steady 
state [AUCτ, ss,], maximum plasma concentration at steady state [Cmax, ss]) to active 
metabolite ACT-333679 and switching back to the initial oral dose of selexipag is safe 
and well tolerated in subjects with stable PAH. 
3.2 Other objectives 
Other objectives of the study are:  
• To evaluate the safety and tolerability of selexipag during each study period. 
• To evaluate the PK of selexipag and its active metabolite, ACT-333679, at a stable 
oral dose at steady state and after the switch from selexipag oral to selexipag i.v. in 
subjects with stable PAH. 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 12/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
4 
ANALYSIS SETS 
4.1 Definitions of analysis sets 
The following analysis sets were introduced in Section 10.1 of the protocol: 
4.1.1 Screened Analysis Set  
The Screened Analysis Set (SCR) includes all subjects who were screened and received 
a subject identification number. 
4.1.2 Full Analysis Set 
Not applicable in this study.  
4.1.3 Safety Analysis Set 
The Safety Analysis Set (SAF) includes all enrolled (included in the study on Day 1) 
subjects who received at least one dose of Uptravi or i.v. selexipag during any of 
Period 1, Period 2, or Period 3 of the study. 
4.1.4 i.v. Safety Analysis Set 
The i.v. Safety Analysis Set (ivSAF) includes all subjects who received at least one dose 
of i.v. selexipag.  
4.1.5 Pharmacokinetic Analysis Set 
The Pharmacokinetic Analysis Set (PKS) comprises all subjects included in the SAF who 
received an Uptravi dose on Day 1 and the three doses of i.v. selexipag, and who 
complied with the protocol in a way that the PK measurements of the study are not 
affected. Protocol deviations resulting in an exclusion from the PKS are shown in 
Table 3.  
Additional rules for exclusion from the PKS may be defined prior to database lock and 
reflected in this document. 




Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 14/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
4.2 Usage of the analysis sets 
An overview on the usage of the analysis sets for summary tables and listings is given in 
Table 4. 
Table 4 
Overview of the different analysis sets and their usage 
Analyses/ Data Displays 
Screened 
analysis set 
Safety 
analysis 
set 
i.v. Safety 
analysis set  
Pharmacokinetic 
analysis set 
Demographic data (ICH E3 14.1) 
Subject disposition 
  
()* 
 
 
Protocol deviations 
 
 
 
 
Inclusion/ Exclusion in Analysis 
Sets  
 
 
 
 
Subject characteristics 
(Demographics, disease 
characteristics, medical history) 
 
  
 
 
Concomitant therapy 
 
 
 
 
Study completion 
 
 
 
 
Study treatment exposure and 
compliance 
 
 
** 
 
PK data  
PK endpoints, Period 1 & 2 
 
 
 
 
Safety data (ICH E3 14.3) 
Adverse Events, Clinical Laboratory, ECG, Vital Signs, Body Weight and WHO FC** 
 
Period 1 
 
 
 
 
 
Period 2 
 
 
 
 
 
Period 3 
 
 
 
 
 
Period 1 & 2 
 
 
 
 
 
Period 2 & 3& FU 
 
 
 
 
 
Period 1 & 2 & 3 & FU 
 
 
 
 
Appendices (ICH E3 16.1.7 and 16.2) 
All data collected in the clinical database 
Listings 
 
 
 
 
* Denominators for disposition will be based on the safety set. ** Tables will be produced for the SAF only if SAF and 
i.v. SAF are identical. ECG = electrocardiograph; FU = Safety Follow-Up; i.v. SAF = intravenous Safety Analysis Set; 
PK = pharmacokinetic; SAF = Safety Analysis Set; WHO FC = World Health Organization functional class.  


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 15/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
5 
STUDY SUBJECTS VARIABLES AND ANALYSES 
All summaries described in this section will be displayed separately for the two subject 
cohorts, i.e., subjects treated with Uptravi 200–1000 μg b.i.d. and 1200–1600 μg b.i.d., as 
well as for all subjects in the analysis set. 
The summary tables, figures and listings will use the analysis sets shown in Table 4. 
5.1 Subject disposition 
The summaries of subject disposition and screening failures will be prepared on the SCR. 
Summaries 
of 
study 
completion/discontinuation 
and 
study 
treatment 
completion/discontinuation will be prepared on the SAF: 
5.1.1 Subject disposition and enrollment into analysis periods 
Subject disposition will be summarized by presenting the number of subjects screened, 
enrolled and then number and percentage of subjects entering each analysis period [see 
Section 2.3], number and percentage of subjects treated with one, two, and three doses of 
i.v. selexipag as well as the number and percentage of subjects completing or 
discontinuing i.v. treatment or the study.  
In addition, a summary of disposition by site and country will be prepared. 
5.1.2 Screening failures 
Screening failures are subjects who were not enrolled into the study, i.e., subjects who 
did not enter Period 1 of the study. 
The number of screening failures will be shown in the disposition table. Reasons for 
screening failure will be listed. 
5.1.3 Study completion/discontinuation 
Subjects who received at least one dose of i.v. selexipag and who have completed the 
follow-up period will be considered study completers. 
Subjects may discontinue from the study by withdrawal of consent, loss to follow-up, 
death, or investigator or sponsor decision. Details of study discontinuation are collected 
in the electronic case report form (eCRF). 
The number and percentages of subjects who completed or prematurely discontinued the 
study, and reasons for discontinuation from the study will be summarized in a table and 
in a listing.  


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 16/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
5.1.4 Study treatment completion/discontinuation 
The number and percentage of subjects who completed or prematurely discontinued i.v. 
selexipag treatment, and reasons for premature discontinuation from i.v. selexipag 
treatment as captured in the eCRF will be summarized in a table and in a listing.  
5.2 Protocol deviations  
The analysis of protocol deviations (PDs) will be prepared on the SCR.  
PDs will be based on the PD code list. The PD code list may be updated during the 
course of the study, but before database closure. The number and percentage of subjects 
who had an important PD will be summarized overall. All PDs will be summarized 
overall and by country.  
All PDs will be listed. This listing includes all deviation descriptions, identifiers and 
categories. 
5.3 Exclusion from analysis sets 
The number and percentage of subjects in each analysis set, as described in Section 4.1, 
will be summarized in a table together with the number and percentage of subjects 
excluded from any analysis set, together with the reasons for exclusion. A listing of 
subject participation in the different analysis sets will be produced. 
5.4 Subject characteristics 
Subject characteristics will be summarized on the SAF. 
5.4.1 Demographics 
Baseline demographics, body weight and height will be summarized. The summary will 
include: 
• Age (years) 
• Sex (categorized as: Male, Female) 
• Race (categorized as: American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander, White, Other) 
• Ethnicity (categorized as: Hispanic or Latino, Not Hispanic or Latino, Unknown) 
• Body weight (kg)  
• Height (cm)  
• Country (assigned in the eCRF based on the list of sites). 
In addition, the following variables will be derived: 
• Age (years) in category, i.e., > = 18 – < 65, > = 65 years 
• Body mass index (kg/m2)  


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 17/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
Demographic characteristics will be summarized using descriptive statistics for 
continuous and categorical data. Demographic characteristics will also be listed. 
For disclosure of results to EudraCT, a summary table will be created showing age 
(years) in categories 18–64, 65–84, and > = 85. 
5.4.2 Baseline disease characteristics 
Baseline disease characteristics comprise the specific medical history (time since the 
initial diagnosis of PAH, and etiology of PAH as well as Uptravi dose) assessed at the 
screening visit and the WHO functional class (WHO FC) at Day 1. 
Baseline disease characteristics will be summarized using descriptive statistics for 
continuous and categorical data. Time since initial diagnosis of PAH will be summarized 
in months.  
Baseline disease characteristics will be listed.  
5.4.3 Other baseline characteristics 
The results of a physical examination will be listed.  
5.4.4 Medical history 
Medical history includes relevant previous and/or concomitant diseases or diagnoses 
prior to or ongoing at Screening visit, respectively. They are recorded on the ‘Medical 
History’ eCRF page. Reported terms will be coded using the latest version of the Medical 
Dictionary for Regulatory Activities (MedDRA) at database lock, Version 21.0. 
Previous diseases or diagnoses are medical history events which are not ongoing at 
screening, i.e., they have an end date prior to or equal to the Screening visit. 
Concomitant diseases or diagnoses are all medical history events that are not 
considered as previous events. 
Previous and concomitant diseases/diagnoses will be summarized separately by 
tabulating the number and percentages of subjects with each disease/diagnosis by system 
organ class (SOC) and preferred term (PT).  
Previous and concomitant medical diseases/diagnoses will be listed. 
5.4.5 Previous and concomitant therapies  
Previous and concomitant therapies are collected continuously in the eCRF. The reported 
names will be coded using the WHO drug code dictionary (WHODD) and the anatomic 
therapeutic chemical (ATC) class code.  
Previous therapies are therapies which ended prior to baseline [see Section 10.2]. 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 18/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
Ongoing therapies are therapies that were started prior to baseline and are ongoing at 
study treatment start. 
Study concomitant therapies are therapies that were started or dose changed (of those 
ongoing at baseline) during the respective analysis period [see Table 2].  
Previous therapies, ongoing therapies, and study concomitant therapies will be 
summarized separately by Level 4 ATC class and PT. The study concomitant therapies 
summary will be displayed by study period. 
The summaries will exclude PAH-specific therapies [see Section 5.4.5.1]. 
All recorded terms will be reported together in one listing together with flags indicating 
the type of therapy.  
5.4.5.1 PAH-specific therapies 
PAH-specific therapies will be identified by a search of WOHDD PTs and ingredients as 
shown in Table 5. Specific summaries will be prepared:  
Ongoing PAH-specific therapies at baseline will be summarized. PAH-specific therapies 
that are newly started, dose changed, or stopped during any study period will be listed in 
a separate listing.  
PAH-specific therapies will be displayed in a listing with the respective study period 
flagged. 
Table 5 
PAH-specific therapies 
Category 
Subcategory 
Ingredient names 
Antihypertensives for 
pulmonary arterial 
hypertension 
ERAs 
Ambrisentan, Bosentan, Macitentan  
 
PDE-5 inhibitors Sildenafil, Tadalafil, Vardenafil 
 
sGC stimulator 
Riociguat  
Prostanoids  
 
Epoprostenol, Treprostinil, Iloprost,  
Uptravi  
 
Selexipag 
Categories are identified by searching the coded WHODRUG preferred terms for occurrence of any of the ingredient 
names, e.g., ‘Sildenafil’ and ‘Sildenafil Citrate’ will both be assigned to PDE-5 inhibitors. 
ERA = endothelin receptor antagonist; PAH = pulmonary arterial hypertension;  PDE-5 = phosphodiesterase type-5; 
sGC = soluble guanylate cyclase. 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 19/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
5.4.5.2 Auxiliary medications 
Oral Uptravi is collected as a mandatory background drug in the previous and 
concomitant medication page. Dose changes will be listed with PAH-specific therapies.  
5.5 Study treatment exposure and compliance 
i.v. selexipag is considered the only study treatment for this study.  
5.5.1 Exposure 
5.5.1.1 Exposure to i.v. selexipag 
The number and percentage of subjects being exposed to one, two, or three infusions of 
i.v. selexipag will be summarized.  
The planned i.v. selexipag dose [μg] for each infusion will be summarized as a 
continuous variable as well as a categorical variable using categories from Table 6. The 
actual i.v. selexipag dose will be summarized separately. Total actual time of infusion in 
minutes will be summarized for each of the three infusions as well.  
The summary will be conducted for each of the three infusions separately.  
The dosage administration records will be listed together with the reasons for dose 
change and dosage end as recorded in the eCRF. 
5.5.1.2 Exposure to Uptravi prior and post- i.v. selexipag 
The actual Uptravi dose [μg] will be collected and summarized by dose category for the 
four time points surrounding the i.v. administration of selexipag, i.e., evening dose before 
Visit 2 Day 1, morning and evening dose at Visit 2 Day 1 and evening dose at Visit 2 
Day 3. 
The Uptravi dosage records will be listed. 
5.5.1.3 Shift in selexipag dose between oral and i.v. treatment 
The shift from actual oral to i.v. and back to oral doses will be analyzed graphically in a 
series plot showing the individual dose in [μg] for each dose administration time point 
during Day 1 through Day 3 of Visit 2.  
The i.v. selexipag doses administered will be converted to their oral dose equivalents [see 
Table 6] to facilitate the review. 
5.5.1.4 Study treatment adjustments or interruptions, end of infusion status 
Incidence of and reasons for i.v. administration interruption as well as the end of infusion 
status (irrespective of whether study treatment was completed as per protocol or not) will 
be summarized for each of three infusions. 






Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 22/135 
Confidential 
Statistical Analysis Plan 
Doc No D-18.239 
7.2 Adverse events 
7.2.1 Variables 
The original verbatim terms used by investigators to identify AEs in the eCRF will be 
mapped to PTs using the MedDRA dictionary using the latest version at data cutoff. The 
AE PTs will be then grouped by MedDRA PTs into frequency tables according to 
primary SOC.  
7.2.1.1 Treatment-emergent adverse events 
The analysis of AEs in Period 2, Period 3 and safety follow-up period is considered 
analysis of treatment-emergent events, as the i.v. formulation is the investigational 
treatment. 
7.2.1.2 Adverse events related to study treatment 
An AE will be considered related to the study treatment if the investigator answered ‘yes’ 
to the question ‘Causal relationship to i.v. selexipag’ or if it is missing. 
7.2.1.3 Serious adverse events 
An AE will be considered serious if the investigator answered ‘Yes’ to the question 
‘Serious?’ or if information is missing.  
7.2.1.4 Adverse events leading to discontinuation of study treatment 
An AE is considered as leading to discontinuation of study treatment if the investigator 
ticked ‘Drug withdrawn’ on the question ‘Action taken with study treatment’.  
7.2.1.5 Injection site reactions 
Injection site reactions will be collected on a separate eCRF page. Clinically significant 
injection site reactions will be reported as an AE. 
7.2.1.6 Prostacyclin-associated AEs 
Prostacyclin-associated AEs are AEs associated with the pharmacological action of 
selexipag that have been observed frequently, in particular during the phase of 
individualized dose titration. According to selexipag Investigator’s Brochure (IB) 
reference safety information, these PTs include headache, diarrhea, nausea, vomiting, jaw 
pain, myalgia, pain in the extremity, flushing, and arthralgia. 
7.2.1.7 AEs of special interest based on the Uptravi Risk Management Plan 
For completeness, AEs will be analyzed according to the Uptravi Risk Management Plan 
(RMP) important identified or potential risks, using searches of MedDRA PTs provided 
by Global Drug Safety at the time of database closure. In accordance with the RMP, the 
following categories will be analyzed: 
•
Hypotension
•
Anemia, decrease in hemoglobin concentration


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 23/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
• Hyperthyroidism 
• Major adverse cardiovascular events  
• Acute renal failure 
• Bleeding events 
• Light-dependent non-melanoma skin tumors 
• Ophthalmological effects associated to retinal vascular system 
• Gastrointestinal disturbances denoting intestinal intussusception (manifested as ileus 
or obstruction). 
7.2.1.8 PAH-related AEs  
PAH-related AEs are AEs that are coded to the following MedDRA (Version 21.0) PTs: 
Atrial fibrillation 
Lung transplant 
Atrial flutter 
Pulmonary arterial hypertension 
Atrial natriuretic peptide abnormal 
Pulmonary arterial pressure abnormal 
Atrial natriuretic peptide increased 
Pulmonary arterial pressure increased 
Acute right ventricular failure 
Pulmonary oedema 
Cardiac failure 
Pulmonary hypertension 
Cardiac index decreased 
Pulmonary hypertensive crisis 
Cardiogenic shock 
Right atrial dilatation 
Cardiopulmonary failure 
Right atrial pressure increased 
Chronic right ventricular failure 
Right ventricular dysfunction 
Cor pulmonale 
Right ventricular failure 
Cor pulmonale acute 
Syncope 
Oedema peripheral 
Vascular resistance pulmonary increased 
Jugular vein distension 
 
7.2.1.9 Non-serious AEs 
For the disclosure of the results to EudraCT and ClinicalTrials.gov, non-serious AEs are 
defined. A non-serious AE is any AE with the question “Serious?” answered “No” by the 
investigator.  


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 24/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
7.2.2 Analysis 
The start date/time of the AE record from the CRF will be used to assign the AE to a 
study period. 
Summary tables will be prepared as described in Table 8 for the periods mentioned in 
Table 7, except for the screening period.  
Summary tables by SOC and PT will display the number and percentages of subjects with 
at least one AE in the respective primary SOC and at least one AE at the PT level. 
Summaries will be sorted by descending total frequency of SOCs and PTs and 
alphabetically in case of ties. 
Summary tables by PT will display the number and percentages of subjects with at least 
one AE in the respective PT. Summaries will be sorted by descending total frequency of 
PTs and alphabetically in case of ties.  
AEs occurring during the Screening period, i.e., prior to first dose of Uptravi on Visit 2 
Day 1, will be listed. 
Due to the small number of subjects, conservative 95% Clopper-Pearson CIs for the 
proportions will be computed using exact methods. 
All AEs occurring during the study from date of informed consent signature to EOS will 
be listed. 
For any injection site reaction (irrespective of clinical significance), the worst grade, 
criteria of the injection site reaction, as well as its clinical significance will be 
summarized. Any AEs associated with clinically significant injection site reactions will 
be summarized by PT and by maximum intensity in the AE table.  




Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 26/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
individual PT within each SOC with the highest number of occurrences appears first). 
Equal frequency of different individual PTs is sorted in alphabetical order of the 
individual PT.  
The following summaries will be prepared according to the guidelines stated above: 
• Summary of treatment-emergent SAEs  
• Summary of treatment-emergent SAEs judged to be treatment related by the 
investigator 
• Summary of treatment-emergent SAEs with fatal outcome 
• Summary of treatment-emergent SAEs with fatal outcome judged to be treatment 
related by the investigator 
• Summary of non-serious AEs with an incidence of 5% or higher in any treatment 
group 
7.3 Deaths 
Date of death and primary cause will be recorded on the ‘Death’ eCRF page. A listing 
including all deaths recorded in the database will be provided.  
A separate listing will be provided displaying all AEs leading to death, i.e., with outcome 
‘fatal’. 
7.4 Laboratory 
A central laboratory will be used for all protocol-mandated tests. Laboratory values 
analyzed by local laboratories will only be listed. 
Laboratory test results will be converted into Standard International units by the 
laboratory. Values outside the laboratory normal ranges will be flagged as well.  
7.4.1 Measurements 
Laboratory test results will be transferred from the central laboratory and provided in the 
SDTM structure, together with corresponding reference ranges in original, conventional, 
and standardized units. Assessments are performed at Screening visit, Visit 2 Day 1 (if 
more than 7 days after screening), Visit 2 Day 3, Visit 3, and at unscheduled visits based 
on the judgment of the investigator.  
The following variables are collected as per protocol: 
Hematology 
• Hemoglobin (g/L) 
• Hematocrit (L/L) 
• Erythrocytes (1012/L) 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 27/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
• Leukocytes with differential counts (109/L) 
• Platelets (109/L) 
Clinical chemistry 
• Alanine aminotransferase (ALT) (U/L) 
• Aspartate aminotransferase (AST) (U/L) 
• Alkaline phosphatase (AP) (U/L) 
• Total and direct bilirubin (μmol/L) 
• Creatinine (μmol/L) 
• Sodium, potassium (mmol/L) 
For women of childbearing potential, urine pregnancy tests are performed at Screening 
Visit, Visit 2 Day 1, and Visit 4 (EOS). A pregnancy will be reported as an SAE; the 
results of the pregnancy tests will not be included in the clinical database. 
7.4.2 Variables 
For parameters assessed as a continuous variable, the following variables will be defined: 
• Baseline 
• Value at each post-baseline visit 
• Absolute change from baseline to each post-baseline visit 
• Position against reference ranges based on normal ranges provided by the laboratory. 
• Position against marked abnormality range based on ranges provided in Appendix D.  
7.4.3 Analysis 
All laboratory values will be listed. Values from local laboratories will be flagged in data 
listings and not used in any analysis. 
7.4.3.1 Values over time 
For continuous laboratory variables, descriptive statistics will be provided for observed 
values as well as for change from baseline at each scheduled study visit.  
7.4.3.2 Individual subject changes 
Laboratory test results from both, scheduled and unscheduled visits will be used to 
determine the incidence of markedly abnormal test results. The date of the sample will 
determine the analysis period the test is assigned to.  


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 28/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
The number of subjects with newly occurring or worsening markedly abnormal 
laboratory values will be displayed for the analysis sets shown in Table 4 and the periods 
shown in Table 7.  
The definitions of marked abnormal lab values are shown in Appendix D. 
7.5 Vital signs, physical findings, and other observations related to safety 
7.5.1 Vital signs 
Vital signs will be collected in an eCRF. Systolic blood pressure (SBP) and diastolic 
blood pressure (DBP) and pulse rate (PR) assessed in supine position will be entered in 
mmHg. Height (cm) and weight (kg) will be assessed in subject wearing indoor clothing 
without shoes. 
7.5.1.1 Measurements 
Height (cm) will be assessed at Screening Visit.  
Body weight will be assessed at Screening visit, Visit 2 Day 1, Visit 2 Day 3, Visit 3 and 
at unscheduled visits.  
SBP, DBP, and PR will be assessed at Screening visit, Visit 2 Day 1, Visit 3 and at 
unscheduled visits. Further assessments will be conducted at pre-specified time points in 
Period 2, i.e., Visit 2 Day 1 and Visit 2 Day 3 as shown in Table 9.  






Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 31/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
7.5.3 WHO functional class 
WHO FC (Class I–IV) as assessed by the investigator will be collected in the eCRF. 
7.5.3.1 Measurements 
WHO FC will be assessed at Screening Visit, Visit 2 Day 1, Visit 2 Day 3 (after the end 
of the last infusion), Visit 3, and at unscheduled visits.  
7.5.3.2 Variables 
For WHO FC, the following variables will be defined: 
• Baseline value 
• Value at each post-baseline visit 
• Shift from baseline to each post-baseline visit 
• Worst (highest) post-baseline value 
• Best (lowest) post-baseline value. 
7.5.3.3 Analysis 
Values over time 
A listing of all WHO FC assessments will be created displaying all values in the 
database, regardless if from scheduled or unscheduled visits.  
Descriptive statistics (frequency tables) will be provided for observed values as well as 
for shift from baseline to all visits. 
Individual subject changes 
The worst/best post-baseline WHO FC will be displayed along with a shift table from 
baseline to worst/best post-baseline value.  
7.6 Electrocardiograph 
A standard 12-lead electrocardiograph (ECG) will be conducted on subjects in fully 
rested supine position. All ECG data from scheduled and unscheduled visits will be 
transferred to a central ECG laboratory. The ECG readouts (see below) will be 
transferred from the central ECG laboratory to trial data management and imported in the 
trial database. 
7.6.1 Variables 
The 12-lead ECG encompasses 3 categories of data obtained via the central ECG 
laboratory: 






Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 34/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
7.7 Subgroup analysis of safety variables 
In general, all safety variable summaries are presented by dose cohort as for study subject 
analyses [see Section 5].  
No a-priori subgroup analyses are planned at this point.  
7.8 Pharmacokinetic variables 
7.8.1 Measurements 
PK blood samples are collected at Visit 2 Day 1 (seven samples) and Visit 2 Day 3 
(seven samples) to obtain 12-hour PK profiles of selexipag and its active metabolite, 
ACT-333679, at steady state for Uptravi and i.v. selexipag, respectively. 
Endpoints derived during Period 1 are thus connected to Uptravi (Day 1) and endpoints 
during Period 2 are connected to i.v. selexipag (Day 3). 
7.8.2 Pharmacokinetic endpoints 
The following PK endpoints will be determined:  
• AUCτ, ss of selexipag and its active metabolite, ACT-333679, after Uptravi (oral 
selexipag) in Period 1 and after i.v. selexipag administration in Period 2.  
• Cmax, ss of selexipag and its active metabolite, ACT-333679, after Uptravi (oral 
selexipag) in Period 1 and i.v. selexipag administration in Period 2.  
• The time to reach maximum plasma concentration at steady state (tmax, ss) of selexipag 
and its active metabolite, ACT-333679, after Uptravi (oral selexipag) in Period 1 and 
i.v. selexipag administration in Period 2.  
• Trough plasma concentration at steady state (Ctrough, ss) of selexipag and its active 
metabolite, ACT-333679, after Uptravi (oral selexipag) in Period 1 and i.v. selexipag 
administration in Period 2.  
7.8.3 Pharmacokinetic variables 
Plasma PK parameters of selexipag and its active metabolite, ACT-333679, will be 
derived by non-compartmental analysis of the concentration-time profiles.  
The PK parameters will be calculated on the basis of the real blood sampling time points 
(in relation to the last selexipag intake during each period).  
The measured individual plasma concentrations of selexipag will be used to directly 
obtain Ctrough, ss, Cmax, ss, and tmax, ss.  
AUCτ, ss will be calculated according to the linear trapezoidal rule using the measured 
concentration-time values above the limit of quantification (LOQ) during one dosing 
interval at steady state.  


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 35/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
7.8.3.1 Dose normalization 
Dose normalization will be conducted to the lowest prescribed selexipag dose (200 μg for 
oral Uptravi and 225 μg for i.v. selexipag).  
Dose normalized plasma concentrations, Ctrough, ss, norm ,Cmax, ss, norm and AUCτ, ss, norm will 
be determined by dividing the respective parameters by the actual dose and multiplying 
with 200 or 225 for Uptravi and i.v. selexipag parameters, respectively.  
7.8.4 Analysis  
All PK parameters will be listed for all subjects providing PK data. All analyses will be 
conducted on the PKS. 
For mean value calculations, all values below the limit of quantification (BLQ) will be 
set to zero. If > 50% of the values at a given time point are BLQ, no mean value will be 
calculated. Mean concentration-time profiles will be generated using these criteria.  
7.8.4.1 Plasma concentrations  
The PK expert will examine the plasma concentration data and identify implausible 
values.  
Plasma concentrations of selexipag and ACT-333679 will be listed per subject, time 
point, and period (i.e., for Uptravi and i.v. selexipag). Implausible plasma concentrations 
of selexipag or ACT-333679 will be flagged in the listings. 
Plasma concentrations of selexipag and ACT-333679 will be summarized per time point 
by dose, including dose normalized, and period (i.e., for Uptravi and i.v. selexipag). 
Implausible plasma concentrations of selexipag or ACT-333679 will not be included in 
the summary statistics.   
Implausible values will be indicated in the comments value variable (COVAL) of the 
comments dataset (CO). The reference link (COREF) will be used to join these 
implausible values with time points of the plasma concentration dataset (PC). 
7.8.4.2 Trough concentrations 
Selexipag and ACT-333679 Ctrough, ss will be listed by dose, subject, and period as well as 
the ratio of the periods per subject.  
Summary statistics will be provided by dose, including dose normalized, and by period. 
Implausible Ctrough, ss values will be flagged in the listings and not included in summary 
statistics.  
7.8.4.3 Cmax, ss, tmax, ss, and AUCτ, ss  
Cmax, ss, tmax, ss, and AUCτ, ss of selexipag and ACT-333679 will be listed by dose, subject, 
and period. The ratio of the parameters between i.v. selexipag (test treatment) and 
Uptravi (reference treatment) per subject will be shown, except for tmax, ss. Any values 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 36/135 
Confidential 
Statistical Analysis Plan 
Doc No D-18.239 
obtained from implausible plasma concentrations of selexipag or ACT-333679 will be 
flagged in the listings and not included in the statistical analysis.  
Summary statistics will be provided by dose and period for selexipag and ACT-333679. 
Dose-normalized Cmax, ss and AUCτ, ss will be listed and summarized by period as well for 
selexipag and ACT-333679. 
Cmax, ss and AUCτ, ss ratio of ACT-333679/selexipag will be listed by dose, subject, and 
treatment and will be summarized by dose and treatment. 
The ratio of Cmax, ss and AUCτ, ss of selexipag and ACT-333679 between Uptravi and i.v. 
selexipag, after dose normalization, within each dose level (if sufficient subjects are 
enrolled per level) will be estimated by fitting a mixed effect model to the data using 
period (i.e., treatment) as fixed, and subject as random effect to the log-transformed 
Cmax, ss and AUCτ, ss values. The ratios of geometric means between i.v. selexipag (test 
treatment) and Uptravi (reference treatment) will be computed and displayed together 
with their 90% CI by back-transforming the period contrasts and interval boundaries of 
the log-transformed data. If dose-proportionality is shown within each dose, then an 
overall model may be considered for robustness.  
The inter-subject coefficient of variation (CVb) of Cmax, ss and AUCτ, ss of selexipag and 
ACT-333679 will be computed by using the mean squared error (MSE) of the mixed 
model as an estimate of variation.  
Based on the previous studies QGUY/2006/NS304/-01, AC-065-101 and AC-065A201 it 
is known that the PK profile of selexipag and its active metabolite ACT-333679 is 
dose-proportional up to a single dose of 800 ug and for multiple doses of up to 1800 ug 
b.i.d. after oral administration.  
Dose proportionality of AUCτ, ss of selexipag and ACT-333679 after i.v. selexipag will be 
analyzed using the power model approach [Gough 1995], if at least three different dose 
levels with a sufficient number of subjects to compute CIs are included in the PKS. A 
plot of log dose versus log AUCτ, ss including the slope of the estimated parameter will be 
displayed. 
Differences in tmax, ss of ACT-333679 between the i.v. selexipag period and the Uptravi 
period will be assessed within each dose level using a Wilcoxon signed rank test and 
displaying the median estimate and exact 90% CI of the location shift using Hodges-
Lehmann estimation. 
If considered appropriate, a sensitivity analysis may be conducted to evaluate the 
statistical impact of the plasma concentrations of selexipag or ACT-333679 that were 
considered implausible by the PK expert. 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 37/135 
Confidential 
Statistical Analysis Plan 
Doc No D-18.239 
8 
GENERAL STATISTICAL METHODOLOGY 
All analyses described in this document will be performed by the contract research 
organization Datamap GmbH, Freiburg, Germany using Statistical Analysis Software 
(SAS®) version 9.3 or higher.  
8.1 General rules for data presentations 
This section describes the general rules applied for all data displays, unless otherwise 
specified in each corresponding section. 
Data listings will show all assessments included in the study database, regardless if used 
in specific summary tables. 
8.1.1 Summary statistics of non-PK data 
Clinical data will be listed and summarized using appropriate descriptive statistics: 
•
For continuous variables: Number of non-missing observations, mean, standard
deviation, minimum, median, and maximum.
•
For dichotomous or categorical variables: Number of non-missing observations, and
frequency with percentage per category. Denominators for percentages are the
number of subjects in the pertinent analysis set and period, unless otherwise specified.
8.1.2 Summary statistics of PK data 
PK data will be listed as described in Section 7.8.4 and summarized using appropriate 
descriptive statistics: 
•
Plasma concentrations of selexipag and ACT-333679 will be summarized using
number of non-missing observations, arithmetic mean, geometric mean, standard
deviation (SD), standard error of the mean (SE), minimum, median, maximum and
95% CIs for the arithmetic and geometric mean.
•
Ctrough, ss of selexipag and ACT-333679 will be summarized using number of non-
missing observations, arithmetic mean, geometric mean, SD, SE, coefficient of
variation of the observed and logarithmized data (CV, CVln) in %, minimum, median,
maximum and 95% CIs for the arithmetic and geometric mean.
•
Cmax, ss and AUCτ, ss of selexipag and ACT-333679 will be summarized using number
of non-missing observations, arithmetic mean, geometric mean, SD, SE, CV%,
CVln%, minimum, median, maximum, 95% CIs for the arithmetic and geometric
mean.
•
tmax, ss of selexipag and ACT-333679 will be summarized using number of
non-missing observations, arithmetic mean, SD, SE, CV%, minimum, median,
maximum and 95% CI for the arithmetic mean.


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 38/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
8.2 Statistical methods 
This section describes in general terms the statistical models and methods applied. 
No confirmatory hypothesis testing will be conducted in this study. All tests and CIs will 
be of descriptive nature. Confidence levels are chosen as 90% for PK geometric means 
and 95% for all other confidence levels and will not be adapted for multiplicity. 
Ctrough, ss, Cmax, ss, and AUCτ, ss, values are assumed to be log-normally distributed. 
8.2.1 Statistical methods for discrete data 
8.2.1.1 Exact Pearson-Clopper CIs for the incidence of AEs 
Due to the small number of subjects included in the trial, broader estimates for the 
incidence rates of AEs need to be computed. The Pearson-Clopper method yields exact, 
while conservative confidence limits, i.e., the CI is at least 95%. They will be computed 
using PROC FREQ as shown below, assuming the input dataset contains counts for each 
aedecod, with 0 indicating subjects without event and 1 indicating subjects with event. 
PROC FREQ data=<input_dataset>; 
BY aedecod; 
TABLES event /exact binomial (level=‘1’); 
WEIGHT count; 
RUN;  
8.2.2 Statistical methods for continuous data 
8.2.2.1 Differences between periods in Cmax, ss and AUCτ, ss of selexipag/ACT-333679  
Within each dose level and after dose normalization, differences between the Uptravi and 
i.v. selexipag periods will be analyzed by computing the geometric mean ratios of the 
respective period with the oral formulation as reference treatment in the denominator. 
This is done by fitting a mixed linear model to the log-transformed Cmax, ss and AUCτ, ss 
values with period as fixed and subject as random effect. The Kenward-Rodgers method 
for calculation of degrees of freedom will be used to obtain degrees of freedom to 
calculate CIs. An unstructured covariance matrix will be assumed. The difference of the 
least squares mean and its 90% CI will be computed and transformed back to normal 
scale to obtain the geometric mean ratio. SAS® code similar to the code shown below will 
be used: 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 39/135 
Confidential 
Statistical Analysis Plan 
Doc No D-18.239 
PROC MIXED data=<input_dataset>; 
CLASS period; 
MODEL log_response=period / DDFM=KR; 
RANDOM intercept /subject=usubjid TYPE=UN; 
ESTIMATE ‘Difference i.v. - oral’ period -1 1 /CL ALPHA=0.1; 
RUN; 
8.2.2.2 CVb in Cmax, ss and AUCτ, ss of selexipag/ACT-333679  
The CVb expressed in percent will be computed using the formula 
where Sb2 is the MSE of the residuals from the mixed effects model described in 
Section 8.2.2.1. 
8.2.2.3 Dose proportionality of AUCτ, ss of selexipag/ACT-333679  
To assess dose proportionality of selexipag the power model approach will be used:  
The power model approach specifies a relationship between the scheduled dose D of i.v. 
selexipag and AUCτ, ss of selexipag / ACT-333679 which is expressed as 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 40/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
Yij = αj’ * Diβ * ε’ij 
Together with α’ denoting exp(α) and ε’ij denoting exp(ε’ij), logarithmizing both sides of 
the equation yields a linear model 
log(Yij) = αj + β log(Di) + εij 
with 
Yij   AUCτ, ss of dose level i in subject j (i=1, …, I), (j=1, …, n) 
αj  intercept parameter (assumed to be a random effect) 
β  the slope parameter 
Di size of dose level i 
εij random error term of subject j in dose level i. 
This model equation can be fitted using a mixed linear model with log(Di) as a covariate 
and subject as random effect. The 90% CI for the parameter estimate for the covariate 
will be computed. In case of dose proportionality, 1 should be included in the 90% CI of 
the parameter estimate. 
SAS® code similar to the following will be used:  
PROC MIXED data=<input_dataset>; 
MODEL log_response=log_dose / DDFM=KR S CL ALPHA=0.1; 
RANDOM intercept /subject=usubjid TYPE=UN; 
RUN; 
The assessment of dose proportionality using the power approach will only be conducted 
when at least three dose levels are included into the study.  


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 41/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
8.2.2.4 Difference of tmax, ss of ACT-333679 
Within each dose level, difference in tmax, ss of ACT-333679 between Periods 1 and 2 will 
be assessed by computing the Hodges-Lehmann estimator for shift in the median from 
Uptravi to i.v. selexipag. The median is computed by computing all shifts between the 
two periods and using the median of the shifts as an estimate. If computationally feasible, 
exact estimates and 90% CIs will be computed. 
9 
INTERIM ANALYSIS 
No interim analysis is planned in this trial. 
10 GENERAL DEFINITIONS AND DERIVATIONS 
This section describes all recurrent general definitions (e.g., study treatment start date, 
baseline, study day) which will be used for the derivations of variables and summary 
tables and are not covered in the sections above. 
10.1 Handling of screening and re-screening data 
Data of re-screened subjects obtained at the re-screening visit will be used as ‘Screening’ 
data. If a data point is not collected at re-screening but was collected at the previous 
screening visit, the data point from the screening visit will be used. 
10.2 Analysis periods and visit windows 
10.2.1 Study treatment start and end date 
The date and time of the first infusion of i.v. selexipag will be considered study treatment 
start date/time. The end date and time of the last infusion of i.v. selexipag will be 
considered study treatment end date/time. 
10.2.2 Study days 
The day of intake of the Uptravi during pre-treatment period, i.e., Period 1 
[see Section 2.3] will be considered Day 1. There is no Day 0; the day before Day 1 will 
be considered Day −1. 
Note that study treatment will be administered on Day 2 and Day 3 according to this 
definition; thus study day definition corresponds to the study days used in the study 
protocol. 
10.2.3 Baseline 
All assessments on Day 1 will be considered baseline. If a Day 1 assessment is not 
available, the last assessment prior to Day 1 will be considered baseline. 
10.2.4 Unscheduled visits and visit windows 
Assessments made on both, scheduled and unscheduled visits will be assigned to an 
analysis period according to Table 2  using the assessment date and time.  
































Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 57/135 
Confidential 
Statistical Analysis Plan 
Doc No D-18.239 
13 REFERENCES 
[D-17.055] AC-065A309: A multicenter, open-label, single-sequence crossover study to 
assess safety, tolerability and pharmacokinetic of intravenous selexipag in subjects 
with stable pulmonary arterial hypertension transitioning from an oral stable dose of 
selexipag. Clinical Study Protocol Version 1. Actelion Pharmaceuticals Ltd; 27 January 
2017. 
[Gough 1995] Gough K, Hutchinson M, Keene O, Byrom B, Ellis S, Lacey L, et al 
Assessment of dose proportionality: Report from the statisticians in The 
Pharmaceutical Industry/Pharmacokinetics UK joint working party. Drug 
Information Journal. 1995;29:1039–48. 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 58/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
14 APPENDICES 
Appendix A 
Protocol synopsis 
PROTOCOL SYNOPSIS AC-065A309 
 
TITLE 
A multicenter, open-label, single-sequence cross-over study to 
assess safety, tolerability, and pharmacokinetics of intravenous 
selexipag in subjects with stable pulmonary arterial hypertension 
switching from an oral stable dose of selexipag 
OBJECTIVES 
Primary objective(s) 
The primary objective of this study is to assess whether temporary 
switching from a stable oral dose of selexipag to an intravenous 
(i.v.) dose of selexipag providing comparable exposure to active 
metabolite ACT-333679 and switching back to the initial oral 
dose of selexipag is safe and well tolerated in subjects with stable 
pulmonary arterial hypertension (PAH). 
 
Other objectives 
Other objectives are described in Section 2.2. 
DESIGN 
This is a prospective, multi-center, open-label, single-sequence, 
cross-over, Phase 3 study. 
 
Subjects with stable PAH, currently treated with Uptravi® at a 
stable dose (i.e., unchanged dose for 28 days), will be enrolled. 
 
Subjects will be hospitalized during Period 1 (pre-treatment 
period) and Period 2 (treatment period). 
No interim analysis is planned. 
PERIODS 
Screening period: 
Up to 28 days; starts with the signing of the Informed Consent 
Form (ICF) and ends with first day (Visit 2, Day 1) of Period 1 
(Uptravi, pre-treatment period). 
 
Treatment and observation period: 
The treatment and observation period includes the following 
consecutive periods: 
 
• Period 1 (Uptravi, pre-treatment period, in-hospital): 1 day 
Starts with intake of the morning dose of Uptravi at Visit 2 Day 
1 and ends the following day, before initiation of the first 
infusion of i.v. selexipag. 
• Period 2 (i.v. selexipag, treatment period, in-hospital): 36 hours 
(3 
doses) 
Starts in the morning of Visit 2 on Day 2 with the start of the 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 59/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
first infusion of i.v. selexipag and ends in the evening of Visit 2 
on Day 3 before the evening administration of Uptravi. Note: 
oral administration of Uptravi is interrupted during the 
treatment period with i.v. selexipag. 
• Period 3 (Uptravi, post-treatment period): 7 to 11 days 
Starts in the evening of Visit 2 on Day 3 with the oral 
administration of Uptravi and ends 7 to 11 days later, at Visit 3. 
Safety Follow-up period: 
Starts at the end of Visit 3 and ends 30 to 37 days after the last 
administration of i.v. selexipag with the End-of-Study telephone 
call (Visit 4). 
PLANNED 
DURATION 
Approximately 9–12 months from first subject first visit to last 
subject last visit. 
SITE(S) / 
COUNTRY(IES) 
10 sites in 2 countries (planned). 
SUBJECTS / 
GROUPS 
Approximately 20 subjects will be enrolled in order to obtain 
18 evaluable subjects. 
 
Two different groups of subjects will be enrolled based on their 
dose of Uptravi: 
• Group A: Subjects with a stable dose of Uptravi between 
200 and 1000 μg twice daily (b.i.d.; inclusive): at least 5 
and up to 8 subjects will be enrolled in this dose group. 
 • Group B: Subjects with a stable dose of Uptravi between 
1200 and 1600 μg b.i.d. (inclusive): At least 12 and up to 
15 subjects will be enrolled in this dose group. 
INCLUSION 
CRITERIA 
1. Signed ICF prior to any study-mandated procedure. 
2. Male and female subjects at least 18 to 75 years inclusive. 
3. Subjects with PAH belonging to the Updated Clinical 
Classification Group 1 [Galiè 2016] 
4. Subjects who have been prescribed Uptravi in compliance 
with local prescribing information (i.e., SmPC or USPI). 
5. Stable PAH defined as WHO Functional Class (FC) I–III at 
Visit 1 and Visit 2 and no change (i.e., introduction or dose 
change) in PAH-specific medication (i.e., ERA, PDE-5 
inhibitor or sGC stimulator) and diuretics in the last 28 days 
prior to Visit 2. 
6. Subjects currently treated with Uptravi at a stable dose (i.e., 
unchanged dose) for at least 28 days before Visit 2. 
7. A woman of childbearing potential is eligible only if she has 
a negative urine pregnancy test at Visit 1 and at Visit 2. 
EXCLUSION 
1. Pregnant, planning to become pregnant or lactating. 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 60/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
CRITERIA 
2. Known and documented moderate or severe hepatic 
impairment. 
3. Subjects having received gemfibrozil at any time since 
initiation of Uptravi. 
4. Treatment with any prostacyclin and prostacyclin analogs 
within 28 days prior to Visit 1. 
5. SBP < 90 mmHg at Visit 1 or at Visit 2. 
6. Known or suspected uncontrolled hyperthyroidism. 
7. Severe renal failure and ongoing or planned dialysis. 
8. 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. 
9. Known concomitant life-threatening disease with a life 
expectancy < 12 months. 
10. Treatment with another investigational treatment within 3 
months of Visit 1. 
STUDY 
TREATMENTS 
Investigational treatment 
The study treatment (i.v. selexipag) will be administered b.i.d. 
intravenously as an infusion over an 87 minute period [see Section 
5.1.4]. The dose of i.v. selexipag will be individualized for each 
subject and will aim to reach an exposure to the active metabolite 
(area under the concentration-time curve [AUC] between two 
doses) comparable to the one obtained with subject’s current oral 
dose of Uptravi. 
 
Comparator and/or placebo 
Not applicable. 
AUXILIARY 
MEDICINAL 
PRODUCTS 
The study population consists of subjects who have been 
prescribed Uptravi (oral selexipag) as part of their standard 
PAH treatment (i.e., Uptravi must not have been prescribed solely 
for the purpose of the study). Subjects will keep using Uptravi 
during their participation in the study as prescribed by their 
physician and in compliance with the USPI/SmPC [Uptravi® 
SmPC; Uptravi® USPI] including the use of contraception for 
women of childbearing potential. Subject’s oral treatment with 
Uptravi will be temporarily interrupted for 36 hours during the 
administration of study treatment (i.v. selexipag). 
ENDPOINTS 
Primary efficacy endpoint(s) 
Not applicable. 
 
Secondary efficacy endpoints 
Not applicable. 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 61/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
Main safety and tolerability endpoints 
The main safety and tolerability endpoints will be analyzed 
over the Period 1, Period 2, and Period 3 combined. 
 • Discontinuations due to prostacyclin-associated adverse 
events (AEs). 
• AEs and serious AEs (SAEs). 
• Prostacyclin-associated AEs. 
• AEs related to injection site reactions. 
• PAH-related AEs. 
 
Other endpoints 
Other endpoints are described in Section 6.2.3. 
PHARMACOKINETIC
ENDPOINTS 
• The AUC during a dose interval at steady state (AUCτ, ss) of 
selexipag and its active metabolite, ACT-333679, at steady 
state after Uptravi (oral selexipag) in Period 1 and after i.v. 
selexipag administration in Period 2. 
• The maximum plasma concentration at steady state (Cmax, ss) of 
selexipag and its active metabolite, ACT-333679 after Uptravi 
(oral selexipag) in Period 1 and i.v. selexipag administration in 
Period 2. 
• The time to reach maximum plasma concentration at steady-state
(tmax, ss) of selexipag and its active metabolite, ACT-333679 after 
Uptravi (oral selexipag) in Period 1 and i.v. selexipag 
administration in Period 2. 
• Trough plasma concentration at steady state (Ctrough, ss) of 
selexipag and its active metabolite, ACT-333679after Uptravi (oral 
selexipag) in Period 1 and i.v. selexipag administration in Period 2. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 2. 
STATISTICAL 
METHODOLOGY 
Approximately 20 patients will be enrolled. In the GRIPHON 
Phase 3 pivotal study of selexipag, a proportion of 7.5% of 
patients on selexipag prematurely discontinued the study (i.e., 
without a morbidity/mortality event) due to prostacyclin- 
associated AEs. 
It is expected that the proportion of 
discontinuations will not be higher than 10%. 
 
The statistical analysis will be mainly descriptive, i.e., no 
hypotheses will be formally tested. 
 
Four analysis sets are defined in this study: 
 • Screened Analysis Set includes all subjects who are screened 
and have a subject identification number. 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 62/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 • i.v. Safety Set comprises all subjects who received at least 
one dose of i.v. study treatment. 
 • Safety Set (SAF) includes all enrolled (included in the study on 
Day 1) subjects who receive at least one dose of selexipag 
(oral or i.v.). 
 • Pharmacokinetic Analysis Set (PKS) comprises all subjects 
included in the SAF who received the 3 doses of i.v. study 
treatment and who complied with the protocol sufficiently and 
did not deviate from the protocol in a way that might affect the 
PK outcome of the study. 
 
The study comprises 3 main periods for analysis: Period 1, Period 
2, and Period 3 and follow-up. AEs and SAEs will be 
tabulated, for the Safety Set and i.v. Safety Set, overall across 
periods as well as by study period. The proportion of 
discontinuations due to prostacyclin-associated AEs will be 
tabulated for the i.v. Safety Set and the SAF to address the 
primary objective. Due to the sample size, the proportion will 
be provided with a conservative 95% Clopper-Pearson 
confidence interval based on exact methods. 
 
All secondary safety endpoints will be listed and tabulated in 
Safety Set and i.v. Safety Set. 
 
Exposure will be summarized. 
 
ECG abnormalities and laboratory variables will be descriptively 
summarized, both longitudinally across the study periods as 
well as separately per period. Death will be summarized by 
cause, by period, and overall. 
 
The proportion of patients in each WHO FC (I , II , III and IV) 
will be tabulated at baseline and post-baseline, as well as the 
change in WHO FC at all assessed time points. Also the 
absence of worsening in WHO FC will be tabulated (i.e., 
patients that are either stable or improve). 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 63/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
Appendix B 
Visit and assessment schedule 
PERIODS 
Name 
SCREENING 
TREATMENT AND OBSERVATION PERIOD 
FOLLOW-UP 
 
 
 
Period 1  
(Pre-treatment Period; 
Uptravi) 
Period 2  
(Treatment Period; i.v. selexipag)  
Period 3  
(Post-treatment 
Period; Uptravi) 
 
VISITS1 
Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 (Phone call) 
 
Name 
Screening 
Baseline  
 
 
EOS 
 
Time 
Day –28 to Day –1 
Day 1 
Day 2 
IV-1 (AM) 
Day 2 
IV-2 (PM) 
Day 3 
IV-3 (AM) 
Day 12 (± 2days) 
30 to 37 days after 
i.v. study treatment 
discontinuation 
Informed consent 
X 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
Demographics / Medical history 
X 
 
 
 
 
 
 
WHO FC 
X 
X 
 
 
X2 
X 
 
Previous/concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
X 
 
Vital signs (BP, pulse rate) 
X 
X 
X5 
 
X5 
X 
 
Body weight and Height3 
X 
X 
 
 
X 
X 
 
Hospitalization4** 
 
 
 
 
Laboratory tests* 
X 
X6 
 
 
X 
X 
 
12-lead ECG* 
 
X 
X7 
X7 
X7 
X 
 
Urine pregnancy test** 
X 
X 
 
 
 
 
X 
PK sampling8 
 
X 
 
 
X 
 
 
Study treatment administration 
(i.v. selexipag) 
 
 
X 
X 
X 
 
 
Infusion solution sampling9 
 
 
X 
X 
X 
 
 
SAEs/AEs10 
X 
X 
X 
X 
X 
X 
X 
 
AE = adverse event; BP = blood pressure; ECG = electrocardiogram; EOS = End-of-Study; FC = Functional Class; i.v. = intravenous; PK = pharmacokinetic; SAE = serious 
adverse event; WHO = World Health Organization. *Electronically transferred to sponsor. ** Assessment not collected in CRF 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 64/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
1 Unscheduled visits may be performed at any time during the study. Assessments performed during unscheduled visits are at the discretion of the investigator. 
2 On Day 3, WHO FC is to be assessed at the end of the i.v. selexipag infusion. 
3 Height will be assessed at Visit 1 (screening) only. 
4 In-patient hospitalization of subjects is mandatory during Visit 2 (Period 1 and Period 2) (i.e., 2 overnight stays from Day 1 to Day 3). For convenience, the hospitalization 
may be extended to the night before Day 1 and to the night of Day 3. 
5 Vital signs (BP and pulse rate) will be assessed at 7 different time points. 
6 If Visit 1 and Visit 2 Day 1 are performed within 7 days, laboratory tests and physical examination do not have to be repeated at Visit 2 Day 1. 
7 ECG will be performed at pre-dose and within 30 minutes after stopping of infusion (i.v. selexipag). 
8 PK profile includes 7 blood samples.  
9 Infusion solution samples will be taken from the tubing before each infusion. 
10 All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after i.v. selexipag study treatment discontinuation must be reported. 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 65/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
Appendix C 
Discussion and further considerations of the applied statistical 
methods  
Not applicable. 
Appendix D 
Definitions of marked abnormalities and elevated liver function 
tests 
Table 14 
Thresholds for marked laboratory abnormalities 
Laboratory test name 
 
LL 
LLL 
HH 
HHH 
Hemoglobin (g/L) 
< 100 
< 80 
Increase of > 20 g/L
above baseline  
Increase of > 40 g/L
above baseline  
Hematocrit (L/L) 
< 0.28 (female) 
< 0.32 (male) 
< 0.20 
> 0.55 (female) 
 0.60 (male) 
> 0.65 
Platelet count (10E9/L) 
< 75 
< 50 
> 600 
> 999 
Leukocytes (10E9/L) 
< 3.0 
< 2.0 
> 20.0 
> 100.0 
Neutrophils (10E9/L) 
< 1.5 
< 1.0 
NA 
NA 
Eosinophils (10E9/L) 
NA 
NA 
> 5.0 
NA 
Lymphocytes (10E9/L) 
< 0.8 
< 0.5 
> 4.0 
> 20 
ALT (U/L) 
NA 
NA 
> 3 × ULN 
> 5 × ULN 
AST (U/L) 
NA 
NA 
> 3 × ULN 
> 5 × ULN 
Alkaline phosphatase (U/L) 
NA 
NA 
> 2.5 × ULN 
> 5 × ULN 
Total bilirubin (μmol/L) 
NA 
NA 
> 2 × ULN 
> 5 × ULN 
Creatinine (μmol/L) 
NA 
NA 
> 1.5 × ULN 
> 3 × ULN 
Sodium (mmol/L) 
NA 
< 130 
> 150 
> 155 
Potassium (mmol/L) 
< 3.2 
< 3.0 
> 5.5 
> 6.0 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; NA = not applicable; SI = international 
system of units; ULN = upper limit of normal. 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 66/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
Appendix E 
Mock layout 
T_DISP 
 
ACT-293987 
Protocol: AC-065A309 
Subject disposition 
Analysis Set: Screened Analysis Set 
 
 
Uptravi b.i.d. dose  
 
 
200-1000 
ug 
1200-1600 
ug 
Total 
 
N=xxx 
N=xxx 
N=xxx 
 
n (%) 
n (%) 
n (%) 
 
 
 
 
Subjects screened 
 
 
xxx 
Screening failures 
 
 
xxx 
 
 
 
 
Subjects enrolled in Period 1  
xxx (100) 
xxx (100) 
xxx (100) 
  Subjects received Uptravi in Period 1 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Subjects entered in Period 2  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Subjects received i.v. infusion 1 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Subjects received i.v. infusion 2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Subjects received i.v. infusion 3 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Subjects completed i.v. selexipag  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Subjects discontinued i.v. selexipag 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Subjects entered in Period 3  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Subjects completed the study  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Subjects discontinued the study 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Percentages are based on the number of enrolled subjects. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Display all categories in shell. 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 67/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_DISP_COU 
 
ACT-293987 
Protocol: AC-065A309 
Subject disposition by country and site 
Analysis Set: Screened Analysis Set 
 
Country 
Uptravi b.i.d. dose  
 
  Site 
200-1000 ug 
1200-1600 ug 
Total 
    Periods 
n (%) 
n (%) 
n (%) 
 
 
 
 
Germany 
 
 
 
  All Sites 
 
 
 
    Subjects screened 
 
 
xxx 
    Screening failures 
 
 
xxx 
 
 
 
 
    Subjects enrolled in Period 1  
xxx (100) 
xxx (100) 
xxx (100) 
     Subjects received Uptravi in Period 1 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
    Subjects entered in Period 2  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
      Subjects received i.v. infusion 1 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
      Subjects received i.v. infusion 2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
      Subjects received i.v. infusion 3 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
      Subjects completed i.v. selexipag  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
      Subjects discontinued i.v. selexipag 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
    Subjects entered in Period 3  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
    Subjects completed the study  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
   Subjects discontinued the study 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
  Site 1001 
 
 
 
    Subjects screened 
 
 
xxx 
    Screening failures 
 
 
xxx 
  ... 
 
 
 
 
 
 
 
Percentages are based on the number of enrolled subjects. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Include all countries and sites where subjects were enrolled. 
Display all categories in shell. 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 68/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_ANA 
 
ACT-293987 
Protocol: AC-065A309 
Overview of analysis sets and reasons for exclusion from analysis sets 
Analysis Set: Screened Analysis Set 
 
 
Uptravi b.i.d. dose  
 
 
200-1000 ug 
1200-1600 ug 
Total 
 
n (%) 
n (%) 
n (%) 
 
 
 
 
Screened analysis set 
 
 
xxx 
 
 
 
 
Safety analysis set 
xxx (100) 
xxx (100) 
xxx (100) 
 
 
 
 
Subjects included in i.v. Safety analysis set 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Subjects excluded from i.v. Safety analysis set 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Reason 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Reason 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Reason 3> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Subjects included in Pharmacokinetic analysis set 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Subjects excluded from Pharmacokinetic analysis set 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Reason 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Reason 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Reason 3> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Percentages are based on the Safety analysis set 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Sort reasons for exclusion in descending order of frequency. 
Display all categories in shell. 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 69/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_PWDS 
 
ACT-293987 
Protocol: AC-065A309 
Reasons for premature discontinuation from the study 
Analysis Set: Safety Analysis Set 
 
 
Uptravi b.i.d. dose  
 
 
200-1000 ug 
1200-1600 ug 
Total 
 
N=xxx 
N=xxx 
N=xxx 
 
n (%) 
n (%) 
n (%) 
 
 
 
 
Subjects completed the study 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Subjects prematurely discontinued the study  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Death 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Lost to follow-up 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Subject decision/Withdrawal of consent 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Reason 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Reason 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Physician decision 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Reason 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Reason 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Sponsor decision 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Reason 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Reason 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
Programming note: Show all categories written out in the shell in the given order, 
even if they have zero subjects. Show reason categories as they occurred in 
descending frequency. 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 70/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
T_PD 
 
ACT-293987 
Protocol: AC-065A309 
<Table title> 
Analysis Set: Screened Analysis Set 
 
Overall 
 
 
 
 
Total 
 
N=xxx 
 
n (%) 
 
 
Subjects with at least one <important> protocol deviation 
xxx (xx.x) 
 
 
<Category 1> 
xxx (xx.x) 
  <Deviation 1> 
xxx (xx.x) 
  <Deviation 2> 
xxx (xx.x) 
  <Deviation 3> 
xxx (xx.x) 
 
 
<Category 2> 
xxx (xx.x) 
  <Deviation 1> 
xxx (xx.x) 
  <Deviation 2> 
xxx (xx.x) 
  <Deviation 3> 
xxx (xx.x) 
 
 
<Category 3> 
xxx (xx.x) 
  <Deviation 1> 
xxx (xx.x) 
  <Deviation 2> 
xxx (xx.x) 
  <Deviation 3> 
xxx (xx.x) 
 
 
A subject may have a deviation in more than one category 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
Programming notes: Repeat with “Germany”, “USA” Show categories as in the PD 
code list and sort deviations by frequency descending order. 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 71/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_DEM 
 
ACT-293987 
Protocol: AC-065A309 
Summary of baseline demographic characteristics  
Analysis Set: Safety Analysis Set 
 
 
Uptravi b.i.d. dose  
 
 
200-1000 ug 
1200-1600 ug 
Total 
 
N=xxx 
N=xxx 
N=xxx 
 
 
 
 
Sex [n (%)] 
 
 
 
  Male 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Female 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Age [years] 
 
 
 
  n 
xx 
xx 
xx 
  Mean 
xx.x  
xx.x  
xx.x  
  SD 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x  
xx.x  
xx.x  
  Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
Age (years) category [n (%)] 
 
 
 
  < 18 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  18 - 64 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  >= 65 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Height [cm] 
 
 
 
  n 
xx 
xx 
xx 
  Mean 
xxx.x  
xxx.x  
xxx.x  
  SD 
xxx.xx 
xxx.xx 
xxx.xx 
  Median 
xxx.x  
xxx.x  
xxx.x  
  Q1, Q3 
xxx.x, xxx.x 
xxx.x, xxx.x 
xxx.x, xxx.x 
  Min, Max 
xxx, xxx 
xxx, xxx 
xxx, xxx 
 
 
 
 
Body weight [kg] 
 
 
 
  n 
xx 
xx 
xx 
  Mean 
xxx.x  
xxx.x  
xxx.x  
  SD 
xxx.xx 
xxx.xx 
xxx.xx 
  Median 
xxx.x  
xxx.x  
xxx.x  
  Q1, Q3 
xxx.x, xxx.x 
xxx.x, xxx.x 
xxx.x, xxx.x 
  Min, Max 
xxx, xxx 
xxx, xxx 
xxx, xxx 
 
 
 
 
BMI [kg/m^2] 
 
 
 
  n 
xx 
xx 
xx 
  Mean 
xx.xx  
xx.xx  
xx.xx  
  SD 
xx.xxx 
xx.xxx 
xx.xxx 
  Median 
xx.xx  
xx.xx  
xx.xx  
  Q1, Q3 
xx.xx, xx.xx 
xx.xx, xx.xx 
xx.xx, xx.xx 
  Min, Max 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
Race [n (%)] 
 
 
 
  <Race 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Race 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Race 3> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Race 4> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Ethnicity [n (%)] 
 
 
 
  <Ethnicity 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Ethnicity 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Country [n (%)] 
 
 
 
  <Country 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Country 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
SD = Standard deviation, BMI = Body Mass Index 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Show race, ethnicity and Countries in descending order of 
frequency. Show ‘Missing’ category only if it occurred. 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 72/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_AGECATEU 
 
ACT-293987 
Protocol: AC-065A309 
EudraCT age categories 
Analysis Set: Safety Analysis Set 
 
 
 
Uptravi b.i.d. dose  
 
 
200-1000 ug 
1200-1600 ug 
Total 
 
N=xxx 
N=xxx 
N=xxx 
 
 
 
 
Age (years) category [n (%)] 
 
 
 
  18 - 64 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  65 - 84 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  >= 85  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
EudraCT = European union drug regulating authorities clinical trials 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 73/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_BAS 
 
ACT-293987 
Protocol: AC-065A309 
Summary of baseline disease characteristics 
Analysis Set: Safety Analysis Set 
 
 
Uptravi b.i.d. dose  
 
 
200-1000 ug 
1200-1600 ug 
Total 
 
N=xxx 
N=xxx 
N=xxx 
 
 
 
 
Time since diagnosis of PAH [months] 
 
 
 
  n 
xx 
xx 
xx 
  Mean 
xx.x  
xx.x  
xx.x  
  SD 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x  
xx.x  
xx.x  
  Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
PAH etiology [n (%)] 
 
 
 
  Idiopathic PAH 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Heritable PAH 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Drug or toxin induced PAH 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  PAH associated with  
 
 
 
    Connective tissue disease 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    HIV infection 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Portal hypertension 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Congenital heart disease 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Schistosomiasis 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Uptravi dose at screening [ug b.i.d.] 
 
 
 
   200 
xxx (xx.x) 
 
xxx (xx.x) 
   400 
xxx (xx.x) 
 
xxx (xx.x) 
   600 
xxx (xx.x) 
 
xxx (xx.x) 
   800 
xxx (xx.x) 
 
xxx (xx.x) 
  1000 
xxx (xx.x) 
 
xxx (xx.x) 
  1200 
 
xxx (xx.x) 
xxx (xx.x) 
  1400 
 
xxx (xx.x) 
xxx (xx.x) 
  1600 
 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
WHO functional class [n (%)] 
 
 
 
  I 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  II 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  III 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  IV 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
 
 
Time since diagnosis of PAH is caculated at baseline visit. WHO functional class is assessed on 
Day 1. 
SD = Standard deviation 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
Programming note: Show all CRF categories, even if empty. Show 'Missing' category 
only if it occurred. 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 74/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_MH_SOC 
 
ACT-293987 
Protocol: AC-065A309 
<Table Title> 
Analysis Set: Safety Analysis Set 
 
System Organ Class 
Uptravi b.i.d. dose  
 
  Preferred Term 
200-1000 ug 
1200-1600 ug 
Total 
 
N=xxx 
N=xxx 
N=xxx 
 
 
 
 
Subjects with at least one <previous> disease or 
diagnosis 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
<System organ class 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Preferred term 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Preferred term 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Preferred term 3> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Preferred term 4> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
<System organ class 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Preferred term 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Preferred term 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Preferred term 3> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Preferred term 4> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
  ... 
 
 
 
 
 
 
 
 
 
 
 
System Organ Classes and Preferred Terms are based on MedDRA version <xx.x>. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
Programming note: Sort by descending frequency in the SOC and then by descending 
frequency and then alphabetically in the PTs. Adapt first line in shell (previous/study 
concomitant). 
 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 75/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_CM 
 
ACT-293987 
Protocol: AC-065A309 
<Table Title> 
Analysis Set: Safety Analysis Set 
 
Period 1: Uptravi, pre-treatment period 
 
ATC Class 
Uptravi b.i.d. dose  
 
  Preferred Term 
200-1000 ug 
1200-1600 ug 
Total 
 
N=xxx 
N=xxx 
N=xxx 
 
 
 
 
Subjects with at least one <ongoing> therapy 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
<ATC class 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Preferred term 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Preferred term 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Preferred term 3> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Preferred term 4> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
<ATC class 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Preferred term 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Preferred term 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Preferred term 3> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  <Preferred term 4> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
  ... 
 
 
 
 
 
 
 
 
 
 
 
Preferred Terms are based on WHO-DRUG dictionary version <xxxx.x>. 
The summary does not include PAH-specific therapies. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Sort by descending frequency in the ATC class in total and then 
by descending frequency and then alphabetically in the PTs. Display Period line only 
where applicable. Use the following labels for the concomitant medication table: 
 
Analysis 
Period 
Label in summary table 
Screening 
Screening Period 
1 
Period 1: Uptravi, pre-treatment period 
2 
Period 2: i.v. selexipag, treatment period 
3&FU 
Period 3: Uptravi, post-treatment period including safety follow-up period 
1&2 
Period 1 & 2: Uptravi, pre-treatment period and i.v. selexipag treatment period 
combined 
2&3&FU 
Period 2 & 3: i.v. selexipag, treatment period and Uptravi, post-treatment period 
including safety follow-up period combined 
1&2&3&FU 
Period 1 & 2 & 3: All post-baseline periods including safety follow-up period 
 
 
Programming note: Use ATC level 4 for ATC class. Sort by descending frequency in 
the ATC class and then by descending frequency and then alphabetically in the PTs. 
Modify first line according to table (previous, ongoing, ...). 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 76/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
T_CMPAH 
 
ACT-293987 
Protocol: AC-065A309 
Summary of ongoing PAH specific therapies at baseline  
Analysis Set: Safety Analysis Set 
 
 
Number of PAH specific therapies 
Uptravi b.i.d. dose  
 
  PAH medication category 
200-1000 ug 
1200-1600 ug 
Total 
    Preferred term 
N=xxx 
N=xxx 
N=xxx 
 
 
 
 
Subjects taking Uptravi 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Subjects with at least one additional PAH specific 
therapy on top of Uptravi 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  ERA  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Preferred term 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Preferred term 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
  PDE5-Inhibitors  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Preferred term 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Preferred term 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
    ... 
 
 
 
 
 
 
 
  ERA + PDE5 Inhibitors 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Preferred term 1> + <Preferred Term 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Preferred term 1> + <Preferred Term 3> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
    ... 
 
 
 
 
 
 
 
Preferred Terms are based on WHO-DRUG dictionary version <xxxx.x>. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Use medication categories based on the PAH specific medication 
search terms. Sort preferred terms by descending order of frequency. Only show 
categories which are actually occurring. Continue for triplicate therapies, if occurring. 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 77/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_EXP_IV 
 
ACT-293987 
Protocol: AC-065A309 
Exposure to i.v. selexipag 
Analysis Set: i.v. Safety Analysis Set 
 
 
Uptravi b.i.d. dose  
 
 
200-1000 ug 
1200-1600 ug 
Total 
 
N=xxx 
N=xxx 
N=xxx 
 
 
 
 
Number of infusions received [n (%)] 
 
 
 
  1 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  3 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
First infusion 
 
 
 
 
 
 
 
  Planned dose level [ug] 
 
 
 
     225 (~ 200 p.o.) 
xxx (xx.x) 
 
xxx (xx.x) 
     450 (~ 400 p.o.) 
xxx (xx.x) 
 
xxx (xx.x) 
     675 (~ 600 p.o.) 
xxx (xx.x) 
 
xxx (xx.x) 
     900 (~ 800 p.o.) 
xxx (xx.x) 
 
xxx (xx.x) 
    1125 (~1000 p.o.) 
xxx (xx.x) 
 
xxx (xx.x) 
    1350 (~1200 p.o.) 
 
xxx (xx.x) 
xxx (xx.x) 
    1575 (~1400 p.o.) 
 
xxx (xx.x) 
xxx (xx.x) 
    1800 (~1600 p.o.) 
 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
  Planned dose [ug] 
 
 
 
    n 
xx 
xx 
xx 
    Mean 
xxxx.x  
xxxx.x  
xxxx.x  
    SD 
xxxx.xx 
xxxx.xx 
xxxx.xx 
    Median 
xxxx.x  
xxxx.x  
xxxx.x  
    Q1, Q3 
xxxx.x, xxxx.x 
xxxx.x, xxxx.x 
xxxx.x, xxxx.x 
    Min, Max 
xxxx, xxxx 
xxxx, xxxx 
xxxx, xxxx 
 
 
 
 
  Actual dose infused [ug] 
 
 
 
    n 
xx 
xx 
xx 
    Mean 
xxxx.x  
xxxx.x  
xxxx.x  
    SD 
xxxx.xx 
xxxx.xx 
xxxx.xx 
    Median 
xxxx.x  
xxxx.x  
xxxx.x  
    Q1, Q3 
xxxx.x, xxxx.x 
xxxx.x, xxxx.x 
xxxx.x, xxxx.x 
    Min, Max 
xxxx, xxxx 
xxxx, xxxx 
xxxx, xxxx 
 
 
 
 
  Actual total time of infusion [minutes] 
 
 
 
    n 
xx 
xx 
xx 
    Mean 
xx.x  
xx.x  
xx.x  
    SD 
x.xx 
x.xx 
x.xx 
    Median 
xx.x  
xx.x  
xx.x  
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
Second infusion 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
Third infusion 
 
 
 
 
 
 
 
.... 
 
 
 
SD = Standard deviation 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
Programming note: Show all dose categories even if empty, except the 'Other' 
category which should only be presented if populated. 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 78/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_EXP_PO 
 
ACT-293987 
Protocol: AC-065A309 
Exposure to Uptravi prior to and after i.v. selexipag 
Analysis Set: <Analysis Set> 
 
 
Uptravi b.i.d. dose  
 
 
200-1000 ug 
1200-1600 
ug 
Total 
 
N=xxx 
N=xxx 
N=xxx 
 
 
 
 
Uptravi evening dose before Day 1 [ug] 
 
 
 
   200  
xxx (xx.x) 
 
xxx (xx.x) 
   400  
xxx (xx.x) 
 
xxx (xx.x) 
   600  
xxx (xx.x) 
 
xxx (xx.x) 
   800  
xxx (xx.x) 
 
xxx (xx.x) 
  1000  
xxx (xx.x) 
 
xxx (xx.x) 
  1200  
 
xxx (xx.x) 
xxx (xx.x) 
  1400  
 
xxx (xx.x) 
xxx (xx.x) 
  1600  
 
xxx (xx.x) 
xxx (xx.x) 
  Other 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Not received / missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Uptravi morning dose at Day 1 [ug] 
 
 
 
   200  
xxx (xx.x) 
 
xxx (xx.x) 
   400  
xxx (xx.x) 
 
xxx (xx.x) 
   600  
xxx (xx.x) 
 
xxx (xx.x) 
   800  
xxx (xx.x) 
 
xxx (xx.x) 
  1000  
xxx (xx.x) 
 
xxx (xx.x) 
  1200  
 
xxx (xx.x) 
xxx (xx.x) 
  1400  
 
xxx (xx.x) 
xxx (xx.x) 
  1600  
 
xxx (xx.x) 
xxx (xx.x) 
  Other 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Not received / missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Uptravi evening dose at Day 1 [ug] 
 
 
 
   200  
xxx (xx.x) 
 
xxx (xx.x) 
   400  
xxx (xx.x) 
 
xxx (xx.x) 
   600  
xxx (xx.x) 
 
xxx (xx.x) 
   800  
xxx (xx.x) 
 
xxx (xx.x) 
  1000  
xxx (xx.x) 
 
xxx (xx.x) 
  1200  
 
xxx (xx.x) 
xxx (xx.x) 
  1400  
 
xxx (xx.x) 
xxx (xx.x) 
  1600  
 
xxx (xx.x) 
xxx (xx.x) 
  Other 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Not received / missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Uptravi evening dose at Day 3 [ug] 
 
 
 
   200  
xxx (xx.x) 
 
xxx (xx.x) 
   400  
xxx (xx.x) 
 
xxx (xx.x) 
   600  
xxx (xx.x) 
 
xxx (xx.x) 
   800  
xxx (xx.x) 
 
xxx (xx.x) 
  1000  
xxx (xx.x) 
 
xxx (xx.x) 
  1200  
 
xxx (xx.x) 
xxx (xx.x) 
  1400  
 
xxx (xx.x) 
xxx (xx.x) 
  1600  
 
xxx (xx.x) 
xxx (xx.x) 
  Other 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Not received / missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
 
 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
Programming note: Show all categories even if empty. The 'Other' and 'Not 
received/missing' categories shall only be shown if populated.  
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 79/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
T_COMPL_IV 
ACT-293987 
Protocol: AC-065A309 
Compliance to i.v. selexipag treatment 
Analysis Set: i.v. Safety Analysis Set 
 
 
Uptravi b.i.d. dose  
 
 
200-1000 ug 
1200-1600 ug 
Total 
 
N=xxx 
N=xxx 
N=xxx 
 
 
 
 
First infusion 
 
 
 
 
 
 
 
  Compliance [%] 
 
 
 
    n 
xx 
xx 
xx 
    Mean 
xxxx.x  
xxxx.x  
xxxx.x  
    SD 
xxxx.xx 
xxxx.xx 
xxxx.xx 
    Median 
xxxx.x  
xxxx.x  
xxxx.x  
    Q1, Q3 
xxxx.x, xxxx.x 
xxxx.x, xxxx.x 
xxxx.x, xxxx.x 
    Min, Max 
xxxx, xxxx 
xxxx, xxxx 
xxxx, xxxx 
 
 
 
 
Second infusion 
 
 
 
 
 
 
 
  Compliance [%] 
 
 
 
    n 
xx 
xx 
xx 
    Mean 
xxxx.x  
xxxx.x  
xxxx.x  
    SD 
xxxx.xx 
xxxx.xx 
xxxx.xx 
    Median 
xxxx.x  
xxxx.x  
xxxx.x  
    Q1, Q3 
xxxx.x, xxxx.x 
xxxx.x, xxxx.x 
xxxx.x, xxxx.x 
    Min, Max 
xxxx, xxxx 
xxxx, xxxx 
xxxx, xxxx 
 
 
 
 
Third infusion 
 
 
 
 
 
 
 
  Compliance [%] 
 
 
 
    n 
xx 
xx 
xx 
    Mean 
xxxx.x  
xxxx.x  
xxxx.x  
    SD 
xxxx.xx 
xxxx.xx 
xxxx.xx 
    Median 
xxxx.x  
xxxx.x  
xxxx.x  
    Q1, Q3 
xxxx.x, xxxx.x 
xxxx.x, xxxx.x 
xxxx.x, xxxx.x 
    Min, Max 
xxxx, xxxx 
xxxx, xxxx 
xxxx, xxxx 
 
 
 
 
Overall 
 
 
 
 
 
 
 
  Compliance [%] 
 
 
 
    n 
xx 
xx 
xx 
    Mean 
xxxx.x  
xxxx.x  
xxxx.x  
    SD 
xxxx.xx 
xxxx.xx 
xxxx.xx 
    Median 
xxxx.x  
xxxx.x  
xxxx.x  
    Q1, Q3 
xxxx.x, xxxx.x 
xxxx.x, xxxx.x 
xxxx.x, xxxx.x 
    Min, Max 
xxxx, xxxx 
xxxx, xxxx 
xxxx, xxxx 
 
 
 
 
Subject with missing infusions have compliance zero. 
SD = Standard deviation 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 80/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
T_EXP_ADJ 
ACT-293987 
Protocol: AC-065A309 
Summary of study treatment administration, reasons for interruptions and end of infusion  
Analysis Set: i.v. Safety Analysis Set 
 
 
Uptravi b.i.d. dose  
 
 
200-1000 ug 
1200-1600 ug 
Total 
 
N=xxx 
N=xxx 
N=xxx 
 
 
 
 
First infusion 
 
 
 
 
 
 
 
  Not received [n (%)] 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
  Temporary interruptions [n (%)] 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Due to an AE  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Not due to an AE 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
  End of infusion [n (%)] 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Premature discontinuation 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Completed as per protocol 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Second infusion 
 
 
 
 
 
 
 
  Not received [n (%)] 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
  Temporary interruptions [n (%)] 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Due to an AE  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Not due to an AE 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
  End of infusion [n (%)] 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Premature discontinuation 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Completed as per protocol 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Third infusion 
 
 
 
 
 
 
 
  Not received [n (%)] 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
  Temporary interruptions [n (%)] 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Due to an AE  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Not due to an AE 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
  End of infusion [n (%)] 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Premature discontinuation 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Completed as per protocol 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
 
 
Subjects may have more than one interruption but are counted only once in each category. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 81/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
T_PWDT 
ACT-293987 
Protocol: AC-065A309 
Reasons for premature discontinuation of  i.v. selexipag treatment 
Analysis Set: i.v. Safety Analysis Set 
 
 
Uptravi b.i.d. dose  
 
 
200-1000 ug 
1200-1600 
ug 
Total 
 
N=xxx 
N=xxx 
N=xxx 
 
n (%) 
n (%) 
n (%) 
 
 
 
 
Subjects completed i.v. selexipag treatment 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Subjects prematurely discontinued i.v. selexipag 
treatment  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Death 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Lost to follow-up 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Pre-specified discontinuation criteria 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Subject decision 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Reason 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Reason 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Physician decision 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Reason 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Reason 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Sponsor decision 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Reason 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    <Reason 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Show all categories written out in the shell in the given order, 
even if they have zero subjects. Show reason categories as they occurred in 
descending frequency. 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 82/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
T_AE_SOC 
ACT-293987 
Protocol: AC-065A309 
<Table title> 
Analysis Set: <Analysis set> 
 
Period 1: Uptravi, pre-treatment period 
 
 
Uptravi b.i.d. dose  
 
 
200-1000 ug 
1200-1600 ug 
Total 
System Organ Class 
N=xxx 
N=xxx 
N=xxx 
  Preferred Term 
n (%) 
95% CI 
n (%) 
95% CI 
n (%) 
95% CI 
 
 
 
 
 
 
 
Subjects with at least one AE 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
 
 
 
 
 
 
 
<System organ class 1> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
  <Preferred term 1> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
  <Preferred term 2> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
  <Preferred term 3> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
  <Preferred term 4> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
 
 
 
 
 
 
 
<System organ class 2> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
  <Preferred term 1> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
  <Preferred term 2> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
  <Preferred term 3> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
  <Preferred term 4> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
 
 
 
 
 
 
 
  ... 
 
 
 
 
 
 
 
 
 
 
 
 
 
CI = Confidence interval 
System Organ Classes and Preferred Terms are based on MedDRA version <xx.x>. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
Programming note: Sort by descending frequency in the SOC in total and then by descending frequency and then alphabetically in 
the PTs. Use the following labels: 
 Analysis 
Period 
Label in summary table 
1 
Period 1: Uptravi, pre-treatment period 
2 
Period 2: i.v. selexipag, treatment period 
3&FU 
Period 3: Uptravi, post-treatment period including safety follow-up period 
1&2 
Period 1 & 2: Uptravi, pre-treatment period and i.v. selexipag treatment period combined 
2&3&FU 
Period 2 & 3: i.v. selexipag, treatment period and Uptravi, post-treatment period including safety follow-up period combined 
1&2&3&FU 
Period 1 & 2 & 3: All post-baseline periods including safety follow-up period 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 83/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_AE_SOC2 
ACT-293987 
Protocol: AC-065A309 
<Table title> 
Analysis Set: <Analysis set> 
 
 
Uptravi b.i.d. dose 
 
 
200-1000 ug 
1200-1600 ug 
Total 
 
N=xxx 
N=xxx 
N=xxx 
MedDRA System organ class 
Subjects 
Events 
Subjects 
Events 
Subjects 
Events 
  Preferred term 
n (%) 
n 
n (%) 
n 
n (%) 
n 
 
 
 
 
 
 
 
Subjects with at least one event 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
 
 
 
 
 
 
 
<System organ class 1> 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
  <Preferred term 1> 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
  <Preferred term 2> 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
  <Preferred term 3> 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
  <Preferred term 4> 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
 
 
 
 
 
 
 
<System organ class 2> 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
  <Preferred term 1> 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
  <Preferred term 2> 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
  <Preferred term 3> 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
  <Preferred term 4> 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
xxx (xx.x) 
xxx 
 
 
 
 
 
 
 
  ... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Classes and Preferred Terms are based on MedDRA version <xx.x>. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
Programming note: Table shell for EudraCT/ClinicalTrails.gov disclosure. See Section 7.2.2.1 of the SAP. 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 84/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_AE_PT 
 
ACT-293987 
Protocol: AC-065A309 
<Table title> 
Analysis Set: <Analysis set> 
 
Period 1: Uptravi, pre-treatment period 
 
 
Uptravi b.i.d. dose  
 
 
200-1000 ug 
1200-1600 ug 
Total 
 
N=xxx 
N=xxx 
N=xxx 
Preferred term 
n (%) 
95% CI 
n (%) 
95% CI 
n (%) 
95% CI 
 
 
 
 
 
 
 
Subjects with at least one AE 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
 
 
 
 
 
 
 
<Preferred term 1> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
<Preferred term 2> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
<Preferred term 3> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
<Preferred term 4> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
<Preferred term 5> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
<Preferred term 6> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
<Preferred term 7> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
<Preferred term 8> 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
xxx (xx.x) 
xx.x, xx.x 
 
 
 
 
 
 
 
  ... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CI = Confidence interval 
Preferred Terms are based on MedDRA version <xx.x>. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
Programming note: Sort by descending frequency and then alphabetically in the PTs in total. Use the following labels: 
 
 Analysis 
Period 
Label in summary table 
1 
Period 1: Uptravi, pre-treatment period 
2 
Period 2: i.v. selexipag, treatment period 
3&FU 
Period 3: Uptravi, post-treatment period including safety follow-up period 
1&2 
Period 1 & 2: Uptravi, pre-treatment period and i.v. selexipag treatment period combined 
2&3&FU 
Period 2 & 3: i.v. selexipag, treatment period and Uptravi, post-treatment period including safety follow-up period combined 
1&2&3&FU 
Period 1 & 2 & 3: All post-baseline periods including safety follow-up period 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 85/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
T_AE_PT_INT 
 
ACT-293987 
Protocol: AC-065A309 
Incidence of adverse events by preferred term and maximum intensity 
Analysis Set: <Analysis set> 
 
 
Uptravi b.i.d. dose  
 
 
200-1000 ug 
1200-1600 ug 
Total 
Preferred Term 
N=xxx 
N=xxx 
N=xxx 
  Intensity 
n (%) 
n (%) 
n (%) 
 
 
 
 
Subjects with at least one AE 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Mild 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Moderate 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Severe 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
<Preferred term 1> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Mild 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Moderate 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Severe 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
<Preferred term 2> 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Mild 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Moderate 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Severe 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
The maximum intensity of the AE is shown. 
All post-baseline AEs are shown (Period 1 & 2 & 3 including safety follow-up) 
Preferred Terms are based on MedDRA version <xx.x>. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
Programming note: Sort by descending frequency and then alphabetically in the PTs. Show missing category only if it occurred in 
the data. 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 86/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
T_AEINJ 
 
ACT-293987 
Protocol: AC-065A309 
Grade and diagnosis criteria of injection site reactions 
Analysis Set: i.v. Safety Analysis Set 
 
 
Uptravi b.i.d. dose  
 
 
200-1000 ug 
1200-1600 ug 
Total 
 
N=xxx 
N=xxx 
N=xxx 
 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
Subjects with at least one injection site reaction 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Subjects with at least one clinically significant 
injection site reaction 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Worst Grade 
 
 
 
  Mild 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Moderate 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Severe 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Potentially life threatening 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Criteria 
 
 
 
  Pain 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Tenderness 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Erythema/redness 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Swelling 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Induration 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Injection site hemorrhage 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
The worst grade of all injection site reactions was counted in a subject. 
A subject may have more than one diagnosis criterion. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: For each subject, display the worst grade of all injection site 
reactions. Display each subject once for all diagnosis criteria reported in a subject. 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 87/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_LB_SUM 
 
ACT-293987 
Protocol: AC-065A309 
<Table Title> 
Analysis Set: Safety Analysis Set 
 
Parameter: Haemoglobin [g/L] 
 
Treatment group 
Baseline 
Time Point 
Change from baseline 
  Time point 
n 
Mean 
SD 
Median 
Min 
Max 
Mean 
SD 
Median 
Min 
Max 
Mean 
SD 
Median 
Min 
Max 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uptravi b.i.d. dose 200-1000 ug (N=xxx) 
  Baseline 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
  Visit 2 Day 3 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
  Visit 3 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uptravi b.i.d. dose 1200-1600 ug (N=xxx) 
  Baseline 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
  Visit 2 Day 3 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
  Visit 3 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total (N=xxx) 
  Baseline 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
  Visit 2 Day 3 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
  Visit 3 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline is the Day 1 assessment or last assessment prior to Day 1. 
SD = Standard deviation 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Continue for all Hematology/Clinical chemistry parameters as stated in Section 7.4 of the SAP. 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 88/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_LB_ABN 
 
ACT-293987 
Protocol: AC-065A309 
Incidence of marked laboratory values, by period 
Analysis Set: Safety Analysis Set 
 
Period 2: i.v. selexipag, treatment period 
 
 
 
 
Uptravi b.i.d. dose  
 
 
 
 
200-1000 ug 
1200-1600 ug 
Total 
Category 
 
 
N = xxx 
N = xxx 
N = xxx 
  Parameter 
Grade 
Severity of abnormality 
n / m (%) 
n / m (%) 
n / m (%) 
 
 
 
 
 
 
Hematology 
 
 
 
 
 
  Hemoglobin 
LL 
< 100 g/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
LLL 
< 80 g/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HH 
Increase > 20 g/L above baseline 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HHH 
Increase > 40 g/L above baseline 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
 
 
  Hematocrit 
LL 
< 0.28 L/L [f], < 0.32 L/L [m] 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
LLL 
< 0.2 L/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HH 
> 0.55 L/L [f], > 0.60 L/L [m] 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HHH 
> 0.65 L/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
 
 
  Platelet count 
LL 
< 75 x10^9/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
LLL 
< 50 x10^9/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HH 
> 600 x10^9/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HHH 
> 999 x10^9/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
 
 
  Leukocytes 
LL 
< 3.0 x10^9/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
LLL 
< 2.0 x10^9/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HH 
> 20.0 x10^9/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HHH 
> 100.0 x10^9/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
 
 
  Neutrophils 
LL 
< 1.5 x10^9/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
LLL 
< 1.0 x10^9/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
 
 
  Eosinophils 
HH 
> 5.0 x10^9/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
 
 
  Lymphocytes 
LL 
< 0.8 x10^9/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
LLL 
< 0.5 x10^9/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HH 
> 4.0 x10^9/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 89/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
HHH 
> 20.0 x10^9/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
 
 
Biochemistry 
 
 
 
 
 
  ALT 
HH 
> 3 xULN 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HHH 
> 5 xULN 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
 
 
  AST 
HH 
> 3 xULN 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HHH 
> 5 xULN 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
 
 
  Alkaline phosphatase 
HH 
> 2.5 xULN 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HHH 
> 5 xULN 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
 
 
  Total bilirubin 
HH 
> 2 xULN 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HHH 
> 5 xULN 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
 
 
  Creatinine 
HH 
> 1.5 xULN 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HHH 
> 3 xULN 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
 
 
  Sodium 
LLL 
< 130 mmol/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HH 
> 150 mmol/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HHH 
> 155 mmol/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
 
 
  Potassium 
LL 
< 3.2 mmol/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
LLL 
< 3.0 mmol/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HH 
> 5.5 mmol/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HHH 
> 6.0 mmol/L 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
 
 
ULN = Upper limit of normal. Subjects are summarized in each category they fall into. 
n = Subjects with event, m = Subjects with assessment in the specified time period (at risk) 
Post-baseline abnormalities not present at baseline or abnormalities worsening after baseline are shown. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Use the following labels: 
 Analysis 
Period 
Label in summary table 
1 
Period 1: Uptravi, pre-treatment period 
2 
Period 2: i.v. selexipag, treatment period 
3&FU 
Period 3: Uptravi, post-treatment period including safety follow-up period 
2&3&FU 
Period 2 & 3: i.v. selexipag, treatment period and Uptravi, post-treatment period including safety follow-up period combined 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 90/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
T_VS_SUM 
 
ACT-293987 
Protocol: AC-065A309 
Summary and change from baseline of vital signs, by visit 
Analysis Set: Safety Analysis Set 
 
Parameter: Systolic blood pressure [mmHg] 
 
Treatment group 
Baseline 
Time Point 
Change from baseline 
  Time point 
n 
Mean 
SD 
Median 
Min 
Max 
Mean 
SD 
Median 
Min 
Max 
Mean 
SD 
Median 
Min 
Max 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uptravi b.i.d. dose 200-1000 ug (N=xxx) 
  Baseline 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Visit 2 Day 2 + 0 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                +25 min 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                +87 min 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 4 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 6 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 8 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                +12 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Visit 2 Day 3 + 0 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                +25 min 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                +87 min 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 4 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 6 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 8 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                +12 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Visit 3  
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uptravi b.i.d. dose 1200-1600 ug (N=xxx) 
  Baseline 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
  Visit 2 Day 2 + 0 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
   ... 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline is the Day 1 assessment or last assessment prior to Day 1. 
SD = Standard deviation 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Continue for Total. Then repeat for DBP and pulse. 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 91/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_VS_PREDS 
 
ACT-293987 
Protocol: AC-065A309 
Summary of post-dose values and change from pre-dose of vital signs, by visit 
Analysis Set: Safety Analysis Set 
 
Parameter: Systolic blood pressure [mmHg] 
 
Treatment group 
Pre-dose (+0 h) 
Time Point 
Change from pre-dose 
  Time point 
n 
Mean 
SD 
Median 
Min 
Max 
Mean 
SD 
Median 
Min 
Max 
Mean 
SD 
Median 
Min 
Max 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uptravi b.i.d. dose 200-1000 ug (N=xxx) 
  Visit 2 Day 2 + 0 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
                +25 min 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                +87 min 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 4 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 6 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 8 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                +12 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Visit 2 Day 3 + 0 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
                +25 min 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                +87 min 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 4 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 6 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 8 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                +12 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uptravi b.i.d. dose 1200-1600 ug (N=xxx) 
  Visit 2 Day 2 + 0 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
                +25 min 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                +87 min 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 4 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 6 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 8 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                +12 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Visit 2 Day 3 + 0 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
                +25 min 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                +87 min 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 4 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 6 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                + 8 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                +12 h 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SD = Standard deviation 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 92/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
Programming note: Continue for Total. Repeat for DBP and pulse. Show only visits where pre-/post-dose assessments were 
conducted (Visit 2 Day 2 and Visit 2 Day 3). 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 93/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_VS_ABN 
 
ACT-293987 
Protocol: AC-065A309 
Incidence of marked blood pressure abnormalities, by period 
Analysis Set: Safety Analysis Set 
 
Period 2: i.v. selexipag treatment period 
 
 
 
 
Uptravi b.i.d. dose  
 
 
 
 
200-1000 ug 
1200-1600 ug 
Total 
 
 
 
N = xxx 
N = xxx 
N = xxx 
Parameter 
Grade 
 
n / m (%) 
n / m (%) 
n / m (%) 
 
 
 
 
 
 
Supine SBP [mmHg] 
L 
SBP < 90 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
SBP decrease > 40 from baseline 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
H 
140 <= SBP <= 159 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
SBP increase > 20 from baseline 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HH 
SBP >= 160 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
 
 
Supine DBP [mmHg] 
L 
DBP < 50 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
DBP decrease > 20 from baseline 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
H 
90 <= DBP <= 99  
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
DBP increase > 20 from baseline 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
HH 
DBP >= 100 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
 
 
SBP = Systolic blood pressure, DBP = Diastolic blood pressure 
n = Subjects with event, m = Subjects with assessment in the specified time period (at risk) 
Post-baseline abnormalities not present at baseline or abnormalities worsening after baseline are shown. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
Programming note: Use the following labels: 
 
Analysis 
Period 
Label in summary table 
1 
Period 1: Uptravi, pre-treatment period 
2 
Period 2: i.v. selexipag, treatment period 
3&FU 
Period 3: Uptravi, post-treatment period including safety follow-up period 
2&3&FU 
Period 2 & 3: i.v. selexipag, treatment period and Uptravi, post-treatment period including safety follow-up period combined 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 94/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_EG_SUM 
 
ACT-293987 
Protocol: AC-065A309 
Summary and change from baseline of quantitative ECG parameters, by visit 
Analysis Set: Safety Analysis Set 
 
Parameter: ECG Mean heart rate [bpm] 
 
Treatment group 
Baseline 
Time Point 
Change from baseline 
  Time point 
n 
Mean 
SD 
Median 
Min 
Max 
Mean 
SD 
Median 
Min 
Max 
Mean 
SD 
Median 
Min 
Max 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uptravi b.i.d. dose 200-1000 ug (N=xxx) 
  Baseline 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Visit 2 Day 2 IV-1 pre 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                IV-1 post 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Visit 2 Day 2 IV-2 pre 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                IV-2 post 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Visit 2 Day 3 IV-3 pre 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                IV-3 post 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Visit 3  
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uptravi b.i.d. dose 1200-1600 ug (N=xxx) 
  Baseline 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Visit 2 Day 2 IV-1 pre 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
                IV-1 post 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   ... 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline is the Day 1 assessment or last assessment prior to Day 1. 
pre = pre-dose assessment prior to infusion, post = post dose assessment (within 30 minutes after end of infusion) 
SD = Standard deviation 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Continue for Total. Then repeat for PR Interval Single Beat [msec]; QRS Duration, Single Beat [msec]; QT 
Interval, Single Beat [msec]; QTcB Interval, Single Beat [msec]; QTcF Interval, Single Beat [msec]. 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 95/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_EG_PREDS 
 
ACT-293987 
Protocol: AC-065A309 
Summary of post-dose values and change from pre-dose of quantitative ECG parameters, by visit 
Analysis Set: Safety Analysis Set 
 
Parameter: ECG Mean heart rate [bpm] 
 
Treatment group 
Pre-dose 
Time Point 
Change from pre-dose 
  Time point 
n 
Mean 
SD 
Median 
Min 
Max 
Mean 
SD 
Median 
Min 
Max 
Mean 
SD 
Median 
Min 
Max 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uptravi b.i.d. dose 200-1000 ug (N=xxx) 
  Visit 2 Day 2 IV-1 pre 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
                IV-1 post 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Visit 2 Day 2 IV-2 pre 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
                IV-2 post 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Visit 2 Day 3 IV-3 pre 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
                IV-3 post 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uptravi b.i.d. dose 1200-1600 ug (N=xxx) 
  Visit 2 Day 2 IV-1 pre 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
                IV-1 post 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   ... 
xx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
xxx.x 
xx.xx 
xxx.x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pre = pre-dose assessment prior to infusion, post = post dose assessment (within 30 minutes after end of infusion) 
SD = Standard deviation 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Continue for Total. Then repeat for PR Interval Single Beat [msec]; QRS Duration, Single Beat [msec]; QT 
Interval, Single Beat [msec]; QTcB Interval, Single Beat [msec]; QTcF Interval, Single Beat [msec]. 
 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 96/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
T_EG_ABN 
 
ACT-293987 
Protocol: AC-065A309 
Incidence of ECG abnormalities - QT prolongation, by period 
Analysis Set: Safety Analysis Set 
 
Period 2: i.v. selexipag treatment period 
 
 
Uptravi b.i.d. dose  
 
 
200-1000 ug 
1200-1600 ug 
Total 
 
N=xxx 
N=xxx 
N=xxx 
Parameter 
n / m (%) 
n / m (%) 
n / m (%) 
 
 
 
 
QTc (Bazett's correction), [msec] 
 
 
 
  Value > 450 # 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
  Value > 480 # 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
  Value > 500 # 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
  Increase from baseline > 30 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
  Increase from baseline > 60 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
  Value > 450 and increase from baseline > 30 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
  Value > 450 and increase from baseline > 60 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
QTc (Fridericia's correction), [msec] 
 
 
 
  Value > 450 # 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
  Value > 480 # 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
  Value > 500 # 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
  Increase from baseline > 30 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
  Increase from baseline > 60 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
  Value > 450 and increase from baseline > 30 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
  Value > 450 and increase from baseline > 60 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
n = Subjects with event, m = Subjects with QTc evaluation (at risk) 
# Baseline value below treshold OR baseline value above treshold and post baseline value worsened (increased) 
If more than one ECG in a period has the same abnormality category, the subject is counted only once. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 97/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
Programming note: Use the following labels: 
 
Analysis 
Period 
Label in summary table 
1 
Period 1: Uptravi, pre-treatment period 
2 
Period 2: i.v. selexipag, treatment period 
3&FU 
Period 3: Uptravi, post-treatment period including safety follow-up period 
2&3&FU 
Period 2 & 3: i.v. selexipag, treatment period and Uptravi, post-treatment period including safety follow-up period combined 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 98/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
T_EG_QUAL 
 
ACT-293987 
Protocol: AC-065A309 
Summary of qualitative ECG findings, by visit 
Analysis Set: Safety Analysis Set 
 
 
Uptravi b.i.d. dose  
 
Visit 
200-1000 ug 
1200-1600 ug 
Total 
  Interpreation 
N=xxx 
N=xxx 
N=xxx 
    Finding 
n / m (%) 
n / m (%) 
n / m (%) 
 
 
 
 
Baseline/Visit 2 Day 1 
 
 
 
  Normal 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
  Unable to interpret 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
  Abnormal 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
    <Finding 1> 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
    <Finding 2> 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
    <Finding 3> 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
    <Finding 4> 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
Visit 2 Day 2 IV-1 pre 
 
 
 
  Normal 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
  Unable to interpret 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
  Abnormal 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
    <Finding 1> 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
    <Finding 2> 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
    <Finding 3> 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
    <Finding 4> 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
xxx / xxx (xx.x) 
 
 
 
 
Visit 2, Day 2 IV-1 post 
 
 
 
 
 
 
 
  ... 
 
 
 
 
 
 
 
 
 
 
 
Any time post baseline 
 
 
 
 
 
 
 
  ... 
 
 
 
 
 
 
 
Baseline is the Day 1 assessment or last assessment prior to Day 1. 
pre = pre-dose assessment prior to infusion, post = post doase assessment (within 30 minutes after end of infusion) 
n = Subjects with event, m = Subjects with qualitative evaluation (at risk in category) 
Findings not present at baseline are shown at post baseline timepoints. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 99/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Continue for all scheduled ECG assessments (Visit 2 Day 2 IV-2 pre/post, Visit 2 Day 3 IV3 pre/post, Visit 3) 
and for any time post baseline. Sort abnormalities by descending total incidence. 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 100/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_WHO_SUM 
 
ACT-293987 
Protocol: AC-065A309 
Summary of WHO functional class, by visit 
Analysis Set: Safety Analysis Set 
 
 
Uptravi b.i.d. dose  
 
 
200-1000 ug 
1200-1600 ug 
Total 
Visit 
N=xxx 
N=xxx 
N=xxx 
 WHO functional class 
n (%) 
n (%) 
n (%) 
 
 
 
 
Baseline 
 
 
 
  WHO FC I 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC II 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC III 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC IV 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Visit 2 Day 3  
 
 
 
  WHO FC I 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC II 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC III 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC IV 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Visit 3  
 
 
 
  WHO FC I 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC II 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC III 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC IV 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Worst post baseline (including unscheduled visits)  
 
 
 
  WHO FC I 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC II 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC III 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC IV 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Best post baseline (including unscheduled visits)  
 
 
 
  WHO FC I 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC II 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC III 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC IV 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Baseline is the Day 1 assessment or last assessment prior to Day 1. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: The missing category will only be presented if occurring in the 
data. 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 101/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_WHO_CHG 
 
ACT-293987 
Protocol: AC-065A309 
Shift table of WHO functional class from baseline to each study visit 
Analysis Set: Safety Analysis Set 
 
Treatment group: Uptravi b.i.d. dose 200-1000 ug (N=xxx) 
 
 
----------------------------- Baseline ------------------------------------ 
Visit 
WHO FC I 
WHO FC II 
WHO FC III 
WHO FC IV 
Missing 
 WHO functional  
 class 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
Visit 2 Day 3  
 
 
 
 
 
  WHO FC I 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC II 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC III 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC IV 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
Visit 3 
 
 
 
 
 
  WHO FC I 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC II 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC III 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC IV 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
Worst post-baseline (including unscheduled visits)  
 
 
  WHO FC I 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC II 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC III 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC IV 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
Best post-baseline (including unscheduled visits)  
 
 
  WHO FC I 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC II 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC III 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  WHO FC IV 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
Baseline is the Day 1 assessment or last assessment prior to Day 1. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: The missing category will only be presented if occurring in the 
data. Repeat for Dose >=1200 ug and total groups. 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 102/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_PK_CON_SUM 
 
ACT-293987 
Protocol: AC-065A309 
Summary of <selexipag/ACT-333679> plasma concentrations [ng/mL] per time point by dose level and 
treatment 
Analysis Set: Pharmacokinetic Analysis Set 
 
Dose group: 200 ug b.i.d. p.o./ 225 ug b.i.d. i.v. 
 
Treatment 
 
 
 
 
 
 
 
 Time 
 point 
n 
Arithmetic mean 
(95% CI) 
Geometric mean  
(95% CI) 
SD 
SE 
Min 
Median 
Max 
 
 
 
 
 
 
 
 
 
Uptravi 
 
 
 
 
 
 
 
   0 h 
xxx 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
xxx 
xxx 
xxx 
xxx 
xxx 
   1 h 
xxx 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
xxx 
xxx 
xxx 
xxx 
xxx 
   2 h 
xxx 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
xxx 
xxx 
xxx 
xxx 
xxx 
   4 h 
xxx 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
xxx 
xxx 
xxx 
xxx 
xxx 
   6 h 
xxx 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
xxx 
xxx 
xxx 
xxx 
xxx 
   8 h 
xxx 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
xxx 
xxx 
xxx 
xxx 
xxx 
  12 h 
xxx 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
i.v. selexipag 
 
 
 
 
 
 
   0 h   
xxx 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
xxx 
xxx 
xxx 
xxx 
xxx 
  25 min 
xxx 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
xxx 
xxx 
xxx 
xxx 
xxx 
  87 min 
xxx 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
xxx 
xxx 
xxx 
xxx 
xxx 
   4 h 
xxx 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
xxx 
xxx 
xxx 
xxx 
xxx 
   6 h 
xxx 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
xxx 
xxx 
xxx 
xxx 
xxx 
   8 h 
xxx 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
xxx 
xxx 
xxx 
xxx 
xxx 
  12 h 
xxx 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
CI = Confidence interval, SD = Standard deviation, SE = Standard error, p.o. = per os, b.i.d. = 
twice daily; i.v. = intravenous 
Implausible plasma concentrations are not included in the summary. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Continue for dose groups 400p.o./450i.v., 600p.o./675i.v., 
800p.o./900i.v., 
1000p.o./1125i.v., 
1200p.o./1350i.v., 
1400p.o./1575i.v., 
1600p.o./1800i.v., and dose normalized. 
 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 103/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
T_PK_EP_SUM 
ACT-293987 
Protocol: AC-065A309 
Summary of PK parameters of <selexipag/ACT-333679> by dose level and treatment 
Analysis Set: Pharmacokinetic Analysis Set 
 
Dose level: 200 ug b.i.d. p.o./ 225 ug b.i.d. i.v. 
 
PK parameter 
Uptravi 
i.v. selexipag 
  Statistic 
N=xxx 
N=xxx 
 
 
 
Subjects in dose level 
xxx 
xxx 
 
 
 
AUCtau,ss [ng.h/mL]  
 
 
  N 
xxx 
xxx 
  Arithmetic mean (95% CI) 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
  Geometric mean (95% CI) 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
  SD 
xx.x 
xx.x 
  SE 
xxx 
xxx 
  CV%  
xx.x 
xx.x 
  CV ln% 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
  Min, Max 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
Ctrough,ss, 0h [ng/mL]  
 
 
  n 
xxx 
xxx 
  Arithmetic mean (95% CI) 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
  Geometric mean (95% CI) 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
  SD 
xx.x 
xx.x 
  SE 
xxx 
xxx 
  CV%  
xx.x 
xx.x 
  CV ln% 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
  Min, Max 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
Ctrough,ss, 12h [ng/mL]  
 
 
  n 
xxx 
xxx 
  Arithmetic mean (95% CI) 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
  Geometric mean (95% CI) 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
  SD 
xx.x 
xx.x 
  SE 
xxx 
xxx 
  CV%  
xx.x 
xx.x 
  CV ln% 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
  Min, Max 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
Cmax,ss [ng/mL]  
 
 
  n 
xxx 
xxx 
  Arithmetic mean (95% CI) 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
  Geometric mean (95% CI) 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
  SD 
xx.x 
xx.x 
  SE 
xxx 
xxx 
  CV%  
xx.x 
xx.x 
  CV ln% 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
  Min, Max 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
tmax,ss [h]  
 
 
  n 
xxx 
xxx 
  Arithmetic mean (95% CI) 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
  SD 
xx.x 
xx.x 
  SE 
xxx 
xxx 
  CV w%  
xx.x 
xx.x 
 
 
 
  Median 
xx.x 
xx.x 
  Min, Max 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
CI = Confidence interval, SD = Standard deviation, SE = Standard error, CV% = Coefficient of 
variation [%], CV_b% = Between-subject coefficient of variation [%], CV_ln% = Coefficient of 
variation of logarithmized values [%], p.o. = per os, b.i.d. = twice daily, i.v. = intravenous 
Values obtained from implausible plasma concentrations are not included in the summary. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
Programming note: Continue for dose all dose levels and dose normalized. 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 104/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
T_PK_RATIO_SUM 
ACT-293987 
Protocol: AC-065A309 
Summary of PK parameters of ratio ACT-333679/selexipag concentration by dose level and treatment 
Analysis Set: Pharmacokinetic Analysis Set 
 
Dose level: 200 ug b.i.d. p.o./ 225 ug b.i.d. i.v. 
 
PK parameter 
Uptravi 
i.v. selexipag 
  Statistic 
N=xxx 
N=xxx 
 
 
 
Subjects in dose level 
xxx 
xxx 
 
 
 
AUCtau,ss [ng.h/mL]  
 
 
  N 
xxx 
xxx 
  Arithmetic mean (95% CI) 
xxx (xx.xx, xx.xx) 
xxx (xx.xx, xx.xx) 
  Geometric mean (95% CI) 
xxx (xx.xx, xx.xx) 
xxx (xx.xx, xx.xx) 
  SD 
xx.xxx 
xx.xxx 
  SE 
xx.xxx 
xx.xxx 
  CV%  
xx.xx 
xx.xx 
  CV ln% 
xx.xx 
xx.xx 
  Median 
xx.xx 
xx.xx 
  Min, Max 
xx.xx, xx.xx 
xx.xx, xx.xx 
 
 
 
Cmax,ss [ng/mL]  
 
 
  n 
xxx 
xxx 
  Arithmetic mean (95% CI) 
xxx (xx.xx, xx.xx) 
xxx (xx.xx, xx.xx) 
  Geometric mean (95% CI) 
xxx (xx.xx, xx.xx) 
xxx (xx.xx, xx.xx) 
  SD 
xx.xxx 
xx.xxx 
  SE 
xx.xxx 
xx.xxx 
  CV%  
xx.xx 
xx.xx 
  CV ln% 
xx.xx 
xx.xx 
  Median 
xx.xx 
xx.xx 
  Min, Max 
xx.xx, xx.xx 
xx.xx, xx.xx 
 
 
 
 
 
 
CI = Confidence interval, SD = Standard deviation, SE = Standard error, CV% = Coefficient of 
variation (SD/mean) [%], CV_ln% = Coefficient of variation of logarithmized values, [%] p.o. = 
per os, b.i.d. = twice daily; i.v.= intravenous 
Values obtained from implausible plasma concentrations are not included in the summary. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Continue for dose all dose levels and dose normalized.  
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 105/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_PK_MM 
ACT-293987 
Protocol: AC-065A309 
Mixed model analysis: Ratio of Uptravi and i.v. selexipag period for <selexipag/ACT-333679> by 
dose level  
Analysis Set: Pharmacokinetic Analysis Set 
 
Endpoint 
 
 
  Statistic 
Cmax,ss 
AUCtau ss 
 
 
 
Dose level: 200 ug b.i.d. p.o./ 225 ug b.i.d. i.v. 
  n 
xxx 
xxx 
  Ratio of geom. means (i.v./p.o) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
  90% CI  
x.xxx, x.xxx 
x.xxx, x.xxx 
  CV b[%] 
xx.xx 
xx.xx 
 
 
 
Dose level: 400 ug b.i.d. p.o./ 450 ug b.i.d. i.v. 
  n 
xxx 
xxx 
  Ratio of geom. means (i.v./p.o) 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
  90% CI  
x.xxx, x.xxx 
xxx (xx.x, xx.x) 
  CV b[%] 
xx.x 
xx.x 
 
 
 
Dose level: ...  
  n 
xxx 
xxx 
  Ratio of geom. means (i.v./p.o) 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
  90% CI  
x.xxx, x.xxx 
xxx (xx.x, xx.x) 
  CV b[%] 
xx.x 
xx.x 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
Dose level: Normalized dose (200 ug) 
  n 
xxx 
xxx 
  Ratio of geom. means (i.v./p.o) 
xxx (xx.x, xx.x) 
xxx (xx.x, xx.x) 
  90% CI  
x.xxx, x.xxx 
xxx (xx.x, xx.x) 
  CV b[%] 
xx.x 
xx.x 
 
 
 
 
 
 
CI = Confidence interval, n.e. = not estimable. p.o. = per os, b.i.d. = twice daily; i.v. = 
intravenous  
Geometric mean ratios were obtained by computing the anti-log of the treatment group difference 
of a mixed model with treatment as fixed and subject as random effect to the log-transformed 
data. CV_b[%] was computed using the mean squared error or residuals as a measure of variation. 
Values obtained from implausible plasma concentrations are not included in the analysis. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Display all dose levels. For dose levels not sufficiently populated 
to allow an estimation populate only 'n' row and show 'n.e.' for the remaining 
statistics. 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 106/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_PK_POW 
ACT-293987 
Protocol: AC-065A309 
Dose proportionality of AUCtau of <selexipag/ACT-333679> after i.v. selexipag: Power model 
estimation 
Analysis Set: Pharmacokinetic Analysis Set 
 
 
 
 
 
n 
beta 
SE(beta) 
90% CI 
 
 
 
 
xxx 
x.xxx 
xx.xxxx 
x.xxx, x.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CI = Confidence interval 
Dose proportionality will be assumed if beta is close to 1, i.e., if the CI of beta includes 1. 
Values obtained from implausible plasma concentrations are not included in the analysis. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Produce table only if sufficient subjects are included in at least 
three dose levels. 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 107/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
T_PK_WIL 
ACT-293987 
Protocol: AC-065A309 
Location shift analysis of tmax, ss of <selexipag/ACT-333679> 
Analysis Set: Pharmacokinetic Analysis Set 
 
 
 
i.v. selexipag - Uptravi 
 
n 
Median 
90% CI 
p-value 
 
 
 
 
xxx 
x.xxx 
x.xxx, x.xxx 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CI = Confidence interval from a Hodges - Lehmann estimation. 
p-value is derived from a Wilcoxon signed rank test. 
Values obtained from implausible plasma concentrations are not included in the analysis. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 108/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
F_EXP 
ACT-293987 
Protocol: AC-065A309 
Shift in selexipag dose between oral and i.v. treatment 
Analysis Set: i.v. Safety Analysis Set 
 
 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
Programming note: This is just a conceptual graphic showing subjects from two dose levels (there will be more levels in the study). 
Adapt to Actelion standards. Jitter series plots such that individual subject lines are clearly visible. Do use color for each series plot. 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 109/135 
Confidential 
Statistical Analysis Plan 
Doc No D-18.239 
F_PK_POW 
ACT-293987 
Protocol: AC-065A309 
Dose proportionality of AUCtau <selexipag/ACT-333679> after i.v. selexipag: Power model estimation 
Analysis Set: Pharmacokinetic Analysis Set 
Values obtained from implausible plasma concentrations are not included in the analysis. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
Programming note: This is just a general sketch: Display log dose vs. log AUC and display a regression line from the model with 
the slope of estimated beta. Add a second line with beta (i.e., slope) =1 as reference. 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 110/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_SCRF 
 
ACT-293987 
Protocol: AC-065A309 
Listing of screening failures 
Analysis Set: Screened Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
 
 
number 
Date 
Reason for screening failure 
 
 
 
1001001 
ddMMMyyyy 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
1001002 
ddMMMyyyy 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Add specification for reason of screening failure, if available from the database. 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 111/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_PWDS 
 
ACT-293987 
Protocol: AC-065A309 
Listing of reasons for premature discontinuation from the study  
Analysis Set: Screened Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
 
 
 
 
number 
Status 
Date / Day 
Reason for discontinuation from the study 
Details 
 
 
 
 
 
1001001 
Completed 
ddMMMyyy / xxx 
 
 
1001002 
Discontinued 
ddMMMyyy / xxx 
Death 
 
1001003 
Discontinued 
ddMMMyyy / xxx 
Physician decision 
xxxx xxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 112/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_PHYS 
 
ACT-293987 
Protocol: AC-065A309 
Listing of physical examination results  
Analysis Set: Screened Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
number 
Visit 
Date / Day 
Body system 
Result 
Specify abnormality 
Clin. 
sign. 
 
 
 
 
 
 
 
1001001 
Screening 
ddMMMyyy / xxx 
General appearance 
Normal 
 
 
 
 
 
Head, ears, eyes, nose, throat 
Abnormal 
XXXXXXXXXX 
No 
 
 
 
... 
 
 
 
 
Visit 2 - Day 1 
ddMMMyyy / xxx 
... 
 
 
 
 
 
 
 
 
 
 
 
Visit 3 
ddMMMyyy / xxx 
 
 
 
 
 
 
 
 
 
 
 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Display ‘not done’ in the result section if a specific physical examination was databased as such. 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 113/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_PWDT 
 
ACT-293987 
Protocol: AC-065A309 
Listing of reasons for premature discontinuation of i.v. selexipag treatment 
Analysis Set: i.v. Safety Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
 
 
 
number 
Status 
Reason for discontinuation of i.v. selexipag 
treatment 
Details 
 
 
 
 
1001001 
Completed 
 
 
1001002 
Discontinued 
Death 
 
1001003 
Discontinued 
Physician decision 
xxxx xxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 114/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_AE 
 
ACT-293987 
Protocol: AC-065A309 
Listing of <Listing title> 
Analysis Set: <Analysis set> 
 
Country: <country>, Site: <Site number> 
 
Subject 
number 
System Organ Class 
  Preferred Term 
    (Reported Term) 
Start 
date/ 
time/Day 
End date/ 
time/Day 
Duration 
(days) 
Seri 
ous 
Ser. 
crit. 
Inten 
sity 
Concom. 
trt.  
given 
Action  
taken i.v. 
selexipag 
Related 
 to i.v. 
selexipag 
Outcome 
 
 
 
 
 
 
 
 
 
 
 
 
1001001 
xxxxxxxxxxxxxxxxxxx 
  XXXXXXXXXXXXXXXX 
    (XXX XXX XXXX) 
ddMMMyyyy/ 
hh:mm/xx 
ddMMMyyyy/ 
hh:mm/xx 
xx 
Y 
2,3 
sev 
Y 
6 
Y 
Revcovered/ 
Resolved 
 
 
 
 
 
 
 
 
 
 
 
 
1001002 
xxxxxxxxxxxxxxxxxxx 
  XXXXXXXXXXXXXXXX 
    (XXX XXX XXXX)§ 
ddMMMyyyy/ 
hh:mm/xx 
ddMMMyyyy/ 
hh:mm/xx 
xx 
N 
 
mod 
N 
6 
N 
Revcovering/ 
Resolving 
 
 
 
 
 
 
 
 
 
 
 
 
§ = Injection site reaction adverse event 
Seriousness criteria: 1 Death, 2 Life-threatening, 3 Results in significant disability, 4 Birth defect/congenital anomaly,  
                      5 Required/Prolonged hospitalization, 6 Other medical importance 
Action taken with i.v. selexipag: 1 Dose not changed, 2 Dose increased, 3 Dose reduced, 4 Drug interrupted, 5 Drug withdrawn,  
                                  6 Not applicable, 7 Unknown 
Intensity: mild = Mild, mod = Moderate,  sev = Severe 
System Organ Classes and Preferred Terms are based on MedDRA version <xx.x>. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 115/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_DTH 
 
ACT-293987 
Protocol: AC-065A309 
Listing of all deaths 
Analysis Set: Safety Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
Death 
Primary cause of death 
number 
Date / Time / Day 
  (Reported term) 
 
 
 
1001002 
ddMMMyyy / hh:mm / xxx 
XXXXXXXX 
 
 
  (XXXXXXXXXXXXXXXXXXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Preferred Terms are based on MedDRA version <xx.x>. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 116/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
L_AEINJ 
 
ACT-293987 
Protocol: AC-065A309 
Listing of all injection site reactions 
Analysis Set: i.v. Safety Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
Onset 
Resolution 
 
 
Clinically 
Adverse event 
number 
Date / Time / Day 
Date / Time / Day 
Criteria 
Grade 
Significant 
Preferred Term 
 
 
 
 
 
 
 
1001002 ddMMMyyy / hh:mm / xxx ddMMMyyy / hh:mm / xxx Swelling 
Moderate 
Y 
XXXXXXXXX 
 
ddMMMyyy / hh:mm / xxx ddMMMyyy / hh:mm / xxx Pain 
Mild 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Preferred Terms are based on MedDRA version <xx.x>. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 117/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_LAB 
 
ACT-293987 
Protocol: AC-065A309 
Listing of laboratory parameters 
Analysis Set: Screened Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
 
 
Study 
 
Reference 
Change from baseline 
number 
Parameter [SI Unit] 
Visit 
Day 
Value 
Range 
Absolute 
Percent 
 
 
 
 
 
 
 
 
1001002 
Hemoglobin [g/L] 
Screening 
 
xxxx    
xxx - xxx 
xxx 
xxx 
 
 
Unscheduled 
 
xxxx H  
xxx - xxx 
xxx 
xxx 
 
 
Unscheduled 
 
xxxx$   
xxx - xxx 
xxx 
xxx 
 
 
Visit 2 - Day 1 
 
xxxx*HH 
xxx - xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* = Baseline, H = Above upper limit of normal range, L = Below lower limit of normal range (as flagged by the laboratory) 
$ = Local lab value, not used for summary tables 
HH, HHH:  Marked abnormally high values, LL, LLL:  Marked abnormally low values (derived using SI units) 
Newly occurring or worsening post-baseline marked abnormalities are flagged. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 118/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_VS 
 
ACT-293987 
Protocol: AC-065A309 
Listing of vital signs, body weight and height 
Analysis Set: Screened Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
 
 
Study 
Time 
 
Change from 
number 
Parameter [SI Unit] 
Visit 
Day 
point 
Value 
baseline 
 
 
 
 
 
 
 
1001002 
Systolic blood pressure [mmHg] 
Screening 
xx 
 
xxxx    
xxxxx 
 
 
Visit 2 - Day 1 
xx 
Pre dose 
xxxx*   
xxxxx 
 
 
 
 
+ 25 min 
xxxxHH  
xxxx 
 
 
 
 
+ 87 min 
xxxx    
xxxxx 
 
 
 
 
+ 4 h 
xxxx    
xxxx 
 
 
 
 
 
 
 
* = Baseline, HH:  Marked abnormally high values, LL:  Marked abnormally low values 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
Newly occurring or worsening post-baseline marked abnormalities are flagged. 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 119/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_PD 
 
ACT-293987 
Protocol: AC-065A309 
Listing of protocol deviations 
Analysis Set: Screened Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
 
 
 
Exclusion from 
Important 
number 
Category 
Identifier 
Description 
PKS 
PD 
 
 
 
 
 
 
1001002 
Screening period 
000 
XXXXXXXXXXXXXXXXX 
Yes 
Yes 
 
Treatment and observation period  
000 
YYYYYYYYYYYYYYYYYY 
No 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 120/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_ANSET 
 
ACT-293987 
Protocol: AC-065A309 
Listing of analysis sets 
Analysis Set: Screened Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
Screened 
Safety 
i.v. Safety 
Pharmacokinetic 
 
number 
analysis set (SCR) 
analysis set (SAF) 
analysis set (ivSAF) 
analysis set (PKS) 
Reason 
 
 
 
 
 
 
1001001 
Yes 
No 
No 
No 
Not treated with i.v. 
selexipag 
1001002 
Yes 
Yes 
Yes 
No 
XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 121/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_DEM 
 
ACT-293987 
Protocol: AC-065A309 
Listing of demographics 
Analysis Set: Screened Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
Age 
Sex 
Race 
Ethnicity 
Weight 
Height 
BMI 
number 
[years] 
 
 
 
[kg] 
[cm] 
[kg/m^2] 
 
 
 
 
 
 
 
 
1001001 
23 
M 
White 
Hispanic or Latino 
81.1 
180 
25.0 
1001002 
65 
F 
Other: xxxxx 
Not Hispanic or Latino 
74.2 
163 
27.9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI = Body mass index 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 122/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_BAS 
 
ACT-293987 
Protocol: AC-065A309 
Listing of baseline disease characteristics  
Analysis Set: Screened Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
number 
Date of initial PAH 
diagnosis 
Months since initial 
diagnosis at baseline 
Etiology of PAH 
PAH associated 
with 
Uptravi dose at 
screening [ug bid] 
WHO functional 
class 
 
 
 
 
 
 
 
1001001 
ddMMMyyyy 
xx.x 
Idiopathic PAH 
 
800 
II 
1001002 
ddMMMyyyy 
xx.x 
PAH associated 
with 
Connective tissue 
disease 
1200 
III 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 123/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_MH 
 
ACT-293987 
Protocol: AC-065A309 
Listing of medical history  
Analysis Set: Safety Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
number 
System Organ Class 
  Preferred Term 
    (Reported Term) 
Start date 
End date 
Ongoing at 
Screening 
 
 
 
 
 
1001001 
xxxxxxxxxxxxxxxxxxx 
  XXXXXXXXXXXXXXXX 
    (XXX XXX XXXX) 
ddMMMyyyy 
ddMMMyyyy 
 
 
 
 
 
 
1001002 
xxxxxxxxxxxxxxxxxxx 
  XXXXXXXXXXXXXXXX 
    (XXX XXX XXXX) 
ddMMMyyyy 
 
Yes 
 
 
 
 
 
System Organ Classes and Preferred Terms are based on MedDRA version <xx.x>. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 124/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_CM 
 
ACT-293987 
Protocol: AC-065A309 
<Title> 
Analysis Set: Safety Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
number 
ATC Class 
  Preferred Term 
    (Reported Term) 
Start date / 
Day 
End date / 
Day 
Start 
in 
Period 
End in 
Period 
Started 
prior to 
start of 
i.v. 
selexipag? 
Ongoing 
at End 
of 
Study 
Dose/Unit/Frequency/Indication/Route 
 
 
 
 
 
 
 
 
 
1001001 xxxxxxxxxxxxxxxxxxx 
  XXXXXXXXXXXXXXXX# [1] 
    (XXX XXX XXXX) 
ddMMMyyyy/xx ddMMMyyyy/xx 
 
1 
Yes 
No 
25/mg/bid/XXXXXX/Oral 
 
 
 
 
 
 
 
 
 
1001002 xxxxxxxxxxxxxxxxxxx 
  XXXXXXXXXXXXXXXX 
    (XXX XXX XXXX) 
ddMMMyyyy/xx 
 
FU 
 
No 
Yes 
XXXX/XXX/XXXX/XXXXXX/XXXX 
 
 
 
 
 
 
 
 
 
ATC Classes and Preferred Terms are based on WHO-DRUG dictionary version <xxx>. 
# PAH specific medication 
[1] Previous therapy, [2] Ongoing therapy, [3] Study concomitant therapy 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 125/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_EXP_PO 
 
ACT-293987 
Protocol: AC-065A309 
Listing of Uptravi dosing records 
Analysis Set: Safety Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject number 
Time point 
Uptravi  
administered 
Date/time 
Uptravi dose [ug] 
 
 
 
 
 
1001001 
Evening before Day 1 
 
ddMMMyyyy/hh:mm 
800 
 
Day 1 - Morning 
 
ddMMMyyyy/hh:mm 
800 
 
Day 1 - Evening 
 
ddMMMyyyy/hh:mm 
600 
 
Day 3 - Evening 
No 
 
 
 
 
 
 
 
1001002 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 126/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_EXP_IV 
 
ACT-293987 
Protocol: AC-065A309 
Listing of study treatment dosing records 
Analysis Set: i.v. Safety Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
number 
Time point/ 
Visit 
Start date/time 
End date/time 
Duration 
[min] 
Concentration 
[ug/mL] 
Infusion rate  
[mL/h] 
Reason for change/end 
 
 
 
 
 
 
 
 
1001001 
Day 2 morning 
ddMMMyyyy/hh:mm 
ddMMMyyyy/hh:mm 
xx 
22.5 
20 
Infusion rate change 
 
Day 2 evening 
ddMMMyyyy/hh:mm 
ddMMMyyyy/hh:mm 
xx 
22.5 
37.5 
Temporarily interrupted due to 
an AE 
 
Day 3 morning 
ddMMMyyyy/hh:mm 
ddMMMyyyy/hh:mm 
xx 
22.5 
20 
Completed as per protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1001002 
.... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 127/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_COMP 
 
ACT-293987 
Protocol: AC-065A309 
Listing of compliance with i.v. selexipag treatment 
Analysis Set: i.v. Safety Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject number 
Time point/ 
Visit 
Planned dose 
[ug] 
Actual dose [ug] 
Compliance [%] 
 
 
 
 
 
1001001 
Day 2 morning 
900 
850 
94.4 
 
Day 2 evening 
900 
870 
96.7 
 
Day 3 morning 
900 
900 
100.0 
 
Overall 
 
 
97.0 
 
 
 
 
 
1001002 
 
 
 
 
 
 
 
 
 
 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 128/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_EG 
 
ACT-293987 
Protocol: AC-065A309 
Listing of quantitative ECG measurements 
Analysis Set: Safety Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
Visit / Time 
Date/time 
Heart rate 
RR  
PR  
QRS  
QT 
QTcB 
QTcF 
number 
point 
 
[bpm] 
[ms] 
[ms] 
[ms] 
[ms] 
[ms] 
[ms] 
 
 
 
 
 
 
 
 
 
 
1001002 
Visit 2 - Day 1 
ddMMMyyyy/hh:mm 
xx*  
xxx*  
xxx*  
xxx*  
xxx*  
xxx*  
xxx*  
 
Unscheduled  
ddMMMyyyy/hh:mm 
xx   
xxx   
xxx   
xxx   
xxx   
xxx   
xxx   
 
Visit 2 - Day 2 IV-1 pre-dose 
ddMMMyyyy/hh:mm 
xx   
xxx   
xxx   
xxx   
xxx   
xxx   
xxx   
 
Visit 2 - Day 2 IV-1 post-dose 
ddMMMyyyy/hh:mm 
xx   
xxx   
xxx   
xxx   
xxx   
xxx # 
xxx   
 
Visit 2 - Day 2 IV-2 pre-dose 
ddMMMyyyy/hh:mm 
xx # 
xxx   
xxx # 
xxx   
xxx   
xxx   
xxx   
 
Visit 2 - Day 2 IV-2 post-dose 
ddMMMyyyy/hh:mm 
xx   
xxx   
xxx   
xxx   
xxx   
xxx # 
xxx   
 
Visit 2 - Day 3 IV-3 pre-dose 
ddMMMyyyy/hh:mm 
xx   
xxx   
xxx # 
xxx   
xxx   
xxx   
xxx   
 
Visit 2 - Day 3 IV-3 post-dose 
ddMMMyyyy/hh:mm 
xx   
xxx   
xxx   
xxx   
xxx   
xxx   
xxx   
 
Visit 3 
ddMMMyyyy/hh:mm 
xx   
xxx   
xxx   
xxx   
xxx   
xxx   
xxx   
 
 
 
 
 
 
 
 
 
 
 
QTcB = QT interval Bazett's correction, QTcF = QT interval Fridericia's correction 
* = Baseline, # = Marked abnormal value 
Newly occurring or worsening post-baseline marked abnormalities are flagged. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 129/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_EG_QUAL 
 
ACT-293987 
Protocol: AC-065A309 
Listing of qualitative ECG findings 
Analysis Set: Safety Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
Visit / Time 
Date/time 
 
 
number 
point 
 
Interpretation 
Findings 
 
 
 
 
 
1001002 
Visit 2 - Day 1 
ddMMMyyyy/hh:mm 
Normal 
 
 
Unscheduled 
ddMMMyyyy/hh:mm 
Abnormal 
XXXX 
 
Visit 2 - Day 2 IV-1 pre-dose 
ddMMMyyyy/hh:mm 
Normal 
 
 
Visit 2 - Day 2 IV-1 post-dose 
ddMMMyyyy/hh:mm 
Normal 
 
 
Visit 2 - Day 2 IV-2 pre-dose 
ddMMMyyyy/hh:mm 
Normal 
 
 
Visit 2 - Day 2 IV-2 post-dose 
ddMMMyyyy/hh:mm 
Normal 
 
 
Visit 2 - Day 3 IV-3 pre-dose 
ddMMMyyyy/hh:mm 
Normal 
 
 
Visit 2 - Day 3 IV-3 post-dose 
ddMMMyyyy/hh:mm 
Normal 
 
 
Visit 3 
ddMMMyyyy/hh:mm 
Normal 
 
 
 
 
 
 
 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: Layout may change with the structure of the data. 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 130/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_WHO 
 
ACT-293987 
Protocol: AC-065A309 
Listing of WHO functional class 
Analysis Set: Screened Analysis Set 
 
Country: <country>, Site: <Site number> 
 
Subject 
 
 
number 
Visit 
WHO functional class 
 
 
 
1001003 
Screening 
II 
 
Visit 2 - Day 1 
II* 
 
Visit 2 - Day 3 
III 
 
Unscheduled 
II 
 
Visit 3 
I 
 
 
 
* = Baseline 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 131/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_PK_CONC 
 
ACT-293987 
Protocol: AC-065A309 
Listing of selexipag / ACT-333679 plasma concentrations 
Analysis Set: Pharmacokinetic Analysis Set 
 
Subject number 
Visit  
Timepoint 
Selexipag concentration 
 [ng/mL] 
ACT-333679 concentration 
 [ng/mL] 
 
 
 
 
 
1001002 
Visit 2 - Day 1 
Pre-dose 
xxx # 
xxx # 
 
 
1 h post-dose 
xxx   
xxx   
 
 
2 h post-dose 
xxx   
xxx   
 
 
... 
 
 
 
 
 
 
 
 
Visit 2 - Day 3 
Pre-infusion start 
xxx # 
xxx # 
 
 
25 min post infusion start 
xxx   
xxx   
 
 
87 min post infusion start 
xxx   
xxx   
 
 
4 h post infusion start 
xxx # 
xxx # 
 
 
... 
 
 
 
 
 
 
 
1001003 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
# = Implausible plasma concentration 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: List by subject. Only list subjects who provided data. Layout may change slightly depending upon data 
structure. 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 132/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_PK_DER 
 
ACT-293987 
Protocol: AC-065A309 
Listing of derived PK parameters of selexipag and ACT-333679 
Analysis Set: Pharmacokinetic Analysis Set 
 
 
 
 
i.v. selexipag 
Uptravi 
Ratio i.v. selexipag / 
Uptravi 
Parameter 
Subject 
number 
Time point 
Dose 
[ug 
bid] 
Selexipag  
ACT-
333679  
Dose 
[ug 
bid] 
Selexipag  
ACT-
333679  
Selexipag  ACT-333679  
 
 
 
 
 
 
 
 
 
 
 
Ctrough,ss [ng/mL] 
1001002 
Pre-dose 
xxxx 
xxx# 
xxx# 
xxx  
xxx  
xxx  
xxx  
xxx  
 
 
12 h post-dose 
xxxx 
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
 
1001004 
Pre-dose 
xxxx 
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
 
 
12 h post-dose 
xxxx 
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
 
 
 
 
 
 
 
 
 
 
 
Dose normalized 
Ctrough,ss,norm 
[ng/mL] 
1001002 
Pre-dose 
xxxx 
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
 
 
12 h post-dose 
xxxx 
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
 
 
 
 
 
 
 
 
 
 
 
Cmax,ss [ng/mL] 
1001002 
 
xxxx 
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
.... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose normalized 
Cmax,ss,norm [ng/mL] 
1001002 
 
 
xxx  
xxx  
 
xxx  
xxx  
xxx  
xxx  
.... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AUCtau,ss [ng*h/mL] 
1001002 
 
xxxx 
xxx# 
xxx# 
xxxx 
xxx  
xxx  
xxx  
xxx  
.... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose normalized 
AUCtau,ss, norm 
[ng*h/mL] 
1001002 
 
 
xxx  
xxx  
 
xxx  
xxx  
xxx  
xxx  
.... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
tmax,ss [h] 
1001002 
 
xxxx 
xxx  
xxx  
xxx  
xxx  
xxx  
 
 
.... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
# = Obtained from implausible plasma concentration 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: List by parameter, then by subject. Do not display ratios for t_max. 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 133/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_PK_RATIO 
 
ACT-293987 
Protocol: AC-065A309 
Listing of Cmax,ss and AUCtau,ss ratio of ACT-333679/selexipag 
Analysis Set: Pharmacokinetic Analysis Set 
 
 
 
Cmax,ss Ratio  
ACT-333679/selexipag 
AUCtau,ss Ratio  
ACT-333679/selexipag 
Dose [ug bid] 
Subject number 
Uptravi 
i.v. selexipag 
Uptravi 
i.v. selexipag 
 
 
 
 
 
 
200 ug b.i.d. p.o. / 225 ug b.i.d. i.v. 
1001002 
xxx  
xxx  
xxx# 
xxx  
 
1001003 
xxx  
xxx  
xxx  
xxx  
 
1001005 
xxx  
xxx  
xxx  
xxx  
 
 
 
 
 
 
400 ug b.i.d. p.o. / 450 ug b.i.d. i.v. 
1001004 
xxx  
xxx  
xxx  
xxx  
 
1001010 
xxx  
xxx  
xxx  
xxx  
 
 
 
 
 
 
... 
1001006 
xxx  
xxx  
xxx  
xxx  
 
 
 
 
 
 
 
 
 
 
 
 
Dose Normalized 
1001002 
xxx  
xxx  
xxx# 
xxx  
 
1001003 
xxx  
xxx  
xxx  
xxx  
 
1001004 
xxx  
xxx  
xxx  
xxx  
 
1001005 
xxx  
xxx  
xxx  
xxx  
 
 
 
 
 
 
 
 
 
 
 
 
# = Obtained from at least one impalusible plasma concentration 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: List by dose, then by subject. Only list subjects who provided steady state data. 
 
 
 


Selexipag (ACT 293987) 
Study AC-065A309 
2 July 2018, page 134/135 
Confidential  
Statistical Analysis Plan 
Doc No D-18.239 
 
 
 
L_IMP_CONC 
 
ACT-293987 
Protocol: AC-065A309 
Listing of selexipag concentration in the infusion solution 
Analysis Set: Pharmacokinetic Analysis Set 
 
Subject number 
Visit / Time point 
Selexipag concentration 
(eCRF) [ug] 
Actual selexipag concentration 
[ug] 
 
 
 
 
1001002 
Visit 2 - Day 2 IV-1  
xxx 
xxx 
 
Visit 2 - Day 2 IV-2  
xxx 
xxx 
 
Visit 2 - Day 3 IV-3  
xxx 
xxx 
 
 
 
 
1001003 
Visit 2 - Day 2 IV-1  
xxx 
xxx 
 
Visit 2 - Day 2 IV-2  
xxx 
xxx 
 
Visit 2 - Day 3 IV-3  
xxx 
xxx 
 
 
 
 
1001006 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Actual selexipag concentration was assessed using a validated liquid chromatography with UV detector assay. 
Output: <Output name>, Produced by DATAMAP on ddMMMyyyy hh:mm (CET), 
SDTM Date: ddMMMyyyy 
Program: /<folder>/<program_name>.sas 
Page x of y 
 
Programming note: List by subject. Only list subjects who provided data. Layout may change slightly depending upon data 
structure.