Clinical trial NCT00667823
Conditions: Pulmonary Arterial Hypertension
Keywords: SERAPHIN Pulmonary Arterial Hypertension ACT-064992
Sponsor: Actelion
Start date: 2008-10-17; Completion date: 2020-12-07
Enrollment: 550 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
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 ACT 064992 in patients with symptomatic PAH.

Detailed description:

Arms: arm 1: ACT-064992
Interventions: intervention 1: Macitentan
Intervention descriptions: intervention 1: Tablet, oral administration, 10 mg dose once daily

Protocol documents:
Prot_000.pdf: 
 
 
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 
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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. 
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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  
 
___________  
 
 
 
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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 


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Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
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CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
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 


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Pulmonary arterial hypertension 
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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– 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 
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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 
 


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Pulmonary arterial hypertension 
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Version 7 
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EudraCT No 2007-003694-27 
Doc No D-20.250 
 
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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 


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Pulmonary arterial hypertension 
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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 
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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. 


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Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
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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. 


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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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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 
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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 
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EudraCT No 2007-003694-27 
Doc No D-20.250 
 
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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 
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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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EudraCT No 2007-003694-27 
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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 
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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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 
17 July 2020, page 21/59 
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 
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. 
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. 


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. 
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 
17 July 2020, page 24/59 
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. 


Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
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Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
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 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
17 July 2020, page 26/59 
Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
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. 


Macitentan/ACT-064992 
Pulmonary arterial hypertension 
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Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
*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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Pulmonary arterial hypertension 
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CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
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.  


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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 


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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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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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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). 


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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: 


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Pulmonary arterial hypertension 
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– 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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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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• 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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EudraCT No 2007-003694-27 
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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. 


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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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• 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. 


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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. 


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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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Inducers 
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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 
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[Giaid 1993] Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in 
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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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[Humbert 2004a] Humbert M, Morell NW, Archer SL, et al. Cellular and Molecular 
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[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. 
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[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; 
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[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–
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[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 
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[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.  


Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
17 July 2020, page 56/59 
Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
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. 


Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
17 July 2020, page 57/59 
Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
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. 
 
 


Macitentan/ACT-064992 
Pulmonary arterial hypertension 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
17 July 2020, page 58/59 
Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
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 
Protocol AC-055-303/SERAPHIN OL 
Version 7 
17 July 2020, page 59/59 
Confidential  
EudraCT No 2007-003694-27 
Doc No D-20.250 
 
CONFIDENTIAL– FOIA Exemptions Apply in U.S. 
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  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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

SAP_001.pdf: 
TPL-000241 v02
STATISTICALANALYSIS PLAN
FOR AC-055-303: SAP FOR CSR
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 subjects with symptomatic 
pulmonary arterial hypertension
Purpose of Analysis
Clinical Study Report
Investigational Drug
JNJ-67896062/ACT-064992/Macitentan
Protocol Number
AC-055-303
Document Number
EDMS-RIM-297091
Document Status/Version Number
Final 
Date
21 December 2020
Author
, Statistician
, Expert Statistician
Reviewer
, Senior Clinical Leader 
Reviewer
Reviewer
, Director Medical Safety Officer
, Director Medical Writing TA FL
Reviewer
Reviewer
, Senior Statistical Programmer
, Director, CTSL, Biometrics (SDS)
Confidential
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
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Statistical Analysis Plan
EDMS-RIM-297091
TPL-000241 v02
TABLE OF CONTENTS
  
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................5
1
INTRODUCTION.........................................................................................................6
2
STUDY DESIGN AND FLOW....................................................................................6
2.1
Study design ...................................................................................................6
2.2
Study Visit and Assessment Schedule..........................................................10
3
STUDY OBJECTIVES...............................................................................................12
3.1
Objectives for SERAPHIN DB ....................................................................12
3.2
Objectives for SERAPHIN OL.....................................................................12
4
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL .................................................................................................12
4.1
Changes to the analyses planned in the study protocol ................................12
4.2
Changes in the conduct of the study / data collection ..................................13
4.3
Clarifications concerning endpoint definitions and related variables or 
statistical methods.........................................................................................13
5
DEFINITIONS OF VARIABLES ..............................................................................13
5.1
Screening failures .........................................................................................15
5.2
Patients characteristics..................................................................................15
5.2.1
Demographics ...................................................................................16
5.2.2
Baseline disease characteristics ........................................................16
5.2.3
Other baseline characteristics ...........................................................16
5.2.4
Medical history .................................................................................16
5.2.5
Previous and concomitant medications.............................................16
5.2.5.1
Previous medications.....................................................17
5.2.5.2
Concomitant medications..............................................17
PAH therapies.....................................................................................17
5.3
Study treatment exposure and compliance ...................................................18
5.3.1
Exposure ...........................................................................................18
5.3.2
Compliance with study treatment .....................................................19
5.3.3
Study treatment discontinuation .......................................................19
5.4
Study discontinuation ...................................................................................19
5.5
Efficacy variables .........................................................................................19
5.5.1
Long term survival............................................................................19


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5.6
Safety variables.............................................................................................20
5.6.1
Adverse events..................................................................................20
5.6.1.1
Treatment-emergent adverse events..............................20
5.6.1.2
Frequency of treatment-emergent adverse events.........20
5.6.1.3
Intensity of treatment-emergent adverse events............20
5.6.1.4
Relationship of treatment-emergent adverse events......20
5.6.2
Deaths ...............................................................................................21
5.6.3
Serious adverse events......................................................................21
5.6.4
Adverse events leading to discontinuation of study treatment .........21
5.6.5
Other significant adverse events.......................................................21
5.6.6
Vital signs and body weight..............................................................21
5.6.7
Electrocardiogram.............................................................................21
5.6.8
Laboratory.........................................................................................21
5.6.8.1
Hematology and blood chemistry..................................22
5.6.8.2
Abnormal liver tests (including unscheduled visits).....23
5.6.8.3
Incidence of abnormal hemoglobin values....................23
6
DEFINITION OF PROTOCOL DEVIATIONS IN AC-055-303 ..............................23
7
ANALYSIS SETS.......................................................................................................24
7.1
Definitions of analysis sets...........................................................................24
7.1.1
Safety analysis set.............................................................................24
7.1.1.1
Macitentan 10 mg OL cohort ........................................24
7.1.1.2
Macitentan 10 mg DB/OL cohort..................................24
7.2
Usage of the analysis set...............................................................................24
8
DEFINITION OF SUBGROUPS................................................................................25
9
GENERAL STATISTICAL METHODOLOGY........................................................26
9.1
Overall testing strategy.................................................................................26
9.2
General rules for data presentations .............................................................26
9.3
Display of patients disposition, protocol deviations and analysis set...........26
9.3.1
Subject disposition............................................................................26
9.3.2
Protocol deviations ...........................................................................27
9.4
Analyses of patient characteristics ...............................................................27
9.4.1
Demographics ...................................................................................27
9.4.2
Baseline disease characteristics ........................................................27
9.4.3
Other baseline characteristics ...........................................................27
9.4.4
Medical history .................................................................................27
9.4.5
Previous and concomitant medications.............................................27
9.5
Analysis of study treatment exposure and compliance.................................28


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9.5.1
Exposure ...........................................................................................28
9.5.2
Compliance with study treatment .....................................................28
9.6
Analysis of the exploratory efficacy variable(s)...........................................28
9.6.1
Hypothesis and statistical model.......................................................28
9.7
Analysis of safety variables..........................................................................29
9.7.1
Adverse events..................................................................................29
9.7.2
Deaths, other serious adverse events ................................................29
9.7.2.1
Death .............................................................................29
9.7.2.2
Time to death.................................................................30
9.7.2.3
Serious adverse events...................................................30
9.7.2.4
Adverse events leading to study treatment 
discontinuations.............................................................31
9.7.2.5
Other significant adverse events....................................31
9.7.3
Laboratory tests.................................................................................31
9.7.4
Incidence of abnormal liver tests (including unscheduled 
visits).................................................................................................33
9.7.5
Incidence of abnormal hemoglobin values .......................................33
9.7.6
Other laboratory parameters .............................................................33
10 GENERAL DEFINITIONS AND DERIVATIONS...................................................33
11 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS ...............36
12 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES .................................40
12.3.1
Demographics and Patient Characteristics .......................................40
12.3.2
Previous and concomitant therapies .................................................41
12.4.1
Exposure ...........................................................................................41
12.5.1
Adverse events..................................................................................42
12.5.2
Deaths ...............................................................................................43
12.5.3
Time to death ....................................................................................43
12.5.4
Serious adverse events......................................................................44
12.5.5
Adverse events leading to treatment discontinuation .......................44
12.5.6
Other significant adverse events.......................................................45
13 REFERENCES............................................................................................................47
14 APPENDICES.............................................................................................................48


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Statistical Analysis Plan
EDMS-RIM-297091
TPL-000241 v02
LIST OF ABBREVIATIONS AND ACRONYMS
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
CRF
Case report form
CL
Confidence limit(s)
CSR
Clinical study report
DB
Double Blind
DOD
eCRF
Date of death
Electronic case report form
EOS
End-of-study
EOT
End-of-treatment
Hgb
Hemoglobin
KM
Kaplan-Meier
MedDRA
Medical Dictionary for Regulatory Activities
OL
Open label
PAH
Pulmonary arterial hypertension
PT
SAE
Preferred Term
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SAS
Statistical analysis system
SOC
STRT302
STRT303
System organ class
first dosing date in SERAPHIN DB
first dosing date in SERAPHIN OL 
TEAE
Treatment-emergent Adverse Event
ULN
Upper limit of the normal range
WHO
World Health Organization


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Statistical Analysis Plan
EDMS-RIM-297091
TPL-000241 v02
1
INTRODUCTION
This Statistical Analysis Plan (SAP) details the final analysis conducted for the purpose of 
the production of the clinical study report (CSR) for the open-label (OL), extension study 
AC-055-303 (SERAPHIN OL) to the double-blind study AC-055-302 (SERAPHIN DB). 
This SAP also provides a description of the general considerations and assumptions, as 
well as the proposed list of tables, figures and listings for the pooled data of AC-055-302 
(SERAPHIN DB) and AC-055-303 (SERAPHIN OL).
The pooling of AC-055-302 (SERAPHIN DB) and AC-055-303 (SERAPHIN OL) means 
that the data from the same patients randomized in SERAPHIN DB will be concatenated 
with their data from the OL extension study (SERAPHIN OL). The concatenation of data 
from the same patients is referred to as ‘pooling’ in this document. 
The pooling will be done only for the survival and safety data of patients initially 
randomized to the Macitentan 10 mg dose in the SERAPHIN DB, up to the end of the study 
(if they did not participate in the SERAPHIN OL study) or end of SERAPHIN OL.
This SAP (unless explicitly specified) follows the derivations and conventions defined in 
the SERAPHIN DB SAP (AC-055-302 Analysis Plan, appendix 16.1.9 to AC-055-302 
[SERAPHIN DB] CSR [D-12.425]).
2
STUDY DESIGN AND FLOW
2.1
Study design
A short summary of study design and its graphical presentation for AC-055-302 
(SERAPHIN DB) and AC-055-303 (SERAPHIN OL) study are presented below.
SERAPHIN DB was a multicenter, randomized, double-blind, placebo-controlled, parallel 
group, event-driven Phase III study that compared oral once daily treatment with 3 mg and 
10 mg doses of Macitentan versus placebo in patients with symptomatic pulmonary arterial 
hypertension (PAH).
Patients aged 12 years or over were eligible to be enrolled if diagnosed with World Health 
Organization (WHO) FC II–IV idiopathic PAH, familial PAH, PAH associated with 
connective tissue disease, PAH associated with simple congenital systemic-to-pulmonary 
shunts at least 1-year post-surgical repair, HIV infection, or drugs and toxins. 
A total of 742 patients were randomized in a 1:1:1 ratio to Macitentan 3 mg (n = 250), 
Macitentan 10 mg (n = 242), and placebo (n = 250) in SERAPHIN DB. 
The study took place from 25 May 2008 (first subject/first visit) until 15 March 2012 (last 
subject/last visit).


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The Macitentan 10 mg treatment effect (active vs. placebo) was highly statistically 
significant and clinically relevant, with a hazard ratio for the composite endpoint (Death; 
Atrial septostomy; Lung transplantation; Initiation of intravenous (i.v.) or subcutaneous 
prostanoids; Other worsening of PAH) of 0.547 (97.5% confidence limits [CLs] 0.392, 
0.762, logrank p < 0.0001). More details are available in the Clinical Study Report 
(D-12.425). The Macitentan 10 mg daily dose was approved by European Medicines 
Agency, Food and Drug Administration, and most other regulatory authorities around the 
world.  
Patients who prematurely discontinued study treatment (DB) due to clinical worsening of 
PAH and obtained written approval from Actelion, and patients who completed the study 
as scheduled, could enter SERAPHIN OL. For patients who had opted not to participate or 
who were not eligible to participate in SERAPHIN OL a 28-day safety follow-up after end 
of treatment (EOT) was performed. 
SERAPHIN OL is an open-label, non-comparative, multicenter, extension study to assess 
long-term safety and tolerability of Macitentan in patients with symptomatic PAH, who 
either completed the DB treatment period of SERAPHIN or had clinical worsening of PAH 
in SERAPHIN. The OL study enrolled 550 patients (first patient enrolled on 17 October 
2008), all of whom received Macitentan 10 mg, irrespective of DB treatment allocation.
The study treatment period for each patient lasts from his/her enrollment date until the end 
of the trial defined as the earliest of: 
(i) approval of Macitentan in this indication is obtained in the patient’s country, 
(ii) the sponsor decides to stop study AC-055-303 (SERAPHIN OL), 
(iii) the subject’s, investigator’s, or sponsor’s decision to discontinue study drug. 


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Figure 1
AC-055-302 (SERAPHIN DB) and AC-055-303 (SERAPHIN OL) 
study design
Table 1
All patients treated in SERAPHIN DB (AC-055-302) and/or 
SERAPHIN OL (AC-055-303)
Study number 
(Acronym)
Number of patients 
randomized to 
Macitentan 3 mg in 
AC-055-302 
(SERAPHIN DB)
N = 250
Number of patients
randomized to 
Macitentan 10 mg 
in AC-055-302 
(SERAPHIN DB)
N = 242
Number of 
patients
randomized 
to placebo in 
in AC-055-
302 
(SERAPHIN 
DB)
N = 250
Number of patients in AC-055-
303 (SERAPHIN OL)
N= 550
AC-055-302 
(SERAPHIN 
DB)
treatment /
AC-055-303 
(SERAPHIN 
OL)
treatment
3 mg / 
none:
N = 65
3 mg / 
10 mg:
N = 185
10 mg / 
none:
N = 60
10 mg / 
10 mg:
N = 182
Placebo /
10 mg:
N = 183
Placebo /
10 mg:
N = 183
3 mg /
10 mg:
N = 185
10 mg /
10 mg:
N = 
182
DB = double-blind, OL = open-label.
Patients who did not enter the open-label study are shown in the columns ‘3 mg / none’ and ‘10 mg / none’. Those who 
received Macitentan in both the double-blind and open-label periods are shown in the ‘3 mg / 10 mg’ and ‘10 mg / 10 
mg’ columns. Finally, those who received placebo in the double-blind study and entered the extension study are shown 
in the ‘Placebo / 10 mg’ column.


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Analyses will be provided for the following cohorts (see below and Table 2):

Macitentan 10 mg OL (550 patients): This cohort comprises all patients enrolled into 
SERAPHIN OL who took at least one dose of Macitentan 10 mg as an OL treatment
(regardless of randomized treatment in SERAPHIN DB). As this group is heterogenous 
(initially the patients were randomized to different treatment regimens) it will be further 
analyzed by randomization groups.
o
Placebo DB/Macitentan 10 mg OL (183 patients)
o
Macitentan 3 mg DB/Macitentan 10 mg OL (185 patients)
o
Macitentan 10 mg DB/Macitentan 10 mg OL (182 patients)

Macitentan 10 mg DB/OL (242 patients): This cohort comprises all patients 
randomized to Macitentan 10 mg in SERAPHIN DB. For this group of patients, data 
from SERAPHIN DB and SERAPHIN OL will be pooled within patient.
Table 2
Template for summary tables
Macitentan 10 mg (OL)
Macitentan 10 mg 
(DB/OL) 
(N=242)
Placebo /
10 mg:
(N = 183)
3 mg /
10 mg:
(N = 185)
10 mg /
10 mg:
(N = 182)
Total 
(N=550)


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2.2
Study Visit and Assessment Schedule
Table 3
Visit and Assessment Schedule for Seraphin DB


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Table 4
Visit and Assessment Schedule for Seraphin OL
ASSESSMENTS
End-of-Study (EOS)
VISITS
Enrolmnent (Visit 1)
Visit 2,3, etc.
End-of-Treatment (EOT)
PERIODS
TREATMENT PERIOD
FOLLOW-UP PERIOD
Serious Adverse Events
X
X
X
X
Study Drug Dispensing
4
X
X
Adverse Events3 
X
X
X
X
Urine Pregnancy Test2, 5 
Required monthly (+/−1 week)
(if applicable) 
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
LFTs
X
Recommended monthly (+/−1 week)
up to at least 28 days after End-of-Treatment
Serum Pregnancy Test
2 
X
X
X
(if applicable) 
Vital signs, Body weight
Performed at each visit; Data will only be kept in patient’s file
Physical examination
Complete Laboratory Tests
X
X
X
Concomitant medication
X
X
X
X
and every 6 months 
thereafter
± 2 weeks
Informed Consent
X
                                   TIMEPOINTS
Day 1
1
Month 6,
Up to 28 days after study 
drug discontinuation
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.


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3
STUDY OBJECTIVES
3.1
Objectives for SERAPHIN DB
Primary objective
The primary objective of this study was to demonstrate that either dose (3 mg or 10 mg) of 
Macitentan reduces the risk of morbidity and mortality in patients with symptomatic PAH.
Secondary objectives

To demonstrate that either dose (3 mg or 10 mg) of Macitentan improves exercise 
capacity, WHO FC, and reduces the risk of death due to PAH or hospitalization 
for PAH up to end-of-treatment (EOT) in patients with symptomatic PAH.

To demonstrate that either dose (3 mg or 10 mg) of Macitentan reduces the risk of
death of all causes up to EOT and up to end-of-study (EOS).

To evaluate the safety and tolerability of Macitentan in patients with symptomatic 
PAH
3.2
Objectives for SERAPHIN OL
To assess long-term safety and tolerability of Macitentan in patients with symptomatic 
PAH.
4
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN 
THE STUDY PROTOCOL 
4.1
Changes to the analyses planned in the study protocol
This SAP was prepared based on the Protocol AC-055-303 OL version 7 (17 July 2020). 
For the two cohorts described in section 2.1, the Safety Set is defined as:
Macitentan 10 mg DB/OL - all patients who received at least one 10 mg dose of Macitentan
in DB/OL and with at least one post-baseline assessment.
Macitentan 10 mg OL (550) - all patients who were enrolled and received Macitentan in 
SERAPHIN OL study.
For details for safety set see Section 7.1.1.
Laboratory data will not be normalized but presented as collected.
Mean daily dose is not analyzed as most patients treated with Macitentan received 10 mg 
(610 / 675 = 90% patients, where 675 is number of patients who received Macitentan either 
in DB or OL period).


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In the protocol no primary efficacy endpoint was defined for this OL extension study. 
However, long-term survival can be evaluated for those patients that entered the study, as 
well as for the pooled DB/OL cohort as defined above.   
4.2
Changes in the conduct of the study / data collection
---
4.3
Clarifications concerning endpoint definitions and related variables or 
statistical methods
For the Macitentan 10 mg DB/OL cohort, time to death will be calculated using start of the 
Macitentan 10 mg treatment at the beginning of dosing in DB period. Full details for time 
to event analysis are given in section 5.5.1.
In this SAP the per-protocol dataset is not defined. Protocol deviations will be reported as 
per section 6.
Adverse events of special interest were not pre-specified in the protocol. They are defined 
in section 5.6.5. 
Table 2 defines the cohorts to be presented for the summaries.
5
DEFINITIONS OF VARIABLES
The following dates will be used to define the treatment durations, survival, censoring and 
safety reporting periods: For imputation of partial/ missing date, refer to section 11. 

Start date of Macitentan in SERAPHIN DB (STRT302): date of first 
administration of Macitentan in patients randomized to Macitentan 10 mg in 
SERAPHIN DB collected in the study drug log. 

Enrollment date into SERAPHIN OL (STRT303): date of enrollment into 
SERAPHIN OL as reported in the Interactive Voice Response System (IVRS) 
system. 

Date of death (DOD): actual date of death of a patient as reported in the 
SERAPHIN DB or SERAPHIN OL Case Report Forms (CRFs) prior to the 
SERAPHIN OL study closure.

CENS: Censoring flag. Categorical: 0 (not censored) or 1 (censored).


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
SERAPHIN DB End Of Study (EOS302): This is the end of study (EOS) visit 
date of a patient from the SERAPHIN DB study.
Note that for all patients who did not withdraw prematurely from SERAPHIN DB, the 
EOS302 occurred shortly after the administrative end of SERAPHIN DB announced by 
Actelion on 30 January 2012.

SERAPHIN OL EOS (EOS303): study completion date. 
Note that the end of the study in SERAPHIN OL is on a patient-by-patient basis,
until the earliest between:
o
Death 
o
The latest date between: Date of visit/ Contact or Date of discontinuation/ 
Last contact on the EOS/Permanent Discontinuation CRF page. 
The EOS occurs when the approval of Macitentan is obtained in the patient’s country or 
when the patient, investigator, or sponsor decides to discontinue study drug.
EOS302 and EOS303 (individual patient’s end of study) will be referred in this SAP as end 
of study (EOS). The overall end of study up to the database lock will be referred as study 
closure.

End of Treatment in SERAPHIN DB (EOT302): end of double-blind treatment 
in SERAPHIN DB, i.e., the last treatment date reported in the SERAPHIN DB 
study drug log.

End of Treatment in SERAPHIN OL (EOT303): EOT in SERAPHIN OL, i.e., 
the last treatment end date reported in the study drug log. 

SERAPHIN OL last contact date (LAST303) No ongoing patients are expected 
anymore, therefore LAST303=EOS303

SERAPHIN DB last contact date (LAST302) No ongoing patients are expected 
anymore, therefore LAST302=EOS302

Last contact date (LCTC) for SERAPHIN OL and DB: This is the latest date 
between LAST303 and EOS302. For patients who did not enter SERAPHIN OL, 
the date will be EOS302.

EOT in SERAPHIN OL and DB: 
o
For patients in the OL cohort this is EOT303.
o
For patients in the DB/OL cohort:

If the patient entered SERAPHIN OL then this is EOT303.


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
If the patient did not enter SERAPHIN OL then this is EOT302.

Time to death (TTD) is estimated by the Kaplan-Meier (KM) product limit method 
and summarized for each cohort, except Macitentan total (SAP for sNDA 
Section 6.1).
For example, for cohort Macitentan 10 mg DB/OL, time to death was defined as the time 
of start of Macitentan 10 mg treatment in SERAPHIN DB up to the date of death (any 
cause) in either the DB or OL period. Patients who did not die prior to the study closure
were censored at their last date of contact.
For patients in the Macitentan 10 mg DB/OL cohort who died prior to study closure, time 
to death is derived:
TTD=DOD - STRT302 and CENS=0 and,
For patients in the Macitentan 10 mg DB/OL cohort who did not die prior study 
closure and therefore censored:
TTD=LCTC - STRT302 and CENS=1 
Where LCTC=max(EOS302, EOS303).
Imputation rules for missing or incomplete dates are listed in section 11.
5.1
Screening failures
Not Applicable for this SAP.
5.2
Patients characteristics
Baseline information for the patients in the Macitentan 10 mg OL cohort is defined as the 
latest available information prior to the first dosing date in the OL study.
Baseline information for patients in the Macitentan 10 mg DB/OL cohort is defined as the 
latest available information prior to the first dosing date in SERAPHIN DB (STRT302). 
For patients in the Macitentan 10 mg DB/OL cohort, completion/discontinuation of study 
drug and the associated reasons will be counted either in SERAPHIN DB if the patients 
did not enter SERAPHIN OL (10 mg / none), or in SERAPHIN OL if the patients entered 
SERAPHIN OL (10 mg / 10 mg). 
For patients in Macitentan 10 mg OL cohort, completion/discontinuation of study drug and 
associated reasons will be counted in SERAPHIN OL. 
The study drug discontinuation rate will be adjusted on person-year of study duration for 
each cohort and each drug dose sequence.


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5.2.1
Demographics
Demographics will include: age (years), age subgroups (Adolescents [< 18 years], from 
18 to 64 years, from 65 to 84 years, and over 84 years), gender (Male, Female), race 
(White [including Hispanic], Asian, Other), height (cm), weight (kg) and body mass 
index (BMI; kg/m2), geographical location (North America including Canada; Western 
Europe including South Africa and Israel; Eastern Europe including Turkey; Asia 
including Australia; Latin America).
Age (years) = (STRT303 - birth date + 1)/365.25 will be reported as number of completed 
years.
For the Macitentan 10 mg DB/OL, age is the age at the first dose in DB.
For the Macitentan 10 mg OL, age is the age at entry into OL.
For imputation of partial birth date, refer to section 11.
5.2.2
Baseline disease characteristics
Baseline disease characteristics will include PAH etiology at baseline (idiopathic, familial, 
associated with HIV infection, associated with drug use or toxin exposure, associated with 
collagen vascular disease, associated with repaired congenital shunts) and WHO FC at 
baseline. 
5.2.3
Other baseline characteristics
Other baseline characteristics will include categorized Estimated Creatinine Clearance:

no renal impairment (creatinine clearance ≥90 mL/min), 

mild renal impairment (creatinine clearance ≥60 and < 90 mL/min)

moderate-severe renal impairment (creatinine clearance < 60 mL/min). 
5.2.4
Medical history
Medical History is not summarized for this analysis as it was previously reported for the 
CSR of AC-055-302 (SERAPHIN DB).
5.2.5
Previous and concomitant medications
Previous and concomitant medications for SERAPHIN DB and SERAPHIN OL are coded 
using WHO Drug Dictionary version March 2019.
In SERAPHIN OL, collection in the CRF of previous and concomitant medications was 
introduced with Global Protocol Amendment 4 (27 August 2013). Medications taken prior
to implementation of this protocol amendment were then collected retrospectively. 
Medications which were ‘ongoing at EOT’ in the SERAPHIN DB are reconciled with 
medications ‘ongoing at the start of AC-055-303’ (SERAPHIN OL). Since the SERAPHIN 
DB was closed prior to the retrospective data collection, any discrepancies identified in 


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this database cannot be corrected. These discrepancies are reported in a Data Management
tracker by the Global Data Manager, and will be reported in a separate listing.
Patients who took the same medication more than once (as qualified by the same preferred 
term (PT) will be counted only once. In case the reported medication was assigned to 
several PTs, patients are counted for each individual PT.
5.2.5.1
Previous medications
A previous medication is any treatment for which the end date of treatment is prior to the 
start of the AC-055-303 (SERAPHIN OL) study (i.e., prior to signing the informed consent
form). These are not included in the analysis as these are part of the AC-055-302 
(SERAPHIN DB) CSR; these data were reported as previous or concomitant therapies.
5.2.5.2
Concomitant medications
Concomitant medications are all treatments that are ongoing or initiated after start of study 
(i.e., from the time of the patient signing the informed consent form) or initiated up to 
28 days after the end of study treatment.
Concomitant medication at baseline is defined as any medication that is taken at the start 
of study drug (STRT303 for Macitentan 10 mg OL, STRT302 for Macitentan 10 mg 
DB/OL). This includes any medication with the tick box “ongoing at Baseline” checked, 
or with a start date before or on the day of study drug start (STRT303 for Macitentan 10 mg 
OL, STRT302 for Macitentan 10 mg DB/OL) and the end date not before study drug start 
(STRT303 for Macitentan 10 mg OL, STRT302 for Macitentan 10 mg DB/OL). Start and 
end dates that are incomplete will be handled according to the rules for partial and missing 
concomitant medication dates in section 11 Appendix A. 
Note: the concomitant medications at baseline for patients in the Macitentan 10 mg DB/OL 
cohort will be derived using only the AC-055-302 (SERAPHIN DB) database. For patients 
in the Macitentan 10 mg OL cohort, both AC-055-302 (SERAPHIN DB) and AC-055-303 
(SERAPHIN OL) databases will be used for the derivation of concomitant medications at 
baseline.
PAH therapies
PAH therapy includes phosphodiesterase-type 5 (PDE-5) inhibitors, prostanoids, and 
soluble guanylate cyclase stimulators, and comprises the following PT:

PDE-5 inhibitors, including:
o
Sildenafil
o
Tadalafil
o
Vardenafil

Drugs acting via prostacyclin pathway / prostanoids, including
o
Iloprost
o
Beraprost


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o
Treprostinil 
o
Epoprostenol
o
Selexipag

Soluable guanylate cyclase stimulators, including:
o
Riociguat
In the medication selection for PAH therapy, any medication coded PT that contains one 
of the PT included in the definition above is used (e.g. "sildenafil citrate" is a PAH specific 
medication that belongs to the PDE-5 inhibitor category.)
Concomitant medications during the study include all concomitant medications at baseline 
plus the medication reported as ‘ongoing at end of treatment/study’ or with the start date 
on or after the start date of study drug treatment:
-
STRT302 for Macitentan 10 mg [DB/OL], 
-
STRT303 for Macitentan 10 mg [OL]  
and on or before the EOT+28 days. 
The following summaries will be presented for each cohort:

A summary of concomitant PAH therapy at baseline (for baseline DB and 
separately baseline OL) including the number and percentages of patients taking at 
least one PAH therapy (i.e., at least one PDE-5 inhibitor, at least one prostanoid). 
Note: patients may receive more than one treatment and may be included in more than one 
treatment class. 

A summary of concomitant medication use at baseline for all medications taken by 
at least 5.0% patients in any cohort, by PT

A summary of concomitant medication use during the study for all medications 
taken by at least 5.0% in any cohort, by PT.
A listing of concomitant medications will be provided.
5.3
Study treatment exposure and compliance
5.3.1
Exposure
The duration of treatment (exposure) is defined as the time from start of dosing of 
Macitentan 10 mg (for the Macitentan 10 mg DB/OL mg cohort it is from STRT302, for 
the Macitentan 10 mg OL cohort it is from STRT303) until EOT inclusive, regardless of 
treatment interruptions.


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Duration of treatment exposure will be calculated by cohort as follows:
Duration (days) = EOT303 - STRT303 1, for patients in the Macitentan 10 mg OL,
or
Duration (days) = max(EOT302, EOT303) - STRT302 1, for patients in the Macitentan 
10 mg DB/OL.
Duration (months) = Duration (days)/ 30.4375
5.3.2
Compliance with study treatment
Not Applicable
5.3.3
Study treatment discontinuation 
Study treatment discontinuations include all patients, i.e., those who prematurely 
discontinued and those who completed treatment as per protocol, from eCRF study Drug 
log.
Reasons for study treatment discontinuation are retrieved from the study drug log CRF 
pages in SERAPHIN DB or OL as appropriate and are coded using Actelion Study Drug 
Log dictionary.
5.4
Study discontinuation
Study completion/discontinuation is collected in the eCRF study completion page.
5.5
Efficacy variables
5.5.1
Long term survival
Time to death (TTD; in months) in the two cohorts is defined as follows:
For the Macitentan 10 mg OL cohort:
TTD (in days) and censoring flag (CENS) will be derived using the dates defined as: 

TTD = DOD - STRT303 and CENS = 0 for patients who died,

TTD = LCTC - STRT303 and CENS = 1 for patients who did not die.
For the Macitentan 10 mg DB/OL cohort:

TTD = DOD - STRT302 and CENS = 0 for patients who died,

TTD = LCTC - STRT302 and CENS = 1 for patients who did not die.


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For both cohorts 
TTD (in months) = TTD (in days) / 30.4375.
Patients censored will be those who did not die prior to study closure.
5.6
Safety variables
AEs are coded using MedDRA v.21.0. For imputation of AE onset/resolution date, refer to 
Section 11.
5.6.1
Adverse events
5.6.1.1
Treatment-emergent adverse events
Treatment-emergent adverse events (TEAEs) are defined as AEs occurring during 
Macitentan OL treatment period (defined in section 10) for the Macitentan 10 mg OL 
cohort and during the Macitentan DB/OL treatment period (defined in section 10) for the 
Macitentan 10 mg DB/OL cohort (see section 10), with onset date ≥ start date (STRT302 for 
Macitentan 10 mg [DB/OL], STRT303 for Macitentan 10 mg [OL]), and up to 28 days 
(inclusive) after EOT. Note: if AEs are recorded before STRT303, these AEs will not be 
included for Macitentan 10 mg (OL) cohort.
5.6.1.2
Frequency of treatment-emergent adverse events
Treatment-emergent AEs reported more than once by a patients will be counted only once 
in the frequency tables.
In the event that the reported TEAE is assigned to several PT, patients will be counted for 
each individual PT.
5.6.1.3
Intensity of treatment-emergent adverse events
The categories of intensity are defined as follows:

Mild 

Moderate

Severe
For TEAEs reported more than once for a patient within a specified analysis time period 
but with different intensities, the worst intensity is considered (i.e. severe). If intensity is 
missing, the event will be considered to be severe.
5.6.1.4
Relationship of treatment-emergent adverse events
Relationship to study treatment is defined as ‘related’ or ‘not related’ in the opinion of the 
investigator. For TEAEs reported more than once for a patients within the same time 
period, the worst relationship will be used (i.e. 'related'). Adverse events with missing 
relationships will be considered in any analysis to be ‘related’.


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5.6.2
Deaths
Cause of death is derived as collected on the disposition CRF page. There can be more 
causes of death recorded per patient. All reported causes of death will be used.
5.6.3
Serious adverse events
SAEs refer to AEs qualified as “serious” by the investigator on the CRF AE page(s). If 
seriousness information is missing, then AEs will be summarized as ‘Serious AEs’ (the 
worst-case scenario).
5.6.4
Adverse events leading to discontinuation of study treatment
Adverse events leading to discontinuation of study treatment are those with an action taken 
with study drug of "permanently discontinued" recorded on the CRF AE page.
5.6.5
Other significant adverse events
AEs of special interest are defined using selection of PTs (Actelion Internal MedDRA 
Query). The selection is defined from medical review of terms in the MedDRA v. 21.0
dictionary and where applicable, Standardized MedDRA Queries (SMQs) were used (see 
SMQ Introductory Guide Version 19.1: September 2016 – MMSO-DI-6226-19.1.0). The 
full definition is included in Appendix C.
The following groups of AEs of special interest will be summarized:
o
liver abnormalities,
o
edema, 
o
anemia/ hemoglobin decrease,
o
hypotension.
5.6.6
Vital signs and body weight
Not Applicable
5.6.7
Electrocardiogram
Not Applicable
5.6.8
Laboratory
All available laboratory data collected at local and central laboratory will be used for 
deriving laboratory abnormalities. 
Baseline laboratory values are defined as the latest values recorded before or on the date 
of first dose of Macitentan for DB/OL and for OL before or on the date of first dose of 
Macitentan in OL. Treatment-emergent values are defined as post-baseline values 
occurring within EOT+28 days and will be considered in the tables.


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5.6.8.1
Hematology and blood chemistry
Hematology and blood chemistry tests 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. 
Marked laboratory abnormalities are defined according to Actelion internal guidelines for 
individual parameters (see Table ). 
Table 5
Laboratory Abnormalities
Parameter 
LL marked
LLL marked
HH marked
HHH marked
Hemoglobin
< 100 g/L
< 80 g/L
post-baseline > 
(baseline + 20 g/L)
post-baseline > 
(baseline + 40 
g/L) 
Hematocrit
< 0.28 L/L for 
females
< 0.32 L/L for 
males
< 0.20 L/L
> 0.55 L/L for 
females
> 0.60 L/L for   
males
> 0.65 L/L 
Platelets 
< 75 × 109/L
< 50 × 109/L
> 600 × 109/L  
> 999 × 109/L  
Leukocytes
< 3.0 × 109/L
< 2.0 × 109/L
> 20.0 × 109/L
> 100.0 × 109/L
Lymphocytes
< 0.8 × 109/L  
< 0.5 × 109/L
> 4.0 × 109/L  
> 20 × 109/L  
ALT 
NA
NA
> 3 × ULN
> 5 × ULN*
AST 
NA
NA
> 3 × ULN
> 5 × ULN*
Alkaline 
phosphatase
NA
NA
> 2.5 × ULN
> 5 × ULN
Total Bilirubin
NA
NA
> 2 × ULN
> 5 × ULN
Creatinine
NA
NA
> 1.5 × ULN
> 3 × ULN
Glucose
< 3.0 mmol/L
< 2.2 mmol/L
> 8.9 mmol/L
> 13.9 mmol/L
Calcium
< 2.0 mmol/L
< 1.75 mmol/L
> 2.9 mmol/L
> 3.1 mmol/L
Sodium
NA
< 130 mmol/L
> 150 mmol/L
> 155 mmol/L
Potassium
< 3.2 mmol/L
< 3.0 mmol/L
> 5.5 mmol/L
> 6.0 mmol/L
Albumin
< 30 g/L
< 20 g/L
NA
NA
* Also HHHH as > 8 × ULN
ALT = alanine aminotransferase; AST = aspartate aminotransferase; NA = not applicable/available; ULN = upper limit 
of normal.


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5.6.8.2
Abnormal liver tests (including unscheduled visits)
Hepatic abnormality criteria are specified below:

(ALT ≥3 upper limit of normal [ULN]) OR (AST ≥3 ULN) 

(ALT ≥5 ULN) OR (AST ≥5 ULN) 

(ALT ≥8 ULN) OR (AST ≥8 ULN)

Total Bilirubin ≥2 ULN

{(ALT ≥3 ULN) OR (AST ≥3 ULN)} AND (Total Bilirubin ≥2 ULN at any 
time)
For each patient, the worst treatment-emergent abnormal value (i.e., the highest ALT, AST 
or Total Bilirubin values) will be considered and assigned to the appropriate category (may 
be more than one category per patient).
5.6.8.3
Incidence of abnormal hemoglobin values
Hemoglobin (Hgb) abnormalities are specified as:

Hgb ≤ 80 g/L

Hgb ≤ 100 g/L 

Hgb decrease from baseline ≥ 20 g/L

Hgb decrease from baseline ≥ 50 g/L
For each patient, the worst treatment-emergent abnormal value (i.e., the lowest Hgb value)
will be considered and assigned to the appropriate category (may be more than one category
per patient).
Hgb abnormalities for increase from baseline are specified as:

Post-baseline Hgb > (baseline + 20 g/L)

Post-baseline Hgb > (baseline + 40 g/L)
For each patient, the worst treatment-emergent abnormal value (i.e., the highest Hgb value)
will be considered and assigned to the appropriate category (may be more than one category 
per patient).
6
DEFINITION OF PROTOCOL DEVIATIONS IN AC-055-303
Protocol deviations will be reported as per Appendix E for the Macitentan 10 mg OL 
cohort. 


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7
ANALYSIS SETS
7.1
Definitions of analysis sets
7.1.1
Safety analysis set 
The safety analysis set (SAF) will include all patients who received at least one dose of 
Macitentan 10 mg. All summaries described in this SAP will be presented on the SAF. 
Safety population will consist of the 2 cohorts described below.
7.1.1.1
Macitentan 10 mg OL cohort 
This cohort includes 550 patients enrolled to the AC -055-303/SERAPHIN OL (regardless 
of the randomized treatment in SERAPHIN DB). As this group is heterogenous (initially 
the patients were randomized to different treatment regimens), so in addition to Overall, it 
will be further analyzed by randomization groups:
o
Placebo DB/Macitentan 10 mg OL (183 patients)
o
Macitentan 3 mg DB/Macitentan 10 mg OL (185 patients)
o
Macitentan 10 mg DB/Macitentan 10 mg OL (182 patients)
7.1.1.2
Macitentan 10 mg DB/OL cohort
This cohort includes 242 patients initially randomized to Macitentan 10 mg SERAPHIN 
DB. For this group of patients, information collected during SERAPHIN DB and 
SERAPHIN OL will be pooled within patient, meaning that the data from the same patients 
randomized in SERAPHIN DB will be concatenated with their data from the OL extension 
study (SERAPHIN OL).
7.2
Usage of the analysis set
Table 6
Summaries by Analyses Cohorts.
Summaries and 
analyses
Macitentan
10 mg
DB/OL
Macitentan 10 mg OL
Placebo 
DB/
Macitentan 
10 mg OL
Macitentan 
3 mg DB/
Macitentan 
10 mg OL
Macitentan 
10 mg DB/
Macitentan 
10 mg OL
Macitentan 
10 mg OL
Total
(N = 242)
(N = 183)
(N =185)
(N = 182)
(N = 550)
Disposition of 
patients
Yes
Yes
Yes
Yes
Yes
Demographics and 
patient 
characteristics
Yes
Yes
Yes
Yes
Yes
Medical history of 
patients
No
No
No
No
No


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Summaries and 
analyses
Macitentan
10 mg
DB/OL
Macitentan 10 mg OL
Placebo 
DB/
Macitentan 
10 mg OL
Macitentan 
3 mg DB/
Macitentan 
10 mg OL
Macitentan 
10 mg DB/
Macitentan 
10 mg OL
Macitentan 
10 mg OL
Total
(N = 242)
(N = 183)
(N =185)
(N = 182)
(N = 550)
Concomitant 
Medication
Yes
Yes
Yes
Yes
Yes
Duration of 
Treatment exposure
Yes
Yes
Yes
Yes
Yes
Adverse events 
(AEs)
Yes
Yes
Yes
Yes
Yes
Serious Adverse 
Events (SAEs)
Yes
Yes
Yes
Yes
Yes
AEs of special 
interest* (as per 
Actelion Internal 
MedDRA Queries 
[AIMQ]) 
Yes
Yes
Yes
Yes
Yes
Deaths
Yes
Yes
Yes
Yes
Yes
AEs leading to 
permanent 
discontinuation of 
study treatment
Yes
Yes
Yes
Yes
Yes
Incidence of AEs 
over time
Yes
Yes
Yes
Yes
Yes
Incidence of 
abnormal liver test
Yes
Yes
Yes
Yes
Yes
Incidence of 
abnormal 
hemoglobin test
Yes
Yes
Yes
Yes
Yes
Time to Death 
(Survival Analysis 
using KM 
approach)
Yes
Yes
Yes
Yes
Yes
AE = adverse event, AIMQ = Actelion Internal MedDRA Query, DB = double-blind, KM = Kaplan-Meier approach, 
OL = open-label, SAE = serious adverse event, SMQ = standardized MedDRA query.
*AEs of special interest includes: liver abnormalities, anemia/ hemoglobin decrease, edema, hypotension.
8
DEFINITION OF SUBGROUPS
Not Applicable


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9
GENERAL STATISTICAL METHODOLOGY
9.1
Overall testing strategy
Not Applicable 
9.2
General rules for data presentations
Data will be listed by country, site and DB treatment group and OL overall. Data will be 
summarized by appropriate descriptive statistics:
Number of non-missing observations, mean, standard deviation, minimum, median and 
maximum for continuous variables.
Number of events, number of censored observations and Kaplan-Meier estimates of the 
survival function for time-to-event variables. 
Number of non-missing observations, number of missing observations and frequency 
with percentage per category for categorical variables. 
Absolute changes from baseline are defined as: post-baseline value minus baseline 
value, i.e., a positive sign indicates an increase as compared to baseline.
A percentage (relative) change from baseline is defined as the absolute change from 
baseline divided by the baseline value (if the baseline value is > 0) and then multiplied 
by 100.
Data will be presented for cohorts defined in section 2.1 (Table 2).
9.3
Display of patients disposition, protocol deviations and analysis set
9.3.1
Subject disposition
The number of patients included in each cohort will be summarized by treatment received 
in DB/OL. 
The number and percentage of patients in analysis populations will be reported per cohort: 
Macitentan 10 mg (DB/OL) cohort broken down by treatment received in OL (10 
mg/None, 10 mg/10 mg) and overall, and Macitentan 10 mg (OL) broken down by DB 
randomization groups (Placebo/ 10 mg, 3 mg / 10 mg, 10 mg / 10 mg) and overall.
Patients who completed study treatment as per protocol, who prematurely discontinued 
study drug as well as the reason for study drug discontinuation, will be reported the same 
way. 
The coded reasons (Actelion Study Drug Log dictionary) are displayed in the summary.
Additionally, study drug discontinuation rates adjusted on person-year of study duration 
will be summarized with associated 95% CL as detailed in section 10.4.


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9.3.2
Protocol deviations
Protocol deviations will be reported as per Appendix E for the Macitentan 10 mg OL
cohort. 
PDs classified as "Important PD" will be summarized with a frequency table for 
SERAPHIN OL, the table should have columns corresponding to DB treatment group and 
total.
A listing of all protocol deviations in OL will be provided with a flag indicating whether 
the deviation is "Important PD".
A separate listing of all protocol deviations related to Covid-19 will be provided.
9.4
Analyses of patient characteristics
9.4.1
Demographics
For each cohort, demographics will be summarized descriptively. Macitentan 10 mg OL 
will be summarized Overall and per initial randomized treatment group.
9.4.2
Baseline disease characteristics
For each cohort baseline disease characteristics will be summarized descriptively. 
Macitentan 10 mg OL will be summarized overall and by initial randomized treatment arm.
9.4.3
Other baseline characteristics
For each cohort other baseline characteristics will be summarized descriptively. Macitentan 
10 mg OL will be summarized overall and per initial randomized treatment group.
9.4.4
Medical history
Medical history will not be summarized for this CSR.
9.4.5
Previous and concomitant medications
For study reporting purposes, all therapies collected in the AC-055-303 (SERAPHIN OL)
CRF page 105 will be reported in the patient listings with the appropriate flags for 
previous/concomitant status, started before/after EOT.
Study-treatment concomitant therapies will be summarized by therapeutic organ class and 
PT. 
A summary of concomitant PAH therapy at baseline (for baseline DB and separately 
baseline OL) will be summarizing the number and percentages of patients taking at least 
one PAH therapy, i.e. at least one PDE-5 inhibitor, at least one prostanoids and will be also 
summarized for each PT in these classifications as per section 5.2.5.2. 
Concomitant medications will be summarized by each cohort, presenting the numbers of 
patients and associated percentages having any concomitant medication, by PT presented 


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by descending frequency of the total macitentan OL cohort PT incidence. Multiple 
medications (PT) taken by a single patient will only be counted once.
The following summaries will be presented for each cohort: 

A summary of concomitant PAH therapy at baseline (for baseline DB and 
separately baseline OL) including the number and percentages of patients 
taking 
o
at least one PAH therapy, i.e., at least one PDE-5 inhibitor, at least one 
prostanoid. Note: patients may receive more than one treatment and may 
be included in more than one treatment class. 

A summary of concomitant medication use at baseline of all medications taken 
by at least 5.0% patients in any cohort, by PT 

A summary of concomitant medication use during the study (at least 5.0% in 
any cohort), by PT. 
A listing of concomitant medications will be provided.
9.5
Analysis of study treatment exposure and compliance
9.5.1
Exposure
Duration of treatment exposure for both cohorts, expressed in months, will be summarized 
descriptively. The distribution of exposure time by class intervals (in 6-month increments 
e.g., < 6 months, 6 < 12 months, 84 – < 90 months, until the end of study) will be also 
tabulated to show the number and percentage of patients in each class interval. In addition, 
patient year exposure is displayed and is derived as the duration of exposure each patient
received treatment in days, as defined above, divided by 365.25.
A listing of duration of Macitentan exposure and reasons for study drug discontinuation 
will be provided for the Macitentan 10 mg OL cohort (overall and by initial randomization). 
9.5.2
Compliance with study treatment
Not applicable
9.6
Analysis of the exploratory efficacy variable(s)
9.6.1
Hypothesis and statistical model
Not applicable - the study is descriptive.


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9.7
Analysis of safety variables
All safety analyses will be presented for Macitentan 10 mg OL overall and by 
randomization group, as well as for the Macitentan 10 mg DB/OL cohort.
All safety data will be included in listings, with flags for treatment-emergent and 
quantitative abnormalities, where appropriate (separately for initial randomization in DB
groups).
9.7.1
Adverse events
For all dosed patients all AEs captured from signature of informed will be reported in the 
patient listings.
A table presenting an overall summary of the proportion of patients with at least one 
treatment-emergent adverse event, one treatment-emergent AE of special interest, one 
treatment-emergent AE leading to treatment discontinuation, one treatment-emergent SAE, 
one treatment-emergent SAE with fatal outcome and the proportion of deaths will be 
provided.
Treatment-emergent AEs will be summarized by presenting the number and percentage of 
patients having any AE, having an AE in each primary system organ class (SOC), and 
having each individual AE (by PT) by descending PT frequency and separately by 
descending SOC/PT. 
Exposure adjusted incidence rates will be also tabulated with two-sided 95% CLs (using 
method 1 and separately method 2).
Treatment-emergent AEs related to study drug will be summarized by presenting the 
number and percentage of patients having any AE, having an AE in each primary SOC,
and having each individual AE (by PT) by descending PT frequency and separately by 
descending SOC/PT. 
Treatment-emergent AEs will be also summarized by worst intensity by presenting the 
number and percentage of patients having any AE, having an AE in each primary SOC,
and having each individual AE (by PT) by descending PT frequency and separately by 
descending SOC/PT. 
9.7.2
Deaths, other serious adverse events
9.7.2.1
Death
Data for deaths will be summarized for both cohorts as below.
The number and percentage of treatment-emergent deaths will be presented from study 
start up to EOT+28 days. The number of deaths after EOT+28 days will be presented 
separately. In addition a summary of all deaths up to the study closure will be summarized.


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Cause of death will be tabulated by SOC (with patients counted once within each SOC), 
and separately by PT (with patients counted once for each PT). SOC and PT will be 
presented by descending frequency in the OL cohort.
Exposure adjusted incidence rates will be also tabulated with two-sided 95% CLs.
A listing of all deaths (i.e., treatment-emergent and non-treatment-emergent events) is
provided. Treatment-emergent deaths are flagged. 
9.7.2.2
Time to death
An analysis for survival up to study closure will be done, with end of study defined on a 
study basis (i.e. the data cut corresponding to data base lock).
For both cohorts, the proportion of patients surviving will be estimated by the Kaplan-
Meier (KM) product-limit method and summarized for each group at pre-specified time-
points (i.e., Day 0/Baseline, Month 6, Month 12, etc.), presenting number of patients at 
risk, number of patients with event (%), number of patients censored (%), KM estimates, 
and two-sided 95% CLs for the KM estimates. The standard error of the KM estimate will 
be calculated using Greenwood’s formula [Collett 1994].
KM plot for time to death will be provided and will be truncated at the time when less than 
10% of the patients within the treatment group are still at risk [Pocock 2002] or up to 108 
months timepoint, whichever comes later.
The median time to death will be estimated from the KM curves, with corresponding 25% 
and 75% percentiles and associated 95% confidence intervals using the method of
Brookmeyer [Brookmeyer 1982].
The corresponding listing of time to death will be provided.
Summary of study follow-up time will be summarized.
Details regarding how time to death is calculated are given in Section 5. SAS code 
examples are given in Appendix F.
9.7.2.3
Serious adverse events
The number and percentage of patients experiencing at least one serious TEAE will be 
presented by descending within each SOC /PT and separately descending PT frequency.
Exposure adjusted incidence rates will be tabulated with two-sided 95% CLs.
The number and percentage of patients experiencing at least one SAE after study drug 
termination will be summarized separately.
A listing of all SAEs (i.e., treatment-emergent and non-treatment-emergent events) will be 
provided for each analysis set. Serious TEAEs are flagged.


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9.7.2.4
Adverse events leading to study treatment discontinuations
Adverse events leading to study treatment discontinuation will be described similarly as 
the SAEs
9.7.2.5
Other significant adverse events
The number and percentage of patients experiencing at least one TEAE of special interest 
will be presented by descending PT frequency for each AE of special interest.
The summaries include the exposure-adjusted incidence rates with associated 95% CLs.
Patient listing of AEs of special interest will be provided.
9.7.3
Laboratory tests
Absolute values and change from baseline values of all laboratory parameters described in 
section 5.6.8.1 will be summarized by visit. Time windows of +/- 15 days will be used as 
per Table 7.
Table 7
Time windows for all assessments up to EOT+28 days
Mapping of visits
LFTs:
Study day
(nominal value)
Lower Limit
study day
Upper Limit
study day
Month 1
30
2
45
Month 2
60
46
75
Month 3
90
76
105
Month 4
120
106
135
Month 5
150
136
165
Month 6
180
166
195
Month 7
210
196
225
Month 8
240
226
255
Month 9
270
256
285
Month 10
300
286
315
Month 11
330
316
345
Month 12
360
346
375
Month 13
390
376
405
Month 14
420
406
435
Month 15
450
436
465
Month 16
480
466
495
Month 17
510
496
525
Month 18
540
526
555


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Mapping of visits
LFTs:
Study day
(nominal value)
Lower Limit
study day
Upper Limit
study day
Month 19
570
556
585
Month 20
600
586
615
Month 21
630
616
645
Month 22
660
646
675
Month 23
690
676
705
Month 24
720
706
735
Month 25
750
736
765
Month 26
780
766
795
Month 27
810
796
825
Month 28
840
826
855
Month 29
870
856
885
Month 30
900
886
915
Month 31
930
916
945
Month 32
960
946
975
Month 33
990
976
1005
Month 34
1020
1006
1035
Month 35
1050
1036
1065
Month 36
1080
1066
1095
Month 37
1110
1096
1125
Month 38
1140
1126
1155
Month 39
1170
1156
1185
Month 40
1200
1186
1215
Month 41
1230
1216
1245
…
Month X
X*30
X*30 
- 14
X*30
+15
…
Month 126
3780
3766
3795
Summary statistics of worst abnormalities post baseline will be provided for each 
parameter as described in Table 5 for Low abnormalities and high abnormalities separately.


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A supportive listing of all laboratory data is provided with a flag for abnormal values.
9.7.4
Incidence of abnormal liver tests (including unscheduled visits)
Liver tests for ALT, AST, and total bilirubin will be presented using incidence (n [%]) with
the two-sided 95% CLs based on Wald approximation, and tabulated for patients with 
abnormalities. Exposure adjusted incidence rates will be tabulated with two-sided 95% 
CLs.
A supportive listing will be provided for with all liver tests laboratory data collected. 
Treatment-emergent results will be flagged.
Using “evaluation of drug-induced serious hepatotoxicity” (eDISH) plots, graphical
representations of total bilirubin versus ALT will be produced for each initial randomized 
treatment group and for Overall Macitentan 10 mg OL cohort to identify possible Hy’s
Law cases. The graph presents, for each patient, the peak total bilirubin ULN against the 
peak ALT ULN in the same reporting period, on a log10 scale. Two reference lines will 
be plotted identifying the 2 ULN for total bilirubin and 3 ULN for ALT. The peak is
the maximum value from treatment start to last available assessment within the treatment
period and up to EOT plus 28 days.
A supportive listing presents all liver test data over time for all patients in Hy’s Law 
quadrant.
9.7.5 Incidence of abnormal hemoglobin values
Patient counts and percent (with corresponding two-sided 95% CLs based on the Wald
method and using Poisson model with time as an offset variable) for the categories of Hgb 
abnormality occurring at any time post-baseline up to EOT + 28 days will be presented.
Exposure adjusted incidence will be tabulated with two-sided 95% CLs.
A 
supportive 
listing 
provides
presents
all 
hemoglobin
values
collected. 
Treatment-emergent results will be flagged.
9.7.6
Other laboratory parameters
All other laboratory parameters collected are listed.
10 GENERAL DEFINITIONS AND DERIVATIONS
10.1
Dates of interest
The dates of interest were defined in section "Definition of Variables".


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10.2
Macitentan DB/OL treatment emergent period (for safety variables 
reporting)
The Macitentan DB/OL treatment-emergent period is defined as the period from the first 
intake of Macitentan to the Macitentan EOT date (max[EOT302, EOT303]) + 28 days.
For laboratory analyses, the Macitentan DB/OL treatment-emergent period defined above 
starts from the first administration of Macitentan.
10.3
Macitentan OL treatment emergent period (for safety variables 
reporting)
The Macitentan OL treatment-emergent period is defined as the period from STRT303 up 
to the EOT303 + 28 days.
For laboratory analyses, the Macitentan OL treatment-emergent period defined above starts 
from Macitentan start date in OL.
10.4
Adjusted incidence rates
In order to account for differences in the duration of exposure of study treatment among 
the patient cohorts, incidence rates of AEs, SAEs, AEs leading to discontinuation, AESI, 
and deaths will be presented as adjusted for patient-years exposure (PYE). 
There will be two slightly different methods:
Method 1: The same approach as in the original NDA submission in 2012 will be applied
[D-12.548], where total treatment exposure for each patient is included in the calculation. 
This will be applied in order to make comparison versus the original submission.
Person-time will be calculated by summing the days of treatment duration (" EOT-
STRT302 1 OR EOT- STRT303 1 as per section 5.3) for each patient. 
PYE will be calculated by dividing the total patient time by 365.25 days.
The incidence rate for an AE per 100 person-years will be calculated by dividing the 
number of patients with AEs by the PYE and multiplying by 100.
Adjusted Incidence Rate = 100 x (Number of patients with at least one AE/PYE) 
Method 2:
A similar approach as in the original NDA submission in 2012 but the treatment exposure
will be calculated up to the first event for patients with events [Siddiqui 2009].The same 
as in the Method 1 except:
Person-time will be calculated:
i) by summing the days of treatment duration (EOT- STRT303 1 as per section 5.3.1) for 
patients without events,


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ii) by summing the days of treatment duration up to the start date of first event (min[date 
of first event, EOT] - STRT303] + 1) for patients with event,
iii) all other calculations for adjusted incidence rate follow the Method-1.
The adjusted incidence rate will be interpreted as the number of events occurring in 
100-patient years. It is based on the assumption that the occurrences of a specific event are 
following an independent Poisson process, so the events occur with a constant rate over 
time. Hence, for each treatment group, the 95% Confidence Limit (CL) of the adjusted 
incidence rate will be computed using a Poisson regression model with log of time at risk 
as an offset (SAS PROC GENMOD, see Appendix B for code example). 
Note for programming: For AEs, SAEs, AEs leading to discontinuation, AESI group level, 
and deaths, the overall adjusted event rates will be presented using method 1 (i.e. adjusted 
rate will not be presented for each PT, except for AEs, where will be presented overall and 
by SOC). Method 2 will be applied only for AEs and AESI group level.


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11 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS
The missing or incomplete dates for the variables defined below will be derived as follows:
1. Dates will be split into 3 parts: year, month and day. Year is the top-level, month is 
medium level and day is low-level. If a part expected to contain a number is numeric 
but the value is outside a valid range, the complete date is handled as missing. For 
example, if date = 44Nov2000 the whole date is considered to be missing.
2. If a part expected to contain a number is not numeric, i.e., contains values such as for 
example ND, NA, --, ??, 2?, it is considered as missing.
3. If a part is missing, all other parts of a lower level are considered to be missing. This 
means that a ddmmyy date ‘21ND99’ is considered as ‘----99’.
4. Missing parts are changed into acceptable non-missing values in a way depending on 
the type of date to be replaced.
‘lower limit’ and ‘upper limit’ refer to the minimum or maximum, respectively, of a 
possible date. For example, if the day is missing, the lowest limit is the first day of the 
given month and the upper limit is the last day of the given month. If the day and month 
are missing, the lower limit refers to the first day of the given year and the upper limit to 
the last day of the given year. The earliest and the latest of different dates refer to the first 
or last date, respectively, when ordered in sequence. All other missing or incomplete data 
not mentioned below are treated as missing.
Type 
of 
date/time 
Date/time is incomplete
Date/time is missing
Date of birth 
Day missing: 15th of the month
Day and month missing: 30th of June
No replacement


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Type 
of 
date/time 
Date/time is incomplete
Date/time is missing
EOT302
Use the earliest date between the:

upper limit

last contact date (LCTC)

date of death (if applicable)

treatment start date of 303-1
Use the earliest date between
the:

6 months after last 
available dispensing visit 
date, i.e., 180 days + 
randomization or Month 6 
or Month 12 or Month 18, 
... visit date

last contact date (LCTC)

date of death (if 
applicable)

Start treatment date of 
303-1
EOT303
Use the earliest date between the:

upper limit

last contact date (LCTC)

date of death (if applicable)
Use the earliest date between
the:

last contact date (LCTC)

date of death (if 
applicable)
DOD - Date of 
death 
Use the lower limit if day is missing 
EOS303
Use the earliest date between the:

upper limit

date of death (if applicable)
AE resolution
date
The upper limit 
No approximation, the AE is 
considered as ongoing.


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Type 
of 
date/time 
Date/time is incomplete
Date/time is missing
AE onset date
If the end date of the AE is not before 
the start of study treatment, and if the 
study treatment start falls in the range 
of possible dates, it is the study 
treatment start date. In all other cases,
it is the lower limit.
Of note, treatment start date is 
STRT302 for Macitentan 3 mg or 
10 mg (DB/OL) and STRT303 for 
Macitentan 10 mg (OL).
The earlier of the end date of 
the AE and the start of study 
treatment 
(STRT302 
for 
Macitentan 3 mg or 10 mg 
[DB/OL] and STRT303 for 
macitentan 10 mg [OL]).
Previous/
concomitant
medication
start date
Lower limit except when:
Not tagged as ongoing at baseline 
AND
Medication stop date not collected or 
with the upper limit after study drug 
start
AND
The treatment start day falls in the 
range of possible dates.
In which case it is the study drug start 
day
No replacement, the
medication is considered to
have started before the study
Previous/
concomitant
medication
end date
Note that Medication stop date will not 
be imputed; however the upper limit 
may be used in determining the 
medication start date derivation.
No replacement


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Type 
of 
date/time 
Date/time is incomplete
Date/time is missing
AE resolution 
time
Time partially entered not allowed 
(considered as missing)
Taken as “23:59” if the 
corresponding AE resolution 
date is not missing, otherwise 
no replacement
Notes: 

Patient 
 in Macitentan 10 mg (DB/OL) group was 
considered as having no PAH therapy at baseline in analysis of DB data in 2012, 
based on a rule that if the end date was partial and upper limit of that end date was 
after the study drug start date and the tick box ongoing at baseline was not ticked 
the medication was ended before the study start date. This patient has a record of 
Sildenafil with a start date of 
’ and end date of 
’ and a study 
drug start date of ‘
’. “ongoing at baseline” is not ticked however 
Month of start date is after the study drug start date. This medication is considered 
as ongoing at baseline.

Patient 
 in Macitentan 3 mg (DB/OL) group (Macitentan
start date 
) was considered as having no PAH therapy at baseline in 
analysis of DB data in 2012 (SILDENAFIL/ Start date=
’/ End 
Date=
’). This patient has a conflicting record of SILDENAFIL collected 
during the OL phase (SILDENAFIL/ Start date=’
’/ End Date=’
). The patient is considered as having no PAH therapy at baseline for DB.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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12 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES
12.1
Patients disposition
Output
name
Display
Title (Description)
Analysis 
set(s)
Table 1
T
Number of Patients in the different 
patient cohorts
SAF
Table 2
T
Number of Patients in the different 
patient cohorts and Reasons for 
Study Drug Discontinuation 
SAF
T=Summary table, L= Listing, F=Figure
12.2
Protocol deviations
Output 
name
Display
Title (Description)
Analysis 
set(s)
Table 3
T
Summary of Important protocol 
deviations.
Macitentan 
10 mg OL
Listing 1
L
All protocol deviations
Macitentan 
10 mg OL
Listing 1.1
L
Protocol deviations related to 
Covid-19
Macitentan 
10 mg OL
12.3
Patients characteristics
12.3.1 Demographics and Patient Characteristics
Output 
name
Display
Title (Description)
Analysis 
set(s)
Table 4
T
Summary of Demographic and 
Patient Characteristics 
SAF


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12.3.2 Previous and concomitant therapies
Output 
name
Display
Title (Description)
Analysis 
set(s)
Table 5
T
Summary of concomitant PAH 
therapy (for baseline DB and 
separately baseline OL)
SAF
Table 6
T
Summary 
of 
concomitant 
medication use at baseline (at least 
5% in any cohort), by preferred 
term
SAF
Table 7
T
Summary 
of 
concomitant 
medication use during the study (at 
least 5% in any cohort), by 
preferred term
SAF
Listing 2
L
Patient listing of concomitant 
medications 
SAF
Listing 3
L
Discrepancies in
previous and 
concomitant medications
SAF
12.4
Study treatment exposure and compliance
12.4.1 Exposure
Output 
name
Display
Title (Description)
Analysis 
set(s)
Table 8
T
Summary of duration of Exposure 
to Study Drug 
SAF
Listing 4
L
Patient listing of exposure and 
reasons 
for 
study 
drug 
discontinuation
SAF


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12.5
Safety analyses
12.5.1 Adverse events
Output 
name
Display
Title (Description)
Analysis 
set(s)
Table 9
T
Proportion of patients with AEs, AEs 
of special interest, SAEs, SAEs with 
fatal outcome, AEs leading to 
permanent study drug 
discontinuation and number of 
patients who died from treatment 
start up to EOT+28 days
SAF
Table 10
T
Proportion of patients with AEs 
occurring from treatment start up to 
EOT+28 days by PT
SAF
Table 11
T
Proportion of patients with AEs 
occurring from treatment start up to 
EOT+28 days by SOC and by PT
SAF
Table 12
T
Proportion of patients with AEs 
related to study drug occurring from 
treatment start up to EOT+28 days 
by PT
SAF
Table 13
T
Proportion of patients with AEs
related to study drug occurring from 
treatment start up to EOT+28 days 
by SOC and by PT
SAF
Table 14
T
Proportion of patients with AEs by 
severity occurring from treatment 
start up to EOT+28 days by PT
SAF
Table 15
T
Proportion of patients with AEs by 
severity occurring from treatment 
start up to EOT+28 days by SOC and 
by PT
SAF
Listing 5
L
Patient listing of all adverse events  
SAF


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12.5.2 Deaths
Output
name
Display
Title (Description)
Analysis 
set(s)
Table 16
T
Deaths occurring from treatment start 
up to EOT+28 days by cause (by 
SOC and by PT)
SAF
Table 17
T
Deaths occurring from treatment start 
up to EOT+28 days by cause (by PT)
SAF
Table 18
T
Deaths occurring after EOT+28 days
(by PT)
SAF
Table 19
T
Deaths occurring after EOT+28 days
(by SOC and by PT)
SAF
Table 20
T
Deaths occurring from treatment start 
up to the study closure by cause (by 
PT)
SAF
Table 21
T
Deaths occurring from treatment start 
up to the study closure by cause (by 
SOC and by PT)
SAF
Listing 6
L
All deaths 
SAF
12.5.3 Time to death
Output 
name
Display
Title (Description)
Analysis 
set(s)
Table 22
T
Summary of Time to Death up to the 
study closure
SAF
Listing 7
L
Patient listing of time to deaths up to 
study closure 
SAF
Table 23
T
Summary of study follow up time -
reverse Kaplan Meier method
SAF
Figure 1.1
F
Kaplan Meier curve of Time to 
Death up to the study closure
Macitentan 
10 
mg 
(DB/OL)
Figure 1.2
F
Kaplan Meier curve of Time to 
Death up to the study closure
Macitentan 
10 mg (OL)


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Output 
name
Display
Title (Description)
Analysis 
set(s)
Figure 1.3
F
Kaplan Meier curve of Time to 
Death up to the study closure by 
randomization group.
Macitentan 
10 mg (OL)
12.5.4 Serious adverse events
Output 
name
Display
Title (Description)
Analysis 
set(s)
Table 24
T
Proportion of patients with SAEs 
occurring from treatment start up to 
EOT28 days by PT
SAF
Table 25
T
Proportion of patients with SAEs 
occurring from treatment start up to 
EOT28 days by SOC and by PT
SAF
Table 26
T
Proportion of patients with SAEs 
occurring after study drug 
termination by PT
SAF
Table 27
T
Proportion of patients with SAEs 
occurring after study drug 
termination by SOC and by PT
SAF
Listing 8
L
Patient listing of all SAEs 
SAF
12.5.5 Adverse events leading to treatment discontinuation
Output 
name
Display
Title (Description)
Analysis 
set(s)
Table 28
T
Proportion of patients with 
treatment-emergent adverse events 
leading to permanent study drug 
discontinuation by PT 
SAF
Table 29
T
Proportion of patients with 
treatment-emergent adverse events 
leading to permanent study drug 
discontinuation by SOC and by PT 
SAF


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Output 
name
Display
Title (Description)
Analysis 
set(s)
Listing 9
L
Treatment-emergent adverse events 
leading to permanent study drug 
discontinuation  
SAF
12.5.6 Other significant adverse events
Output 
name
Display
Title (Description)
Analysis 
set(s)
Table 30
T
Proportion of Patients with AEs of 
special interest occurring from 
treatment start up to EOT28 days 
by PT: <SMQ X> 
SAF
Listing 
10
L
Averse events of special interest 
<SMQ X>  
SAF
12.6
Laboratory tests
Output 
name
Display
Title (Description)
Analysis 
set(s)
Table 31
T
Summary of absolute and absolute 
change for laboratory parameters 
from Macitentan 10 mg DB baseline, 
by analysis visit - Macitentan 10 mg
(DB/OL)
SAF
Table 32
T
Summary of absolute and absolute 
change for laboratory parameters 
from Macitentan 10 mg OL baseline, 
by analysis visit - Macitentan 10 mg
(OL)
SAF
Table 33
T
Proportion of patients with incidence 
of all laboratory abnormalities 
occurring from treatment start up to 
EOT+28 days   
SAF
Table 34
T
Proportion of patients with Liver 
tests Abnormalities occurring from 
treatment start up to EOT28 days
SAF
Listing 11
L
Abnormal Liver tests (ALT or 
AST > 3 x ULN) or total bilirubin > 
2 x ULN 
SAF


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Figure 2
F
Peak Total Bilirubin vs. peak ALT 
(eDish plot) (one per cohort) 
SAF
Listing 12
L
Patient listing of liver test data for all 
patients in Hy's Law quadrant over 
time.
SAF
Table 35
T
Proportion of patients with incidence 
of hemoglobin abnormalities 
occurring from treatment start up to 
EOT28 days
SAF
Listing 13
L
Hemoglobin abnormalities (Hgb ≤ 
100 g/L) 
SAF
Listing 14
L
Patient listing of all other 
abnormalities
SAF
Listing 15
L
Patient listing of all laboratory data
SAF


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13 REFERENCES
[D-12.425] A multicenter, double-blind, randomized, placebo controlled, parallel group, 
event driven, Phase III study to assess the effects of macitentan on morbidity and 
mortality in patients with symptomatic pulmonary arterial hypertension. Actelion 
Pharmaceuticals Ltd; Final Study Report AC-055-302, 31 August 2012. Previously 
submitted to NDA 204410, sequence 0000 on 19 October 2012, Module 5.3.5.1.
[D-12.548] Statistical Analysis Plan for Integrated Safety Analysis. Actelion 
Pharmaceuticals Ltd; 31 August 2012. Previously submitted to NDA 204410, 
sequence 0000 on 19 October 2012, Module 5.3.5.3, Appendix 1A.
[Brookmeyer 1982] Brookmeyer R, Crowley JA. CI for the median survival time. 
Biometrics. 1982; 38:29-41.
[Collett 1994] Collett D. Modelling survival data in medical research. London: 
Chapman & Hall; 1994.
[Holden 2003] Holden WL, Juhaeri J, Dai W. Benefit-risk analysis: a proposal using 
quantitative methods. Pharmacoepidemiol Drug Saf. 2003; 2:611-6. 
[Pocock 2002] Pocock SJ, Clayton TC, Altman DG. Survival plots of time-to-event 
outcomes in clinical trials: good practice and pitfalls. The Lancet 2002;359:1686-89.
[Siddiqui 2009]. Siddiqui O. Statistical Methods to Analyze Adverse Events Data of 
Randomized Clinical Trials. Journal of Biopharmaceutical Statistics. 2009;19(5):
889-899.
[Ware 2000] Ware JE, Kosinski M, Dewey JE. How to Score Version Two of the SF-36 
Health Survey. Lincoln, RI: QualityMetric, Incorporated, 2000.


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14 APPENDICES
Appendix A
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 ACT-064992 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
Approximately 180 centers in about 40 countries.
PATIENTS / GROUPS
Up to 699 patients in one group.
INCLUSIONCRITERIA
•
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.


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EXCLUSIONCRITERIA
• 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 ACT-064992 or any of the excipients.


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Appendix B
Example SAS code for incidence rates and 95% CL
Note: time should be in years for GENMOD 
** example code to show derivation of rate and CI based on dummy data ** ;
** Create dummy data **;
data aA;
  tot_eve=0;
  tot_time=0;
  do pn=1 to 110;
    time=ranuni(546546)*1000; ** time to event**;
    eve=(ranuni(5454)<.10);   ** event or censor **;
    tot_eve+eve;
    tot_time+time;
    l_time=log(time/365.25);
    if pn=110 then do;
      incidence=100*tot_eve/(tot_time/365.25); **incidence rate **;
    end;
    output;
  end;
run;
proc genmod data=aa;
  model eve= / dist=poisson link=log offset=l_time; /*** here is the exposure time in offset***/
  output out=out p=pcount xbeta=xb stdxbeta=std;
  ods output ParameterEstimates=param;
run;
data predrates;
  set out;
  obsrate=eve/time;         /* observed rate */
  lograte=xb-l_time;
  prate=100*exp(lograte);   /* predicted rate */
  lcl=100*exp(lograte-probit(.975)*std); ** Lower Limit **;
  ucl=100*exp(lograte+probit(.975)*std); ** upper Limit **;
run;
** derivation also available in PARAM**;
data param2;
  set param(WHERE=(parameter=(“Intercept”)));
  prate=100*exp(estimate);
  lcl=100*exp(LowerWaldCL);
  ucl=100*exp(UpperWaldCL);
run;


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Appendix C
Definition of AEs of special interest 
1
LIVER ABNORMALITIES
AEs are included in this grouping if they contain an event PT within the ‘Hepatic disorders’ 
SMQ, including all of its sub-SMQs, with the exception of the ‘Liver-related coagulation 
and bleeding disturbances’ sub-SMQ and the PTs ‘Ascites’, ‘Bacterascites’, ‘Biliary 
ascites’, and ‘Haemorrhagic ascites’1, i.e., any of the following MedDRA PTs: 
5'nucleotidase increased
Accessory liver lobe
Acquired hepatocerebral degeneration
Acute fatty liver of pregnancy
Acute graft versus host disease in liver
Acute hepatic failure
Acute hepatitis B
Acute hepatitis C
Acute on chronic liver failure
Acute yellow liver atrophy
Adenoviral hepatitis
Alagille syndrome
Alanine aminotransferase abnormal
Alanine aminotransferase increased
Alcoholic liver disease
Allergic hepatitis
Alloimmune hepatitis
Ammonia abnormal
Ammonia increased
Anorectal varices
Anorectal varices haemorrhage
Aspartate aminotransferase abnormal
Aspartate aminotransferase increased
AST/ALT ratio abnormal
Asterixis
                                                
1 Excluded PTs: Ascites, Bacterascites, Biliary ascites, Haemorrhagic ascites, Acquired factor IX deficiency, Acquired 
factor VIII deficiency, Acquired factor XI deficiency, Acquired antithrombin III deficiency, Acquired protein S 
deficiency, Anti factor X activity abnormal, Anti factor X activity decreased, Anti factor X activity increased, 
Antithrombin III decreased, Blood fibrinogen abnormal, Blood fibrinogen decreased, Blood thrombin abnormal, 
Blood thrombin decreased, Blood thromboplastin abnormal, Blood thromboplastin decreased, Coagulation factor 
decreased, Coagulation factor IX level abnormal, Coagulation factor IX level decreased, Coagulation factor V 
level abnormal, Coagulation factor V level decreased, Coagulation factor VII level abnormal, Coagulation factor 
VII level decreased, Coagulation factor X level abnormal, Coagulation factor X level decreased, 
Hyperfibrinolysis, Hypocoagulable state, Hypofibrinogenaemia, Hypoprothrombinaemia, Hypothrombinaemia, 
Hypothromboplastinaemia, International normalised ratio abnormal, International normalised ratio increased, 
Protein C decreased, Protein S abnormal, Protein S decreased, Prothrombin level abnormal, Prothrombin level 
decreased, Prothrombin time abnormal, Prothrombin time prolonged, Prothrombin time ratio abnormal, 
Prothrombin time ratio increased, Thrombin time abnormal, Thrombin time prolonged.


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Asymptomatic viral hepatitis
Autoimmune hepatitis
Benign hepatic neoplasm
Benign hepatobiliary neoplasm
Bile output abnormal
Bile output decreased
Biliary cirrhosis
Biliary fibrosis
Bilirubin conjugated abnormal
Bilirubin conjugated increased
Bilirubin excretion disorder
Bilirubin urine present
Biopsy liver abnormal
Blood alkaline phosphatase abnormal
Blood alkaline phosphatase increased
Blood bilirubin abnormal
Blood bilirubin increased
Blood bilirubin unconjugated increased
Blood cholinesterase abnormal
Blood cholinesterase decreased
Bromosulphthalein test abnormal
Cardiohepatic syndrome
Cerebrohepatorenal syndrome
Child-Pugh-Turcotte score abnormal
Child-Pugh-Turcotte score increased
Cholaemia
Cholangiosarcoma
Cholestasis
Cholestasis of pregnancy
Cholestatic liver injury
Cholestatic pruritus
Chronic graft versus host disease in liver
Chronic hepatic failure
Chronic hepatitis
Chronic hepatitis B
Chronic hepatitis C
Cirrhosis alcoholic
Coma hepatic
Complications of transplanted liver
Computerised tomogram liver abnormal
Congenital absence of bile ducts
Congenital cystic disease of liver
Congenital hepatic fibrosis
Congenital hepatitis B infection
Congenital hepatobiliary anomaly


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Congenital hepatomegaly
Cryptogenic cirrhosis
Cystic fibrosis hepatic disease
Cytomegalovirus hepatitis
Deficiency of bile secretion
Diabetic hepatopathy
Dilatation intrahepatic duct congenital
Drug-induced liver injury
Duodenal varices
Fatty liver alcoholic
Focal nodular hyperplasia
Foetor hepaticus
Galactose elimination capacity test abnormal
Galactose elimination capacity test decreased
Gallbladder varices
Gamma-glutamyltransferase abnormal
Gamma-glutamyltransferase increased
Gastric variceal injection
Gastric variceal ligation
Gastric varices
Gastric varices haemorrhage
Gastrooesophageal variceal haemorrhage prophylaxis
Gianotti-Crosti syndrome
Glutamate dehydrogenase increased
Glycocholic acid increased
Glycogen storage disease type I
Glycogen storage disease type III
Glycogen storage disease type IV
Glycogen storage disease type VI
Graft versus host disease in liver
Granulomatous liver disease
Guanase increased
Haemangioma of liver
Haemorrhagic hepatic cyst
HBV-DNA polymerase increased
Hepaplastin abnormal
Hepaplastin decreased
Hepatectomy
Hepatic adenoma
Hepatic amoebiasis
Hepatic angiosarcoma
Hepatic artery flow decreased
Hepatic atrophy
Hepatic calcification
Hepatic cancer


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Hepatic cancer metastatic
Hepatic cancer recurrent
Hepatic cancer stage I
Hepatic cancer stage II
Hepatic cancer stage III
Hepatic cancer stage IV
Hepatic candidiasis
Hepatic cirrhosis
Hepatic congestion
Hepatic cyst
Hepatic cyst infection
Hepatic cyst ruptured
Hepatic echinococciasis
Hepatic encephalopathy
Hepatic encephalopathy prophylaxis
Hepatic enzyme abnormal
Hepatic enzyme decreased
Hepatic enzyme increased
Hepatic failure
Hepatic fibrosis
Hepatic fibrosis marker abnormal
Hepatic fibrosis marker increased
Hepatic function abnormal
Hepatic gas gangrene
Hepatic haemangioma rupture
Hepatic hamartoma
Hepatic hydrothorax
Hepatic hypertrophy
Hepatic infection
Hepatic infection bacterial
Hepatic infection fungal
Hepatic infection helminthic
Hepatic infiltration eosinophilic
Hepatic lesion
Hepatic lymphocytic infiltration
Hepatic mass
Hepatic necrosis
Hepatic neoplasm
Hepatic pain
Hepatic sequestration
Hepatic steato-fibrosis
Hepatic steatosis
Hepatic vascular resistance increased
Hepatic venous pressure gradient abnormal
Hepatic venous pressure gradient increased


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Hepatitis
Hepatitis A
Hepatitis A antibody abnormal
Hepatitis A antibody positive
Hepatitis A antigen positive
Hepatitis A virus test positive
Hepatitis acute
Hepatitis alcoholic
Hepatitis B
Hepatitis B antibody abnormal
Hepatitis B antibody positive
Hepatitis B core antibody positive
Hepatitis B core antigen positive
Hepatitis B DNA assay positive
Hepatitis B DNA increased
Hepatitis B e antibody positive
Hepatitis B e antigen positive
Hepatitis B reactivation
Hepatitis B surface antibody positive
Hepatitis B surface antigen positive
Hepatitis B virus test positive
Hepatitis C
Hepatitis C antibody positive
Hepatitis C core antibody positive
Hepatitis C RNA increased
Hepatitis C RNA positive
Hepatitis C virus test positive
Hepatitis cholestatic
Hepatitis chronic active
Hepatitis chronic persistent
Hepatitis D
Hepatitis D antibody positive
Hepatitis D antigen positive
Hepatitis D RNA positive
Hepatitis D virus test positive
Hepatitis E
Hepatitis E antibody abnormal
Hepatitis E antibody positive
Hepatitis E antigen positive
Hepatitis E virus test positive
Hepatitis F
Hepatitis fulminant
Hepatitis G
Hepatitis H
Hepatitis infectious mononucleosis


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Hepatitis mumps
Hepatitis neonatal
Hepatitis non-A non-B
Hepatitis non-A non-B non-C
Hepatitis post transfusion
Hepatitis syphilitic
Hepatitis toxic
Hepatitis toxoplasmal
Hepatitis viral
Hepatitis viral test positive
Hepatobiliary cancer
Hepatobiliary cancer in situ
Hepatobiliary cyst
Hepatobiliary disease
Hepatobiliary infection
Hepatobiliary neoplasm
Hepatobiliary scan abnormal
Hepatoblastoma
Hepatoblastoma recurrent
Hepatocellular carcinoma
Hepatocellular damage neonatal
Hepatocellular foamy cell syndrome
Hepatocellular injury
Hepato-lenticular degeneration
Hepatomegaly
Hepatopulmonary syndrome
Hepatorenal failure
Hepatorenal syndrome
Hepatosplenic abscess
Hepatosplenic candidiasis
Hepatosplenomegaly
Hepatosplenomegaly neonatal
Hepatotoxicity
Hereditary haemochromatosis
Herpes simplex hepatitis
Hyperammonaemia
Hyperbilirubinaemia
Hyperbilirubinaemia neonatal
Hypercholia
Hypertransaminasaemia
Hypoalbuminaemia
Icterus index increased
Immune-mediated hepatitis
Increased liver stiffness
Intestinal varices


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Intestinal varices haemorrhage
Intrahepatic portal hepatic venous fistula
Ischaemic hepatitis
Jaundice
Jaundice cholestatic
Jaundice hepatocellular
Jaundice neonatal
Kayser-Fleischer ring
Kernicterus
Leucine aminopeptidase increased
Liver ablation
Liver abscess
Liver and pancreas transplant rejection
Liver carcinoma ruptured
Liver dialysis
Liver disorder
Liver function test abnormal
Liver function test decreased
Liver function test increased
Liver induration
Liver injury
Liver iron concentration abnormal
Liver iron concentration increased
Liver operation
Liver palpable
Liver sarcoidosis
Liver scan abnormal
Liver tenderness
Liver transplant
Liver transplant failure
Liver transplant rejection
Lupoid hepatic cirrhosis
Lupus hepatitis
Magnetic resonance imaging liver abnormal
Magnetic resonance proton density fat fraction 
measurement
Minimal hepatic encephalopathy
Mitochondrial aspartate aminotransferase increased
Mixed hepatocellular cholangiocarcinoma
Mixed liver injury
Model for end stage liver disease score abnormal
Model for end stage liver disease score increased
Molar ratio of total branched-chain amino acid to tyrosine
Multivisceral transplantation
Neonatal cholestasis


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Neonatal hepatomegaly
Nodular regenerative hyperplasia
Nonalcoholic fatty liver disease
Non-alcoholic steatohepatitis
Non-cirrhotic portal hypertension
Ocular icterus
Oedema due to hepatic disease
Oesophageal varices haemorrhage
Parenteral nutrition associated liver disease
Partial splenic embolisation
Perihepatic discomfort
Perinatal HBV infection
Peripancreatic varices
Periportal oedema
Peritoneal fluid protein abnormal
Peritoneal fluid protein decreased
Peritoneal fluid protein increased
Peritoneovenous shunt
Pneumobilia
Polycystic liver disease
Porphyria acute
Porphyria non-acute
Portal fibrosis
Portal hypertension
Portal hypertensive colopathy
Portal hypertensive enteropathy
Portal hypertensive gastropathy
Portal pyaemia
Portal shunt
Portal shunt procedure
Portal tract inflammation
Portal vein cavernous transformation
Portal vein dilatation
Portal vein flow decreased
Portal vein pressure increased
Portal venous system anomaly
Portopulmonary hypertension
Primary biliary cholangitis
Progressive familial intrahepatic cholestasis
Radiation hepatitis
Regenerative siderotic hepatic nodule
Renal and liver transplant
Retinol binding protein decreased
Retrograde portal vein flow
Reye's syndrome


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Reynold's syndrome
Schistosomiasis liver
Small-for-size liver syndrome
Spider naevus
Splenic varices
Splenic varices haemorrhage
Splenorenal shunt
Splenorenal shunt procedure
Spontaneous intrahepatic portosystemic venous shunt
Steatohepatitis
Stomal varices
Subacute hepatic failure
Sugiura procedure
Sustained viral response
Total bile acids increased
Transaminases abnormal
Transaminases increased
Ultrasound liver abnormal
Urine bilirubin increased
Urobilinogen urine decreased
Urobilinogen urine increased
Varices oesophageal
Varicose veins of abdominal wall
Viral hepatitis carrier
Weil's disease
White nipple sign
Withdrawal hepatitis
X-ray hepatobiliary abnormal
Yellow skin
Zieve syndrome
2
EDEMA
AEs are included in this grouping if they contain an event with the MedDRA Preferred 
Term "Pulmonary congestion" or if within the SMQ "Haemodynamic oedema, effusions 
and fluid overload (SMQ)" with the exception of PTs containing "site", ie the case will be 
included if it contains an event with any of the following MedDRA PTs:
Acute pulmonary oedema
Amyloid related imaging abnormalities
Amyloid related imaging abnormality-microhaemorrhages and haemosiderin 
deposits
Amyloid related imaging abnormality-oedema/effusion
Ascites
Bone marrow oedema


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Bone marrow oedema syndrome
Bone swelling
Brain oedema
Bronchial oedema
Capillary leak syndrome
Cerebral oedema management
Cervix oedema
Circumoral swelling
Compression garment application
Cytotoxic oedema
Durotomy procedure
Effusion
Elephantiasis nostras verrucosa
Extensive swelling of vaccinated limb
Fluid overload
Fluid retention
Gallbladder oedema
Gastrointestinal oedema
Generalised oedema
Gestational oedema
Gravitational oedema
Heat oedema
Hydraemia
Hydrothorax
Hydrovarium
Hypervolaemia
Hypoosmolar state
Joint effusion
Joint swelling
Lipoedema
Localised oedema
Lymphoedema
Modified Rodnan skin score abnormal
Mouth swelling
Muscle oedema
Muscle swelling
Myocardial oedema
Negative pressure pulmonary oedema
Non-cardiogenic pulmonary oedema
Oedema
Oedema blister
Oedema due to cardiac disease
Oedema due to hepatic disease
Oedema due to renal disease
Oedema mucosal


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Oedema neonatal
Oedema peripheral
Oedematous kidney
Oesophageal oedema
Oropharyngeal oedema
Pelvic fluid collection
Pericardial effusion
Perinephric collection
Perinephric oedema
Peripheral oedema neonatal
Peripheral swelling
Pleural effusion
Prevertebral soft tissue swelling of cervical space
Pulmonary congestion
Pulmonary oedema
Pulmonary oedema neonatal
Reexpansion pulmonary oedema
Retroperitoneal effusion
Retroperitoneal oedema
Scleroedema
Skin oedema
Skin swelling
Spinal cord oedema
Subdural effusion
Swelling
Testicular swelling
Vasogenic cerebral oedema
Visceral oedema
Excluded PTs
Administration site joint effusion
Administration site oedema
Administration site swelling
Application site joint effusion
Application site joint swelling
Application site oedema
Application site swelling
Catheter site oedema
Implant site oedema
Implant site swelling
Incision site oedema
Incision site swelling
Infusion site joint effusion
Infusion site joint swelling
Infusion site oedema
Infusion site swelling


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Injection site joint swelling
Injection site oedema
Injection site swelling
Instillation site oedema
Medical device site joint effusion
Medical device site joint swelling
Puncture site oedema
Vaccination site joint effusion
Vaccination site joint swelling
3
ANEMIA/HEMOGLOBIN DECREASE
AEs are included in this grouping if they contain an event Preferred Term (PT) within 
either of the following Standardised MedDRA Queries (SMQs): ‘Haematopoietic 
erythropenia’, or ‘Haematopoietic cytopenias affecting more than one type of blood cell’ 
(with the exception of 2 unspecific PTs: ‘Blood disorder’, ‘Blood count abnormal’), or if 
they contain an event with any MedDRA PT containing the text ‘anaemia’, i.e., any of the 
following MedDRA PTs: 
Anaemia
Anaemia folate deficiency
Anaemia Heinz body
Anaemia macrocytic
Anaemia megaloblastic
Anaemia neonatal
Anaemia of chronic disease
Anaemia of malignant disease
Anaemia of pregnancy
Anaemia postoperative
Anaemia prophylaxis
Anaemia splenic
Anaemia vitamin B12 deficiency
Anaemia vitamin B6 deficiency
Aplasia pure red cell
Aplastic anaemia
Aspiration bone marrow abnormal
Autoimmune anaemia
Autoimmune aplastic anaemia
Autoimmune haemolytic anaemia
Autosomal recessive megaloblastic anaemia


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Bicytopenia
Biopsy bone marrow abnormal
Blood incompatibility haemolytic anaemia of newborn
Blood loss anaemia
Blood loss anaemia neonatal
Bone marrow disorder
Bone marrow failure
Bone marrow infiltration
Bone marrow myelogram abnormal
Bone marrow necrosis
Bone marrow toxicity
Cardiac haemolytic anaemia
Cold type haemolytic anaemia
Congenital anaemia
Congenital aplastic anaemia
Congenital dyserythropoietic anaemia
Coombs negative haemolytic anaemia
Coombs positive haemolytic anaemia
Cytopenia
Deficiency anaemia
Erythroblast count abnormal
Erythroblast count decreased
Erythroid maturation arrest
Erythropenia
Erythropoiesis abnormal
Febrile bone marrow aplasia
Foetal anaemia
Full blood count decreased
Gelatinous transformation of the bone marrow
Haematocrit abnormal
Haematocrit decreased
Haematotoxicity
Haemoglobin abnormal
Haemoglobin decreased
Haemolytic anaemia
Haemolytic anaemia enzyme specific
Haemolytic icteroanaemia
Hand and foot syndrome secondary to sickle cell anaemia


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Hereditary haemolytic anaemia
Hereditary sideroblastic anaemia
Hexokinase deficiency anaemia
Hyperchromic anaemia
Hypochromic anaemia
Hypoplastic anaemia
Immune-mediated pancytopenia
Iron deficiency anaemia
Leukoerythroblastic anaemia
Melanaemia
Microangiopathic haemolytic anaemia
Microcytic anaemia
Myelodysplastic syndrome
Myelodysplastic syndrome transformation
Myelofibrosis
Myeloid metaplasia
Nephrogenic anaemia
Normochromic anaemia
Normochromic normocytic anaemia
Normocytic anaemia
Pancytopenia
Panmyelopathy
Pernicious anaemia
Plasmablast count decreased
Primary myelofibrosis
Proerythroblast count abnormal
Proerythroblast count decreased
Protein deficiency anaemia
Pyruvate kinase deficiency anaemia
Red blood cell count abnormal
Red blood cell count decreased
Refractory anaemia with an excess of blasts
Refractory anaemia with ringed sideroblasts
Reticulocyte count abnormal
Reticulocyte count decreased
Reticulocyte percentage decreased
Reticulocytopenia
Scan bone marrow abnormal


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Sickle cell anaemia
Sickle cell anaemia with crisis
Sideroblastic anaemia
Spherocytic anaemia
Spur cell anaemia
Warm type haemolytic anaemia
4
HYPOTENSION
AEs are included in this grouping if their coded PTs are included in the following list of 
PTs: 
Blood pressure ambulatory decreased, Blood pressure decreased, Blood pressure diastolic 
decreased, Blood pressure orthostatic decreased, Blood pressure systolic decreased, 
Diastolic hypotension, Hypotension, Mean arterial pressure decreased, Orthostatic 
hypotension, Procedural hypotension.


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Appendix D
Discussion and further considerations of the applied statistical 
methods
NA


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Appendix E
Protocol deviation code list
Document Revision History:
TV-eFRM-10509_Pro
tocol Violation Code
Appendix F. Outputs and SAS code for KM estimates
The LIFETEST SAS procedure in t-t2dth_sas.txt is used for the computation of the estimates. A selection of the relevant part of code to generate the 
results for the cohort Macitentan 10mg (DB/OL)  is shown below for illustrative purposes with further elucidation for clarity:
    data d1;
      set adam.addeath;
      where (saf1fl='Y' or saf2fl='Y');
    proc sort data=d1 nodupkey;
      by usubjid cestdt;  
    run;
    proc lifetest data=d1 
        method=KM
        alphaqt=0.05
        CONFTYPE=loglog
        plots=survival(atrisk=0 to 126 by 6)
        outsurv=sci_1(rename=(_censor_=censor))
        timelist=0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 126;
        time ttd1*cnsr(1) ;
        by pool1fl;
        where pool1fl='Y' and saf1fl='Y';
  run;


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The key elements for the analysis are:
i) Dataset ADDEATH included in
ii) ADDEATH variables:
POOL1FL, SAF1FL for the selection of safety set in the cohort 10mg DB/OL data 
POOL2FL, SAF2FL for the selection of safety set in the cohort 10mg OL data
TTD1 time to death in months for DB/OL cohort
TTD2 time to death in month for OL cohort
CNSR that is 0 for events and 1 for censoring
iii) Documentation: a full description of the datasets and variables including source and derivation is included in the define.xml and define.pdf 


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Document history
Version
Effective Date
Reason
Final 1.0
21-Dec-2020