Long-term Single-arm Open-label Study, to Assess the Safety and Tolerability of ACT-293987 in Patients With Pulmonary Arterial Hypertension
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Sponsor: Actelion

TPL-000052_v12
Selexipag / ACT-293987 
Pulmonary Arterial Hypertension 
Protocol AC-065A303 
GRIPHON OL 
Long-term single-arm open-label study, to assess the safety and tolerability of 
selexipag (ACT-293987) in patients with pulmonary arterial hypertension 
Document type 
Clinical Study Protocol 
Study Phase 
3 
EudraCT Number 
2009-014992-31 
Document status 
Final Version 9 
Date 
6 February 2019 
Number of pages 
65 
Actelion number 
D-19.045
Confidentiality statement 
The information contained in this document, especially unpublished data, is the property of the sponsor of 
this study, Actelion Pharmaceuticals Ltd. It is therefore provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an Ethics Committee or Institutional 
Review Board. It is understood that this information will not be disclosed to others without written 
authorization from Actelion Pharmaceuticals Ltd, except to the extent necessary to obtain informed consent 
from those persons to whom the study drug may be administered. 
NCT01112306

Selexipag / ACT-293987 
Pulmonary arterial hypertension 
Protocol AC-065A303/GRIPHON OL 
Final Version 9 
6 February 2019, page 4/65 
Confidential 
EudraCT 2009-014992-31 
Doc No D-19.045 
 
INVESTIGATOR SIGNATURE PAGE 
Drug name / number 
Selexipag / ACT-293987 
Disease 
Pulmonary arterial hypertension. 
Protocol number and acronym 
AC-065A303 / GRIPHON OL 
Long-term single-arm open-label study, to assess the safety and tolerability of selexipag 
(ACT-293987) in patients with pulmonary arterial hypertension 
I agree to the terms and conditions relating to this study as defined in this protocol, the Case 
Report Form (CRF), and any other protocol-related documents. I fully understand that any 
changes instituted by the investigator(s) without previous agreement with the sponsor would 
constitute a protocol deviation, including any ancillary studies or procedures performed on study 
subjects (other than those procedures necessary for the wellbeing 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 or legally designated representatives have understood the nature, 
objectives, benefits, implications, risks and inconveniences for participating in this study. During 
the conduct of the study, I will constantly monitor the risk/benefit balance for an individual 
subject. I confirm herewith that the sponsor is allowed to enter and utilize my professional contact 
details and function in an electronic database for internal purposes and for submission to health 
authorities worldwide. 
 
 
Country 
 Center 
number 
 
Town 
 
Date 
 
Signature 
Center 
Principal 
Investigator 
 
 
 
 
 
 
 
 
 

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Pulmonary arterial hypertension 
Protocol AC-065A303/GRIPHON OL 
Final Version 9 
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Confidential 
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TABLE OF CONTENTS 
SPONSOR AND CRO CONTACT DETAILS ...................................................................2 
SUBSTANTIAL GLOBAL AMENDMENT 8 .................................................................12 
PROTOCOL SYNOPSIS AC-065A303/GRIPHON OL...................................................16 
1 
BACKGROUND AND RATIONALE .......................................................................24 
1.1 
Pulmonary arterial hypertension ...................................................................24 
1.2 
Prostacyclin and pulmonary hypertension ....................................................25 
1.3 
Selexipag – a non-prostanoid IP receptor agonist ........................................26 
1.3.1 
Preclinical information .....................................................................26 
1.3.2 
Clinical information ..........................................................................27 
1.3.2.1 
Phase 1 studies in healthy subjects ..........................................27 
1.3.2.2 
Phase 2 studies in patients with pulmonary arterial 
hypertension ............................................................................29 
1.4 
Study rationale ..............................................................................................30 
1.4.1 
Medical and regulatory background .................................................30 
1.4.2 
Patient population .............................................................................31 
1.4.3 
Study design ......................................................................................31 
1.4.4 
Comparative drug(s) and/or placebo .................................................31 
1.4.5 
Dose selection ...................................................................................31 
1.4.6 
Treatment duration ............................................................................33 
1.4.7 
Primary endpoint ...............................................................................33 
1.4.8 
Statistical hypotheses and sample size ..............................................33 
2 
STUDY OBJECTIVES ...............................................................................................33 
3 
INVESTIGATIONAL PLAN .....................................................................................33 
3.1 
Overall study design .....................................................................................33 
3.2 
Study population ...........................................................................................35 
3.2.1 
Patient population .............................................................................35 
3.2.2 
Inclusion criteria ...............................................................................35 
3.2.3 
Exclusion criteria ..............................................................................36 
3.2.4 
Concomitant medications .................................................................36 
3.2.4.1 
Allowed concomitant medications ..........................................36 
3.2.4.2 
Prohibited concomitant medications .......................................37 
3.3 
Study drug .....................................................................................................38 
3.3.1 
Investigational drug ..........................................................................38 

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Pulmonary arterial hypertension 
Protocol AC-065A303/GRIPHON OL 
Final Version 9 
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3.3.2 
Study drug up-titration ......................................................................38 
3.3.3 
Study drug dosing scheme (titration period only) ............................39 
3.4 
Study drug discontinuation and study withdrawal .......................................39 
3.4.1 
Study drug interruption or permanent discontinuation .....................39 
3.4.2 
Patient’s follow-up after study drug discontinuation ........................40 
3.4.3 
Study withdrawal ..............................................................................40 
3.4.4 
Study completion ..............................................................................40 
3.4.5 
Replacement policy ...........................................................................40 
3.4.5.1 
Patients ....................................................................................40 
3.4.5.2 
Centers .....................................................................................40 
3.5 
Treatment exposure, compliance and drug accountability ...........................41 
3.6 
Treatment assignment ...................................................................................41 
3.6.1 
Treatment assignment .......................................................................41 
3.6.2 
Blinding ............................................................................................41 
3.6.3 
Emergency procedure for unblinding ...............................................41 
3.7 
Study drug packaging and labeling ..............................................................41 
3.7.1 
Study drug packaging .......................................................................41 
3.7.2 
Study drug labeling ...........................................................................41 
3.7.3 
Study drug storage and dispensing ...................................................41 
3.8 
Study endpoints ............................................................................................42 
3.8.1 
Efficacy endpoints ............................................................................42 
3.8.2 
Safety and tolerability endpoints ......................................................42 
3.9 
Study assessments .........................................................................................42 
3.9.1 
Safety and tolerability assessments ...................................................42 
3.9.1.1 
Vital signs and body weight ....................................................42 
3.9.1.2 
Laboratory assessments ...........................................................42 
3.9.2 
Physical examination and concomitant medications ........................43 
3.9.2.1 
Physical examination ...............................................................43 
3.9.2.2 
Concomitant medications ........................................................44 
3.10 
Visit and assessment schedule ......................................................................44 
3.10.1 
Visit 1 ................................................................................................44 
3.10.2 
Titration period (if applicable) ..........................................................45 
3.10.2.1 
Week 1 (telephone call) ...........................................................45 
3.10.2.2 
Week 2 (telephone call) ...........................................................45 
3.10.2.3 
Week 3 (telephone call) ...........................................................45 
3.10.2.4 
Visit 2 (Week 4) ......................................................................45 
3.10.2.5 
Week 5 (telephone call) ...........................................................45 
3.10.2.6 
Week 6 (telephone call) ...........................................................45 
3.10.2.7 
Week 7 (telephone call) ...........................................................46 
3.10.2.8 
Visit 3 (Week 8) ......................................................................46 

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Pulmonary arterial hypertension 
Protocol AC-065A303/GRIPHON OL 
Final Version 9 
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3.10.2.9 
Week 12 (telephone call) .........................................................46 
3.10.2.10 
Visit 4 (Week 16) ....................................................................46 
3.10.3 
Maintenance period ...........................................................................47 
3.10.3.1 
Visit 5 and 6-monthly visits (Visit 6, 7, etc.) ..........................47 
3.10.3.2 
Telephone call Month 9 (and every 6 months thereafter) .......47 
3.10.4 
End of study visit or permanent discontinuation of study drug ........47 
3.10.5 
30-day follow-up ...............................................................................48 
3.10.6 
Unscheduled visits ............................................................................48 
4 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................49 
4.1 
Summary table ..............................................................................................49 
4.2 
Adverse events ..............................................................................................49 
4.2.1 
Definitions of adverse events ............................................................49 
4.2.2 
Intensity of adverse events ................................................................50 
4.2.3 
Relationship to study drug ................................................................51 
4.2.4 
Reporting of adverse events ..............................................................52 
4.2.5 
Follow-up of adverse events .............................................................52 
4.3 
Serious adverse events ..................................................................................52 
4.3.1 
Definitions ........................................................................................52 
4.3.1.1 
Serious adverse events .............................................................52 
4.3.1.2 
Hospitalization – prolongation of existing hospitalization ......53 
4.3.1.3 
Serious adverse events related to study-mandated 
procedures ...............................................................................53 
4.3.2 
Reporting of serious adverse events .................................................53 
4.3.2.1 
Screening period ......................................................................53 
4.3.2.2 
Treatment period .....................................................................53 
4.3.2.3 
Follow-up period .....................................................................54 
4.3.2.4 
Reporting procedures ..............................................................54 
4.3.3 
Follow-up of serious adverse events .................................................55 
4.3.4 
Reporting of serious adverse events after the 30-day follow-up 
period ................................................................................................55 
4.4 
Pregnancy .....................................................................................................55 
4.4.1 
Teratogenicity ...................................................................................55 
4.4.2 
Reporting of pregnancy ....................................................................55 
4.4.3 
Follow-up of pregnancy ....................................................................55 
5 
STATISTICAL METHODOLOGY AND ANALYSES ............................................56 
5.1 
Populations for analyses ...............................................................................56 
5.2 
Statistical analyses ........................................................................................56 
5.2.1 
Efficacy analyses ..............................................................................56 

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Pulmonary arterial hypertension 
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Final Version 9 
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5.2.2 
Safety analyses ..................................................................................56 
5.2.2.1 
Adverse events ........................................................................56 
5.2.2.2 
Clinical laboratory tests ...........................................................57 
5.2.2.3 
Vital signs ................................................................................57 
6 
PROCEDURES AND GOOD CLINICAL PRACTICE .............................................57 
6.1 
Procedures ....................................................................................................57 
6.1.1 
Protocol amendments ........................................................................57 
6.1.1.1 
Non-substantial amendment ....................................................57 
6.1.1.2 
Substantial amendment ............................................................58 
6.1.1.3 
Urgent amendment ..................................................................58 
6.1.2 
Monitoring ........................................................................................58 
6.1.3 
Data management .............................................................................59 
6.1.3.1 
Data collection .........................................................................59 
6.1.3.2 
Database management and quality control ..............................59 
6.1.4 
Recording of data and retention of documents .................................60 
6.1.5 
Audit .................................................................................................61 
6.1.6 
Handling of study drug(s) .................................................................61 
6.1.7 
Publication and reporting of study results ........................................61 
6.1.8 
Disclosure and confidentiality ..........................................................62 
6.1.9 
Premature termination or suspension of the study ............................62 
6.2 
Good Clinical Practice ..................................................................................63 
6.2.1 
Ethics and Good Clinical Practice ....................................................63 
6.2.2 
Ethics Committee / Institutional Review Board ...............................63 
6.2.3 
Informed consent ..............................................................................63 
6.2.4 
Compensation to subjects and investigators .....................................63 
7 
REFERENCES ............................................................................................................64 
 
LIST OF TABLES 
Table 1 
Visit and Assessment Schedule for patients who need to up-titrate 
their dose ................................................................................................... 21 
Table 2 
Visit and Assessment Schedule for patients treated with selexipag in 
the GRIPHON study .................................................................................. 23 
 
LIST OF FIGURES 
Figure 1 
Study design .............................................................................................. 35 
 
 

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Pulmonary arterial hypertension 
Protocol AC-065A303/GRIPHON OL 
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LIST OF ABBREVIATIONS 
6MWD  
6-minute walk distance 
ACT-293987  
Actelion’s investigational drug selexipag, formerly known as NS-304 
ACT-333679  
The active metabolite of selexipag 
AE  
Adverse event 
ALT  
Alanine aminotransferase / serum glutamic pyruvic transaminase 
(SGPT) 
AST  
Aspartate aminotransferase / serum glutamic oxaloacetic transaminase 
(SGOT) 
ATC  
Anatomic therapeutic chemical 
AUC  
Area under the concentration-time curve 
b.i.d.  
Bis in diem / twice a day 
BMI  
Body mass index 
cAMP  
Cyclic adenosine monophosphate 
CEC  
Critical Event Committee 
CRF  
Case Report Form 
CRO  
Contract Research Organization 
DP receptor  
Prostaglandin D2 receptor 
dyn  
Dyne (1 g·cm/s²) 
EC  
Ethics Committee 
ECG  
Electrocardiogram 
EMEA  
European Medicines Agency 
EOS  
End of study  
EP receptor  
Prostaglandin E receptor 
ERA  
Endothelin receptor antagonist 
FDA  
Food and Drug Administration 
FP receptor  
Prostaglandin F2 receptor 
GCP  
Good Clinical Practice 
GPCR  
G-protein coupled receptor 

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Pulmonary arterial hypertension 
Protocol AC-065A303/GRIPHON OL 
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GRIPHON 
Prostacyclin (PGI2) Receptor agonist In Pulmonary arterial 
HypertensiON 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IP receptor 
Prostacyclin receptor, PGI2 receptor 
IPAH 
Idiopathic pulmonary arterial hypertension 
IRB 
Institutional Review Board 
i.v.
Intravenous  
MLA 
Marked laboratory abnormality 
mPAP 
Mean pulmonary arterial pressure 
NDA 
New drug application 
NS-304 
Original Nippon Shinyaku name of selexipag 
NYHA 
New York Heart Association 
OL 
Open-label 
p.o.
Per os / orally 
PAH 
Pulmonary arterial hypertension 
PAP 
Pulmonary arterial pressure 
PCWP 
Pulmonary capillary wedge pressure 
PD 
Pharmacodynamic(s) 
PDE-5 
Phosphodiesterase type-5  
PGI2 
Prostacyclin (Prostaglandin I2) 
PH 
Pulmonary hypertension 
PK 
Pharmacokinetic(s) 
PVR 
Pulmonary vascular resistance 
RHC 
Right heart catheterization 
RVH 
Right ventricular hypertrophy 

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Pulmonary arterial hypertension 
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RVSP  
Right ventricular systolic pressure  
s.c.  
Subcutaneous 
SAE  
Serious adverse event 
SAP  
Statistical analysis plan 
SOC  
System organ class 
SOP  
Standard Operating Procedure 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
SVR  
Systemic vascular resistance 
t½  
Elimination half-life 
tmax  
Time to maximum plasma concentration 
TP receptor  
Thromboxane A2 (TXA2) receptor 
TXA2  
Thromboxane A2  
ULN  
Upper limit of normal 
UV  
Ultraviolet 
WHO  
World Health Organization 
 

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Pulmonary arterial hypertension 
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SUBSTANTIAL GLOBAL AMENDMENT 8 
 
Amendment rationale 
 
This amendment applies to global protocol AC-065A303 version 8, dated 30 June 2017. 
The resulting amended global protocol is version 9, dated 6 February 2019. 
The main reason for this amendment is to include guidance for concomitant 
administration of selexipag and moderate inhibitors of CYP2C8 (e.g., clopidogrel, 
deferasirox, teriflunomide) as described in the current Investigator’s Brochure (IB) 
Version 13 [Selexipag IB]. 
Results of the completed Phase 1 study AC-065-117 showed that concomitant 
administration of selexipag (200 μg b.i.d.) with clopidogrel (300 mg as a loading dose or 
maintenance dose of 75 mg once daily), a moderate inhibitor of CYP2C8, had no relevant 
effect on the exposure to selexipag but increased the exposure to the active metabolite by 
approximately 2.2-fold and 2.7-fold following loading dose and maintenance dose, 
respectively. If a moderate inhibitor of CYP2C8 is concomitantly administered with 
selexipag, the dosing frequency of selexipag should be reduced to once daily (resulting in 
halving of the daily dose) unless, based on medical judgment, continuation of b.i.d. 
therapy is indicated. Dosing frequency of selexipag should be reverted to twice daily 
when co-administration of moderate CYP2C8 inhibitor is stopped.  
Clinical information [Section 1.3.2] has been updated to include reference to the recently 
completed studies. Results of these studies are summarized in the current Selexipag IB. 
The statistical analysis section has been updated according to ICH E6.  
The data collection section is updated to allow the use of a standard ballpoint pen to 
complete the Case Report Forms (CRF).  
Sponsor and CRO contact details have been updated.  
Changes to the protocol 
Two versions of the amended protocol will be prepared: 1) a clean version and 2) a 
Word comparison document, showing deletions and insertions in comparison to the 
previous protocol version. 
 

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Pulmonary arterial hypertension 
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Amended protocol sections 
The main sections of the protocol affected by this amendment are listed below. Where 
applicable, the same changes have also been made to the corresponding sections of the 
protocol synopsis. 
 
1.3.2.1 Phase 1 studies in healthy subjects 
1.3.2.2 Phase 2 studies in patients with pulmonary arterial hypertension  
3.2.4.1 Allowed concomitant medications 
5 
Statistical Methodology and Analyses. 
6.1.3.1 Data collection  
7 
References 
 
Summary of previous amendments 
Amendment Date 
Main reason(s) 
7 
30 June 2017 
• 
To add contraindication of strong CYP2C8 inhibitors such as 
gemfibrozil in accordance to IB Version 11 (Amendment 2) 
• 
To add information on the lack of studies to determine the 
effect of moderate inhibitors of CYP2C8, and strong 
inhibitors of UGT1A3 and UGT2B7 on the exposure to 
selexipag or its active metabolite.  
6 
25 January 
2017 
• 
Further to new drug-drug interaction study results: 
– 
concomitant administration of strong CYP2C8 inhibitors 
such as gemfibrozil should be avoided. 
– 
in case of concomitant administration of rifampicin, dose 
adjustment of selexipag may be required. 
5 
15 June 2016 
• 
Disbandment of the Data Monitoring Committee involved in 
the AC-065A302 (GRIPHON) study as of 1 July 2016. 
• 
Disbandment of the Ophthalmology Safety Board as of 1 July 
2016. 
• 
In the protocol, the reference to the selexipag IB section 6 was 
replaced with the complete list of AEs. 
4 
16 March 
2015 
• 
The possibility to up-titrate selexipag at unscheduled visits 
(for patients who have not reached the maximum allowed 
dose) was introduced. 
• 
The overall duration of the AC-065A303 (GRIPHON OL) 

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Pulmonary arterial hypertension 
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study was changed from “until the approval of selexipag in 
PAH” to “until selexipag is commercially available”. 
• 
Temporary concomitant use of selexipag and intravenous 
(i.v.), subcutaneous (s.c.), or inhaled prostacyclin and 
prostacyclin analogs was now allowed when deemed 
medically indicated for the patient. 
• 
A discontinuation criterion for patients diagnosed with 
pulmonary veno-occlusive disease (PVOD) was introduced. 
• 
The Informed Consent Form (ICF) was updated with safety 
and efficacy information from the pivotal GRIPHON study. 
3 
19 April 
2013 
• 
Sample size was increased from 670 to 1150. 
• 
Collection of safety data in the clinical database was 
extended 
to 
vital 
signs, 
body 
weight, 
concomitant 
medications, and laboratory results. 
• 
Guidance for management of patients with liver impairment 
was provided. 
• 
Eligibility of GRIPHON patients to GRIPHON OL was 
extended to patients with worsening of PAH during the 
Treatment Extension period of the GRIPHON study. 
• 
It was clarified that GRIPHON OL results will be reported in 
combination with the GRIPHON study results. 
• 
The core ICF was updated to include the definition of reliable 
methods of contraception consistent with the definition 
already used for the same patients in the GRIPHON study. 
• 
Considering the protocol Amendment 6 of the GRIPHON 
study, GRIPHON OL could no longer be considered a 
stand-alone study. Consequently, the statistical section was 
shortened. 
2 
20 December 
2010 
• 
The precautionary wording regarding sun exposure was 
removed. 
• 
The independent Data Monitoring Committee reviewing 
unblinded safety data of GRIPHON was also assigned the 
review of safety data from the GRIPHON OL study. 
1 
19 March 
2010 
• 
Further to the merge of the double-blind studies AC-065A301 
and AC-065A302 into one single study, all references to 
these 2 studies in the protocol AC-065A303 (GRIPHON OL) 
were removed and replaced by the reference to the merged 

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protocol AC-065A302 (GRIPHON). 
• 
Patients 
who 
experienced 
a 
CEC-confirmed 
clinical 
worsening event during GRIPHON study could only enter 
GRIPHON OL study after their GRIPHON Week 16 visit and 
after written approval from the Sponsor. These restrictions 
were removed. 
• 
A time limit of 2 weeks after the last visit in GRIPHON was 
introduced for entering the GRIPHON OL study. 
• 
Clarification that prostacyclin and prostanoid therapy were 
prohibited not only during the GRIPHON OL study but also 
in the transition period between GRIPHON and GRIPHON 
OL. 
• 
Additional telephone calls alternating with the scheduled 
visits were introduced. 
• 
The text of the core patient information was updated to reflect 
the changes in the protocol described above. In addition to 
these changes, the risk and discomfort section was updated to 
include information on nonclinical study signals regarding 
intussusception, changes in the bone structure, and inhibition 
of platelet aggregation. 

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Pulmonary arterial hypertension 
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PROTOCOL SYNOPSIS AC-065A303/GRIPHON OL 
TITLE 
Long-term, single-arm, open-label study, to assess the safety and 
tolerability of selexipag (ACT-293987) in patients with 
pulmonary arterial hypertension 
ACRONYM 
GRIPHON OL: Prostacyclin (PGI2) Receptor agonist In 
Pulmonary arterial HypertensiON Open Label. 
OBJECTIVES 
To assess the long-term safety and tolerability of selexipag in 
patients with pulmonary arterial hypertension (PAH). 
DESIGN / PHASE 
Multicenter, open-label (OL) extension, single-arm, Phase 3 
study. 
STUDY PLANNED 
DURATION 
First 
patient 
First visit 
07Jul2010 
Last 
patient 
First visit 
open 
Last 
patient 
Last visit 
open 
CENTER(S) 
/ COUNTRY(IES)  
190 centers in 44 countries (planned). 
PATIENTS / GROUPS 
Up to 1150 patients 
INCLUSION CRITERIA 
1. Signed informed consent prior to initiation of any 
study-mandated procedure. 
2. Patients who have completed the double-blind study 
AC-065A302 as scheduled per protocol (i.e., treated until 
unblinding of the study), 
or 
Patients who have experienced a morbidity event (confirmed 
by the Critical Event Committee [CEC]) during study 
AC-065A302, 
or 
Patients experiencing a worsening of PAH during the 
Treatment Extension period of AC-065A302 and for whom a 
written approval to roll over into this study has been obtained 
from the sponsor. 
3. Women of child-bearing potential1 included in study 
AC-065A303 must use a reliable method of contraception 
                                                     
1 A woman is considered to have childbearing potential unless she meets at least one of the following criteria: 
 

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(with a failure rate of less than 1% per year) until one month 
after study drug discontinuation. 
EXCLUSION 
CRITERIA 
1. Pediatric patients (i.e., < 18 years of age). 
2. Patients who are not able to perform the Visit 1 of 
AC-065A303/GRIPHON OL within 2 weeks (i.e., 14 days) 
of the last visit in AC-065A302/GRIPHON. 
3. Patients 
who 
have 
started 
receiving 
prostacyclin 
(epoprostenol) or prostacyclin analogs (i.e., treprostinil, 
iloprost, beraprost) since the last study drug intake in 
AC-065A302/GRIPHON2. 
4. Severe hepatic impairment (Child-Pugh C). 
5. Females who are pregnant or plan to become pregnant during 
the study, or are breastfeeding. 
6. 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. 
7. Known hypersensitivity to selexipag or any of the excipients. 
CONCOMITANT 
MEDICATIONS 
Allowed 
• Endothelin receptor antagonists (ERAs), phosphodiesterase 
type-5 (PDE-5) inhibitors, and/or riociguat are permitted for 
the treatment of PAH. 
• Inhaled, i.v., and s.c. prostacyclin and prostacyclin analogs 
(i.e., epoprostenol, treprostinil, iloprost) are permitted as 
deemed medically indicated by the Investigator. 
• Single 
administration 
of 
intravenous 
[i.v.]/inhaled 
prostacyclin and analogs used for acute vasodilator testing 
during a right heart catheterization (RHC) procedure is 
                                                                                                                                                              
• 
previous bilateral salpingo-oophorectomy or hysterectomy 
• 
premature ovarian failure confirmed by a specialist gynecologist 
• 
pre-pubescence, XY genotype, Turner syndrome, uterine agenesis 
• 
age > 50 years with amenorrhea for at least 24 consecutive months prior to screening 
2 Single administration of i.v./inhaled prostacyclin or analogs used for acute vasodilator testing during a RHC 
procedure is allowed. 

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allowed. 
• Treatment with moderate inhibitors of CYP2C8 is allowed. If 
a moderate inhibitor of CYP2C8 (e.g., clopidogrel, 
deferasirox, teriflunomide) is concomitantly administered 
with selexipag, the dosing frequency of selexipag should be 
reduced to once daily (resulting in halving of the daily dose) 
unless, based on medical judgment, continuation of twice 
daily (b.i.d.) therapy is indicated. Dosing frequency of 
selexipag should be reverted to b.i.d. when co-administration 
of moderate CYP2C8 inhibitor is stopped. 
• If rifampicin is administered concomitantly with selexipag, 
dose adjustment of selexipag may be required. 
Prohibited  
• Oral IP-receptor agonists (e.g., beraprost, treprostinil) are 
prohibited 
from 
the 
last 
study 
drug 
intake 
in 
AC-065A302/GRIPHON until end of study (EOS) in 
AC-065A303/GRIPHON OL. 
• Concomitant use of strong inhibitors of CYP2C8 such as 
gemfibrozil until EOS in AC-065A303/GRIPHON OL. 
• Any investigational drug other than selexipag. 
STUDY PERIODS 
Titration period:  
• For patients randomized to placebo in AC-065A302 who 
completed the double-blind study as scheduled per protocol 
(i.e., treated until unblinding of the study).  
• For patients who experienced a morbidity event (confirmed 
by the CEC) in the study AC-065A302. 
• For patients enrolled with a written approval from the 
sponsor after experiencing a worsening of PAH during the 
Treatment Extension period of AC-065A302/GRIPHON. 
These patients’ dose will be up-titrated starting from 200 µg 
b.i.d. in increments of 200 µg b.i.d. until their individual highest 
tolerated dose is reached, independently of the treatment arm 
they were allocated to during the study AC-065A302. 
Maintenance period:  
• For patients randomized to active treatment in AC-065A302 
who completed the double-blind study as scheduled per 
protocol (i.e., treated until unblinding of the study) and for all 

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patients who completed the titration period in this OL study.  
Study treatment for each patient lasts from his/her Visit 1 date 
until the end of the trial i.e., until whichever of the following 
occurs first: (i) selexipag is commercially available in this 
indication in the patient’s country, (ii) the sponsor decides to stop 
study AC-065A303/GRIPHON OL, or (iii) the patient, or the 
investigator decide to discontinue study drug. 
Post-treatment safety follow-up: 30 days after study drug 
discontinuation. 
End of Study: 
The overall study is considered completed when all patients have 
completed their individual safety follow-up phone call or have 
died, withdrawn consent or have been lost to follow-up. 
INVESTIGATIONAL 
DRUG 
Tablets of 200 µg selexipag for oral administration  
Depending on the highest tolerated dose of the patient, a single 
dose will consist of 1 to 8 tablets (200 μg to 1600 μg) b.i.d. 
Any interruption of study drug intake of 3 days or more will 
require a new up-titration. 
Patients who were on placebo, experienced a confirmed 
morbidity event during study AC-065A302/GRIPHON, or for 
whom written approval has been obtained from sponsor after a 
PAH worsening during the AC-065A302/GRIPHON Treatment 
Extension period will enter the titration period.  
Patients coming from study AC-065A302/GRIPHON already 
taking selexipag will continue on the same dose.  
During the maintenance period, the dose of patients who did not 
reach the maximum of 1600 µg b.i.d, can be up-titrated based on 
the investigators’ medical judgment, only after a site visit 
(scheduled or unscheduled) and in increments of 200 µg b.i.d. 
each time. Re-uptitrations to a previously reached dose can be 
done based on phone calls and do not need site visits. The dose 
can be reduced at any time if the investigator identifies a 
tolerability concern for a patient. 
Study drug discontinuation: 
If the investigator becomes aware that a patient has developed 

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moderate hepatic impairment (e.g., Child-Pugh B) at any time 
during the AC-065A302/GRIPHON or the AC-065A303 
/GRIPHON OL study, then it is the responsibility of the 
investigator to evaluate the benefit-risk of keeping the patient on 
study drug. 
In case a patient has developed severe hepatic impairment (e.g., 
Child-Pugh C), the study drug must be discontinued. 
Should signs of pulmonary edema occur, the possibility of 
associated 
pulmonary 
veno-occlusive 
disease 
should 
be 
considered. If confirmed, selexipag must be discontinued. 
COMPARATOR DRUG  NA 
TOLERABILITY / 
SAFETY ENDPOINTS 
• Treatment-emergent AEs up to 3 days after study drug 
discontinuation. 
• Treatment-emergent SAEs up to 3 days after study drug 
discontinuation. 
• AEs leading to permanent discontinuation of study drug. 
STATISTICAL 
METHODOLOGY  
This 
study 
will 
be 
analyzed 
using 
data 
from 
both 
AC-065A302/GRIPHON 
and 
AC-065A303/GRIPHON 
OL 
databases. 
A statistical analysis plan (SAP) will be written and finalized 
before database lock of the AC-065A303/GRIPHON OL study. 
The SAP will provide full details of the analyses, the data 
displays and the algorithms to be used for data derivation. 
STUDY COMMITTEES 
The 
Steering 
Committee 
involved 
in 
the 
study 
AC-065A302/GRIPHON will provide guidance on the conduct 
of the study. 
The Data Monitoring Committee involved in the study 
AC-065A302/GRIPHON will also review safety data from this 
study up to 1 July 2016 (date of disbandment of the committee). 
An Ophthalmology safety board will be consulted up to 1 July 
2016 (date of disbandment of the board) for their opinion and 
recommendation in case of specific ophthalmological findings. 
 
 

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1 Only for patients who were on placebo, patients who experienced a confirmed morbidity event during AC-065A302/GRIPHON, or patients experiencing a 
worsening of PAH during the Treatment Extension period of AC-065A302/GRIPHON and for whom a written approval to roll over into this study has been 
obtained from the sponsor; 2 Visit 1 should correspond to the last visit in the double-blind study or, if not possible, must be within 2 weeks (14 days). When 
Visit 1 is performed on the same day as the last visit of the double-blind study, assessments that are common to both studies are not to be repeated. Results are to 
be reported on CRF pages of both studies; 3 Monthly urine (or serum) pregnancy test for women of childbearing potential until 1 month after study drug 
discontinuation; 4 Scheduled telephone call; 5 Hematology and blood chemistry tests to be performed at Visit 1 only if the last assessment in 
AC-065A302/GRIPHON was performed more than 4 weeks before, and then at every visit until EOS. 6 Physical examination results will not be collected in the 
CRF but clinically relevant changes from baseline must be reported as adverse events. 7 Throughout the course of the study, it is recommended to regularly 
discuss with the patient whether new PAH therapy is becoming available. 
* 6 months correspond to 26 weeks. 
CRF = Case Report Form; EOS = End of Study; EOT = End of Treatment. 
 
 

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1 
BACKGROUND AND RATIONALE 
1.1 Pulmonary arterial hypertension 
The most serious chronic disorder of the pulmonary circulation is pulmonary arterial 
hypertension (PAH). PAH is characterized by pulmonary arterial vasoconstriction and 
vascular remodeling resulting in a progressive increase in pulmonary arterial pressure 
(PAP) and pulmonary vascular resistance (PVR), ultimately leading to right ventricular 
failure and death. PAH is defined as a sustained elevation of mean pulmonary arterial 
pressure (mPAP) > 25 mmHg at rest (or > 30 mmHg with exercise), with a pulmonary 
capillary 
wedge 
pressure 
(PCWP) 
≤ 15 mmHg 
and 
PVR 
> 3 Wood 
units 
(> 240 dyn s cm−5) [Rubin 2004].  
The Updated Clinical Classification of Pulmonary Hypertension [Simonneau 2009] 
classifies the numerous conditions that are known to lead to, or to be associated with, the 
development of PAH into five groups, based on their similar clinical presentation, 
pathology, pathophysiology, prognosis, and, most of all, similar therapeutic approach. 
PAH may occur in the absence of a demonstrable cause (idiopathic or heritable), as the 
result of the use of drugs and toxins, or as a complication of congenital heart disease, 
systemic conditions such as connective tissue disease, particularly scleroderma, HIV 
infection, portal hypertension, schistosomiasis, or chronic hemolytic anemia. 
The pathophysiology of PAH involves multiple pathways, which are influenced by many 
overlapping secondary messenger systems. Vasoconstriction, obstructive remodeling of 
the pulmonary vessel wall caused by extensive cell proliferation and reduced rates of 
apoptosis, inflammation, and thrombosis within the pulmonary arteries are promoted by 
activation of these pathways, and lead to elevated PAP and PVR, and eventually right 
ventricular failure.  
Currently, there is no cure for PAH. However, improved understanding of the pathogenic 
factors of the disease has led to the development of new therapies targeting specific 
pathways (the prostacyclin pathway; the endothelin pathway; and the nitric oxide 
pathway) [Humbert 2004, Farber 2004] that are believed to play an important role in the 
pathogenesis of PAH. 
Today, a total of seven agents are currently approved for the treatment of PAH in the 
United States and/or in Europe: intravenous prostacyclin (epoprostenol), other prostanoid 
analogs, i.e., treprostinil (intravenous [i.v.], subcutaneous [s.c.] and inhaled), and iloprost 
(inhaled), endothelin receptor antagonists (ERAs; bosentan, ambrisentan) and 
phosphodiesterase type-5 (PDE-5) inhibitors (sildenafil, tadalafil). All of these agents 
have been shown to improve exercise capacity as assessed by 6-minute walk test in 
short-term randomized placebo-controlled trials. 

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Pure vasodilators, such as calcium channel blockers, are effective only in a minority of 
patients who have an acute response to vasodilator testing [Rich 1992, Sitbon 2005]. 
The available therapies have positive effects in PAH, but in many patients the disease 
will progress and PAH remains a serious life-threatening condition.  
Early recognition and an understanding of the selection and timing of therapeutic options 
remain critical elements in the optimal management of patients with this disorder. 
Before the development of recent therapeutic options, idiopathic PAH (IPAH) was 
rapidly progressive and led to right heart failure and death. In the early 1990s, it was 
reported that the median survival of patients was 2.8 years after diagnosis 
[D’Alonzo 1991]. The first large prospective studies showed an actuarial survival rate of 
68 to 77%, 40 to 56%, and 22 to 38% at one, three, and five years, respectively 
[D’Alonzo 1991, Galiè 2009]. 
1.2 Prostacyclin and pulmonary hypertension 
Prostacyclin (Prostaglandin I2 / PGI2), a metabolite of arachidonic acid, is formed via the 
cyclooxygenase pathway. Endothelial cells are the main source of PGI2 and its action is 
directed to both the local vascular wall and to blood cells, particularly those that adhere to 
the endothelium. It is a potent endogenous vasodilator, inhibitor of platelet aggregation 
and smooth muscle cell proliferation through its activity at the prostacyclin (IP) receptor 
[O’Grady 1980]. 
The IP receptor is a G protein-coupled receptor (GPCR) that activates adenylate cyclase, 
leading to increased cyclic adenosine monophosphate (cAMP) levels in the target cells. 
cAMP has been widely implicated in the control of pulmonary vascular tone and 
inhibition of mitogenic pathways in vascular smooth muscle cells. 
Patients with PAH have been shown to have a deficiency of PGI2 [Christman 1998] and 
of PGI2 synthase [Tuder 1999] causing an imbalance in PGI2 and thromboxane A2 
(TXA2), its physiological antagonist. These findings led to the rationale that targeting the 
PGI2 pathway with IP receptor agonists could be beneficial.  
The first, epoprostenol, the chemical analog of PGI2, was approved in 1996 for 
NYHA/WHO functional class III-IV IPAH and PAH associated with scleroderma, and 
was shown to improve exercise tolerance and survival in patients with IPAH 
[Barst 1996]. Since continuous intravenous epoprostenol became available, the prognosis 
for patients suffering from PAH has significantly improved. However, due to its short 
half-life and chemical instability, long-term epoprostenol therapy requires a permanently 
implanted central venous catheter and a portable infusion pump, exposing patients to a 
series of complications including catheter-related embolism or thrombosis, infection, and 
delivery system malfunctions resulting in poorly tolerated overdosing or underdosing. 

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The complexity of epoprostenol therapy has led to attempts to develop other prostanoids 
with simpler modes of delivery. Treprostinil, a stable PGI2 analog with a half-life of 3 h, 
has been developed for intravenous, subcutaneous delivery, and inhalation. It has 
beneficial effects on exercise and hemodynamics, which depend on the dose achieved. 
This, in turn, is determined by the patient’s ability to tolerate the drug’s side effects. 
Iloprost, another PGI2 analog, has been approved for intravenous delivery and inhalation. 
Inhaled iloprost shows some selectivity of the hemodynamic effects to the lung 
vasculature, thus reducing systemic side effects, but has to be inhaled between 6 to 
9 times per day, which may limit compliance.  
The inconveniences of the administration routes of the above-mentioned drugs, such as 
injection site pain and reaction (redness and swelling) for subcutaneous administrations, 
or line infections, sepsis, hematoma, and local pain for intravenous infusions, are another 
factor influencing the patient’s benefit from these treatments. 
1.3 Selexipag – a non-prostanoid IP receptor agonist 
Selexipag is an orally available drug that is readily hydrolyzed to the active metabolite 
ACT-333679. Both selexipag and ACT-333679 are potent and selective agonists at the 
human IP receptor. 
ACT-333679 has a 13-fold higher affinity for the human IP receptor [Selexipag IB] and 
is 15-fold more potent than selexipag in activating the human IP receptor. In vitro studies 
showed that ACT-333679 has at least 130-fold lower affinity for other human prostanoid 
receptors such as the prostaglandin E1–4, D2, and F2 receptors, as well as the TXA2. 
Selexipag has been selected for further clinical development based on its 
pharmacokinetic (PK) profile observed in Phase 1 studies and the results from the 
Phase 2 study [Section 1.3.2]. 
1.3.1 Preclinical information 
In vivo pharmacology studies demonstrated that orally administered selexipag 
significantly reduced right ventricular systolic pressure (RVSP) and right ventricular 
hypertrophy (RVH) in a rat model of PAH. Selexipag also ameliorated the impaired 
relaxant response of the pulmonary artery from these animals.  
Furthermore, 
selexipag 
significantly 
increased 
survival 
of 
rats 
with 
monocrotaline-induced PAH [Kuwano 2008].  
In normotensive rats prolonged administration of selexipag did not attenuate the acute 
increase in femoral skin blood flow induced by the compound, suggesting lack of 
desensitization of the IP receptor [Kuwano 2007]. 

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1.3.2 Clinical information 
1.3.2.1 Phase 1 studies in healthy subjects 
During the Phase 1 program selexipag was well tolerated after single and multiple daily 
oral doses of up to and including 1600 µg b.i.d. No serious adverse events (SAEs) were 
reported in any of the Phase 1 studies and the majority of the adverse events (AEs) were 
of mild intensity. The most frequently reported AEs were headache, myalgia, jaw pain, 
dizziness, nausea, vomiting, arthralgia, diarrhea, and abdominal pain. No clear dose 
relationship could be established for the above-mentioned AEs.  
Multiple doses of selexipag up to 1600 µg b.i.d. (study AC-065-101), starting with 
400 µg b.i.d. and up-titrated in increments of 200 µg every 3rd day, were well tolerated. 
Most AEs were mild or moderate in intensity. The incidence of AEs was similar for all 
treatment groups, which suggests improved tolerability after repeated dosing. Tolerability 
decreased at a dose of 1800 µg selexipag b.i.d. and led to an increase in moderate AEs 
(headache, myalgia, and nausea) that required concomitant medication. The maximum 
dose tested in Japanese subjects was 600 µg b.i.d. There were no consistent differences in 
the number and type of AEs with increasing dose of selexipag.  
Treatment with selexipag up-titrated in increments of 200 µg to 1800 µg (the highest 
dose tested in Caucasian subjects) or 600 µg (the highest dose tested in Japanese 
subjects) (study AC-065-101 and NS304/P1/01), were not associated with clinically 
relevant changes in systolic and diastolic blood pressures, heart rate, electrocardiogram 
(ECG) intervals and morphology, vital signs and laboratory tests. In addition, in the 
AC-065-101 study, no changes were observed in thyroid markers, orthostatic 
hypotension, platelet aggregation test, bone formation, bone resorption markers, and 
coagulation markers. 
Plasma concentration-time profiles and PK parameters of selexipag and ACT-333679 
were comparable across the studies performed in healthy subjects. The plasma 
concentration-time profiles of selexipag revealed that, in general, maximum plasma 
concentrations were achieved in about 1–2 h after single-dose and multiple-dose 
administration. Thereafter, plasma concentrations of selexipag decreased quickly. The 
plasma concentration-time profiles of ACT-333679 showed that, in general, maximum 
plasma concentrations were achieved in about 3–4 h after single- and multiple-dose 
administration. Thereafter, plasma concentrations of ACT-333679 compared to selexipag 
decreased more slowly. In the study AC-065-101 the exposure (area under the 
concentration-time curve [AUC]) to ACT-333679 is approximately four times higher 
than to selexipag.  
Following multiple oral administrations of selexipag, the apparent elimination half-lives 
of selexipag and its active metabolite ACT-333679 were between 0.9 and 1.9 hours and 

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between 7.9–14.5 h, respectively, which supports twice daily oral administration. The PK 
of selexipag, after both single- and multiple-dose administration, were approximately 
dose-proportional over the tested dose range, i.e., up to a single dose of 800 µg and 
multiple doses of 1800 µg b.i.d. of selexipag. After multiple-dose administration, 
steady-state conditions of selexipag and ACT-333679 were reached on Day 3. No 
relevant accumulation in plasma either of selexipag or ACT-333679 occurred after 
multiple-dose administrations.  
Results from study QGUY/2006/NS304/-01 indicate that food intake delayed the 
exposure to ACT-333679, as the median tmax increased from 2.5 hours during fasting to 
4 hours in fed state, and decreased the exposure to ACT-333679 by 27%. 
More subjects reported AEs in the fasted period than in the fed period. These results may 
indicate better tolerability of selexipag when administered with food. 
Selexipag did not influence the PK or pharmacodynamics (PD) of warfarin. Similarly, 
co-administration of warfarin with selexipag did not have an impact on the exposure to 
selexipag or its active metabolite ACT-333679. 
The metabolism and excretion of selexipag were studied following a single dose 
administration of radioactively labeled ACT-293987A (400 μg) (study 186933). 105% of 
the radioactivity was excreted primarily via feces (93%) and urine (12%). Excretion was 
complete after 5 days indicating no relevant retention of drug-related material in man. 
When 
comparing 
the 
PK 
of 
selexipag 
and 
ACT-333679 
from 
study  
QGUY/2006/NS30/-01, which mainly included Caucasian subjects, to those of study 
NS304/P1/01, which included only Japanese subjects, the concentrations of both 
selexipag and ACT-333679 were higher in Japanese subjects. The difference in the PK 
was mainly due to the difference in body weight. When corrected for body weight a small 
residual difference was observed, however this difference was within one standard 
deviation of the mean and not consistent between the different dose levels. The clinical 
relevance of this observation is currently unknown.  
In study AC-065-102, investigating the photosensitizing potential of selexipag, doses of 
800 and 1200 µg selexipag did not show any difference in the phototoxic index compared 
to placebo and the mild photosensitizing agent ciprofloxacin. The study did not indicate 
that selexipag has clinically relevant photosensitizing potential in humans. 
Results of study AC-065-113 (Part I) showed that in the presence of multiple-dose 
gemfibrozil (600 mg b.i.d.), a strong CYP2C8 inhibitor, a 2-fold increase in selexipag 
exposure and 11-fold increase in ACT-333679 exposure was observed.  

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Results of study AC-065-113 (Part II) showed that concomitant administration of 
selexipag and multiple-dose rifampicin (600 mg once daily; a moderate inducer of 
CYP2C8) led to no relevant change in exposure to selexipag in terms of AUC, while 
exposure to the active metabolite in terms of AUC decreased by half.  
Results of study AC-065-117 showed that concomitant administration of selexipag 
(200 μg b.i.d.) with clopidogrel (300 mg as a loading dose or maintenance doses of 
75 mg once daily), a moderate inhibitor of CYP2C8, had no relevant effect on the 
exposure to selexipag but increased the exposure to the active metabolite by 
approximately 2.2-fold and 2.7-fold following loading dose and maintenance dose, 
respectively. 
The effects of strong inhibitors of UGT1A3 and UGT2B7 on the exposure to selexipag or 
its active metabolite have not been studied. Concomitant administration may result in a 
significant increase in exposure to selexipag or its active metabolite. 
Results of the completed Phase 1 studies are described in the current version of the 
Investigator’s Brochure [Selexipag IB]. 
1.3.2.2 Phase 2 studies in patients with pulmonary arterial hypertension 
A Phase 2a proof-of-concept study in PAH (NS-304/-02) was completed in July 2009. 
Study NS-304/-02 was conducted in seven European centers and enrolled 43 patients 
with PAH, who were randomized in a 3:1 ratio to selexipag (n = 33) or placebo (n = 10). 
All enrolled patients received double-blind study treatment, which was prematurely 
discontinued in three patients (two on selexipag and one on placebo). Median exposure to 
study treatment was 146 days in the placebo group and 149 days in the selexipag group. 
For most patients, PAH was idiopathic (70% and 73% of patients in the placebo and 
selexipag groups, respectively). At baseline, all patients were receiving either an ERA 
(bosentan, 70% and 61% of patients in the placebo and the selexipag group, respectively, 
or sitaxentan in four patients in the selexipag group only) or a PDE-5 inhibitor (sildenafil 
60% and 64% of patients in the placebo and the selexipag group, respectively). Three 
patients in the placebo group (30%) and 12 patients in the selexipag (36%) were 
receiving both an ERA and a PDE-5 inhibitor. 
After 17 weeks of treatment, mean PVR was decreased from baseline in the selexipag 
group 
(−168 
± 
45 
dyn·sec/cm5) 
and 
increased 
in 
the 
placebo 
group 
(137 ± 35 dyn·sec/cm5). Values at Week 17 expressed as a percent of baseline values 
showed a significant 30.3% reduction in PVR with selexipag compared with placebo 
(P = 0.0045, Wilcoxon rank sum test). Similar improvements in PVR were observed in 
the all randomized analysis set. 

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After 17 weeks of treatment, the mean 6-minute walk distance (6MWD) increased from 
baseline in the selexipag group (+24.7 ± 12.9 meters) and was unchanged in the placebo 
group (+0.4 ± 8.9 meters), which resulted in a mean treatment effect of 
24.2 ± 23.7 meters (P = 0.2218, Wilcoxon rank sum test). Three subjects showed 
aggravation of PAH during the double-blind study, two patients in the placebo group 
(20%) and one (3.3%) patient in the selexipag group. All three patients were in 
NYHA/WHO functional class III at baseline. A statistically significant increase of 
Cardiac Index was observed in the selexipag group when compared to a decrease in the 
placebo group, which resulted in a mean treatment effect: 0.48 ± 0.17 L/min/m2, 
(± standard error) (P = 0.0137, Wilcoxon rank sum test). A statistically significant 
decrease of systolic vascular resistance (SVR) was observed in the selexipag group when 
compared to an increase in the placebo group, which resulted in a mean treatment effect: 
−407.8 ± 164.2 dyn·sec/cm5, (± standard error) (P = 0.0071, Wilcoxon rank sum test). 
Ten (100%) patients in the placebo group reported a total of 39 treatment 
emergent-adverse events, whilst 31 (93.9%) patients in the selexipag group reported a 
total of 182 adverse events (AE). The most frequently reported AE in the active group 
was headache, reported in 22 (66.7%) patients in the selexipag compared to two (20%) 
patients in the placebo group. In the selexipag group, pain in jaw, pain in extremity, 
nausea, diarrhea, flushing, dizziness, cough and myalgia were reported in 12 patients 
(36.4%), 10 patients (30.3%), nine patients (27.3%), six patients (18.2%), six patients 
(18.2%), five patients (15.2%), four patients (12.1%) and four patients (12.1%), 
respectively. Most AEs in both treatment groups were of mild or moderate intensity, but a 
severe event was experienced by a larger proportion of patients on placebo (40%) than in 
the selexipag group (18.2%). Seven SAEs were reported in four patients (40%) in the 
placebo group. Fourteen SAEs were reported in six patients (18.2%) in the selexipag 
group. There were no changes from baseline to the end of treatment in either systolic or 
diastolic blood pressure, or in pulse rate in the placebo group and in the selexipag group. 
The analysis of marked laboratory abnormalities (MLA) in the selexipag compared to the 
placebo group did not reveal any relevant increase of the incidence of MLA after 
selexipag treatment. No clinically relevant ECG changes were observed in either 
treatment group.  
Results of completed studies are described in the current version of the IB 
[Selexipag IB].  
1.4 Study rationale 
1.4.1 Medical and regulatory background 
Selexipag is a new, selective, orally active non-prostanoid IP receptor agonist selected for 
clinical development in PAH.  

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Prostacyclin (epoprostenol) and analogs like treprostinil (intravenous, subcutaneous, and 
inhaled) and iloprost (inhaled) have been approved for the treatment of PAH. However, 
the administration routes are not always convenient. For subcutaneous administrations, 
injection site pain and reaction (redness and swelling) occur in the majority of patients. 
For intravenous infusions, line infections, sepsis, hematoma, and local pain are most 
common. Inhaled iloprost has to be given between 6 to 9 times per day, which may limit 
compliance. An orally available medicinal product, such as selexipag, which, by targeting 
the prostacyclin pathway could affect the progressive course of PAH, would represent an 
important advancement in the clinical management of PAH patients, and provide a 
significant contribution in the treatment options for these patients. 
To date, several medicinal products have been approved for the treatment of pulmonary 
hypertension (PH), specifically PAH. The majority of controlled trials performed in PAH 
have been relatively short-term studies in selected populations. 
The main objective of the AC-065A303/GRIPHON OL study will be to assess the long-
term safety and tolerability of selexipag in patients with PAH.  
1.4.2 Patient population 
The patient population will consist of: 
• Patients who have completed the double-blind study AC-065A302/GRIPHON as 
scheduled per protocol (i.e., treated until unblinding of the study). 
• Patients experiencing a morbidity event (confirmed by the Critical Event 
Committee [CEC]) during the study AC-065A302/GRIPHON. 
• Patients who have experienced a worsening of PAH during the Treatment 
Extension period of AC-065A302/GRIPHON and for whom a written approval to 
enter this study has been obtained from the sponsor. 
1.4.3 Study design 
The study is designed as an open-label, non-comparative, multicenter study following the 
AC-065A302/GRIPHON study to assess long-term safety and tolerability of selexipag in 
patients with PAH. 
1.4.4 Comparative drug(s) and/or placebo 
Not applicable 
1.4.5 Dose selection  
Up-titration to the individual patient’s highest tolerated dose appears to be the most 
adequate treatment regimen for IP receptor agonists, including epoprostenol (i.v.), 
treprostinil (i.v., s.c. and inhaled) and iloprost (inhaled). Starting with high doses of these 
compounds is associated with poor tolerability due to typical prostanoid-associated 

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pharmacological effects such as headache, myalgia, flushing, nausea, and vomiting. 
Clinical experience with IP receptor agonists has shown that it is important to start at 
lower doses and up-titrate in order to improve tolerability.   
This approach is used in the AC-065A302/GRIPHON study and will be kept in the 
open-label study. 
During AC-065A303/GRIPHON OL, the selexipag starting dose will depend on the dose 
of selexipag received during AC-065A302/GRIPHON as well as at which time point of 
AC-065A302/GRIPHON patients are enrolled in AC-065A303/GRIPHON OL: 
• Patients who enter AC-065A303/GRIPHON OL following a morbidity event during 
AC-065A302/GRIPHON (confirmed by the CEC) and patients experiencing a 
worsening 
of 
PAH 
during 
the 
Treatment 
Extension 
period 
of 
AC-065A302/GRIPHON for whom a written approval to roll over into this study has 
been obtained from the sponsor will be transferred without knowledge of their 
previous study treatment allocation (selexipag or placebo) to preserve the integrity of 
the double-blind study. Therefore all these patients will enter the titration period, i.e. 
start treatment with selexipag at the lowest dose (200 µg b.i.d.) and will be up-titrated 
until their individual highest tolerated dose is reached. During the maintenance period 
they will receive selexipag at their individual highest tolerated dose. 
• Patients who enter AC-065A303/GRIPHON OL after AC-065A302/GRIPHON Study 
Closure and completion of the Treatment Extension period will enter the study with 
knowledge of their previous study treatment allocation (selexipag or placebo) 
following unblinding of AC-065A302/GRIPHON: 
– Patients who were receiving selexipag will remain on the same dose they were 
receiving at the end of the AC-065A302/GRIPHON Treatment Extension period. 
If the treatment with selexipag was interrupted for 3 days or more between the last 
intake in study AC-065A302/GRIPHON and the initiation of selexipag in 
AC-065A303/GRIPHON OL, the patient will have to enter the titration period 
(i.e. start treatment with selexipag at the lowest dose 200 µg b.i.d.); 
– Patients who were receiving placebo will enter the titration period and start 
selexipag at the lowest dose (200 µg b.i.d.), and will be up-titrated until their 
individual highest tolerated dose is reached. They will receive selexipag at their 
individual highest tolerated dose during the maintenance period. 
The dose of patients who did not reach the maximum of 1600 µg b.i.d. can be up-titrated 
based on the investigators’ medical judgment, only after a site visit (scheduled or 
unscheduled) and in increments of 200 µg b.i.d. each time. The dose can be reduced at 
any time if the investigator identifies a tolerability concern for a patient. 

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The dose of the study drug must be up-titrated again in any case if the patients’ treatment 
is interrupted 3 days or more between the last visit in study AC-065A302/GRIPHON and 
the start of study AC-065A303/GRIPHON OL, or within study AC-065A303/GRIPHON 
OL [Section 3.4.1]. 
1.4.6 Treatment duration 
Study treatment for each patient lasts from his/her Visit 1 date until the end of the trial 
i.e., until whichever of the following occurs first: (i) selexipag is commercially available 
in this indication in the patient’s country, (ii) the sponsor decides to stop study 
AC-065A303/GRIPHON OL, or (iii) the patient, or the investigator decide to discontinue 
study drug. 
1.4.7 Primary endpoint 
No primary efficacy endpoint is considered for this OL study. 
1.4.8 Statistical hypotheses and sample size 
No statistical hypothesis is considered for this OL study. 
2 
STUDY OBJECTIVES 
To assess long-term safety and tolerability of selexipag in patients with PAH. 
3 
INVESTIGATIONAL PLAN 
3.1 Overall study design 
This will be a multicenter, open-label study to assess long-term safety and tolerability of 
selexipag in patients with PAH. 
Patients 
(males 
or 
females 
aged 
18 
years 
or 
older) 
from 
the 
study 
AC-065A302/GRIPHON will be enrolled in this OL study [Section 1.4.2]. The study will 
be conducted in approximately 190 centers in 44 countries.  
Visit 1 in the AC-065A303/GRIPHON OL study should correspond to the last visit in 
study AC-065A302/GRIPHON. If this is not possible, Visit 1 must be performed not later 
than 2 weeks (14 days) after the last visit in study AC-065A302/GRIPHON. 
Patients who complete the AC-065A302/GRIPHON Treatment Extension period will 
enter the AC-065A303/GRIPHON OL study with knowledge of their previous study 
treatment 
allocation 
(selexipag 
or 
placebo) 
following 
unblinding 
of 
AC-065A302/GRIPHON. Patients who were receiving selexipag will enter directly into 
the maintenance period with the same dose they were receiving at the end of the 
AC-065A302/GRIPHON Treatment Extension period. Patients who were receiving 
placebo will enter the titration period, i.e. start selexipag at the lowest dose 
(200 µg b.i.d.). 

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Patients with a morbidity event (confirmed by the CEC), and patients experiencing 
worsening of PAH during the Treatment Extension period of AC-065A302/GRIPHON, 
and for whom a written approval to roll over into this study has been obtained from the 
sponsor, will be transferred from the double-blind study AC-065A302/GRIPHON to the 
OL study without knowledge of their previous treatment arm (selexipag or placebo) to 
preserve the integrity of the double-blind study. Therefore, all these patients will enter the 
titration period, i.e. start selexipag at the lowest dose (200 µg b.i.d.). 
Each patient will have his/her selexipag dose up-titrated up to his/her individual highest 
tolerated dose. Patients will receive new medication bottles at Visit 1, Visit 5 and every 
6 months until the end of the AC-065A303/GRIPHON OL study. If a patient enters the 
titration period, additional medication bottles will be given at Visit 2, 3, and 4. 
At the end of the open-label study or after permanent discontinuation of study drug, the 
end of study (EOS) visit will be performed and a post-treatment safety follow-up period 
(30 days) will follow.  
The Steering Committee involved in the study AC-065A302/GRIPHON will provide 
guidance on the conduct of the study. 
The Ophthalmology safety board involved in the AC-065A302/GRIPHON study will be 
consulted for their opinion and recommendation in case of specific ophthalmological 
findings up to 1 July 2016 (date of disbandment of the board). 
The Data Monitoring Committee involved in the study AC-065A302/GRIPHON will also 
review safety data from this study up to 1 July 2016 (date of disbandment of the 
committee). 
No interim analysis is planned. 

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Patients experiencing a worsening of PAH during the Treatment Extension period of 
AC-065A302/GRIPHON and for whom a written approval to roll over into this study 
has been obtained from the sponsor. 
3. Women of child-bearing potential3 included in study AC-065A303 must use a reliable 
method of contraception (with a failure rate of less than 1% per year) until 1 month 
after study drug discontinuation.  
3.2.3 Exclusion criteria 
1. Pediatric patients (i.e., < 18 years of age). 
2. Patients who are not able to perform Visit 1 of AC-065A303/GRIPHON OL within 
2 weeks (i.e., 14 days) of the last visit in AC-065A302/GRIPHON. 
3. Patients who have started receiving prostacyclin (epoprostenol) or prostacyclin 
analogs (i.e., treprostinil, iloprost, beraprost) since the last study drug intake in 
AC-065A302/GRIPHON4. 
4. Severe hepatic impairment (Child-Pugh C) 
5. Females who are pregnant or who plan to become pregnant during the study or are 
breast-feeding. 
6. 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. 
7. Known hypersensitivity to selexipag or any of the excipients. 
3.2.4 Concomitant medications 
3.2.4.1 Allowed concomitant medications 
PAH-specific therapies including ERAs, PDE-5 inhibitors, and/or riociguat. 
Concomitant use of inhaled, i.v., and s.c. prostacyclin and prostacyclin analogs (e.g., 
epoprostenol, treprostinil, iloprost) is permitted, as deemed medically indicated by the 
                                                     
3 A woman is considered to have childbearing potential unless she meets at least one of the following criteria: 
• 
previous bilateral salpingo-oophorectomy or hysterectomy 
• 
premature ovarian failure confirmed by a specialist gynecologist 
• 
pre-pubescence, XY genotype, Turner syndrome, uterine agenesis 
• 
age > 50 years with amenorrhea for at least 24 consecutive months prior to screening 
4 Single administration of i.v./inhaled prostacyclin or analogs used for acute vasodilator testing during a RHC 
procedure is allowed. 

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investigator, to stabilize a patient with worsening of PAH or to switch a patient to i.v. or 
s.c. treatment. 
If a patient is scheduled for an intervention that may temporarily prevent him/her from 
taking oral medications, it is allowed to interrupt selexipag treatment and temporarily 
switch to another IP receptor agonist medication with a more convenient route of 
administration with regard to the patient’s medical condition. The patient will be allowed 
to restart selexipag once he/she can take oral medications again. When re-starting 
selexipag, it is recommended to begin with the lowest dose (i.e., 1 tablet/200µg b.i.d.) 
and to progressively increase the selexipag dose to reach the maximum dose that was 
previously tolerated by the patient. The decrease of the other IP receptor agonist dose will 
be done in parallel with the increase of selexipag dose based on patient’s individual 
tolerability. If the patient experiences pharmacological side effects that cannot be 
tolerated while he/she is concomitantly taking selexipag and the other IP receptor agonist 
medication, a dose reduction or stop of this other IP receptor agonist will be considered 
before considering a dose reduction or a stop of selexipag. 
Single administration of i.v./inhaled prostacyclin or analogs used for acute vasodilator 
testing during a right heart catheterization (RHC) procedure is allowed. 
Treatment with moderate inhibitors of CYP2C8 is allowed. If a moderate inhibitor of 
CYP2C8 (e.g., clopidogrel, deferasirox, teriflunomide) is concomitantly administered 
with selexipag, the dosing frequency of selexipag should be reduced to once daily 
(resulting in halving of the daily dose) unless, based on medical judgment, continuation 
of b.i.d. therapy is indicated. Dosing frequency of selexipag should be reverted to b.i.d. 
when co-administration of moderate CYP2C8 inhibitor is stopped.  
Due to potential drug-drug interactions [see Section 1.3.2.1], in case of concomitant 
administration of rifampicin, dose adjustment of selexipag may be required. 
3.2.4.2 Prohibited concomitant medications 
• Due to the similar mode of action and the same route of administration, other oral 
IP-receptor agonists (e.g., treprostinil, beraprost) are prohibited from the last study 
drug intake in AC-065A302/GRIPHON until EOS in AC-065A303/GRIPHON OL.  
• Concomitant administration of strong inhibitors of CYP2C8 such as gemfibrozil until 
EOS in AC-065A303/GRIPHON OL. 
• Any investigational drug other than selexipag. 

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3.3 Study drug 
3.3.1 Investigational drug  
Patients who meet all inclusion criteria and none of the exclusion criteria will receive 
selexipag (200 µg tablets) at each individual patient’s highest tolerated dose in addition to 
their usual treatment.  
• The study drug will be provided by the sponsor in child-proof bottles containing 
120 tablets which must not be stored above 25 °C and be protected from moisture. 
• The study drug is administered orally (p.o.) in tablets of 200 μg selexipag.  
• The dose regimen is b.i.d. (twice daily) with an interval of approximately 12 h.  
• It is recommended to take the study medication with food. 
• Depending on the highest tolerated dose of the patient, a single dose of study drug 
will consist of 1 to 8 tablets (200 μg to 1600 μg) b.i.d.  
• If a patient was on placebo or experienced a morbidity event during 
AC-065A302/GRIPHON (confirmed by the CEC), he/she will enter the titration 
period. 
• Patients already taking selexipag will continue with the same dose or will be 
up-titrated based on the investigators’ medical judgment, only after a site visit 
(scheduled or unscheduled) and in increments of 200 µg b.i.d, each time. The dose 
cannot exceed 1600 μg b.i.d.  
• Patients enrolled with a written approval from the sponsor after experiencing a 
worsening 
of 
PAH 
during 
the 
Treatment 
Extension 
period 
of 
AC-065A302/GRIPHON will enter the titration period. 
• Any interruption of study drug intake of 3 days or more will require a new 
up-titration [Section 3.4.1]. For re-uptitration to a previously reached dose, site visits 
are not systematically required. In such case, re-uptitration can be done via phone 
calls, based on tolerability reported during the initial titration. 
3.3.2 Study drug up-titration 
The study drug must be up-titrated to each individual patient’s highest tolerated dose in 
the range of 200 µg to 1600 µg b.i.d. 
Patients whose dose needs to be up-titrated will start with one tablet of selexipag 
(200 µg) b.i.d. from Day 1. If this dose is well tolerated, the dose will be up-titrated by 
the investigator in 200 µg increments at weekly intervals during scheduled telephone 
calls or visits until reaching the patient’s highest tolerated dose. 

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The decision to stop further up-titration of the dose will be based on the investigators’ 
medical judgment, based on the occurrence and severity of typical pharmacological 
effects of IP receptor agonists, such as headache, jaw pain, myalgia, flushing and nausea, 
which cannot be tolerated by the patient. The dose will then be reduced by 200 μg b.i.d, if 
needed.  
3.3.3 Study drug dosing scheme (titration period only) 
Period 
Duration 
Dose regimen  
First dose 
Day 1 in the evening (p.m.) 
200 µg  
1 tablet 
Up-titration  
Day 2 a.m. to Day 8 a.m. 
200 µg b.i.d. 
1 tablet b.i.d.  
 
Day 8 p.m. to Day 15 a.m. 
400 µg b.i.d. 
2 tablets b.i.d. 
 
Day 15 p.m. to Day 22 a.m. 
600 µg b.i.d. 
3 tablets b.i.d. 
 
Day 22 p.m. to Week 4 p.m. 
800 µg b.i.d. 
4 tablets b.i.d. 
 
Week 4 p.m. to Week 5 a.m. 
1000 µg b.i.d. 
5 tablets b.i.d. 
 
Week 5 p.m. to Week 6 a.m. 
1200 µg b.i.d. 
6 tablets b.i.d. 
 
Week 6 p.m. to Week 7 a.m.  
1400 µg b.i.d. 
7 tablets b.i.d. 
 
Week 7 p.m. to Week 8 a.m.  
1600 µg b.i.d. 
8 tablets b.i.d. 
 
At the beginning of each up-titration phase, patients will be recommended to take the first 
dose in the evening in order to reduce the likelihood of the occurrence of headache, jaw 
pain, flushing and nausea. It is recommended to take the study drug with food. 
3.4 Study drug discontinuation and study withdrawal 
3.4.1 Study drug interruption or permanent discontinuation 
The investigator must interrupt or permanently discontinue the study drug if continued 
administration is believed to be contrary to the best interest of the patient.  
In case liver impairment is suspected, a clinical assessment of severity (e.g., Child-Pugh 
score) should be performed. If the investigator becomes aware that a patient has 
developed moderate hepatic impairment (e.g., Child-Pugh B) at any time during the 
AC-065A302/GRIPHON or the AC-065A303/GRIPHON OL study, then it is the 
responsibility of the investigator to evaluate the benefit-risk of keeping the patient on 
study drug. In case a patient has developed severe hepatic impairment (e.g., 
Child-Pugh C), the study drug must be discontinued. Assessment of Child-Pugh score is 
not a mandatory study assessment. 
Should signs of pulmonary edema occur, the possibility of associated pulmonary 
veno-occlusive disease should be considered. If confirmed, selexipag must be 
discontinued. 

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The interruption or permanent discontinuation of study drug might be triggered by an AE, 
a diagnostic or therapeutic procedure, an abnormal assessment (e.g., ECG or laboratory 
abnormalities), or for administrative reasons, in particular withdrawal of the patient’s 
consent. The reason for study drug interruption or permanent discontinuation must be 
documented in the CRF. 
Any study drug interruption of 3 days or more will require new up-titration. Patients will 
start again with 1 tablet of selexipag (200 µg) b.i.d. If this dose is well tolerated, the dose 
will be up-titrated by the investigator in 200 µg increments up to the patient’s highest 
tolerated dose before study drug interruption. For each patient, the up-titration frequency 
will be up to the medical judgment of the investigator and based on his/her clinical 
evaluation of the patient’s tolerability to study drug prior to its interruption. 
Interruptions of 1 day and more must be recorded on the study drug log in the CRF. 
3.4.2 Patient’s follow-up after study drug discontinuation 
An EOS visit must be performed [Section 3.10.4] after permanent discontinuation of the 
study drug. It is recommended to perform the EOS visit within 7 days of the last study 
drug intake. The patient will be followed for 30 days after the permanent study drug 
discontinuation to collect information on SAEs. If discontinuation is considered study 
drug-related, the patient will remain under the supervision of the investigator until 
satisfactory health has returned. 
3.4.3 Study withdrawal 
A patient will be considered as withdrawn from the study if, and only if, he/she withdrew 
consent or is lost to follow-up after exhausting all means of contact. 
The potential follow-up of patients after their withdrawal of consent will depend upon 
local regulations or specific agreement with the patients. 
3.4.4 Study completion 
The overall study is considered completed when all patients have completed their 
individual safety follow-up phone call or have died, withdrawn consent or have been lost 
to follow-up. 
3.4.5 Replacement policy 
3.4.5.1 Patients 
Patients prematurely discontinued from the study drug for any reason will not be 
replaced. 
3.4.5.2 Centers 
Not applicable. 

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3.5 Treatment exposure, compliance and drug accountability 
Records of study drug used, dosages administered, and intervals between visits, are kept 
during the study. Study drug accountability is performed on an ongoing basis by the 
study staff and checked by the monitor during site visits and at completion of the study. 
Patients are asked to return all unused study drug at each visit. 
3.6 Treatment assignment 
3.6.1 Treatment assignment 
Not applicable 
3.6.2 Blinding 
Not applicable. 
3.6.3 Emergency procedure for unblinding 
Not applicable.  
3.7 Study drug packaging and labeling 
3.7.1 Study drug packaging 
Actelion will provide study drug as tablets in child-proof bottles containing 120 tablets. 
3.7.2 Study drug labeling 
The labeling and packaging of selexipag will be conducted according to Good 
Manufacturing Practice, Good Clinical Practice, and any local or national regulatory 
requirements. 
3.7.3 Study drug storage and dispensing 
The investigator is responsible for the safe and proper handling and storage of the study 
drug at the investigational site, and for ensuring that the study drug is administered only 
to patients enrolled in the study and in accordance with the protocol. 
Study drug must be kept in a locked room, which can only be accessed by the pharmacist, 
the investigator, or another duly designated person. The study drug must not be stored 
above 25°C and must be protected from moisture. The study centers will be supplied with 
study drug according to the centers’ needs, depending on the number of patients 
participating in the study. The site should check at regular intervals whether enough 
medication is available. 
Patients will receive medication bottles at Visit 1, (Visit 2, Visit 3, and Visit 4, for the 
titration period, if applicable), Visit 5, and at the 6-monthly visits thereafter, up to EOS. 
The patient will receive enough study medication at each of these visits. 

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Each medication bottle will have a label with a tear-off part specifying the study protocol 
number and the batch number. When the medication is issued to the patient, the 
investigator or pharmacist must remove the tear-off part and affix it to the Drug 
Dispensing Log. 
3.8 Study endpoints 
3.8.1  Efficacy endpoints 
Not applicable.  
3.8.2 Safety and tolerability endpoints 
• Treatment-emergent AEs up to 3 days after study drug discontinuation. 
• Treatment-emergent SAEs up to 3 days after study drug discontinuation. 
• AEs leading to permanent discontinuation of study drug. 
3.9 Study assessments 
3.9.1 Safety and tolerability assessments 
The definitions, reporting and follow-up of AEs, SAEs and potential pregnancies are 
described in Section 4. 
3.9.1.1 Vital signs and body weight 
Vital signs (blood pressure and heart rate) and body weight will be assessed at each visit 
and recorded in the CRF.  
3.9.1.2 Laboratory assessments 
3.9.1.2.1 Type of laboratory 
Both central and local laboratories are used in the study. 
Until approval of global protocol Version 4, blood sample analysis (hematology and 
biochemistry) is to be performed by local laboratories. For all the blood samples analyzed 
up to approval of the global protocol Version 4, anonymized copies of the print-outs of 
the local laboratory reports will be sent to the central laboratory in original language 
together with the local normal ranges valid at the time of analysis. In case re-test or 
unscheduled blood samples were analyzed between regular visits for the purpose of 
monitoring an adverse event, the lab reports will also be collected. The central laboratory 
will be responsible for entering the results into a database, converting the results and 
normal ranges to SI units, and transferring all data to Actelion. 
After approval of the global protocol Version 4, the hematology and biochemistry blood 
samples must be sent to the central laboratory for analysis (see contact details on page 2). 
The central laboratory reports will be available to the investigator. In case a complete or 

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partial re-test is deemed necessary to follow up an AE or to verify an unexpected 
abnormal value, the re-test blood sample should also be analyzed by the central 
laboratory. 
The results (whether obtained via local or central laboratory) will be kept in the patient’s 
file. Any clinically significant laboratory abnormality must be reported by the 
investigator as an AE and/or SAE, as appropriate [Section 4]. 
Details about collection and shipment of samples, and the reporting of results and 
abnormalities, can be found in the laboratory manual provided to the investigator. 
3.9.1.2.2 Laboratory parameters 
Hematology and blood chemistry 
Hematology and blood chemistry tests will be performed at Visit 1, if the last 
assessments in AC-065A302/GRIPHON were performed more than 4 weeks ago, and 
then at every visit until EOS. They include hemoglobin, hematocrit, platelet, leukocyte 
and erythrocyte counts, liver aminotransferases (AST/ALT), alkaline phosphatase, total 
and direct bilirubin, creatinine, urea, glucose, sodium, potassium, and albumin.  
Local 
assessment 
of 
thyroid 
function 
(Thyroid-stimulating 
hormone, 
free 
triiodothyronine, free thyroxin) may be performed for individual patients if deemed 
clinically indicated by the investigator. 
Pregnancy test (for women of childbearing potential) 
Monthly urine (or serum) pregnancy tests must be performed from Visit 1 and up to at 
least 1 month after permanent discontinuation of the selexipag treatment. The monthly 
urine pregnancy tests are performed by the patient at home with validated kits provided 
by the site, or during a scheduled visit, or in a local laboratory. A serum pregnancy test is 
mandatory if pregnancy is suspected during the course of the study. Results of pregnancy 
tests will be documented in the patient’s records (pregnancy test card). 
Any pregnancy occurring during the treatment period and up to 30 days after study drug 
discontinuation must be reported immediately to the Actelion Drug Safety Department 
using the Actelion Pregnancy Form [Section 4]. 
3.9.2 Physical examination and concomitant medications 
3.9.2.1 Physical examination 
Physical examination (i.e., inspection, percussion, palpation and auscultation) is 
performed at every visit up to EOS. Clinically relevant findings meeting the definition of 
an AE (new AE or worsening of previously existing condition) must be documented in 
patient’s medical records and noted on an AE page of the CRF. 

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3.9.2.2 Concomitant medications 
All concomitant medications (ongoing, initiated, discontinued) including PAH specific 
medications and diuretics taken in the period between Visit 1 and up to EOS will be 
recorded on the Concomitant Medication pages of the CRF. Any dose changes in PAH 
specific medications (e.g., ERAs, PDE-5 inhibitors, riociguat, prostacyclin, prostacyclin 
analogs, and initiation of continuous chronic oxygen therapy) must be recorded in the 
CRF. 
3.10 Visit and assessment schedule 
For a tabulated summary of all visits and assessments described in the following sections 
see Table 1. 
3.10.1 Visit 1 
Visit 1 should correspond to the last visit in AC-065A302/GRIPHON or, if not possible, 
must be within 2 weeks (14 days) of the last visit in study AC-065A302/GRIPHON. 
It is the responsibility of the Investigator to obtain written informed consent from each 
patient participating in this OL study after adequate explanation of the aims, methods and 
objectives of the study. 
The informed consent form (ICF) must be signed and dated at the latest during the Visit 1 
and prior to the execution of any study assessment or procedure. 
The visit includes: 
• Physical examination 
• Measurement of vital signs and body weight 
• Laboratory tests including: 
– Hematology 
– Blood chemistry 
• Urine pregnancy test (for women of childbearing potential)  
• Concomitant medication 
• Dispensing of study drug. 
If Visit 1 is performed on the same day as the last visit (EOS visit or End of Treatment 
Extension visit) in AC-065A302/GRIPHON, assessments that are common to both 
studies are not to be repeated. Results are to be reported in the CRF pages of both studies. 
The laboratory tests are not to be repeated if they were performed within 4 weeks of this 
visit. 

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3.10.2 Titration period (if applicable) 
3.10.2.1 Week 1 (telephone call) 
– Recording of AEs/SAEs 
– Titration to next dose (2 tablets selexipag b.i.d.) 
3.10.2.2 Week 2 (telephone call) 
– Recording of AEs/SAEs  
– Titration to next dose (3 tablets selexipag b.i.d.) 
3.10.2.3 Week 3 (telephone call) 
– Recording of AEs/SAEs 
– Titration to next dose (4 tablets selexipag b.i.d.) 
3.10.2.4 Visit 2 (Week 4) 
• Physical examination 
• Recording of AEs/SAEs 
• Concomitant medication 
• Measurement of vital signs and body weight 
• Laboratory tests including: 
– Hematology  
– Blood chemistry  
• Urine pregnancy test (for women of childbearing potential) 
• Dispensing of study drug (selexipag).  
– Titration to next dose (5 tablets selexipag b.i.d.) 
3.10.2.5 Week 5 (telephone call) 
– Recording of AEs/SAEs 
– Titration to next dose (6 tablets selexipag b.i.d.) 
3.10.2.6 Week 6 (telephone call) 
– Recording of AEs/SAEs 
– Titration to next dose (7 tablets selexipag b.i.d.) 

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3.10.2.7 Week 7 (telephone call) 
– Recording of AEs/SAEs 
– Titration to next dose (8 tablets selexipag b.i.d.) 
3.10.2.8 Visit 3 (Week 8) 
• Physical examination 
• Recording of AEs/SAEs 
• Concomitant medication 
• Measurement of vital signs and body weight 
• Laboratory tests including: 
– Hematology  
– Blood chemistry  
• Urine pregnancy test (for women of childbearing potential) 
• Dispensing of study drug (selexipag).  
3.10.2.9 Week 12 (telephone call) 
– Recording of AEs/SAEs 
– Urine pregnancy test result for women of childbearing potential  
3.10.2.10 
Visit 4 (Week 16) 
• Physical examination 
• Recording of AEs/SAEs 
• Concomitant medication 
• Measurement of vital signs and body weight 
• Laboratory tests including: 
– Hematology  
– Blood chemistry  
• Urine pregnancy test (for women of childbearing potential)  
• Dispensing of study drug (selexipag) 

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3.10.3 Maintenance period 
3.10.3.1 Visit 5 and 6-monthly visits (Visit 6, 7, etc.) 
From Visit 5 onwards, all following visits are scheduled every 6 months ± 7 days. In 
between the 6-monthly visits, the investigator will call the patient to assess safety and 
tolerability by inquiring about AEs and SAEs. 
The morning dose of the study drug should be taken as usual. 
These visits include: 
• Physical examination 
• Recording of AEs/SAEs 
• Concomitant medication 
• Measurement of vital signs and body weight 
• Laboratory tests including: 
– Hematology  
– Blood chemistry  
• Urine pregnancy test (for women of childbearing potential) 
• Dispensing of study drug (selexipag) for a 6 months’ treatment period.  
3.10.3.2 Telephone call Month 9 (and every 6 months thereafter) 
Telephone calls are performed every 6 months, alternating with the 6-monthly visits. For 
patients who do not perform the titration period, the first phone call will occur at 
Week 12. 
• Recording of AEs/SAEs 
• Urine pregnancy test result for women of childbearing potential  
 
3.10.4 End of study visit or permanent discontinuation of study drug  
Actelion will notify all sites when the end of study will occur. It can be at different dates 
depending on the sites and/or the country (see definition in Section 1.4.6). For all patients 
still participating to the study, the EOS visit must be scheduled within 4 weeks after the 
end of study notification.  
For patients prematurely discontinuing selexipag treatment, it is recommended to perform 
the EOS visit within 7 days of the last study drug intake. 

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This visit includes: 
• Physical examination 
• Recording of AEs/SAEs 
• Concomitant medication 
• Measurement of vital signs and body weight 
• Laboratory tests including: 
– Hematology  
– Blood chemistry  
• Urine pregnancy test (for women of childbearing potential) 
• Return of unused medication including empty bottles. 
3.10.5 30-day follow-up 
All patients will be contacted by phone 30 to 37 days after study drug discontinuation 
(safety follow-up call) [Sections 4.2.4 and 4.3.2]. 
• Urine pregnancy test result for women of childbearing potential  
3.10.6 Unscheduled visits 
Unscheduled visits may be performed at any time during the study. Depending on the 
reason for the unscheduled visit (e.g., loss of efficacy, AE, study drug dispensing, etc.), 
appropriate assessments may be performed based on the medical judgment of the 
investigator. Assessments that are included in the protocol schedule of assessments 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. 

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4 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
4.1 Summary table 
Periods 
Treatment 
Follow-up 
After follow-up 
Timeframe 
During study drug 
administration and until 3 
days after last study drug 
administration 
From 3 days to 30 
days after study drug 
discontinuation 
After 30 days 
AE/SAE 
reporting  
on CRF AE page 
All AEs/SAEs 
(treatment-emergent1) 
None  
None 
SAE reporting 
on SAE form 
All SAEs (treatment-
emergent1) 
All SAEs 
If felt 
appropriate by 
investigator 
Final study 
report 
Analyzed 
Described 
Might be 
described 
1A treatment-emergent AE is any AE temporally associated with the use of study drug (from study drug initiation 
until 3 days after study drug discontinuation), whether or not considered related to the study drug. 
 
The resolution date and outcome of AEs reported during the double-blind study 
AC-065A302/GRIPHON that are ongoing at the time of the patient’s Visit 1 in 
AC-065A303/GRIPHON OL, must be recorded on specific CRF pages (Ongoing AEs 
from the GRIPHON study). If the AE worsens (i.e., changes intensity, seriousness or 
relationship) during AC-065A303/GRIPHON OL, a new AE must be recorded on the 
standard AE pages with the onset date equal to the date of worsening. 
4.2 Adverse events 
4.2.1 Definitions of adverse events 
An AE is any adverse change from the subject’s/patient’s baseline condition, i.e., any 
unfavorable and unintended sign, including an abnormal laboratory finding, symptom or 
disease, that occurs during the course of the study, whether or not considered related to 
the study drug.  
A treatment-emergent AE is any AE temporally associated with the use of a study drug 
(from study drug initiation up to 3 days after study drug discontinuation), whether or not 
considered related to the study drug.  
Adverse events include: 
• Exacerbation of a pre-existing disease. 

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• Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 
• Disease or medical condition detected or diagnosed after study drug administration 
even though it may have been present prior to the start of the study. 
• Continuous persistent disease or symptoms present at baseline that worsen following 
the start of the study. 
• Lack of efficacy in the acute treatment of a life-threatening disease. 
• Events considered by the investigator to be related to study-mandated procedures.  
• Abnormal assessments, e.g., change on physical examination, ECG findings, if they 
represent a clinically significant finding that was not present at baseline 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 baseline or worsened during the course 
of the study or led to dose reduction, interruption or permanent discontinuation of 
study drug. 
Adverse events do not include: 
• Medical or surgical procedure, e.g., surgery, endoscopy, tooth extraction, transfusion. 
However, the event leading to the procedure is an AE. If this event is serious, the 
procedure must be described in the SAE narrative. 
• Pre-existing disease or medical condition that does not worsen. 
• Situations in which an adverse change did not occur, e.g., hospitalizations for 
cosmetic elective surgery or for social and/or convenience reasons. 
• Overdose of either study drug or concomitant medication without any signs or 
symptoms. However, overdose of study drug must be mentioned in the Study Drug 
Log. For selexipag, “overdose” is defined as the intake of any single dose greater than 
1600 μg (8 tablets) or a total daily dose greater than 3200 μg (16 tablets). 
4.2.2 Intensity of adverse events 
The intensity of clinical AEs is graded on a three-point scale – mild, moderate, severe – 
and is reported on specific AE pages of the CRF.  
If the intensity of an AE worsens during study drug administration, only the worst 
intensity should be reported on the AE page. If the AE lessens in intensity, no change in 
the severity is required. 
The three categories of intensity are defined as follows: 
• Mild 
The event may be noticeable to the subject/patient. It does not influence daily activities, 
and usually does not require intervention. 

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• Moderate 
The event may make the subject/patient uncomfortable. Performance of daily activities 
may be influenced, and intervention may be needed. 
• Severe 
The event may cause noticeable discomfort, and usually interferes with daily activities. 
The subject/patient may not be able to continue in the study, and treatment or 
intervention is usually needed. 
A mild, moderate or severe AE may or may not be serious [Section 4.3.1]. These terms 
are used to describe the intensity of a specific event (as in mild, moderate or severe 
myocardial infarction). However, a severe event (such as severe headache) may be of 
relatively minor medical significance and is not necessarily serious. For example, nausea 
lasting several hours may be rated as severe, but may not be clinically serious. Fever of 
39 °C that is not considered severe may become serious if it prolongs hospital discharge 
by a day [Section 4.3.1.2]. Seriousness rather than severity serves as a guide for defining 
regulatory reporting obligations. 
These definitions do not apply to clinically significant and asymptomatic laboratory test 
abnormalities or abnormal assessments (e.g., ECG findings) considered as AEs. The 
investigator should tick “non-applicable” on the AE page of the CRF to qualify the 
intensity of the AE. 
4.2.3 Relationship to study drug  
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the study drug, and reported as either related or 
unrelated. 
Related to study drug 
This category applies to any AE (whether serious or not) that appears to have a 
reasonable possibility of causal relationship to the use of the study drug (i.e., a 
relationship cannot be ruled out). Guidelines to determine whether an event might be 
considered related include (but are not limited to) the following:  
• The event occurred in close temporal relationship to study drug administration. 
• The event abated (diminished) or disappeared when treatment with the study drug 
was down-titrated, interrupted or discontinued.  
• The event reoccurred when treatment was reintroduced. 
• Environmental factors such as clinical state and other treatments could equally have 
caused the event. 

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Unrelated to study drug 
This category applies to any AE (whether serious or not) that does not appear to have a 
reasonable relationship to the use of study drug (see above guidelines). 
4.2.4 Reporting of adverse events 
All AEs occurring after study drug initiation and up to 3 days after study drug 
discontinuation must be recorded on specific AE pages of the CRF. 
All AEs ongoing from the AC-065A302/GRIPHON study must be reported on the 
dedicated AC-065A303/GRIPHON OL CRF pages and outcome must be reported when 
it is known. 
4.2.5 Follow-up of adverse events 
Adverse events still ongoing after study drug discontinuation for a given patient must be 
followed until 30 days after study drug discontinuation or until resolution or stabilization 
or until the event is otherwise explained. 
4.3 Serious adverse events 
4.3.1 Definitions  
4.3.1.1 Serious adverse events 
An SAE is defined by the International Council for Harmonisation (ICH) guidelines as 
any AE fulfilling at least one of the following criteria: 
• Fatal 
• Life-threatening 
• Requiring inpatient hospitalization, or prolongation of existing hospitalization 
• Resulting in persistent or significant disability or incapacity 
• Congenital anomaly or birth defect 
• Medically significant, or requires intervention to prevent at least one of the outcomes 
listed above. 
Life-threatening refers to an event in which the subject/patient was at risk of death at the 
time of the event. It does not refer to an event that hypothetically might have caused 
death had it been more severe. 
Important medical events that may not immediately result in death, be life-threatening, or 
require hospitalization may be considered to be SAEs when, based upon appropriate 
medical judgment, they may jeopardize the subject/patient, and may require medical or 
surgical intervention to prevent one of the outcomes listed in the definitions above.  

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4.3.1.2 Hospitalization – prolongation of existing hospitalization 
The following reasons for hospitalizations are not considered AEs, and are therefore also 
not SAEs:  
• Hospitalizations for cosmetic elective surgery, or social and/or convenience reasons. 
• Standard monitoring of a pre-existing disease or medical condition that did not 
worsen, e.g., hospitalization for coronary angiography in a patient with stable angina 
pectoris. 
• Elective treatment of a pre-existing disease or medical condition that did not worsen, 
e.g., elective hip replacement for arthritis. Complications that occur during 
hospitalization are AEs or SAEs (for example if a complication prolongs 
hospitalization). 
4.3.1.3 Serious adverse events related to study-mandated procedures  
A SAE is defined as related to study-mandated procedures if it appears to have a 
reasonable possibility of a causal relationship (i.e., a relationship cannot be ruled out) to 
such procedures (other than administration of study drug). Examples of study-mandated 
procedures include complication of a mandated invasive procedure such as blood 
sampling, or a car accident on the way to the hospital for a study visit, etc. 
4.3.2 Reporting of serious adverse events  
4.3.2.1 Screening period  
Serious adverse events occurring between signing the ICF and study drug initiation are 
only required to be reported if they are considered by the investigator to be related to 
study-mandated procedures. 
As these SAEs are not reported as AEs in the CRF, they are collected only on an SAE 
form, and entered only into the drug safety database.  
4.3.2.2 Treatment period 
All SAEs, regardless of causal relationship, must be reported, including those related to 
study-mandated procedures. Those SAEs occurring during study drug administration, 
i.e., between study drug initiation and three days after study drug discontinuation, are 
defined as treatment-emergent SAEs. 
These SAEs are reported on SAE forms and also on AE pages in the CRF. They are 
therefore entered into both the drug safety and clinical databases, and must be reconciled 
before study closure.  

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4.3.2.3 Follow-up period 
All SAEs regardless of causal relationship occurring from 3 days after study drug 
discontinuation until 30 days after study drug discontinuation must be reported.  
All SAEs occurring during the follow-up period must be recorded on an SAE form. 
These SAEs are therefore entered only into the drug safety database.  
4.3.2.4 Reporting procedures 
All new SAEs as well as new information regarding SAEs ongoing from the 
AC-065A302/GRIPHON study must be reported by the investigator to the Actelion drug 
safety department within 24 hours of the investigator’s first knowledge of the event. 
All SAEs must be recorded on SAE forms, irrespective of the study drug received by the 
patient, and whether or not this event is considered by the investigator to be related to 
study drug. These SAE forms must be faxed to the Actelion drug safety department 
(contact details for which are provided at the beginning of this protocol). The investigator 
must complete the SAE form in English (unless otherwise specified), and must assess the 
relationship of the event to study drug. 
Such preliminary reports will be followed by detailed descriptions that may include 
copies of hospital case reports, autopsy reports, hospital discharge summaries and other 
documents when requested and applicable. Follow-up information about a previously 
reported SAE must also be reported within 24 hours of receiving it. The Actelion drug 
safety department may contact the investigator to obtain further information.  
Suspected (considered related to the study drug) Unexpected (not previously described in 
the reference safety document) Serious Adverse Reactions (SUSARs) will be expedited 
by Actelion to Health Authorities, ECs/IRBs and investigators, as appropriate.  
The reference safety document to assess expectedness of a suspected serious adverse 
reaction and need for reporting by the sponsor to regulatory authorities, ECs/IRBs, and 
investigators is the Investigator’s Brochure [Selexipag IB, section 6 Reference Safety 
Information].  
The following events are anticipated to occur in subjects with PAH, and will be 
considered as ‘disease-related’: signs and symptoms of PAH worsening/exacerbation/ 
progression, abdominal pain, anorexia, chest pain, cyanosis, diaphoresis, dizziness, 
pre-syncope, syncope, dyspnea, orthopnea, fatigue, hemoptysis, heart failure, hypoxia, 
palpitations, collapse, systemic arterial hypotension, and tachycardia. These events 
therefore do not require expedited reporting to Health Authorities, ECs/IRBs, and 
investigators. Like all other SAEs, these SAEs must be reported on an SAE form by the 
investigator to the Actelion drug safety department within 24 hours of the investigator’s 
first knowledge of the event, and be reported on the AE page of the CRF. 

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4.3.3 Follow-up of serious adverse events 
Serious adverse events still ongoing at the EOS visit must be followed up until resolution 
or stabilization, or until the event is otherwise explained.  
4.3.4 Reporting of serious adverse events after the 30-day follow-up period  
New SAEs occurring at any time after the 30-day follow-up period after study drug 
discontinuation may be reported on a SAE form to the Actelion drug safety department 
within 24 hours of the investigator’s knowledge of the event, if considered related to the 
previous exposure to study drug by the investigator. These SAEs are only entered in the 
drug safety database, and hence will not affect study closure. 
4.4 Pregnancy 
4.4.1 Teratogenicity 
In the reproductive and developmental toxicity studies in animals, no changes were 
observed in fertility and teratogenicity. 
However, appropriate precautions must be taken by women of childbearing potential. 
Women must not become pregnant during the study and up to 1 month after study drug 
discontinuation. 
If a woman becomes pregnant while on study drug, permanent discontinuation of study 
drug must be considered. The investigator must counsel the patient and discuss the risks 
of continuing with the pregnancy and the possible effects on the fetus.  
4.4.2 Reporting of pregnancy 
Irrespective of the treatment received by the patient, any pregnancy occurring during 
study drug administration or during the first month following study drug discontinuation 
must be reported within 24 hours of the investigator’s knowledge of the event. 
Pregnancies must be reported on the Actelion Pregnancy form, which is faxed to the 
Actelion drug safety department (see contact details provided on the pregnancy form), 
and on an AE page of the CRF, as applicable. 
4.4.3 Follow-up of pregnancy  
Any pregnancy must be followed to its conclusion and its outcome must be reported to 
the Actelion drug safety department. 
Such follow-up information will only be entered in the drug safety database, and hence 
will not affect study closure. 

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5 
STATISTICAL METHODOLOGY AND ANALYSES 
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A 
general description of the statistical methods to be used to analyze the safety data is 
outlined below. Specific details will be provided in the Statistical Analysis Plan.  
This is an open-label extension study. No formal hypothesis testing will be conducted. 
Data will be summarized using descriptive statistics. Continuous variables will be 
summarized using the number of observations, mean, SD, coefficient of variation, 
median, and range as appropriate. Categorical values will be summarized using the 
number of observations and percentages as appropriate. 
5.1 
Populations for analyses 
For purposes of analysis, the following populations are defined: 
All patients who sign an ICF / ICFs will be used for disposition summary.   
All analyses will be performed on the selexipag-initiated set (SIS) that comprises all 
patients who initiated selexipag treatment at any time during AC-065A302/GRIPHON or 
AC-065A303/GRIPHON OL study. The baseline for this analysis set is the last 
assessment before selexipag initiation. 
5.2 
Statistical analyses 
5.2.1 Efficacy analyses 
Not applicable. 
5.2.2 Safety analyses  
5.2.2.1 Adverse events 
The verbatim terms entered in the CRF by investigators to denote adverse events will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs are AEs with onset during the selexipag treatment phase (up to 
3 days after the treatment end) or AEs that are a consequence of a pre-existing condition 
that has worsened since baseline. All reported AEs will be included in the analysis. For 
each AE, the percentage of patients who experience at least 1 occurrence of the given 
event will be summarized. 
Summaries, listings, or figures may be provided, as appropriate, for those patients who 
die, who discontinue selexipag treatment due to an AE, or who experience a severe or a 
serious AE. 
AEs of special interest, based on the latest risk management plan at the time of database 
lock, will be summarized. 

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5.2.2.2 Clinical laboratory tests 
Laboratory data will be summarized by type of laboratory test. Reference ranges and 
markedly abnormal results (specified in the Statistical Analysis Plan) will be used in the 
summary of laboratory data. Descriptive statistics will be calculated for each laboratory 
analyte at baseline and for observed values and changes from baseline at selected 
scheduled time points. Frequency tabulations of the treatment-emergent marked 
laboratory abnormalities will be presented. A listing of patients with any laboratory 
results outside the reference ranges will be provided. A listing of patients with any 
markedly abnormal laboratory results will also be provided. 
5.2.2.3 Vital signs 
Descriptive statistics of heart rate and blood pressure (systolic and diastolic) values and 
changes from baseline will be summarized at selected scheduled time points. The 
percentage of patients with values beyond clinically important limits will be summarized. 
6 
PROCEDURES AND GOOD CLINICAL PRACTICE 
6.1 Procedures 
6.1.1 Protocol amendments 
Any change to a protocol must be considered to be an amendment if the documents have 
already been submitted to ECs/IRBs or Health Authorities. An amendment could 
therefore occur before or after the approval of these documents by ECs/IRBs or Health 
Authorities. Each amendment must be documented in writing and approved by Actelion, 
and must be reviewed by the Coordinating/Principal Investigator or Steering Committee, 
as appropriate. 
Changes to the Core Subject/Patient Information and Informed Consent requested by 
ECs/IRBs are not considered to be formal amendments, as long as they do not 
significantly change the core document or affect the protocol. 
6.1.1.1 Non-substantial amendment 
Purely administrative or minor logistical changes require only a non-substantial 
amendment. Such changes include but are not limited to changes in study staff or contact 
details (e.g., Actelion instead of CRO monitors), or minor changes in the packaging or 
labeling of study drug.  
The implementation of a non-substantial amendment may be undertaken with or without 
notification to the appropriate ECs/IRBs and Health Authorities (subject to national 
regulations).  

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6.1.1.2 Substantial amendment 
A substantial amendment is required for significant changes. These include, but are not 
limited to, new data affecting the safety of subjects/patients, and changes to the 
objectives or endpoints of the study, eligibility criteria, dose regimen, study 
assessments/procedures, or treatment or study duration, with or without the need to 
modify the Core Subject/Patient Information and Informed Consent. 
Substantial amendments must be approved by the appropriate ECs/IRBs, and in some 
jurisdictions by the Health Authorities. The implementation of a substantial amendment 
may only occur after formal approval by the appropriate ECs/IRBs and/or Health 
Authorities, and must be signed by the investigators. 
6.1.1.3 Urgent amendment 
An urgent amendment might become necessary to preserve the safety of the 
subjects/patients included in the study. The requirements for approval must not prevent 
any immediate action being taken by the investigators or Actelion in the best interests of 
the subjects/patients. If deemed necessary, an investigator may therefore implement an 
immediate change to the protocol for safety reasons, and in such exceptional cases the 
implementation of urgent amendments will occur before submission to, and approval by, 
ECs/IRBs and Health Authorities.  
In such cases, the investigator must notify Actelion within 24 hours. A related substantial 
amendment will be prepared and submitted by Actelion to the appropriate ECs/IRBs and 
Health Authorities within 10 working days of receiving the notification.  
6.1.2 Monitoring 
The monitor will contact and visit the investigator regularly, and on request must be 
permitted to have access to all source documents needed to verify the entries on the CRF 
and other protocol-related documents, provided that patient confidentiality is maintained 
in accordance with local regulations. It will be the monitor’s responsibility to inspect the 
CRFs at regular intervals throughout the study, to verify adherence to the protocol and 
the completeness, consistency and accuracy of the data being entered on the CRFs. 
Actelion monitoring standards require full verification that informed consent has been 
provided, and verification of adherence to the inclusion/exclusion criteria, documentation 
of SAEs, and the recording of the main efficacy, safety and tolerability endpoints. 
Additional checks of the consistency of the source data with the CRFs will be performed 
according to the study-specific monitoring plan. 
The rules regarding identification of any data recorded directly on the CRFs and 
considered to be source data are specified in the following document: Site Guidelines and 
CRF Completion Guideline. The investigator must ensure that subject/patient anonymity 
is maintained. On CRFs or other documents submitted to Actelion, subjects/patients must 

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be identified only by number, and never by name. The investigator must keep a 
subject/patient identification log showing the subject number, the subject/patient’s name, 
date of birth and any other locally accepted identifiers. Documents identifying the 
subjects/patients (e.g., signed informed consent forms) should not be sent to Actelion, 
and must be kept in strict confidence by the investigator. 
The investigator and co-investigators agree to cooperate with the monitor(s) to ensure 
that any issues detected in the course of these monitoring visits are resolved. If the 
subject/patient is hospitalized or dies in a hospital other than the study center, the 
investigator is responsible for contacting that hospital in order to document the SAE. 
The investigator must, on request, supply Actelion with any required background data 
from the study documentation or clinical records. This is particularly important when 
CRFs are illegible or when errors in data transcription are suspected. In the case of 
special problems and/or governmental queries, it is also necessary to have access to the 
complete study records, provided that patient confidentiality is protected. 
An initiation visit will be performed before the first patient is included in the study. 
Monitoring visits and contacts will occur at regular intervals thereafter, according to a 
frequency defined in the study-specific monitoring plan. A close-out visit will be 
performed after study closure. 
6.1.3 Data management 
6.1.3.1 Data collection 
A Subject Enrollment Log will be completed for all patients enrolled in the study. 
For each patient enrolled, regardless of study drug initiation, a paper CRF must be 
completed and signed by the principal investigator or co-investigator. This also applies to 
those patients who fail to complete the study. If a patient withdraws from the study, the 
reason must be noted on the CRF. Case report forms are to be completed on an ongoing 
basis and will be collected by the monitor(s). 
All case report forms must be completed in a legible way. Errors must be crossed out but 
not obliterated, the correction inserted, and the change initialed and dated by the Principal 
Investigator, co-investigator, or study nurse. Detailed descriptions of how to complete the 
CRF, including the use of either a digital or a standard ballpoint pen, can be found in the 
current version of the CRF completion guidelines. 
6.1.3.2 Database management and quality control 
All data from the CRF will be entered into the database twice, by two different 
individuals. 

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The entered data will be systematically checked by Actelion staff, using error messages 
printed from validation programs and database listings. Errors with obvious corrections 
will be corrected and communicated to the site. Data clarification requests will be entered 
on Data Clarification Forms, which will be returned to the investigational site for 
resolution. A copy of the signed Data Clarification Form is to be kept with the CRFs, and 
once received at Actelion, the resolutions will be entered into the clinical database.  
A second review of the data will be performed by medically trained staff.  
Quality control audits of the database will be made before study closure. 
After the database has been declared complete and accurate, the database will be locked. 
Any changes to the database after that time may only be made by joint written agreement 
between the Global Trial Leader and the Head of Clinical Development. 
6.1.4 Recording of data and retention of documents 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, and the study data to be subsequently verified. These 
documents are to be classified into two different categories: investigator’s file, and 
patient clinical source documents. 
The investigator’s file will contain the protocol and all protocol amendments, the FDA 
form 1572 for studies conducted under a US IND, a financial disclosure form, the CRFs 
and data clarification and query forms, EC/IRB and Health Authority approval with 
correspondence, informed consent, drug records, staff curricula vitae and authorization 
forms, screening and enrollment logs, and other appropriate documents/correspondence 
in accordance with ICH GCP and local regulations. 
Subject/patient clinical source documents include, but are not limited to, hospital/clinic 
records, physicians’ and nurses’ notes, appointment book, original laboratory reports, 
ECG, X-ray, pathology and special assessment reports, consultant letters, etc. 
These two categories of documents must be kept on file by the investigator for as long as 
is necessary to comply with national and international regulations (generally 2 years after 
either discontinuation of clinical development, or the last marketing approval, of the 
investigational drug). 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. 
When source documents are required for the continued care of the subject/patient, 
appropriate copies should be made for storing off site. 

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6.1.5 Audit 
The Actelion Global Quality Management Department may conduct audits of clinical 
research activities in accordance with internal standard operating procedures (SOPs) to 
evaluate compliance with the principles of GCP- and ICH-related guidelines.  
Health Authorities may also wish to conduct an inspection (during the study or after its 
completion). Should an inspection be requested by a Health Authority, the investigator 
must inform Actelion immediately that such a request has been made. 
The investigator must permit such audits by Actelion or Health Authorities, and must 
facilitate them by providing access to the relevant source documents. 
6.1.6 Handling of study drug(s) 
Actelion will supply all study drug(s) to the site according to local regulations. Drug 
supplies must be kept in an appropriate, secure area and stored according to the 
conditions specified on the drug labels. The site must maintain an accurate record of the 
shipment and dispensing of study drug(s) on an accountability form, which must be given 
to the monitor at the end of the study. An accurate record of the date and amount of study 
drug(s) dispensed to each subject must be available for inspection at any time. 
All drug supplies are to be used only in accordance with this protocol, and not for any 
other purpose. The responsible person must not destroy any drug labels or unused drug 
supply. On termination of the study, the monitor will collect used and unused study drug 
bottles which will be sent to the warehouse, where the sponsor or its deputy will check 
drug accountability. In certain circumstances, used and unused drug containers may be 
destroyed at the site once drug accountability is final and has been checked by the 
sponsor or its deputy, and written permission for destruction has been obtained from 
Actelion. 
6.1.7 Publication and reporting of study results 
Study results will be documented in a clinical study report that will be signed by Actelion 
representatives and the Coordinating Investigator (or Principal Investigator for 
single-center studies). 
In accordance with standard editorial and ethical practice, the results of 
Actelion-sponsored studies will be published. Results from multicenter studies must be 
published or presented at congresses only in their entirety and not as individual center 
data, except for ancillary studies. 
The Coordinating Investigator and the Steering Committee, if any, will have the 
opportunity to review the analysis of the data and to discuss with the sponsor the 
interpretation of the study results prior to publication. 

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Any study-related article or abstract written independently by investigators must be 
submitted to Actelion for review at least 60 days prior to submission for publication or 
presentation. 
The list of authors of any formal publication or presentation of study results may include, 
as appropriate, representatives of Actelion, and will be determined by mutual agreement. 
6.1.8 Disclosure and confidentiality 
By signing this protocol, the investigator agrees to keep all information provided by 
Actelion in strict confidence, and to request similar confidentiality from his or her staff 
and the EC/IRB. Study documents provided by Actelion (including Investigator’s 
Brochures, protocols, CRFs and other protocol-related documents) will be stored 
appropriately to ensure their confidentiality. The information provided by Actelion to the 
investigator may not be disclosed to others without direct written authorization from 
Actelion, except to the extent necessary to obtain informed consent from subjects/patients 
who wish to participate in the trial.  
6.1.9 Premature termination or suspension of the study 
Both Actelion and the investigator reserve the right to terminate the study at any time.  
If a study is prematurely terminated or suspended, Actelion will promptly inform the 
investigators, the ECs/IRBs and Health Authorities, as appropriate, and provide the 
reasons for the termination or suspension.  
If the study is prematurely terminated or suspended for any reason, the investigator in 
agreement with Actelion must promptly inform all enrolled subjects/patients, and ensure 
their appropriate treatment and follow-up. 
In addition, if the investigator terminates or suspends a study without prior agreement 
from Actelion, the investigator must promptly inform Actelion and the EC/IRB, and must 
provide Actelion and the EC/IRB with a detailed written explanation of the termination 
or suspension. 
If the EC/IRB terminates or suspends its approval/favorable opinion of a study, the 
investigator must promptly notify Actelion and provide Actelion with a detailed written 
explanation of the termination or suspension. 
Any premature termination or suspension of the study must be discussed with the 
Steering Committee. 

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6.2 Good Clinical Practice 
6.2.1 Ethics and Good Clinical Practice 
The investigator will ensure that this study is conducted in full compliance with the 
principles of the ‘Declaration of Helsinki’ (as amended in Tokyo, Venice, Hong Kong, 
Somerset West, Edinburgh and Seoul), and with the laws and regulations of the country 
in which the clinical research is conducted. A copy of the Declaration of Helsinki will be 
provided to each investigational site.  
All studies must follow ICH GCP Guidelines and, if applicable, the US Code of Federal 
Regulations. In other jurisdictions in which GCP Guidelines exist, the investigators will 
strictly ensure adherence to the stated provisions. 
6.2.2 Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document provided to the 
subject/patient (such as subject/patient information used to obtain informed consent) to 
an EC or IRB. Approval from the committee must be obtained before starting the study, 
and must be documented in a dated letter to the investigator, clearly identifying the trial, 
the documents reviewed, and the date of approval. A list of members participating in the 
meeting must be provided, including the functions of these members. If study staff were 
present, it must be clear that none of these persons voted. 
Modifications made to the protocol after receipt of the EC/IRB approval must also be 
submitted as amendments by the investigator to the EC/IRB in accordance with local 
procedures and regulations [Section 6.1.1]. 
6.2.3 Informed consent 
It is the responsibility of the investigator to obtain informed consent according to GCP 
and local regulations from each individual participating in this study, after adequate 
explanation of the aims, methods, objectives and potential hazards of the study. The 
investigator must also explain to the subjects/patients that they are completely free to 
refuse to enter the study, or to withdraw from it at any time for any reason. Appropriate 
forms for documenting informed consent will be provided to the sites prior to the study. 
The Informed Consent and Patient Information will be provided in the local language. 
6.2.4 Compensation to subjects and investigators 
The sponsor provides insurance in order to indemnify (with both legal and financial 
coverage) the investigator/center against claims arising from the study, except for claims 
that arise from malpractice and/or negligence. 
The compensation of the subject/patient in the event of study-related injuries will comply 
with applicable regulations. 

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7 
REFERENCES 
[Barst 1996] Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous 
intravenous epoprostenol (prostacyclin) with conventional therapy for primary 
pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N 
Engl J Med 1996;334:296–302. 
[Christman 1998] Christman BW. Lipid mediator dysregulation in primary pulmonary 
hypertension. Chest 1998;114(3 Suppl):205S–7S. 
[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. 
[Farber 2004] Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 
2004;351:1655–65. 
[Galiè 2009] Galiè N, Manes A, Negro L, et al. A meta-analysis of randomized controlled 
trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394–403. 
[Humbert 2004] Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular 
pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43(12 
Suppl):13S–24S. 
[Kuwano 2007] Kuwano K, Hashino A, Asaki T, et al. 2-[4-[(5,6-diphenylpyrazin-2-
yl)(isopropyl)amino]butoxy]-N-(methylsulfonyl)acetamide (NS-304), an orally 
available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp 
Ther 2007;322:1181–8 
[Kuwano 2008] Kuwano K, Hashino A, Noda K, et al. A long-acting and highly selective 
prostacyclin 
receptor 
agonist 
prodrug, 
2-{4-[(5,6-diphenylpyrazin-2-
yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl )acetamide (NS-304), ameliorates 
rat pulmonary hypertension with unique relaxant responses of its active form,  
{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl) amino] butoxy} acetic acid (MRE-269), 
on rat pulmonary artery. J Pharmacol Exp Ther 2008;326:691–9. 
[O’Grady 1980] O’Grady J, Warrington S, Moti MJ, et al. Effects of intravenous infusion 
of prostacyclin (PGI2) in man. Prostaglandins 1980;19:319–32. 
[Rich 1992] Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel 
blockers on survival in primary pulmonary hypertension. N Engl J Med 
1992;327(2):76–81. 

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[Rubin 2004] Rubin LJ. Diagnosis and management of pulmonary arterial hypertension: 
ACCP evidence-based clinical practice guidelines. Chest 2004;126(1 Suppl): 
7S–10S. 
[Selexipag IB] Selexipag Investigator’s Brochure, Version 13, Actelion Pharmaceuticals 
Ltd, September 2018. 
[Simonneau 2009] Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical 
classification 
of 
pulmonary 
hypertension. 
J 
Am 
Coll 
Cardiol 
2009; 
54(1 Suppl):S43–54. 
[Sitbon 2005] Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium 
channel blockers in idiopathic pulmonary arterial hypertension. Circulation 
2005;111:3105–11. 
[Tuder 1999] Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is 
decreased in lungs from patients with severe pulmonary hypertension. Am J Respir 
Crit Care Med 1999;159:1925–32. 
 

CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Status: Approved, Date: 16 June 2020  
1 
Actelion Pharmaceuticals Ltd 
Janssen Research & Development* 
Clinical Protocol 
COVID-19 Appendix 
Protocol Title 
AC-065A303: Long-term single-arm open-label study, to assess the safety and tolerability 
of selexipag (ACT-293987) in patients with pulmonary arterial hypertension  
GRIPHON OL 
Protocol AC-065A303; Phase 3 
 JNJ-67896049/ACT-293987 Selexipag 
*Janssen Research & Development is a global organization that operates through different legal entities in various
countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development studies may vary,
such as, but not limited to Actelion Pharmaceuticals Ltd; Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term “sponsor” is used throughout the
protocol to represent these various legal entities; the sponsor is identified on the Contact Information page that
accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration Investigational New 
Drug (IND) regulations (21 CFR Part 312). 
EudraCT NUMBER: 2009-014992-31 
Status: 
Approved  
Date: 
16 June 2020 
Prepared by: Janssen Research & Development, LLC; Janssen Research & Development, a division 
of Janssen Pharmaceutica NV  
Document number: 
D-20.209 
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL 
GCP Compliance:  This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements.  
Confidentiality Statement 
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise. 
NCT01112306

COVID-19 Appendix   
 
 
 
 
 
 
JNJ-67896049/ACT-293987 Selexipag 
  
 Clinical Protocol AC-065A303 (GRIPHON OL) 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Status: Approved, Date: 16 June 2020  
 
2 
COVID-19 APPENDIX 
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC 
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by patients and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks.  
In alignment with recent health authority guidance, the sponsor is providing options for study 
related patient management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgement of the 
investigator to protect the health and well-being of patients and site staff. If, at any time, a patient’s 
safety is considered to be at risk, study drug will be discontinued, and study follow-up will be 
conducted.  
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, patients will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Patients will also be questioned regarding general 
health status to fulfill any physical examination requirement.  
Every effort should be made to adhere to protocol-specified assessments for patients on study drug, 
including follow up. Modifications to protocol-required assessments may be permitted via 
COVID-19 Appendix after consultation with the patient, investigator, and the sponsor. Missed 
assessments/visits will be captured in the clinical trial management system for protocol deviations. 
Discontinuations of study drug and withdrawal from the study should be documented with the 
prefix “COVID-19-related” in the case report form (CRF).  
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance. 
If a patient has tested positive for COVID-19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study drug and follow-up. Modifications made to 
the study conduct as a result of the COVID-19 pandemic will be summarized in the clinical study 
report. 
GUIDANCE SPECIFIC TO THIS PROTOCOL 
In addition to the general measures described above, certain protocol-specific measures may not 
be possible during the COVID-19 outbreak. Therefore, temporary measures may be implemented 
if considered appropriate by the sponsor and investigator to maintain continuity of patient care and 
study integrity, and in accordance with applicable (including local) laws, regulations, guidelines, 
and procedures: 
• 
Related to Protocol Section 3.9.1.2.1: “Analyses of blood samples for hematology and 
biochemistry are to be performed by a central laboratory. In case a re-test is necessary, this 

COVID-19 Appendix   
JNJ-67896049/ACT-293987 Selexipag 
 Clinical Protocol AC-065A303 (GRIPHON OL) 
CONFIDENTIAL - FOIA Exemptions Apply in U.S. 
Status: Approved, Date: 16 June 2020  
3 
should also be analyzed by the central laboratory”. If a patient cannot visit the site, the 
investigator will judge whether the patient needs to go to a certified local laboratory close to 
the patient’s home in order to perform specific laboratory tests or if these can be delayed. If 
the patient can visit the site but central laboratory kits are not available due to customs delay 
related to COVID-19, the site can use the hospital laboratory facilities. Missed or delayed 
laboratory tests and replacement of central laboratory by local laboratory will be captured in 
the clinical database and in the clinical trial management system, and will be identified as 
such under “COVID-19-related protocol deviation”. 
•
Related to Protocol Section 3.7.3: “Patients will receive medication bottles at the 6-monthly
visits from Visit 5 up to EOS”. For patients unable to visit the clinic/hospital, direct-to-patient
(DTP) shipment of study drug may be implemented, where allowed per local regulations and
if requested by the treating study physician. Where DTP shipments are deemed necessary, the
process should be coordinated between the site and sponsor staff following the “COVID-19
DTP Guidance Document”.
•
Related to Protocol Section 6.2.3: Informed consent. Consenting and reconsenting of
patients will be performed as applicable for the measures taken (including remote consenting
by phone or video consultation) and according to local guidance for informed consent as
applicable.
Missed assessments/visits will be captured in the clinical trial management system for protocol 
deviations. Temporary or permanent discontinuations of study drugs for a COVID-19 related issue 
(other than adverse event) should be documented with the prefix “COVID-19-related” in the case 
report form (CRF). Instructions for data entry are described in the CRF completion guidance.