Long-term Single-arm Open-label Extension Study of the SERAPHIN Study, to Assess the Safety and Tolerability of ACT 064992 in Patients With Symptomatic Pulmonary Arterial Hypertension
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Sponsor: Actelion

 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
Macitentan/ACT-064992 
Pulmonary Arterial Hypertension 
Protocol AC-055-303 OL 
SERAPHIN-OL: Study with an ERA in Pulmonary arterial Hypertension to 
Improve cliNical outcome (Open Label) 
Long-term single-arm open-label extension study of the SERAPHIN study, to assess 
the safety and tolerability of macitentan/ACT-064992 in patients with symptomatic 
pulmonary arterial hypertension 
Author(s): 
, DVM, BVSc; 
, MD, MSc; 
, Msc 
Document type: 
Clinical Study Protocol  
Study Phase: 
III 
EudraCT Number: 
2007-003694-27 
Status and version: 
Final Version 7 
Date: 
17 July 2020 
Number of pages: 
59 
Actelion number: 
D-20.250 
 
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. 
NCT00667823
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Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
17 July 2020, page 2/59 
Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
SPONSOR AND CRO CONTACT DETAILS 
SPONSOR  
ACTELION Pharmaceuticals Ltd 
Gewerbestrasse 16 
CH – 4123 Allschwil 
Switzerland 
Global Trial Leader  
 
 
 
 
Fax 
 
e-mail 
 
Clinical Trial Scientist 
 
, DVM, BVSc 
 
 
Fax 
 
e-mail 
 
Clinical Trial Physician 
 
, MD, MSc 
 
 
Fax 
 
e-mail 
 
Drug Safety Physician 
, MD 
 
 
Fax 
 
e-mail 
 
CENTRAL LABORATORY 
 
 
 
Contact person 
ACM Global Central Laboratory 
23 Hospital Fields Road 
York, UK YO10 4DZ 
 
 
Senior Project Manager 
 
 
e-mail  
 
MEDICAL HOTLINE 
Toll-free Hotline phone numbers for participating 
countries can be found in the site guidelines. 
For countries where no toll-free phone number is 
available, a toll phone number will be used.  
The medical hotline is intended for the use by 
health care professionals. Patient should be asked 
to contact the Investigator in case of any medical 
emergency or any other health problem. 
PPD
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Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
17 July 2020, page 3/59 
Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
SIGNATURE PAGE FOR ACTELION PHARMACEUTICALS LTD 
Hereinafter called Actelion 
 
Drug name/number 
Macitentan/ACT-064992 
Disease 
Pulmonary arterial hypertension. 
Protocol number. acronym, title 
AC-055-303/SERAPHIN OL: 
Long-term single-arm open-label extension study of the SERAPHIN study, to assess the 
safety and tolerability of macitentan/ACT-064992 in patients with symptomatic pulmonary 
arterial hypertension 
I approve the design of this study. 
Title  
 
Name  
 
Date  
 
Signature 
Clinical Trial  
Wassim 
Physician 
 
Fares  
 
___________  
 
Clinical Trial  
Bartosz  
Statistician 
 
Jenner  
 
___________  
 
 
 
PPD

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
17 July 2020, page 4/59 
Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
SIGNATURE PAGE FOR INVESTIGATOR(S) 
Drug name/number  
Macitentan/ACT-064992 
Disease  
Pulmonary arterial hypertension. 
Protocol number, acronym, title 
AC-055-303 OL/SERAPHIN OL: Long-term single-arm open-label extension study of the 
SERAPHIN study, to assess the safety and tolerability of macitentan/ACT-064992 in patients with 
symptomatic 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) 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 
Coordinating 
Investigator 
Name 
 
Title 
Country 
 
 
 
Signature 
 
 
Date 
Center Principal 
Investigator 
Name 
 
 
Title 
Center number 
 
Town 
 
Country 
 
 
 
 
Signature 
 
 
 
 
Date 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
17 July 2020, page 5/59 
Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
TABLE OF CONTENTS 
 
SPONSOR AND CRO CONTACT DETAILS ...................................................................2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..............................11 
PROTOCOL SYNOPSIS AC-055-303/SERAPHIN OL ..................................................13 
PROTOCOL ......................................................................................................................18 
1 
BACKGROUND AND RATIONALE .......................................................................18 
1.1 
Pulmonary hypertension ...............................................................................18 
1.2 
Endothelin-1 and pulmonary hypertension ...................................................19 
1.3 
Macitentan – Endothelin Receptor Antagonist .............................................19 
1.3.1 
Macitentan – Preclinical information ...............................................19 
1.3.2 
Macitentan – Clinical information ....................................................20 
1.3.2.1 
Phase I studies in healthy subjects ..........................................20 
1.3.2.2 
Phase II study in patients with essential hypertension ............22 
1.3.2.3 
Phase III study in patients with pulmonary arterial 
hypertension ............................................................................23 
1.4 
Study rationale ..............................................................................................23 
1.4.1 
Medical background .........................................................................23 
1.4.2 
Patient population .............................................................................24 
1.4.3 
Study design ......................................................................................24 
1.4.4 
Dose selection ...................................................................................24 
1.4.5 
Treatment duration ............................................................................24 
1.4.6 
Primary endpoint ...............................................................................25 
1.4.7 
Statistical hypotheses and sample size ..............................................25 
2 
STUDY OBJECTIVES ...............................................................................................25 
3 
INVESTIGATIONAL PLAN .....................................................................................25 
3.1 
Study population ...........................................................................................26 
3.1.1 
Patient population .............................................................................26 
3.1.2 
Inclusion criteria ...............................................................................26 
3.1.3 
Exclusion criteria ..............................................................................27 
3.1.4 
Concomitant medications .................................................................27 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
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Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
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3.1.4.1 
Prohibited concomitant medications .......................................27 
3.2 
Study drug .....................................................................................................28 
3.2.1 
Study drug packaging, labeling ........................................................28 
3.2.2 
Study drug storage and dispensing ...................................................28 
3.2.3 
Treatment dose and administration ...................................................29 
3.3 
Study drug discontinuation and study withdrawal .......................................29 
3.3.1 
Study drug interruption or permanent discontinuation .....................29 
3.3.2 
Patient’s follow-up after study drug discontinuation ........................30 
3.3.3 
Replacement policy ...........................................................................30 
3.3.3.1 
Patients ....................................................................................30 
3.4 
Treatment exposure, compliance and drug accountability ...........................30 
3.5 
Treatment assignment ...................................................................................30 
3.5.1 
Treatment assignment .......................................................................30 
3.5.2 
Blinding ............................................................................................30 
3.5.3 
Emergency procedure for unblinding ...............................................30 
3.6 
Study endpoints ............................................................................................31 
3.6.1 
Efficacy endpoints ............................................................................31 
3.6.2 
Safety and tolerability endpoints ......................................................31 
3.7 
Study assessments .........................................................................................31 
3.7.1 
Safety and tolerability assessments ...................................................31 
3.7.1.1 
Vital signs and body weight ....................................................31 
3.7.1.2 
Laboratory assessments ...........................................................31 
3.8 
Visit and assessment schedule ......................................................................35 
3.8.1 
Enrollment visit .................................................................................35 
3.8.2 
Treatment period ...............................................................................35 
3.8.2.1 
Visits at 6-monthly intervals (Visit 2, 3, etc.) .........................35 
3.8.2.2 
End-of-Treatment Visit (EOT) or Permanent 
discontinuation ........................................................................36 
3.8.3 
End-of-Study (EOS) Visit or 28-day follow-up ...............................36 
4 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................37 
4.1 
Summary table ..............................................................................................37 
4.2 
Adverse events ..............................................................................................37 
4.2.1 
Definitions of adverse events ............................................................37 
4.2.2 
Intensity of adverse events ................................................................38 
4.2.3 
Relationship to study drug ................................................................39 
4.2.4 
Reporting of adverse events ..............................................................39 
4.2.5 
Follow-up of adverse events .............................................................39 
4.3 
Serious adverse events ..................................................................................40 
4.3.1 
Definitions ........................................................................................40 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
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Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
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4.3.1.1 
Serious adverse events .............................................................40 
4.3.1.2 
Hospitalization – Prolongation of existing hospitalization .....40 
4.3.1.3 
Serious adverse events related to study-mandated 
procedures ...............................................................................41 
4.3.2 
Reporting of serious adverse events .................................................41 
4.3.2.1 
Enrollment period ....................................................................41 
4.3.2.2 
Treatment period .....................................................................41 
4.3.2.3 
Reporting procedures ..............................................................42 
4.3.3 
Follow-up of serious adverse events .................................................42 
4.4 
Pregnancy .....................................................................................................43 
4.4.1 
Teratogenicity ...................................................................................43 
4.4.2 
Reporting of pregnancy ....................................................................43 
4.4.3 
Follow-up of pregnancy ....................................................................43 
5 
STATISTICAL METHODOLOGY AND ANALYSES ............................................44 
5.1 
Statistical analysis plan .................................................................................44 
5.2 
Analysis sets .................................................................................................44 
5.2.1 
All-treated set ....................................................................................44 
5.2.2 
Safety set ...........................................................................................44 
5.3 
Primary efficacy endpoint ............................................................................44 
5.4 
Secondary efficacy endpoints .......................................................................44 
5.5 
Safety and tolerability endpoints ..................................................................44 
5.6 
Exposure to study drug(s) .............................................................................45 
5.7 
Baseline parameters ......................................................................................46 
5.8 
Exploratory analyses .....................................................................................46 
5.9 
Interim analyses ............................................................................................46 
6 
REFERENCES ............................................................................................................47 
7 
PROCEDURES AND GOOD CLINICAL PRACTICE .............................................51 
7.1 
Procedures ....................................................................................................51 
7.1.1 
Protocol amendments ........................................................................51 
7.1.2 
Monitoring ........................................................................................52 
7.1.3 
Data management .............................................................................53 
7.1.3.1 
Data collection .........................................................................53 
7.1.3.2 
Database management and quality control ..............................53 
7.1.4 
Recording of data and retention of documents .................................53 
7.1.5 
Audit .................................................................................................54 
7.1.6 
Handling of study drug(s) .................................................................54 
7.1.7 
Publication and reporting of study results ........................................55 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
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Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
7.1.8 
Disclosure and confidentiality ..........................................................55 
7.1.9 
Premature termination or suspension of the study ............................55 
7.2 
Good Clinical Practice ..................................................................................56 
7.2.1 
Ethics and Good Clinical Practice ....................................................56 
7.2.2 
Ethics Committee / Institutional Review Board ...............................56 
7.2.3 
Informed consent ..............................................................................57 
7.2.4 
Compensation to subjects and investigators .....................................57 
8 
APPENDIX .................................................................................................................58 
 
LIST OF TABLES 
 
Table 1 
Visit and Assessment Schedule.......................................................................17 
Table 2 
Study treatment adjustment in the event of ALT and/or AST elevations .......34 
 
LIST OF FIGURES 
 
Figure 1 
Study design ....................................................................................................26 
 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
17 July 2020, page 9/59 
Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
LIST OF ABBREVIATIONS 
6MWT 
6-minute walk test 
AE 
Adverse event 
ALT 
Alanine aminotransferase/serum glutamic pyruvic 
transaminase (SGPT) 
AST 
Aspartate aminotransferase/serum glutamic oxaloacetic 
transaminase (SGOT) 
BP 
Blood pressure 
Cmax 
Maximum observed plasma concentration 
CRF 
Case report form 
CRO 
Contract research organization 
CYP 
Cytochrome 
EC 
Ethics committee 
ECG 
Electrocardiogram/graphy/graphic 
EOS 
End-of-Study 
EOT 
End-of-Treatment 
ERA 
Endothelin receptor antagonist 
ET-1 
Endothelin-1 
ETA 
Endothelin receptor A 
ETB 
Endothelin receptor B 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HRT 
Hormone replacement therapy 
HIV 
Human immunodeficiency virus 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
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Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
IXRS 
Interactive Voice/Web Recognition System 
IRB 
Institutional review board 
LFT 
Liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
OL 
Open label 
PAH 
Pulmonary arterial hypertension 
PD 
Pharmacodynamic 
PH 
Pulmonary hypertension 
PK 
Pharmacokinetic 
PVR 
Pulmonary vascular resistance 
RSI 
Reference Safety Information 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
t.i.d.  
Three times a day 
ULN 
Upper limit of normal 
WOCBP 
Woman of childbearing potential 
 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
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Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment 6 
17 Jul 2020 
Amendment 5 
10 June 2016 
Amendment 4 
27 Aug 2013 
Amendment 3 
22 Sep 2009 
Amendment 2 
18 Jul 2008 
Amendment 1 
15 Nov 2007 
Original Protocol 
01 Oct 2007 
 
Amendment 6 (17 July 2020) 
Overall Rationale for the Amendment: The purpose of this amendment is to update 
concomitant therapy section pertaining to newly identified drug-drug interactions (DDI) 
between macitentan and fluconazole (a dual moderate inhibitor of CYP3A4 and CYP2C9) 
from a pre-clinical study on implications of role of CYP2C9 in the metabolism of 
macitentan. 
A Protocol Amendment Summary of Changes Table for the current amendment is 
provided below. 
 
Section Number and 
Name 
Description of Change 
Brief Rationale 
3.1.4.1 Prohibited 
concomitant 
medications 
Changes made to prohibited medications. 
• 
Current bullet point was modified as 
below: 
“Concomitant use of macitentan with 
strong 
inhibitors 
of 
CYP3A4 
(ketoconazole, 
itraconazole, 
voriconazole, 
clarithromycin, 
telithromycin, nefazodone, ritonavir, 
and saquinavir) or moderate dual 
CYP3A4/CYP2C9 inhibitors (e.g., 
fluconazole, 
amiodarone) 
or 
co-
administration of a combination of 
moderate 
CYP3A4 
(e.g., 
ciprofloxacin, cyclosporine, diltiazem, 
New DDI identified with 
implication on role of 
CYP2C9 in the 
metabolism of macitentan 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
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Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
Section Number and 
Name 
Description of Change 
Brief Rationale 
erythromycin, verapamil) should be 
avoided.” 
• 
Following paragraph was added. 
“If patients are currently stable on a 
moderate 
dual 
CYP3A4/CYP2C9 
inhibitors 
(e.g., 
fluconazole, 
amiodarone) or co-administration of 
a combination of moderate CYP3A4 
(e.g., 
ciprofloxacin, 
cyclosporine, 
diltiazem, erythromycin, verapamil) 
and moderate CYP2C9 inhibitors 
(e.g., 
miconazole, 
piperine), 
the 
patient may remain on current 
treatment 
per 
the 
investigator's 
discretion based on his/her clinical 
judgement 
and 
risk-benefit 
assessment.” 
 
3.1.4.1 Prohibited 
concomitant 
medications;6 
References 
A new reference was added to Section 3.1.4.1 and 
updated in the reference list. 
To provide investigators 
with some examples of 
CYP3A4 and CYP2C9 
inhibitors. 
Abbreviations: CYP=cytochrome P450 
 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
17 July 2020, page 13/59 
Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
PROTOCOL SYNOPSIS AC-055-303/SERAPHIN OL 
TITLE 
Long-term, single-arm, open label extension study of the 
SERAPHIN study to assess the safety and tolerability of 
macitentan/ACT-064992 in patients with symptomatic 
pulmonary arterial hypertension. 
ACRONYM 
SERAPHIN OL: Study with an ERA in Pulmonary arterial 
Hypertension to Improve cliNical outcome (Open Label). 
OBJECTIVES 
To assess the long-term safety and tolerability of macitentan 
in patients with symptomatic pulmonary arterial hypertension 
(PAH). 
DESIGN / PHASE 
Multicenter, open-label (OL) extension, single-arm, Phase III 
study 
STUDY PLANNED 
DURATION 
First 
patient 
First visit 
Q4/07 Last 
patient 
First visit 
Q1/12 Last 
patient 
Last visit 
Open 
CENTERS 
/ COUNTRIES 
118 centers in 34 countries. 
PATIENTS / GROUPS 550 patients in one group. 
INCLUSION 
CRITERIA 
• Signed informed consent prior to initiation of any study-
mandated procedure. 
• Patients with pulmonary arterial hypertension and having 
completed the event-driven study, 
AC-055-302/SERAPHIN, or 
Patients who have experienced a clinical worsening of 
PAH in AC-055-302/SERAPHIN and for whom a written 
approval to roll over into this study has been obtained 
from the Sponsor. 
• Women of childbearing potential must have a negative 
pre-treatment serum pregnancy test and must use a 
reliable method of contraception during study treatment 
and for at least 28 days after study treatment termination. 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
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Confidential  
EudraCT No 2007-003694-27 
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EXCLUSION 
CRITERIA 
• Any major violation of protocol 
AC-055-302/SERAPHIN. 
• Pregnancy or breast-feeding. 
• AST and/or ALT > 3 times the upper limit of the normal 
range. 
• 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. 
• Known hypersensitivity to macitentan or any of the 
excipients. 
CONCOMITANT 
MEDICATIONS 
Prohibited 
• Endothelin receptor antagonists (other than study drug).  
Note: If the investigator considers a switch to 
commercial Opsumit®, treatment with commercial 
Opsumit® is allowed immediately after the EOT visit but 
the subject must still present for an EOS visit after the 
follow-up period.  
If the investigator considers a switch to another 
commercial ERA, treatment with that ERA must only 
begin after the follow-up period / EOS visit. 
• Specific immune suppressants: cyclosporine A and 
tacrolimus, everolimus, sirolimus (calcineurin or mTOR 
inhibitors). 
• Concomitant use of macitentan with strong CYP3A4 
inducers (carbamazepine, rifampin, rifabutin and St. 
John’s wort) should be avoided. 
• Concomitant use of macitentan with strong inhibitors of 
CYP3A4 (ketoconazole, itraconazole, voriconazole, 
clarithromycin, telithromycin, nefazodone, ritonavir, and 
saquinavir) or moderate dual CYP3A4/CYP2C9 
inhibitors (e.g., fluconazole, amiodarone) or co-
administration of a combination of moderate CYP3A4 
(e.g., ciprofloxacin, cyclosporine, diltiazem, 
erythromycin, verapamil) should be avoided. 
• Any investigational drug other than macitentan. 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
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Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
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STUDY PERIODS 
Treatment period: until the approval of macitentan for this 
indication is obtained or the sponsor decides to stop study 
AC-055-303/SERAPHIN OL. 
Post-treatment safety follow-up: up to 28 days after study 
drug discontinuation. 
INVESTIGATIONAL 
DRUG 
Macitentan tablet oral administration / dose 10 mg / once 
daily. 
COMPARATIVE 
DRUG  
Not applicable. 
TOLERABILITY / 
SAFETY 
ENDPOINTS 
• Treatment-emergent AEs up to 28 days after study drug 
discontinuation. 
• Treatment-emergent SAEs up to 28 days after study drug 
discontinuation. 
• AEs leading to premature discontinuation of study drug. 
• Occurrence of liver function test (ALT and/or AST) 
abnormality (> 3 and ≤ 5 × ULN; > 5 and ≤ 8 × ULN; 
> 8 × ULN) and hemoglobin abnormality (≤ 8 g/dL; 
> 8 and ≤ 10 g/dL) up to 28 days after study drug 
discontinuation.  
STATISTICAL 
METHODOLOGY  
This study will not be individually analyzed, but only in 
combination with data from the AC-055-302/SERAPHIN 
study. More precisely, the analysis set comprises (i) all 
patients in the AC-055-303/SERAPHIN OL study plus (ii) all 
patients 
who 
received 
macitentan 
during 
the 
AC-055-302/SERAPHIN study and did not participate in the 
AC-055-303/SERAPHIN OL study. In this set, the 
observation period for the individual patient starts at the time 
of the first administration of macitentan and ends with the 
permanent discontinuation of macitentan regardless of 
administration type (i.e., double blind or open label). 
The statistical evaluation of the safety and tolerability 
endpoints will be carried out descriptively. 
STUDY 
COMMITTEES 
A Steering Committee is involved in the study design and will 
provide guidance on the conduct of the study. 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
17 July 2020, page 16/59 
Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
An Independent Liver Safety Board is established to monitor 
the liver safety of macitentan including reviewing cases of 
confirmed elevations of aminotransferases > 3 × ULN. 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
17 July 2020, page 17/59 
Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
Table 1 
Visit and Assessment Schedule 
PERIODS 
 
TREATMENT PERIOD 
FOLLOW-UP 
PERIOD 
VISITS 
Enrollment 
(Visit 1) 
Visit 2,3, etc. 
End-of-Treatment (EOT) 
End-of-Study 
(EOS) 
                                   TIMEPOINTS 
 
ASSESSMENTS 
Day 11 
Month 6,  
and every 6 months 
thereafter 
± 2 weeks 
 
Up to 28 days 
after study drug 
discontinuation 
Informed Consent 
X 
 
 
 
Concomitant medication 
X 
X 
X 
X 
Vital signs, Body weight 
Physical examination 
Performed at each visit; Data will only be kept in patient’s file 
 
Complete Laboratory Tests 
X 
X 
X 
 
LFTs 
X 
Recommended monthly (+/−1 week) 
up to at least 28 days after End-of-Treatment 
Serum Pregnancy Test2  
(if applicable)  
X 
X 
X 
 
Urine Pregnancy Test2, 5  
(if applicable)  
 
Required monthly (+/−1 week) 
up to at least 28 days after End-of-Treatment 
Phone call for pregnancy test reminder and 
contraception counseling2 
 
Required monthly (+/−1 week) 
up to at least 28 days after End-of-Treatment 
Study Drug Dispensing4 
X 
X 
 
 
Adverse Events3  
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 
1The tests are not to be repeated if measured during the End-of-Treatment visit of study AC-055-302/SERAPHIN that has been performed within 
4 weeks of this visit. 2Women of childbearing potential only; 3AE reporting and follow-up: all AEs up to 28 days after study drug discontinuation. 
4Study drug may be dispensed on a monthly basis at each LFT visit. 5Urine pregnancy test is required if no serum pregnancy test is performed. 
AE = adverse event; LFT = liver function test.

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
17 July 2020, page 18/59 
Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
PROTOCOL 
1 
BACKGROUND AND RATIONALE 
1.1 Pulmonary hypertension 
The most serious chronic disorder of the pulmonary circulation is pulmonary arterial 
hypertension (PAH), a syndrome of diverse etiology and pathogenesis characterized by the 
persistent increase in pulmonary vascular resistance (PVR) potentially leading to right 
heart failure and death [Barst 2004, McLaughlin 2004, D’Alonzo 1991]. Pulmonary 
arterial hypertension is hemodynamically defined as a resting mean pulmonary arterial 
pressure greater than 25 mmHg with normal pulmonary capillary or left atrial pressure 
(< 15 mmHg) [McLaughlin 2004, Rubin 1997]. Numerous conditions are known to lead to 
or to be associated with the development of PAH. These conditions are classified into five 
groups based on their similar clinical presentation, pathology, pathophysiology, prognosis, 
and, most of all, similar therapeutic approach [Simonneau 2004]. Pulmonary arterial 
hypertension may occur in the absence of a demonstrable cause (idiopathic or familial) 
[Thomson 2003, McGoon 2004], or as a complication of congenital heart disease, systemic 
conditions such as connective tissue disease, particularly scleroderma [Battle 1996, 
Ungerer 1983, Tanaka 2002, Fagan 2004, Love 1990], HIV infection [Opravil 1997, 
Petitpretz 1994, Mehta 2000], sickle-cell disease [Gladwin 2004], chronic liver disease 
[Kuo 1997, Castro 1996], obstructive or restrictive lung disease [Weitzenblum 2005, 
Chaouat 2005, Thabut 2005], thromboembolic disease [Fedullo 2001, Pengo 2004], 
sarcoidosis [Shorr 2005], or as the result of the use of fenfluramine anorexigens [Gurther 
1985, Fishman 1999, Abenhaim 1996, Delcroix 1998]. 
Pulmonary arterial hypertension is associated with structural changes in both the 
pulmonary vasculature and the right ventricle. The changes in vascular structure involve 
three combined elements: vasoconstriction, vascular-wall remodeling and thrombosis in 
situ [Humbert 2004a].  
Recent advances [Farber 2004] in the understanding of the pathogenic factors leading to 
pulmonary vascular disease have led to the development of new therapies targeting specific 
pathways (the prostacyclin pathway, the endothelin pathway, and the nitric oxide pathway) 
[Humbert 2004b] that are believed to play pathogenic roles. 
The available therapies have positive effects in PAH, but they do not provide a cure, and 
in many patients the disease will progress. Pure vasodilators, such as calcium channel 
blockers, are effective only in a minority of patients who have an acute response to 
vasodilator testing. Seven agents are currently approved for the treatment of PAH in the 
United States and Europe. Intravenous prostacyclin (epoprostenol), other prostanoid 
analogues (i.e., beraprost, treprostinil, and iloprost), a dual endothelin receptors antagonist 
(bosentan), and more recently, phosphodiesterase type 5 inhibitors (sildenafil) and 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
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selective endothelin receptor antagonists (sitaxsentan and ambrisentan) have been shown 
to improve exercise capacity as assessed by the 6-minute walk test (6MWT) in short-term 
randomized placebo-controlled trials. 
Despite these achievements, however, PAH remains a serious life-threatening condition 
[Humbert 2004b, Humbert 2004a]. 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. 
1.2 Endothelin-1 and pulmonary hypertension 
Endothelin-1 (ET-1), a 21-amino-acid peptide, is one of the most potent vasoconstrictors 
and mitogens for smooth muscle and contributes to increased vascular tone and 
proliferation in pulmonary vasculopathy [Galie 2004].  
There are two distinct receptors for ET-1: endothelin receptor A (ETA) and endothelin 
receptor B (ETB). The two receptors have unique binding locations and affinities for the 
endothelin peptide [Banigni 1995, Massaki 1998]. The ETA receptors are expressed on 
pulmonary vascular smooth muscle cells, whereas ETB receptors are present both on 
pulmonary vascular cells and on smooth muscle cells.  
When activated, the ETA receptor located in pulmonary vascular smooth muscle cells 
mediates a potent vasoconstrictive response and ETB receptors on endothelial cells mediate 
vasodilatation via increased production of nitric oxide and prostacyclin [Hirata 1993, de 
Nucci 1988]. ET-1 is also known to be a potent mitogen, with the ability to induce cell 
proliferation in vascular smooth muscle cells. It has been shown that both the ETA and ETB 
mediate the mitogenic action of ET-1 [Clarke 1989, Chua 1992, Davie 2002, Sugawara 
1996]. 
Laboratory and clinical investigations have clearly shown that ET-1 is overexpressed in 
several forms of pulmonary vascular disease. ET-1 is likely a major player in the 
vasodilator and vasoconstrictor imbalance, as well as in the abnormal pulmonary vascular 
remodeling present in the development and progression of PH of various etiologies 
[Stewart 1991, Giaid 1993]. 
1.3 Macitentan – Endothelin Receptor Antagonist 
1.3.1 Macitentan – Preclinical information 
Macitentan is a new, orally active, non-peptide, potent dual ETA and ETB receptor 
antagonist selected for clinical development in PAH and other indications associated with 
an activated ET-system. Macitentan shows dose-dependent efficacy similar to that 
observed with bosentan (Tracleer®, the first ERA registered for the treatment of patients 
with PAH) in preclinical models of hypertension and PAH, but macitentan is 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
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Confidential  
EudraCT No 2007-003694-27 
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approximately 10 times more potent than bosentan based on administered dose. In 
hypertensive rats, acute oral administration of macitentan dose-dependently decreases 
mean arterial blood pressure without affecting heart rate. Chronic oral administration of 
macitentan to hypertensive rats causes a sustained decrease in blood pressure that is not 
associated with accumulation, tachyphylaxis, rebound effect after cessation of treatment, 
or an increase in heart rate. In rats with monocrotaline-induced pulmonary hypertension, 
chronic oral administration of macitentan increases survival and dose-dependently reduces 
pulmonary pressure, pulmonary vascular hypertrophy, and right ventricular hypertrophy, 
without decreasing systemic blood pressure. 
In preclinical safety studies, no effects on normal physiological functions or 
electrocardiographic (ECG) variables, including cardiac repolarization, were observed, 
with the exception of a decrease in arterial blood pressure observed in a cardiovascular 
study in dogs. Macitentan has no genotoxic potential. In the pivotal 26-week and 39-week 
toxicity studies, the exposures in animals found at the no-observed-adverse-effect-level are 
above the anticipated clinical exposures and provide a margin of safety for studies in man. 
A study conducted in hairless rats showed that macitentan is not phototoxic in vivo. 
Macitentan does not bind relevantly to melanin. Reproductive toxicity studies showed that 
macitentan is teratogenic without affecting male or female fertility. Teratogenicity is 
considered to be an ERA class effect. 
Macitentan has been selected for further clinical development due to the following 
characteristics: 
• Its potency and selectivity for endothelin receptors 
• Its efficacy in preclinical models of hypertension and PAH 
• The absence of significant inhibitory effects on bile salt transport, suggesting an 
improved liver safety profile compared to bosentan 
• A pharmacokinetic profile consistent with once-daily dosing 
• A good safety and tolerability profile 
More detailed information on Macitentan can be found in the Macitentan Investigator’s 
Brochure [Macitentan IB]. 
1.3.2 Macitentan – Clinical information 
1.3.2.1 Phase I studies in healthy subjects 
During the Phase I program about 150 healthy male subjects were treated with macitentan, 
administered as a capsule formulation. Macitentan was well tolerated in all studies. The 
most frequently reported adverse event (AE) was headache. No clear dose relationship 
could be discerned for any AE. However, in the single-ascending dose study, compared to 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
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Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
subjects receiving placebo, subjects receiving a dose of 600 mg reported markedly more 
AEs (headache, nausea, vomiting, rhinitis, and others). A dose of 300 mg was identified as 
the maximum tolerated dose. 
Treatment with macitentan up to 600 mg as a single dose and 30 mg as multiple doses for 
10 days (highest doses tested) was not associated with clinically relevant changes in 
systolic and diastolic blood pressures, heart rate, or ECG parameters and morphology.  
Eight cases of asymptomatic increases in liver function tests (LFTs) were observed in the 
Phase I program. These increases in AST, ALT and/or GGT were below 2, 4, and 3 times 
the upper limit of normal (ULN), respectively. The increase in LFTs was not associated 
with any AE and resolved within 14 days of observation. 
In healthy male subjects, the plasma concentration-time profile of macitentan, administered 
as a capsules formulation, can be described by slow absorption with maximum plasma 
concentrations achieved approximately 8 hours after dosing. The apparent elimination half-
life was approximately 16 hours. After multiple dosing, the pharmacokinetics (PK) of 
macitentan were dose-proportional over the dose range tested. Steady-state conditions were 
reached by Day 3 and macitentan accumulated approximately 1.5-fold. In plasma, one 
metabolite was identified, ACT-132577. This metabolite was pharmacologically active, 
reached steady state by Day 7 and had an apparent elimination half-life of about 2 days. 
The accumulation factor was approximately 8.5. Also for the metabolite the PK after 
multiple dose administration were dose-proportional. Based on the PK of macitentan and 
its metabolite ACT-132577, as well as the observation that macitentan had no effect on the 
urinary 6β-hydroxycortisol/cortisol ratio, no signs of auto-induction were detected in this 
study. 
Macitentan increased plasma ET-1 concentrations for all single doses from 5 mg upwards. 
When given as multiple doses, an increase in ET-1 levels was observed for all tested doses. 
Results from the food interaction study showed that macitentan can be taken irrespective 
of food intake. 
Macitentan did not influence the PK and pharmacodynamics (PD) of warfarin. Similarly, 
co-administration of warfarin with macitentan appeared not to have an impact on the 
exposure of macitentan.  
There are no clinically relevant effects of sildenafil 20 mg t.i.d. on the PK of macitentan 
and its metabolite (ACT-132577). Also, no effect of macitentan was observed on the PK 
of sildenafil and its metabolite (N-desmethyl sildenafil). 
In the presence of the strong CYP3A4 inhibitor ketoconazole, an increase of approximately 
2-fold in area under the curve was observed for macitentan, while exposure to ACT-132577 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
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Confidential  
EudraCT No 2007-003694-27 
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was reduced by 26%. Therefore, concomitant use of macitentan with strong inhibitors of 
CYP3A4 should be avoided. 
The results from the biocomparison study indicated a lower Cmax of macitentan of the 
tablets when compared to the capsule formulation, which was deemed not to be clinically 
relevant as the total exposure of macitentan and ACT-132577 and Cmax of ACT-132577 of 
the different formulations were found to be similar. 
More detailed information on macitentan Phase I studies can be found in the Macitentan 
Investigator’s Brochure [Macitentan IB]. 
1.3.2.2 Phase II study in patients with essential hypertension 
A Phase II dose-finding study was conducted over 8 weeks in 379 patients with mild to 
moderate essential hypertension. Four doses of macitentan (0.3, 1, 3, and 10 mg) and 
enalapril (20 mg) once daily were evaluated versus placebo. The primary efficacy endpoint 
was the change from baseline to Week 8 in mean sitting diastolic blood pressure (BP) at 
trough (i.e., 24 hours post dose). 
This study has demonstrated that macitentan is efficacious in reducing the blood pressure 
in subjects with mild to moderate essential hypertension. Treatment with the 10-mg dose 
showed a statistically significant reduction versus placebo in sitting diastolic and systolic 
BP at trough, and a dose-response for effect was indicated. The point estimates of the 
treatment effect at the two highest doses of macitentan tested were higher than that with 
enalapril 20 mg once a day (study was not powered to compare to enalapril). Most of the 
BP reduction with macitentan was reached within 4 weeks of treatment. The PK/PD 
analysis supported the clinical findings, and indicated that the 10 mg dose is close to the 
plateau of the pharmacological effect.  
Macitentan was well tolerated across all four dose levels. The overall frequency of AEs 
was similar to that observed in the placebo group. The numbers of subjects with at least 
one serious adverse event (SAE) were equally distributed across groups. There were no 
deaths.  
The study was terminated prematurely following the Sponsor’s decision to break the blind 
for a safety evaluation of five cases of increased liver enzymes > 3 × ULN. These five cases 
occurred in the macitentan groups, without obvious dose relationship (one, two, one, and 
one in the 0.3-mg, 1-mg, 3-mg, and 10-mg dose groups, respectively). In three cases, there 
were other, plausible reasons for increased liver enzymes (pancreatic cancer, surgery with 
general anesthesia, and concomitant antibiotic therapy, respectively). All episodes of liver 
enzyme elevations resolved without sequelae within 14 days of observation. However, 
these data suggest that like other ERAs, macitentan may cause liver enzyme elevations in 
some patients. 

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Pulmonary arterial hypertension 
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More detailed information on macitentan Phase II studies can be found in the Macitentan 
Investigator’s Brochure [Macitentan IB]. 
1.3.2.3 Phase III study in patients with pulmonary arterial hypertension 
A Phase III study in patients with PAH (AC-055-302/ SERAPHIN) was conducted in 
742 patients randomized to placebo or macitentan 3 or 10 mg in a 1:1:1 ratio. In this event 
driven study, macitentan or placebo was administered in a double-blind fashion for up to 
3.6 years. 
Mean exposure to study treatment was 85.3 weeks for placebo patients (n = 249), 
99.5 weeks for patients on 3 mg (n = 250) and 103.9 weeks for patients on 10 mg (n = 242). 
Macitentan, at both the 3 mg and 10 mg dose, decreased the risk of a morbidity/mortality 
event over the treatment period versus placebo. This risk was reduced by 45% in the 10 mg 
dose group (p < 0.0001). At 3 mg, the observed risk reduction was 30% (p = 0.0108).  
A dose-dependent effect (p < 0.05 for either dose) was also observed in all secondary 
efficacy variables including exercise capacity assessed with the 6MWT, PAH symptoms 
assessed by the WHO FC and hospitalization and mortality. 
Additionally, in a hemodynamic sub-study, the observed treatment effect of reduction in 
PVR after 6 months of treatment with macitentan 3 mg and 10 mg was 30.0% (97.5% 
confidence limits 17.9, 44.0) and 36.5% (97.5% confidence limits 21.7, 49.2), respectively. 
Treatment with macitentan was well tolerated. The number of AEs reported and patients 
discontinuing treatment due to AEs was similar across all groups. The overall incidence of 
elevations in liver aminotransferases was similar to placebo (4.5%, 3.6% and 3.4% 
incidence of ALT or AST > 3 × upper limit of the ULN in the placebo, macitentan 3 mg 
and macitentan 10 mg groups, respectively). In addition, no differences were observed 
between macitentan and placebo on fluid retention (edema). AEs associated with decreased 
hemoglobin was observed more frequently on macitentan 10 mg than placebo, with no 
difference in treatment discontinuation between groups. 
More detailed information on macitentan Phase III studies can be found in the Macitentan 
Investigator’s Brochure [Macitentan IB]. 
1.4 Study rationale 
1.4.1 Medical background 
Macitentan is a new orally active, non-peptide, dual ETA and ETB receptor antagonist 
selected for clinical development. In animal models of PAH and systemic hypertension, 
macitentan shows dose-dependent efficacy, similar to that observed with bosentan. In rats 
with monocrotaline-induced PH, oral chronic macitentan increased survival and dose-

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
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Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
dependently reduced pulmonary pressure, pulmonary vascular hypertrophy, and right 
ventricular hypertrophy, without decreasing blood pressure [Macitentan IB]. 
Macitentan was chosen for development in PAH because it is approximately 10 times more 
potent than bosentan, has shown a PK profile consistent with once-daily dosing, and a 
reduced potential to inhibit bile salt elimination and therefore a more attractive safety 
margin, especially in regard to liver enzyme injury [Macitentan IB]. 
The main objective of the AC-055-303/SERAPHIN OL study, which will follow the 
AC-055-302/SERAPHIN study, will be to assess the long-term safety and tolerability of 
macitentan in patients with symptomatic PAH. 
1.4.2 Patient population 
The patient population will consist of 
• Patients who complete the event-driven treatment period of protocol 
AC-055-302/SERAPHIN as scheduled 
• Patients experiencing a clinical worsening of PAH, as defined in the 
AC-055-302/SERAPHIN protocol, and leading to permanent study treatment 
discontinuation in the AC-055-302/SERAPHIN study. The enrollment of these 
patients can only be performed after a formal request from the site and after written 
approval from the Sponsor 
1.4.3 Study design 
An 
open-label, 
non-comparative, 
multicenter, 
extension 
study 
following 
the 
AC-055-302/SERAPHIN study to assess long-term safety and tolerability of macitentan in 
patients with symptomatic PAH. 
The OL study design has been discussed and approved by the Steering Committee 
Members. 
1.4.4 Dose selection  
The proposed dose (10 mg once daily) is the higher dose used in the Phase III study 
(AC-055-302/SERAPHIN).  
1.4.5 Treatment duration 
Study treatment for each patient lasts from his/her enrollment date until the end of the trial 
i.e., until the earliest of: (i) the approval of macitentan in this indication is obtained in the 
patient’s country, or (ii) the sponsor decides to stop study AC-055-303/SERAPHIN OL, 
or (iii) the patient’s, investigator’s or Sponsor’s decision to discontinue study drug. 

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1.4.6 Primary endpoint 
No primary efficacy endpoint is considered for this OL extension study. 
1.4.7 Statistical hypotheses and sample size 
No statistical hypothesis is considered for this OL extension study. 
2 
STUDY OBJECTIVES 
To assess long-term safety and tolerability of macitentan in patients with symptomatic 
PAH. 
3 
INVESTIGATIONAL PLAN 
This will be a multicenter, open-label, extension study to assess long-term safety and 
tolerability of macitentan in patients with symptomatic PAH. 
550 patients (males or females aged 12 years or older) from the event-driven study 
AC-055-302/SERAPHIN are enrolled in this Phase III OL study (see Section 1.4.2). The 
study will be conducted in 118 centers in 34 countries. The patients are rolled over from 
the event-driven study to the OL study without knowledge of their previous study drug 
(macitentan or placebo). 
Enrollment in the AC-055-303/SERAPHIN OL study (OL Visit 1) should correspond to 
the last visit in the AC-055-302/SERAPHIN study. If this is not possible, enrollment in the 
OL study must occur within 2 months of the AC-055-302/SERAPHIN End-of-Treatment 
(EOT) Visit.  
The target study drug tablet, 10 mg of macitentan, will be taken orally once daily, 
irrespective of food intake. 
At the end of the open-treatment period/discontinuation of treatment, a post-treatment 
safety follow-up period (28 days) will follow.  
A Steering Committee is involved in the study design and will provide guidance on the 
conduct of the study. 
No interim analysis is planned. 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
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Figure 1 
Study design 
 
Placebo 
 
 
 
Macitentan 3 mg 
 
 
 
Macitentan 10 mg 
Macitentan 10 mg 
 
 
 
 
Follow-up 
 
Study 
AC-055-302 
Study AC-055-303 / 
SERAPHIN OL 
28 days 
                                                  Informed consent                                            
Discontinuation of  
                                                  Enrollment                                                     
treatment 
3.1 Study population 
3.1.1 Patient population 
The patient population will consist of patients who complete the event-driven treatment 
period of protocol AC-055-302/SERAPHIN as scheduled, and patients who have 
experienced a clinical worsening of PAH in AC-055-302/SERAPHIN and for whom a 
written approval to roll over into this study has been obtained from the Sponsor. 
3.1.2 Inclusion criteria 
• Signed informed consent prior to initiation of any study-mandated procedure. 
• Patients with pulmonary arterial hypertension and having completed the event-driven 
study, AC-055-302/SERAPHIN, or 
• Patients who have experienced a morbidity event and for whom a written approval to 
roll over into this study has been obtained from the Sponsor. 
• Pregnancy – Not allowed during the study:  
Women of childbearing potential* with a negative pre-treatment serum pregnancy 
test and who consistently and correctly use (from screening and up to 28 days after 
study treatment discontinuation) a reliable method of contraception with a Pearl 
index of < 1% (oral hormonal contraceptive, implant, vaginal hormone ring, 
intrauterine system, or tubal ligation only in combination with condom), are 
sexually abstinent or have a vasectomized partner are allowed in the study. 

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*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, 
– fulfilling the criteria of postmenopausal at the screening of 
AC-055-302/SERAPHIN, 
– age > 50 years and not treated with any kind of hormone replacement 
therapy for at least 2 years prior to Visit 1 of the 
AC-055-303/SERAPHIN OL study with amenorrhea for at least 
24 consecutive months prior to this visit and a serum follicle stimulating 
hormone level of > 40 IU/L if the investigator has insufficient evidence 
that the woman is postmenopausal. 
3.1.3 Exclusion criteria 
• Any major violation of protocol AC-055-302/SERAPHIN. 
• Pregnancy or breast-feeding. 
• AST and/or ALT > 3 times the upper limit of the normal range. 
• 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. 
• Known hypersensitivity to macitentan or any of the excipients. 
3.1.4 Concomitant medications 
All concomitant medications (ongoing, initiated, and discontinued) including PAH specific 
medications and diuretics, herbal drugs and implanted/vaginal hormonal contraceptives 
taken in the period between Visit 1 and up to End-of-Study (EOS) must be recorded on the 
Concomitant Medication pages of the CRF. 
Any dose changes in PAH-specific medications only (e.g., endothelin receptor antagonists, 
prostanoids, and phosphodiesterase type 5 inhibitors, initiation of continuous chronic 
oxygen therapy), must be recorded in the CRF. Dose changes of other medications may be 
recorded in the CRF at the investigator’s discretion. 
3.1.4.1 Prohibited concomitant medications 
• Endothelin receptor antagonists (other than study drug)  
Note: If the investigator considers a switch to commercial Opsumit®, treatment with 
commercial Opsumit® is allowed immediately after the EOT visit but the subject must 
still present for an EOS visit after the follow-up period.  

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If the investigator considers a switch to another commercial ERA, treatment with that 
ERA must only begin after the follow-up period / EOS visit.), 
• Specific immune suppressants: cyclosporine A and tacrolimus, everolimus, sirolimus 
(calcineurin or mTOR inhibitors), 
• Concomitant use of macitentan with strong CYP3A4 inducers (carbamazepine, 
rifampin, rifabutin and St. John’s wort) should be avoided, 
• Concomitant use of macitentan with strong inhibitors of CYP3A4 (ketoconazole, 
itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and 
saquinavir) or moderate dual CYP3A4/CYP2C9 inhibitors (e.g. fluconazole, 
amiodarone) or co-administration of a combination of moderate CYP3A4 (e.g. 
ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) should be avoided, 
refer to the Food and Drug Administration website [FDA 2020], 
• Any investigational drug other than the macitentan. 
 
If patients are currently stable on a moderate dual CYP3A4/CYP2C9 inhibitors (e.g. 
fluconazole, amiodarone) or co-administration of a combination of moderate CYP3A4 
(e.g. ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) and moderate 
CYP2C9 inhibitors (e.g. miconazole, piperine), the patient may remain on current 
treatment per the investigator's discretion based on his/her clinical judgement and risk-
benefit assessment.  
3.2 Study drug 
3.2.1 Study drug packaging, labeling 
Patients who meet all inclusion criteria and none of the exclusion criteria will receive 
macitentan, 10 mg, in addition to their usual treatment. Actelion will provide study drug as 
tablets in childproof bottles containing 36 tablets. The study drug will be provided in: 
• One medication kit containing 6 bottles for a 6 month treatment period or 
• 6 individual bottles covering a 6 month treatment period 
The labeling and packaging of macitentan will be conducted according to Good 
Manufacturing Practice, Good Clinical Practice, and any local or national regulatory 
requirements.  
3.2.2 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 be accessed only by the pharmacist, 
the investigator, or another duly designated person. The study drug must not be stored 

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above 30 °C and must be protected from moisture. The study centers will be supplied with 
study drug according to the centers’ needs, depending on the enrolled number of patients. 
Each center will have an individual stock of study drug, which will be re-supplied in a 
timely manner as soon as a pre-defined minimum level of study drug has been reached as 
controlled by an Interactive Voice/Web Recognition System (IXRS). 
At each visit the medication kit or bottle numbers will be allocated to the subject through 
IXRS. 
Patients will receive study drug at enrollment (Visit 1) and at the 6-monthly visits thereafter 
up to EOT. The frequency of dispensing of study drug must be documented in the patient’s 
file. The patients will either receive a medication kit containing 6 bottles or 6 individual 
bottles covering a 6 months’ treatment period at scheduled visits (one bottle contains 36 
tablets). Patients may receive study drug at monthly visits (if applicable) if deemed 
necessary due to logistical reasons. 
Each medication kit or bottle will have a label with a tear-off part specifying the study 
protocol number and the batch number. At study drug dispensing, the investigator or 
pharmacist (if applicable) must remove the tear-off label from the medication kit or from 
the individual bottle (whatever applies) and attach the label to the Investigational Medicinal 
Product Label Dispensing Log. 
3.2.3 Treatment dose and administration 
One tablet must be taken orally once daily, irrespective of food intake. 
3.3 Study drug discontinuation and study withdrawal 
The permanent discontinuation of study drug corresponds to the EOT for an individual 
patient. 
3.3.1 Study drug interruption or permanent discontinuation 
The investigator must temporally interrupt or permanently discontinue the study drug if 
continued administration of the study drug is believed to be contrary to the best interests 
of the patient.  
The interruption or premature 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 such as withdrawal of the patient’s consent. 
The reason for study drug interruption or premature discontinuation must be documented 
in the case report form (CRF).  

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Interruptions should be for less than 4 weeks; longer interruptions should lead to permanent 
discontinuation of study drug. 
A patient will be considered lost to follow up only after exhausting all means of contact. 
3.3.2 Patient’s follow-up after study drug discontinuation 
If the patient is permanently withdrawn from the study, a complete EOT visit will be 
performed (see Section 3.8.2.2) and the patient will be followed for 28 days after the 
permanent study drug discontinuation and perform an EOS visit to collect information on 
serious adverse events related to macitentan. If withdrawal is considered study 
drug-related, the patient will remain under the supervision of the investigator until 
satisfactory health has returned. 
3.3.3 Replacement policy 
3.3.3.1 Patients 
Patients prematurely discontinued from the study drug for any reason will not be replaced. 
3.4 Treatment exposure, compliance and drug accountability 
Adequate records of study drug received, dispensed, used, lost, and intervals between visits 
must be 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 (including empty bottles and 
cartons) at each visit. At the conclusion of each patient’s participation in the study, all 
remaining drug supplies must be returned to the Sponsor for an accurate accounting of 
delivered and returned drugs. 
All remaining drug supplies shall be collected and returned to the Sponsor for destruction 
by the Sponsor representative. Destruction must be documented. 
3.5 Treatment assignment 
3.5.1 Treatment assignment 
Treatment is macitentan 10-mg tablets for all patients. 
3.5.2 Blinding 
Not applicable. 
3.5.3 Emergency procedure for unblinding 
Not applicable.  

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
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3.6 Study endpoints 
3.6.1  Efficacy endpoints 
Not applicable.  
3.6.2 Safety and tolerability endpoints 
• Treatment-emergent AEs up to 28 days after study drug discontinuation. 
• Treatment-emergent SAEs up to 28 days after study drug discontinuation. 
• AEs leading to premature discontinuation of study drug. 
• Occurrence of treatment-emergent increase in ALT and/or AST up to 28 days after 
study drug discontinuation: 
– > 3 and ≤ 5 × ULN 
– > 5 and ≤ 8 × ULN 
– > 8 × ULN 
• Occurrence of treatment-emergent hemoglobin abnormality up to 28 days after study 
drug discontinuation: 
– ≤ 8 g/dL 
– > 8 and ≤ 10 g/dL 
3.7 Study assessments 
The assessment performed at the EOT Visit for the event-driven study 
(AC-055-302/SERAPHIN) should not be repeated at enrollment (Visit 1) in the OL study 
if the EOT Visit was performed within 4 weeks of Visit 1. However, enrollment in the OL 
study must occur within 2 months of the AC-055-302/SERAPHIN EOT Visit.  
3.7.1 Safety and tolerability assessments 
The definitions, reporting and follow-up of AEs, SAEs and potential pregnancies are 
described in Section 4. 
3.7.1.1 Vital signs and body weight 
Vital signs (blood pressure and heart rate) and body weight will be assessed at the 6-
monthly visits. The data will be kept in the patient’s file (i.e., not recorded in the CRF).  
3.7.1.2 Laboratory assessments 
3.7.1.2.1 Type of laboratory 
Both Central and Local Laboratories are used in the study. 
Until approval of the Global Protocol version 5, blood sample analyses (hematology and 
biochemistry) were performed by local laboratories. For all the blood samples analyzed 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
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EudraCT No 2007-003694-27 
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CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
from beginning of the study up to approval and implementation of the Global Protocol 
version 5, local laboratory reports present at the site were used to record protocol mandated 
laboratory results in the Actelion database. If re-test or unscheduled blood samples had 
been analyzed between regular visits for the purpose of monitoring an AE, the results of 
the analyses were also be recorded in the Actelion database. 
After approval and implementation of Global Protocol version 5, the hematology and 
biochemistry blood samples are to be collected at site and sent to the Central Laboratory 
for analysis whenever possible (see contact details on page 2). The Central Laboratory 
reports will be sent to the Investigator. Any complete or partial re-test blood sample 
deemed necessary to follow-up an AE or to verify an unexpected abnormal value should 
also be sent to the Central Laboratory. 
Under specific circumstances (e.g., patient lives far away from the site and cannot return 
every month), laboratory samples could be drawn in a local laboratory using Central 
Laboratory kits which will be sent to and analyzed by the Central Laboratory. 
In the exceptional event (e.g., patient is admitted in a different hospital from the site) where 
a local laboratory is utilized for analysis of blood samples, data of these tests must be 
recorded in the Actelion database. 
The results (whether obtained via Local or Central Laboratory) will be kept in the patient’s 
file. Any clinically significant marked laboratory abnormalities must be reported by the 
investigator as an AE and/or SAE as appropriate (see Section 4). All Laboratory reports 
must be reviewed, signed and dated upon receipt. 
Any pregnancy occurring during the treatment period and up to 28 days after study drug 
discontinuation must be reported immediately to the Actelion Drug Safety Department 
using the Actelion Pregnancy Form (see 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. 
3.7.1.2.2 Laboratory parameters 
The laboratory tests from the last visit in AC-055-302/SERAPHIN can be used at the 
AC-055-303/SERAPHIN OL Enrollment Visit (OL Visit 1). The tests should not be 
repeated if enrollment in AC-055-303/SERAPHIN OL is within 4 weeks of the latest 
known results. 
Hematology and blood chemistry 
Hematology and blood chemistry tests will be performed at the Enrollment Visit (OL Visit 
1), if it occurs more than 4 weeks after the last visit in AC-055-302/SERAPHIN, and then 

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Pulmonary arterial hypertension 
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EudraCT No 2007-003694-27 
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CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
every 6 months until EOT. 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.  
Pregnancy test 
A serum pregnancy test for women of childbearing potential (WOCBP) must be performed 
at the Enrollment Visit (OL Visit 1), if it occurs more than 4 weeks after the last visit in 
AC-055-302/SERAPHIN, and then every 6 months until EOT. 
At the 6-monthly visits, a serum pregnancy test will be obtained using the blood draw 
already scheduled at this visit.  
For all other interim months, urine pregnancy tests will be performed by the patients at 
home. The urine pregnancy test kits provided to the patients by the site should be used. 
In order to ensure proper pregnancy monitoring and contraception counseling, site staff 
must call each WOCBP once per month to: 
• remind her to perform an urine pregnancy test and 
• collect the outcome of the urine pregnancy test 
During each visit at site / at each telephone call, it must be verified whether the method of 
contraception used previously is still valid, in accordance to the protocol and correctly used 
by the subject. For prepubescent women, childbearing potential must be assessed at each 
visit / telephone call and the women must be advised to use reliable methods of 
contraception as soon as childbearing potential has been established.  
Urine pregnancy test kits will be provided by the central laboratory to the sites for 
dispensing to the patients. 
Liver aminotransferase monitoring in all patients 
Liver aminotransferase levels must be measured at the Enrollment Visit (OL Visit 1), if it 
occurs more than 4 weeks after the last visit in AC-055-302/SERAPHIN, and then every 6 
months until EOT. 
Monthly liver aminotransferase monitoring is recommended for up to at least 28 days after 
EOT but it is at the investigator’s discretion to decide (taking into account the patient’s 
medical history and AEs) if those additional monthly tests are required/justified. 

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Pulmonary arterial hypertension 
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EudraCT No 2007-003694-27 
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CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
Table 2 
Study treatment adjustment in the event of ALT and/or AST 
elevations 
ALT and/or AST 
Treatment and monitoring recommendations 
> 3 and ≤ 8 × ULN 
Confirm by another test adding total and direct bilirubin 
and alkaline phosphatase measurements. If confirmed, 
interrupt treatment, monitor aminotransferase, bilirubin 
and alkaline phosphatase levels weekly until levels return 
to pre-treatment values. If the aminotransferase values 
return to pre-treatment levels re-introduction of study 
treatment can be considered. Interruptions should be for 
less than 4 weeks; longer interruptions should lead to 
permanent discontinuation of study drug. 
Re-introduction of study treatment after treatment 
interruption should only be considered if the potential 
benefits of treatment with macitentan outweigh the 
potential risks and when liver aminotransferase values are 
within pre-treatment levels. The advice of a hepatologist 
is recommended. 
Liver aminotransferase levels must then be checked within 
3 days after re-introduction, then again after a further 
2 weeks and thereafter according to the recommendations 
above (i.e., at monthly intervals). 
ULN = Upper Limit of Normal 
 
In case of associated clinical symptoms of liver injury, e.g., nausea, vomiting, fever, 
abdominal pain, jaundice, unusual lethargy or fatigue, flu-like syndrome (arthralgia, 
myalgia, fever), and/or increases in total bilirubin ≥ 2 × ULN or aminotransferases > 8 × 
ULN, treatment must be stopped and re-introduction of study treatment is not to be 
considered. Aminotransferase, bilirubin and alkaline phosphatase levels must be monitored 
weekly after study drug discontinuation until values return to pre-treatment levels. 
Other diagnoses should be considered and ruled out by performing the appropriate tests 
(e.g., viral 
hepatitis, 
mononucleosis, 
toxoplasmosis, 
cytomegalovirus, 
etc.). 
A 
“SERAPHIN LFT increase questionnaire” must be completed for confirmed elevations of 
aminotransferases > 3× ULN. 
All LFT abnormalities leading to study drug discontinuation must be recorded as AEs 
(see Section 4). 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
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EudraCT No 2007-003694-27 
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3.8 Visit and assessment schedule 
For a tabulated summary of all visits and assessments described in the following sections 
see Table 1. 
3.8.1 Enrollment visit  
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 visit includes: 
• Patient information and consent form signature 
• Physical examination 
• Measurement of vital signs and body weight 
• Laboratory tests including: 
– Complete laboratory tests including:  
o Hematology (including hemoglobin), 
o Blood chemistry (including LFTs), 
– 
Serum pregnancy test (for women of childbearing potential), NOTE: monthly 
monitoring from enrollment and up to at least 28 days after permanent 
discontinuation of the macitentan treatment, 
• Concomitant medication 
• Dispensing of study drug. 
The tests are not to be repeated if they were measured during the EOT Visit in 
AC-055-302/SERAPHIN, and if that visit was performed within 4 weeks of this visit. 
3.8.2 Treatment period 
After approval and implementation of Global Protocol version 6, LFTs and pregnancy (for 
women of childbearing potential) will be assessed as outlined in Table 1. 
During this period, AEs/SAEs and concomitant medication will be reported in the CRF. 
3.8.2.1 Visits at 6-monthly intervals (Visit 2, 3, etc.) 
After the OL Visit 1, all following visits are scheduled every 6 months ± 2 weeks. The 
morning dose of the study drug should be taken as usual. 
These visits include: 
• Physical examination 
• Measurement of vital signs and body weight 
• Laboratory tests including: 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
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Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
– Complete laboratory tests including: 
o Hematology (including hemoglobin), 
o Blood chemistry (including LFTs), 
– Serum pregnancy test (for women of childbearing potential), NOTE: monthly 
monitoring from enrollment and for up to at least 28 days after permanent 
discontinuation of the macitentan treatment, 
• AEs and SAEs since last visit will be reported in the CRF 
• Concomitant medication will be reported in the CRF (for details see Section 3.1.4) 
• Dispensing of study drug macitentan.  
3.8.2.2 End-of-Treatment Visit (EOT) or Permanent discontinuation  
Actelion will notify all sites when an EOT Visit should be planned. At the end of the OL 
study (see Section 1.4.5 for definition), the EOT Visit is scheduled for all patients. Any 
visit formerly scheduled within 2 weeks of the end of the study will not be performed. 
Patient permanently discontinuing macitentan treatment must also undergo the EOT Visit 
as soon as the treatment is discontinued. 
This visit includes: 
• Physical examination 
• Measurement of vital signs and body weight 
• Laboratory tests including: 
– Complete laboratory tests including: 
o Hematology (including hemoglobin), 
o Blood chemistry (including LFTs), 
– Serum pregnancy test (for women of childbearing potential),  
• AEs and SAEs since last visit will be reported in the CRF 
• Concomitant medication will be reported in the CRF (for details see Section 3.1.4) 
• Return of unused medication including empty bottles and cartons. 
All patients will have an EOS Visit (except for withdrawals and patients lost to follow-up).  
3.8.3 End-of-Study (EOS) Visit or 28-day follow-up 
Adverse events (serious or not) occurring up to 28 days after EOT should be reported in 
the CRF and in the SAE form, if applicable. Serious adverse events occurring thereafter, 
and ongoing SAEs, must be followed-up for 28 days after study drug discontinuation and 
reported in the SAE form.  
Liver function tests, hemoglobin assessments and pregnancy tests (for women of 
childbearing potential) must also be performed up to at least 28 days after study drug 
discontinuation. 

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Pulmonary arterial hypertension 
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EudraCT No 2007-003694-27 
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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 
Up to 28 days after study 
drug discontinuation 
After 28 days 
AE/SAE reporting  
on CRF AE page 
All AEs/SAEs 
All AEs/SAEs 
None 
SAE reporting on SAE 
form 
All SAEs 
All SAEs 
At investigator’s 
discretion2 
Reconciliation 1 
Yes 
Yes 
Not applicable 
Final study report 
Described 
Described 
Might be described 
1 Reconciliation between clinical and drug safety databases. 
2 Local laboratories must to be used to follow up on any laboratory abnormalities after the EOS visit. 
 
4.2 Adverse events 
4.2.1 Definitions of adverse events 
An AE is any adverse change from the 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, 
whether or not considered related to the study drug.  
Adverse events include: 
• Exacerbation of a pre-existing disease. 
• Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 
• Disease or medical condition detected or diagnosed 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.  

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Pulmonary arterial hypertension 
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• Abnormal assessments, e.g., ECG findings, must be reported as AEs if they represent 
a clinically significant finding that was not present at baseline or worsened during the 
course of the study. 
• Laboratory test abnormalities must be reported as AEs 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 occurred, 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. 
4.2.2 Intensity of adverse events 
The intensity of clinical AEs is graded on a three-point scale: mild, moderate, severe.  
 Mild 
Event may be noticeable to subject; does not influence daily activities; usually does not 
require intervention. 
 Moderate 
Event may make subject uncomfortable; performance of daily activities may be influenced; 
intervention may be needed. 
 Severe 
Event may cause noticeable discomfort; usually interferes with daily activities; subject may 
not be able to continue in the study; treatment or intervention is usually needed. 
A mild, moderate or severe AE may or may not be serious. These terms are used to describe 
the intensity of a specific event (as in mild, moderate, or severe myocardial infarction). 
However, a severe event may be of relatively minor medical significance (such as severe 
headache) 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 (see Section 4.3.1.2). 

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Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
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Confidential  
EudraCT No 2007-003694-27 
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CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
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., LFT 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  
Adverse events should be assessed by the investigators 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 (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 interrupted, or discontinued.  
• The event re-occurred when treatment was re-introduced. 
• Environmental factors such as clinical state and other treatments could equally have 
caused the event. 
 Unrelated to study drug 
This category applies to any AE (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 28 days after study drug 
discontinuation must be recorded on specific AE pages of the CRF. 
4.2.5 Follow-up of adverse events 
Adverse events still ongoing after study drug discontinuation for a given patient must be 
followed up to 28 days after study drug discontinuation. 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
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EudraCT No 2007-003694-27 
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4.3 Serious adverse events 
4.3.1 Definitions  
4.3.1.1 Serious adverse events 
A serious adverse event (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 patient’s 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 
if it had been more severe. 
Important medical events that may not immediately result in death, be life-threatening, or 
require hospitalization may be considered as SAEs when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed in the definitions above.  
The reference safety document to assess whether or not an SAE should be reported by the 
sponsor to Health Authorities, ECs/IRBs and investigators in an expedited fashion is the 
Macitentan Investigator’s Brochure [Macitentan IB]. 
4.3.1.2 Hospitalization – Prolongation of existing hospitalization 
Hospitalization is defined as an overnight stay in a hospital unit and/or emergency room 
due to an adverse event.  
An additional overnight stay defines a prolongation of existing hospitalization. 
The following is not considered an SAE: 
• Treatment on an emergency or outpatient basis for an event not fulfilling the 
definition of seriousness given above and not resulting in hospitalization. 
The following reasons for hospitalizations are not considered AEs/SAEs:  
• Hospitalizations for cosmetic elective surgery, social and/or convenience reasons. 

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EudraCT No 2007-003694-27 
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• 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., hospitalization for chemotherapy for cancer, elective hip replacement for 
arthritis. 
4.3.1.3 Serious adverse events related to study-mandated procedures  
Such SAEs are defined as SAEs that appear to have a reasonable possibility of causal 
relationship (i.e., a relationship cannot be ruled out) to study-mandated procedures 
(excluding administration of study drug) such as complication of a mandated invasive 
procedure (e.g., blood sampling, heart catheterization), or 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 Enrollment period  
Serious adverse events occurring from signature of the Informed Consent to study drug 
initiation must be reported only if they are considered by the investigator to be related to 
study-mandated procedures. 
An SAE not temporally associated with the use of a study drug, should be considered by 
the investigator as study-related if it appears to have a reasonable possibility of relationship 
(i.e., a relationship cannot be ruled out) to protocol-mandated procedures (e.g., 
complication of a mandated invasive procedure or car accident on the way to the hospital 
for a study visit, etc.).  
These SAEs are not reported in the CRF. Therefore, they are only collected on the 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. These SAEs occurring between study drug initiation and up 
to 28 days after study drug discontinuation must be reported, are defined as treatment-
emergent SAEs. 
These SAEs are reported on SAE forms and also on AE pages in the CRF. Therefore, they 
are entered both in the drug safety and clinical databases, and must be reconciled before 
study closure. 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
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EudraCT No 2007-003694-27 
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CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
4.3.2.3 Reporting procedures 
All SAEs must be reported by the investigator to the Actelion Drug Safety department 
within 24 hours of the investigator’s knowledge of the event. 
All SAEs must be recorded on SAE forms, irrespective of the study drug received by the 
patient, whether or not this event is considered by the investigator to be related to study 
drug. 
These SAE forms must be faxed to Actelion Drug Safety (see SAE Form). The investigator 
must complete the SAE form in English (unless otherwise specified) and assess the 
relationship to study drug. 
Such preliminary reports will be followed by detailed descriptions that should 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. Actelion Drug Safety 
department may contact the investigator to obtain further information.  
Suspected (considered related to the study drug) and unexpected (not previously described 
in the reference safety document), serious adverse reactions will be expedited by Actelion 
to Health Authorities, ECs/IRBs and investigators, as appropriate. 
The AE/SAEs listed below are commonly seen with the underlying PAH disease. For 
reporting, these SAEs will be treated as “disease-related” and therefore will not be subject 
to regulatory expedited reporting to Health Authorities, IRBs/IECs, and investigators: 
Signs and symptoms of PAH include worsening/exacerbation/progression, including fatal 
outcome, heart failure, worsening right heart failure, collapse, syncope, hemoptysis, 
anorexia, abdominal pain, chest pain, cyanosis, diaphoresis, dizziness, pre-syncope, 
hypoxia, fatigue, dyspnea, orthopnea, palpitations, systemic arterial hypotension, and 
tachycardia. These SAEs must be reported on an SAE form and also on AE pages in the 
eCRF. 
4.3.3 Follow-up of serious adverse events  
Serious adverse events still ongoing at the EOS Visit must be followed until resolution or 
stabilization or until the event is otherwise explained.  
New SAEs occurring at any time after the 28-day follow-up period after study drug 
discontinuation may be reported on a SAE form to Actelion drug safety within 24 hours of 
the investigator’s knowledge of the event, if felt appropriate by the investigators. 
Therefore, these SAEs are entered only into the drug safety database and hence will not 
affect study closure. 

Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
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4.4 Pregnancy 
4.4.1 Teratogenicity 
Due to the potential teratogenicity of macitentan, women of childbearing potential must 
take appropriate precautions. Women must not become pregnant during the study and for 
up to 28 days after study drug discontinuation. 
If a woman becomes pregnant or if pregnancy is suspected the study drug must be 
immediately withheld until the result of a laboratory pregnancy test is available. Should 
pregnancy be confirmed, the patient must be discontinued from the study and the Sponsor 
must be notified within 24 hours. The investigator must counsel the patient and discuss the 
risks of continuing with the pregnancy and the possible effects on the fetus. 
Under certain circumstances, it will be acceptable for women who became pregnant during 
the study to remain in the study, if all of the following conditions are met: 
• Study drug has been withdrawn immediately after confirmation of pregnancy and 
• Absence of pregnancy is confirmed within the maximal drug interruption period, i.e., 
within 4 weeks, before study drug is re-started and  
• Documentation of appropriate contraceptive counseling has taken place and 
• The patient agrees to practice reliable and effective contraception as required by this 
protocol during the remaining study treatment and for at least 28 days after study 
treatment termination and 
• The re-introduction of study drug has been approved by Actelion 
4.4.2 Reporting of pregnancy 
Any pregnancy occurring during study drug administration or up to 28 days 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 Actelion 
Drug Safety (see 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 
Actelion Drug Safety. 
Such follow-up information will only be entered into the drug safety database and hence 
will not affect study closure. 

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5 
STATISTICAL METHODOLOGY AND ANALYSES 
5.1 Statistical analysis plan 
A statistical analysis plan (SAP) will be written and finalized before study closure, i.e., 
database closure. The SAP will provide full details of the analyses, the data displays and 
the algorithms to be used for data derivations.  
The SAP will include the definition of major and minor protocol deviations and the link of 
major protocol deviations to the analysis sets.  
Before study closure, medically trained staff will identify major and minor protocol 
deviations.  
5.2 Analysis sets 
Two different analysis sets are defined. 
5.2.1 All-treated set 
This analysis set comprises (i) all patients in the AC-055-303/SERAPHIN OL study plus 
(ii) all patients who received macitentan during the AC-055-302/SERAPHIN study and did 
not participate in the AC-055-303/SERAPHIN OL study.  
This analysis set is used for the patient disposition summary. 
5.2.2 Safety set 
This analysis set comprises all subjects included in the All-treated set, who had at least one 
post-baseline 
safety 
assessment. 
Baseline 
is 
defined 
as 
the 
Baseline 
of 
AC-055-302/SERAPHIN 
for 
the 
patients 
who 
received 
macitentan 
during 
AC-055-302/SERAPHIN and as macitentan initiation in AC-055-303/SERAPHIN OL for 
the patients who received placebo during AC-055-302/SERAPHIN. This analysis set is 
used as the denominator for the calculation of AE rates.  
5.3 Primary efficacy endpoint 
Not applicable. 
5.4 Secondary efficacy endpoints 
Not applicable. 
5.5 Safety and tolerability endpoints  
For a detailed description of the safety endpoints see Section 3.6.2. 

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The safety set is used to perform all safety analyses.  
All AEs and all SAEs are coded using the MedDRA dictionary. 
Treatment-emergent AEs are tabulated by system organ class (SOC), and individual 
preferred terms within each SOC. The incidence of patients who experienced AEs coded 
with the same preferred term is tabulated by treatment group (in descending order 
according to the incidence in the investigational study drug group). Adverse events will 
also be tabulated by severity and by relationship to study drug. Summary tables will be 
accompanied by individual patient listings broken down by treatment group and center.  
Adverse events leading to premature discontinuation of study drug will be listed and 
summarized similarly to AEs. 
Treatment-emergent SAEs will be listed and summarized similarly to AEs, separately for 
treatment-emergent SAEs and SAEs occurring before study drug initiation (only those 
related to study-mandated procedures) and after study drug discontinuation. 
Reasons for death will be listed and summarized similarly to AEs, separately for treatment 
emergent deaths and deaths occurring before study drug initiation (only those related to 
study mandated procedures) and after study drug discontinuation. 
Reasons for premature discontinuation of study drug will be listed and summarized by 
frequency tables. 
Treatment-emergent marked laboratory abnormalities will be summarized for each 
laboratory parameter by treatment group providing their incidence and frequency. Actelion 
internal guidelines will be used for the definition of marked laboratory abnormalities and 
for the standardization of numeric values obtained from different laboratories and/or using 
different normal ranges. Standard numeric laboratory parameters are transformed to 
standard units. Absolute values and changes during the course of the study of laboratory 
parameters values converted to standardized units will be summarized by computing the 
usual location and scale statistics by period and treatment group. 
5.6 Exposure to study drug(s) 
Exposure to macitentan will be described in terms of duration and dose. The duration of 
exposure is defined as the time elapsing between study drug initiation and discontinuation, 
inclusive. The exposure time will be tabulated using the usual location and scale statistics 
by treatment group. The cumulative distribution of exposure time by different class 
intervals (e.g., at least 4 weeks, at least 8 weeks, etc.) will be tabulated to show the number 
and percentage of patients in each class interval. The mean daily dose per patient is defined 
as the ratio between the total dose administered during the treatment period and the total 

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exposure time. The mean daily dose is tabulated using the usual location and scale statistics 
by treatment group. 
5.7 Baseline parameters 
Continuous demographic variables (age, height, weight, others) and baseline disease 
characteristics will be summarized by the usual location and scale statistics (mean, median, 
standard deviation, Q1, Q3, minimum, and maximum).  
Qualitative demographic characteristics (gender, race, others) and baseline disease 
characteristics will be summarized by counts and percentages. 
5.8 Exploratory analyses 
Not applicable. 
5.9 Interim analyses 
No interim efficacy analysis is planned. 

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6 
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[Barst 2004] Barst RJ, Langleben D, Badesch D, et al. Pulmonary arterial hypertension: 
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[Battle 1996] Battle RW, Davitt MA, Cooper SM, et al. Prevalence of pulmonary 
hypertension in limited and diffuse scleroderma. CHEST 1996; 110: 1515–9. 
[Castro 1996] Castro M, Krowka MJ, Schroeder DR, et al. Frequency and clinical 
implication of increased pulmonary artery pressures in liver transplant patients. 
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[Chaouat 2005] Chaouat A, Bugnet AS, Kadaoui N, et al. Severe Pulmonary hypertension 
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[Fagan 2004] Fagan KA, Badesch DB. Pulmonary hypertension associated with connective 
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Arnold Publishers; 2004: 181–90. 
[Farber 2004] Farber HW, Loscalzo J. Mechanisms of disease: pulmonary arterial 
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[FDA 2020] Food and Drug Administration. Drug Development and Drug Interactions: 
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interactions-table-substrates-inhibitors-and-inducers. Accessed 09 July 2020. 
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Pulmonary Hypertension. N Engl J Med 2001; 345: 1465–72. 
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[Galie 2004] Galie N, Manes A, Branzi A. The endothelin system in pulmonary arterial 
hypertension. Cardiovasc Res 2004; 61: 227–37. 
[Giaid 1993] Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in 
the lungs of patients with pulmonary hypertension. N Engl J Med. 1993; 328: 1732–
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[Gladwin 2004] Gladwin MT, Sachdev V, Jison ML et al. Pulmonary hypertension as a 
risk factor for death in-patient with sickle cell disease. N Engl J Med 2004; 350: 886–
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[Gurther 1985] Gurther HP. Aminorex and pulmonary hypertension: a review. Cor Vasa 
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[Hirata 1993] Hirata Y, Emori T, Eguchi S. Endothelin receptor subtype B mediates 
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1367–73. 
[Humbert 2004a] Humbert M, Morell NW, Archer SL, et al. Cellular and Molecular 
Pathobiology of pulmonary Arterial Hypertension. J Am Coll Cardiol 2004; 43: 13S–
24S. 
[Humbert 2004b] Humbert M, Sitbon O, Simonneau G. treatment of pulmonary arterial 
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[Kuo 1997] Kuo PC, Plotkin JS, Johnson LB, et al. Distinctive clinical features of 
portopulmonary hypertension. Chest 1997; 112: 980–6. 

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[Love 1990] Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the 
lupus anticoagulant in systemic lupus erythematous (SLE) and in non-SLE disorders. 
Relevance and clinical significance. Ann Intern Med 1990; 112: 682–98. 
[Massaki 1998] Massaki T. The discovery of endothelins. Cardiovasc Res 1998; 39: 530–
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[McGoon 2004] McGoon M, Gutterman D, Steen V, et al. Screening early detection and 
diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice 
guidelines. CHEST 2004; 126 (1): 14S–34S. 
[McLaughlin 2004] McLaughlin V, Presberg K, Doyle R, et al. Diagnosis and management 
of pulmonary arterial hypertension: ACCP evidence-based clinical practice 
guidelines. CHEST 2004; 126 (1): 1S–92S. 
[Mehta 2000] Mehta NJ, Khan IA, Mehta RN et al. HIV-related pulmonary hypertension: 
analytic review of 131 cases. Chest 2000; 118: 1133–41. 
[Opravil 1997] Opravil M, Pechere M, Speich R, et al. HIV-associated primary pulmonary 
hypertension. A case control study. Swiss HIV Cohort Study. Am J Respir Crit Care 
Med. 1997; 155: 990–5. 
[Pengo 2004] Pengo V, Lensing A.W.A, Prins M.H, et al. Incidence of chronic 
Thromboembolic Pulmonary Hypertension after Pulmonary Embolism. N Engl J 
Med 2004; 350: 2257–64. 
[Petitpretz 1994] Petitpretz P, Brenot F, Azarian R, et al. Pulmonary hypertension in 
patients with human immunodeficiency virus infection. Comparison with primary 
pulmonary hypertension. Circulation 1994; 89: 2722–7. 
[Rubin 1997] Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997; 111–7. 
[Shorr 2005] Shorr AF, Helman DL, Davies DB, et al. Pulmonary hypertension in 
advanced sarcoidosis: epidemiology and clinical characteristics. Eur Respir J 2005; 
25: 783–8. 
[Simonneau 2004] Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of 
pulmonary hypertension. J Am Coll Cardiol 2004; 43: 5S–12S. 
[Stewart 1991] Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in 
pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991; 114: 
464–9. 
[Sugawara 1996] Sugawara F, Ninomiya H, Okamoto Y, et al. Endothelin-1-
inducedmitogenic responses of Chinese hamster ovary expressing human endothelin 

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A: the role of a wortmannin-sensitive signalling pathway. Molec Pharmacol 1996; 
49: 447–57. 
[Tanaka 2002] Tanaka E, Harigai M, Tanaka M, et al. Pulmonary hypertension in systemic 
lupus erythematosus: evaluation of clinical characteristics and response to 
immunosuppressive treatment. J Rheumatol 2002; 29: 282–7. 
[Thabut 2005] Thabut G, Dauriat G, Stem JB, et al. Pulmonary hemodynamics in advanced 
COPD candidates for lung volume reduction surgery or lung transplantation. Chest 
2005; 127:1531–6. 
[Thomson 2003] Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary 
pulmonary hypertension is associated with germline mutation of the gene encoding 
BMPR-II, a receptor member of the TGF-beta family. J Med Genet. 2003; 37: 741–
5. 
[Ungerer 1983] Ungerer RG, Tashkin DP, Furst D, et al. Prevalence and clinical correlates 
of pulmonary arterial hypertension in progressive systemic sclerosis. Am J Med 
1983;75:65–74. 
[Weitzenblum 2005] Weitzenblum E and Chaouat A. Severe pulmonary hypertension in 
COPD: Is it a distinct disease. Chest 2005; 127: 1480–2. 
 
 

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7 
PROCEDURES AND GOOD CLINICAL PRACTICE  
7.1 Procedures 
7.1.1 Protocol amendments 
Any change to a protocol has to be considered as an amendment as soon as these documents 
have been submitted to ECs/IRBs or Health Authorities. Therefore, an amendment could 
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. It should be 
reviewed by the Principal Investigator(s) or Steering Committee, as appropriate. 
Adaptations of the core Subject/Patient Information and Informed Consent requested by 
ECs/IRBs are not considered as amendments, as long as they do not significantly change 
the core document or affect the protocol. 
 Non-substantial amendment 
Administrative or logistical minor changes require 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 could be done with or without 
(according to national regulations) notification to the appropriate ECs/IRBs and Health 
Authorities. It does not require their approval or to be signed by the investigators.  
 Substantial amendment 
Significant changes require a substantial amendment. Significant changes include but are 
not limited to: new data affecting the safety of subjects/patients, change of the 
objectives/endpoints 
of 
the 
study, 
eligibility 
criteria, 
dose 
regimen, 
study 
assessments/procedures, treatment or study duration, with or without the need to modify 
the core Subject/Patient Information and Informed Consent. 
Substantial amendments are to be approved by the appropriate ECs/IRBs and in some 
countries by the Health Authorities. The implementation of a substantial amendment can 
only occur after formal approval by the appropriate ECs/IRBs and/or Health Authorities 
and must be signed by the investigators. 
 Urgent amendment 
An urgent amendment might become necessary to preserve the safety of the 
subjects/patients included in the study. The requirements for approval should in no way 
prevent any immediate action being taken by the investigators or Actelion in the best 
interests of the subjects/patients. Therefore, if deemed necessary, an investigator can 

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implement an immediate change to the protocol for safety reasons. This means that, 
exceptionally, 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 written within 10 working days by Actelion and submitted to the 
appropriate ECs/IRBs and Health Authorities. 
7.1.2 Monitoring 
The monitor will contact and visit the investigator regularly and will be allowed, on 
request, 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 
agreement with local regulations. It will be the monitor’s responsibility to inspect the CRF 
at regular intervals throughout the study, to verify the adherence to the protocol and the 
completeness, consistency and accuracy of the data being entered on them. Actelion 
monitoring standards require full verification for the presence of informed consent, 
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 are performed according to the study-specific monitoring 
plan. 
The identification of any data recorded directly on the CRFs and considered to be source 
data are specified in the following document: “Site Guidelines”. The investigator must 
ensure that patients’ anonymity will be maintained. On CRFs or other documents submitted 
to Actelion, patients should not be identified by their names, but by the patient number. 
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 patients (e.g., patients’ signed informed consent forms) should 
not be sent to Actelion and must be kept by the investigator in strict confidence. 
The investigator and co-investigators agree to cooperate with the monitor(s) to ensure that 
any issue detected in the course of these monitoring visits are resolved. If the patient is 
hospitalized or dies in a hospital other than the study center, the investigator is in charge 
of contacting this hospital in order to document this SAE. 
The investigator shall supply Actelion on request with any required background data from 
the study documentation or clinic records. This is particularly important when CRFs are 
illegible or when errors in data transcription are suspected. In 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. 

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An initiation visit will be performed before the first patient is included. 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. 
7.1.3 Data management 
7.1.3.1 Data collection 
For each patient enrolled, regardless of study drug initiation, a 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. Completed 
CRFs will be collected by the monitor(s). 
All forms should be completed using a digital pen (or in case it is not working a black 
ballpoint pen), and must be legible. Errors should be crossed out but not obliterated, the 
correction inserted, and the change initialed and dated by the investigator, co-investigator 
or study nurse. 
7.1.3.2 Database management and quality control 
All data from the CRF will be entered into the database twice, by two different individuals. 
Subsequently, the entered data is 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 can only be made by joint written agreement 
between the Global Trial Leader and the Head of Clinical Development. 
7.1.4 Recording of data and retention of documents 
The investigator will 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 will be classified into two different categories: investigator’s file, and patient 
clinical source documents. 

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The investigator’s file will contain the protocol/amendments, FDA form 1572 for studies 
conducted under an US IND, financial disclosure form, CRFs and data clarification and 
query forms, EC/IRB and Health Authority approval with correspondence, informed 
consent, drug records, staff curriculum vitae and authorization forms, screening and 
enrollment logs, and other appropriate documents/correspondence as per ICH / Good 
Clinical Practice (GCP) and local regulations. 
Patient clinical source documents include, but are not limited to patient hospital/clinic 
records, physician’s and nurse’s 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 
needed to comply with national and international regulations (generally 2 years after 
discontinuing clinical development or after the last marketing approval). 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 patient, appropriate 
copies should be made for storing outside of the site. 
7.1.5 Audit 
The Actelion Global Quality Management Department may conduct audits of clinical 
research activities in accordance with internal standard operating procedures 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 Health Authorities, the investigator 
must inform Actelion immediately that such request has been made. 
The investigator will permit such audits by Actelion or Health Authorities and facilitate 
them by providing access to the relevant source documents. 
7.1.6 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. 

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All drug supplies are to be used only for this protocol and not for any other purpose. The 
responsible person must not destroy any drug labels, or unused drug supply. Upon 
termination of the study, the monitor will collect used and unused drug patient kits. They 
will be sent to the warehouse, where the sponsor or its deputy will check drug 
accountability. In certain circumstances, used and unused drug containers can be destroyed 
at the site once drug accountability is final and checked by the sponsor or its deputy and 
written permission for destruction has been obtained from Actelion. 
7.1.7 Publication and reporting of study results 
Study results will be documented in a study report that will be signed by Actelion 
representatives and only one study coordinating investigator, for example the main 
investigator or the chairman of the Steering Committee. 
In accordance with standard editorial and ethical practice, results of Actelion sponsored 
studies will be published. Results from multi-center studies must be published or presented 
at congresses only in their entirety and not as individual center data, except for ancillary 
studies. 
The main investigator(s) 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. 
Any study-related article or abstract written independently by investigators should 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. 
7.1.8 Disclosure and confidentiality 
By signing the protocol, the investigator agrees to keep all information provided by 
Actelion in strict confidence and to request similar confidentiality from his/her staff and 
the EC/IRB. Study documents provided by Actelion (investigators’ 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.  
7.1.9 Premature termination or suspension of the study 
Both Actelion and the investigator reserve the right to terminate the study at any time.  

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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 
reason(s) for the termination or suspension.  
If the study is prematurely terminated or suspended for any reason, the investigator in 
agreement with Actelion should promptly inform the enrolled subjects/patients and ensure 
their appropriate treatment and follow-up. 
In addition, if the investigator terminates or suspends a study without prior agreement of 
the sponsor, the investigator should promptly inform Actelion and the EC/IRB, and should 
provide the sponsor 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 should 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 as appropriate. 
7.2 Good Clinical Practice 
7.2.1 Ethics and Good Clinical Practice 
The investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” 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 in the investigator site.  
All studies must follow the ICH GCP Guidelines and, if applicable, the Code of Federal 
Regulations. In other countries in which GCP Guidelines exist, the investigators will 
strictly ensure adherence to the stated provisions. 
7.2.2 Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document provided to the patient 
(such as patient information used to obtain informed consent) to an Ethics Committee (EC) 
or Institutional Review Board (IRB). Approval from the committee must be obtained 
before starting the study, and should 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 staff were present, it must be clear that none of these persons voted. 

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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 (see Section 7.1.1). 
7.2.3 Informed consent 
It is the responsibility of the investigator to obtain written informed consent 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 
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 written 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. 
7.2.4 Compensation to subjects and investigators 
The sponsor is providing insurance in order to indemnify (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 the applicable regulations. 
 
 

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Pulmonary arterial hypertension 
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EudraCT No 2007-003694-27 
Doc No D-20.250 
 
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8 
APPENDIX 
Appendix 1: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents. Summary of previous amendments is 
provided below. 
 
Amendment 
Date 
Main reason(s) 
1 
15-Nov-2007 
Non-substantial amendment: As only macitentan is to be 
administered, the reference to placebo / treatment code 
break in affected sections has been removed. 
As local laboratories will be used for blood and urine tests, 
reference to central laboratory has been removed. 
2 
18-Jul-2008 
Substantial amendment: Addition of CYP3A inducers to 
the list of prohibited concomitant medication. 
Definition of certain SAEs (expected in a PAH 
population) which will not require immediate reporting to 
Actelion Global Drug Safety on an SAE form unless the 
event is fatal. 
3 
22-Sep-2009 
Substantial amendment: Increase in sample size from 
525 to 699 subjects because the double-blind study 
AC-055-302 is expected to enroll more subjects than 
originally planned. Consequently, more subjects are 
expected to roll over into this open-label study. 
Request by the Data and Safety Monitoring Board for a 
weekly rather than bi-weekly follow-up of subjects with 
elevated liver transaminases. 
4 
27-Aug-2013 
Substantial amendment: In order to facilitate the 
evaluation of the safety and tolerability data all 
concomitant treatments taken during the study will be 
collected.  
In accordance with the draft FDA “Guidance for Industry 
Determining the Extent of Safety Data Collection Needed 
in Late Stage Premarket and Post-approval Clinical 
Investigations” (February 2012), to better characterize 
safety and tolerability of macitentan, a central laboratory 

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Pulmonary arterial hypertension 
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Amendment 
Date 
Main reason(s) 
will be used for prospective biochemistry and hematology 
analysis. 
An Independent Liver Safety Board is established to 
monitor the liver safety of macitentan including reviewing 
cases of confirmed elevations of aminotransferases > 3× 
ULN. 
5 
10 June 2016 
The main reason for this amendment is to adjust the Liver 
Function Test (LFT) monitoring in SERAPHIN-OL 
considering safety data from available macitentan 
exposure data. 
 
 

 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
1 
Status: Approved, Date: 1 July 2020 
Actelion Pharmaceuticals Ltd 
Janssen Research & Development * 
 
Clinical Protocol 
 
COVID-19 Appendix 
 
Protocol Title 
Long-term single-arm open-label extension study of the SERAPHIN study, to assess the 
safety and tolerability of macitentan/ACT 064992 in patients with symptomatic pulmonary 
arterial hypertension 
 
SERAPHIN OL 
 
Protocol AC-055-303; Phase 3 
 
JNJ-67896062/ACT-064992 Macitentan  
 
*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: 2007-003694-27 
Status: 
Approved  
Date: 
1 July 2020 
Prepared by:  
Actelion Pharmaceuticals Ltd, a division of Janssen Research & Development   
EDMS number: 
 
D-20.229 
 
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. 
NCT00667823

COVID-19 Appendix  
 
JNJ-67896062/ACT-064992 Macitentan  
Clinical Protocol AC-055-303  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
2 
Status: Approved, Date: 1 July 2020 
COVID-19 APPENDIX 
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC 
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants 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 participant 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 participants and site staff. If, at any time, a 
participant’s safety is considered to be at risk, study intervention 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, participants will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Participants 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 participants on study 
intervention, including follow up. Modifications to protocol-required assessments may be 
permitted via COVID-19 Appendix after consultation with the participant, investigator, and the 
sponsor. Missed assessments/visits will be captured in the clinical trial management system for 
protocol deviations. Discontinuations of study interventions 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 participant has tested positive for COVID 19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the 
clinical study report. 
 
 

COVID-19 Appendix  
 
JNJ-67896062/ACT-064992 Macitentan  
Clinical Protocol AC-055-303  
 
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3 
Status: Approved, Date: 1 July 2020 
GUIDANCE SPECIFIC TO THIS PROTOCOL 
• 
Scheduled Visits 
In the event that a subject is unable to come to the site due to COVID-19-related restrictions 
for a protocol-required visit, the visit may be conducted by phone or using telemedicine, when 
permitted by local regulations and in line with local standard of care. The date of the phone 
call should be recorded as the visit date. If a visit is conducted by phone at a minimum data 
should be recorded for the following in the CRF:  
- Adverse event (AE) 
- Serious AE 
- Concomitant therapy 
- Pregnancy test results (as applicable for women of childbearing potential) 
In the event that a subject cannot come to the site for laboratory safety tests due to 
COVID-19-related restrictions, required tests may be conducted at a certified local laboratory. 
If samples are analyzed by a local laboratory, results, including units and normal ranges, must 
be recorded in the CRF. The investigator must review all safety assessments to confirm that 
the participant can pursue his/her study treatment. If the safety assessments cannot be 
performed and reviewed by the investigator in a timely manner, the investigator may decide 
to interrupt or permanently discontinue study intervention, if it is in the best interests of the 
participant. 
For women of childbearing potential, monthly pregnancy tests are required. Pregnancy test 
kits to be used at home were provided per protocol.  
• Missed visits and/or assessments 
If a visit is missed entirely due to COVID-19-related restrictions (no site visit or phone visit 
performed), it will be captured as a protocol deviation in the clinical trial management system 
with the prefix “COVID-19-related”. 
Missed assessments will be captured in the clinical database as protocol deviations with the 
prefix “COVID-19 related”. 
In the exceptional situation that laboratory or pregnancy tests are missed or delayed due to the 
COVID-19 pandemic, they will be identified in the clinical database as protocol deviations 
with the prefix “COVID-19 related”. 
• Investigational Medical Product (IMP) 
In the event that a subject cannot come to the site due to COVID-19-related restrictions to 
receive IMP, a caregiver or family member may pick up the IMP on behalf of the subject. 
This must first be discussed with the subject and the conversation must be documented in the 
subject source records. The subject must name the individual who will pick up the study drug 
on their behalf. Identification of the person who picks up the IMP must be confirmed and 
documented in the subject source record. 
If no other alternative is feasible, direct-to-patient (DTP) shipment of study drug from the site 
may be considered with prior approval from the sponsor. Site staff need to obtain permission 
from the subject and record this in the subject source record for DTP shipments. DTP 
shipments must be done in accordance with local regulations. 

COVID-19 Appendix  
 
JNJ-67896062/ACT-064992 Macitentan  
Clinical Protocol AC-055-303  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
4 
Status: Approved, Date: 1 July 2020 
Used, partially used, and unused study treatment bottles, including empty study treatment 
bottles, must be returned to the site for treatment accountability.  
• Informed Consent 
An informed consent form (ICF) addendum will be prepared outlining the above mitigations. 
If allowed by local health authority / Institutional Review Board / Ethics Committee, verbal 
consent is acceptable and must be documented in the subject source notes. Documentation of 
verbal consent must include who consented, when they were consented, what they were told 
at the time, how they consented (eg, telephone, etc), who captured the oral/verbal consent 
(including signature of the investigator or staff member who captured the consent), and the 
identification of an impartial witness who was present at the time of consent, as well as how 
the impartial witness was selected. 
• Statistical Analysis 
The sponsor will evaluate the totality of impact of COVID-19 on collection and missingness 
of key study data and the need for additional data analyses, which will be added to the clinical 
study report and statistical analysis plan.  
 
 

COVID-19 Appendix  
 
JNJ-67896062/ACT-064992 Macitentan  
Clinical Protocol AC-055-303  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
5 
Status: Approved, Date: 1 July 2020 
INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out this study. 
I will conduct the study as outlined herein and will complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that they 
are fully informed regarding the study intervention, the conduct of the study, and the obligations 
of confidentiality. 
Coordinating Investigator (where required): 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Principal (Site) Investigator: 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Telephone Number: 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Sponsor's Responsible Medical Officer: 
 
Name (typed or printed): 
Wassim Fares 
Institution: 
Actelion Pharmaceuticals Ltd, a division of Janssen Research & Development  
Signature: 
Date: 
 
 
 
(Day Month Year) 
 
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required. 
 
PPD