SERAPHIN OL: Clinical Study to Assess the Long-term Safety and Tolerability of ACT 064992 in Patients With Symptomatic Pulmonary Arterial Hypertension

• Sponsor: Actelion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00667823
• Collaborator: (none)
• Enrollment: 550
• Locations: 158
• Arm: 1
• Actual Duration (Months): 145.7
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension	Drug: Macitentan	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 550 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Long-term Single-arm Open-label Extension Study of the SERAPHIN Study, to Assess the Safety and Tolerability of ACT 064992 in Patients With Symptomatic Pulmonary Arterial Hypertension
• Actual Study Start Date: Oct 17, 2008
• Actual Primary Completion Date: Dec 7, 2020
• Actual Study Completion Date: Dec 7, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ACT-064992 ACT-064992	Drug: Macitentan; Tablet, oral administration, 10 mg dose once daily; Other Names: ACT-064992

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment Emergent Adverse Events (TEAEs) up to 28 Days After Study Treatment Discontinuation [Up to 28 days after study treatment discontinuation (Up to 12 years)]

   An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAE are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline.

2. Number of Participants With Death up to 28 Days After Study Treatment Discontinuation [Up to 28 days after study treatment discontinuation (Up to 12 years)]

   Number of participants with deaths up to 28 days after study treatment discontinuation were reported.

3. Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) up to 28 Days After Study Treatment Discontinuation [Up to 28 days after study treatment discontinuation (Up to 12 years)]

   An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAE are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically significant, or requires intervention to prevent at least one of the outcomes listed above.

4. Number of Participants With AEs Leading to Permanent Discontinuation of Study Treatment [Up to 28 days after study treatment discontinuation (Up to12 years)]

   Number of participants with AEs leading to permanent discontinuation of study treatment were reported. An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.

5. Number of Participants With Treatment Emergent Abnormal Liver Tests up to 28 Days After Study Treatment Discontinuation [Up to 28 days after study treatment discontinuation (Up to12 years)]

   Number of participants with treatment-emergent abnormal liver tests: Alanine aminotransferase (ALT) greater than (>) 3*upper limit of normal (ULN) or aspartate aminotransferase (AST) >3* ULN, ALT >5* ULN or AST >5*ULN, ALT >8*ULN or AST >8*ULN, total bilirubin (TBIL) >2*ULN, ALT >3*ULN or AST >3*ULN and TBIL >2*ULN at any time were reported.

6. Number of Participants With Treatment Emergent Hemoglobin Abnormality up to 28 Days After Study Treatment Discontinuation [Up to 28 days after treatment discontinuation (Up to 12 years)]

   Number of participants with treatment-emergent hemoglobin (HGB) abnormality up to 28 days after study treatment discontinuation were reported. Participants assessed for different categories of HGB were <=80 grams/Liter (g/L), <=100g/L, decrease from baseline >=20 g/L, and decrease from baseline >=50 g/L.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

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 ACT 064992 or any of the excipients.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35249-0001
2	Arizona Pulmonary Specialists	Phoenix	Arizona	United States	85012
3	University of California, San Diego	La Jolla	California	United States	92037
4	GLVA Healthcare Center	Los Angeles	California	United States	90073
5	Santa Barbara Cottage Hospital	Santa Barbara	California	United States	93105
6	Liu Center for Pulmonary Hypertension	Torrance	California	United States	90502-2006
7	University of Colorado CARDIAC AND VASCULAR CENTER	Aurora	Colorado	United States	80045-2548
8	University of Florida - Division of Pulmonology	Gainesville	Florida	United States	32610
9	Mayo Clinic, Jacksonville	Jacksonville	Florida	United States	32259
10	Emory University Hospital - McKelvey Center for Lung Transplantation & Pulmonary Vascular Disease	Atlanta	Georgia	United States	30322
11	Pulmonary & Critical Care of Atlanta	Atlanta	Georgia	United States	30342-1713
12	Atlanta Institute for Medical Research	Decatur	Georgia	United States	30030
13	University of Chicago	Chicago	Illinois	United States	60637-1432
14	University of Iowa, Pulmonary Hypertension Program	Iowa City	Iowa	United States	52242-1081
15	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
16	Kentuckiana Pulmonary Associate, PLLC	Louisville	Kentucky	United States	40202
17	Louisiana State University Health Sciences Center	New Orleans	Louisiana	United States	70112-1393
18	Maine Medical Center	Portland	Maine	United States	04102-3134
19	University of Maryland School of Medicine; Division of Cardiology	Baltimore	Maryland	United States	21201-1544
20	Pulmonary/Critical Care Division/Tufts New England Medical Center	Boston	Massachusetts	United States	02111-1552
21	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
22	Boston University School of Medicine	Boston	Massachusetts	United States	02118
23	University of Michigan	Ann Arbor	Michigan	United States	48109
24	Harper Univ. Hospital/ Wayne State University	Detroit	Michigan	United States	48201
25	Washington University School of Medicine	Saint Louis	Missouri	United States	63110-1010
26	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
27	University of NJ - Robert Wood Johnson Medical School	New Brunswick	New Jersey	United States	08903-0010
28	Columbia University Medical Center - Pediatric Cardiology	New York	New York	United States	10032
29	Duke University Medical Center	Durham	North Carolina	United States	27710-0001
30	University of Cincinnati Ohio Heart Health Center	Cincinnati	Ohio	United States	45219-2906
31	Ohio State University, Div. of Pul. & Critical Care	Columbus	Ohio	United States	43210
32	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
33	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
34	University of Texas Medical Center - St. Paul University	Dallas	Texas	United States	75390-8550
35	Baylor College of Medicine and the Methodist Hospital,	Houston	Texas	United States	77030
36	University of Texas Houston Health Center	Houston	Texas	United States	77030
37	Intermountain Med Ctr- Pulm Dept Heart and Lung Ctr	Murray	Utah	United States	84157-5701
38	Sentara Hospitals T/A Sentara Cardiovascular Research Intitute	Norfolk	Virginia	United States	23507-1904
39	Aurora St. Luke's Medical Center	Milwaukee	Wisconsin	United States	53125
40	Sanatorio Otamendi y Miroli S.A.	Buenos Aires	Ciudad Autonoma	Argentina	C1121ABL
41	Hospital Britanico	Buenos Aires	Ciudad Autonoma	Argentina	C1280AEB
42	Sanatorio MITRE	Buenos Aires		Argentina	C1039AAO
43	Fundacion Favaloro	Buenos Aires		Argentina	C1093AAS
44	Htal Italiano Cordoba	Cordoba		Argentina	X5004BAL
45	Htla privado de Cordoba	Cordoba		Argentina	x5016keh
46	Instituto Cardiologia Corrientes	Corrientes		Argentina	W3400AMZ
47	Hospital Italiano - Garibaldi de Rosario	Santa Fe		Argentina	S2001ODA
48	St. Vincent's Hospital	Darlinghurst		Australia	2010
49	The Alfred Hospital	Melbourne		Australia	3004
50	Royal Brisbane Hospital	Sunshine Coast		Australia	4558
51	Medical University of Vienna/ Department of Internal Medicine II, Division of Cardiology	Vienna		Austria	1090
52	Republican reserach - Pratical Centre of Cardiology	Minsk		Belarus	220036
53	Minsk Regional Clinical Hospital	Minsk		Belarus	223041
54	Vitebsk Regional Clinical Hospital	Vitebsk		Belarus	210037
55	University Hospital Gasthuisberg	Leuven		Belgium	3000
56	Mhat Nat Card Hosp - Pediatric Clinic	Sofia	BG	Bulgaria	1309
57	Peter Lougheed Centre	Calgary	Alberta	Canada	T1Y 6J4
58	London Health Sciences Centre	London	Ontario	Canada	N6C 2R5
59	Toronto General Hospital	Toronto	Ontario	Canada	M5G 2N2
60	L'Hopital Laval	Sainte-Foy	Quebec	Canada	G1V 4G5
61	Hospital del Torax	Santiago de Chile		Chile	7500691
62	Pontificia Universidad Catolica de Chile	Santiago de Chile		Chile	833034
63	Hospital San Juan de Dios	Santiago		Chile	8350488
64	Beijing Anzhen Hospital of the Capital University of Medical Sciences, Cardiology Department	Beijing		China	100029
65	Peking Union Medical College Hospital, Rheumatology Department	Beijing		China	100032
66	Guangdong General Hospital, Cardiology Department	Guangzhou		China	510080
67	Jiangsu Province Hospital - Pneumology Department	Nanjing		China	210029
68	Renji Hospital, Rheumatology Department	Shanghai		China	200001
69	Zhongshan Hospital Fudan University, Cardiology Department	Shanghai		China	200032
70	Renji Hospital, Cardiology Department	Shanghai		China	200127
71	Shanghai Pulmonary Hospital Department of Pulmonary Circulation	Shanghai		China	200433
72	Fundacion Cardiovascular de Colombia	Floridablanca	Santander	Colombia
73	Fundacion Clinica Shaio	Bogota		Colombia
74	Clinical Hospital Center	Rijeka		Croatia	51 000
75	Helsinki University Central Hospital	Helsinki		Finland	00290
76	Hosp Bicetre - Dept Pulmo & Resp Intensive Care	Le Kremlin-Bicêtre cedex		France	94275
77	Hopital Arnaud de Villeneuve Service des Maladies Respiratoires	Montpellier		France	34295
78	Hopital Haut-Leveque-Maison du Haut-Leveque	Pessac		France	33604
79	Unfallkrankenhaus Berlin, Klinik für Innere Medizin	Berlin		Germany	12683
80	Medizinische Klinik und Poliklinik I Universitätsklinikum Carl Gustav Carus	Dresden		Germany	01307
81	Universitätsklinikum Essen, Klinik für Kardiologie , Zentrum für Innere Medizin	Essen		Germany	45122
82	Universitätsklinikums Gießen und Marburg GmbH / Medizinische Klinik und Poliklinik II, Innere Med. / Pneumologie	Giessen		Germany	35392
83	Universität Greifswald / Klinik für Innere Medizin B,	Greifswald		Germany	17475
84	Universitätsklinikum Hamburg-Eppendorf / Onkologie, Hämatologie und Knochenmarktransplantation mit Sektion Pneumologie	Hamburg		Germany	20246
85	Medizinische Hochschule Hannover / Klinik für Pneumologie	Hannover		Germany	30625
86	Thoraxklinik am Universitätsklinikum Heidelberg	Heidelberg		Germany	69126
87	Universitätskliniken des Saarlandes / Medizinische Klinik und Poliklinik, Innere Medizin V	Homburg/Saar		Germany	66421
88	Universität zu Köln, Medizinische Klinik III, Abteilung Kardiologie	Koln		Germany	50924
89	Universtätsklinik Leipzig	Leipzig		Germany	04103
90	Medizinische Klinik und Poliklinik I der Ludwig-Maximilians-Universität München / Klinikum Großhadern, Schwerpunkt Pneumologie	Munich		Germany	81377
91	Universitatsklinikum Regensburg/Innere Medizin II	Regensburg		Germany	93053
92	Prince of Wales Hospital/ Division of Rheumatology, Department of Medicine & Therapeutics	Hong Kong		Hong Kong
93	Gottsegen György Országos Kardiológiai Intézet (Hungarian Institute of Cardiology)	Budapest		Hungary	1096
94	"Semmelweis Egyetem, Pulmonológiai Klinika"	Budapest		Hungary	1125
95	University of Pecs, Medical School/Heart Institute and 1st Department of Internal Medicine	Pecs		Hungary	7624
96	University of Szeged Albert Szent-Gyorgyi Medical & Pharmaceutical Center	Szeged		Hungary	6720
97	Life Care Institute of Medical Science & Research, Ahmedabad	Ahmedabad		India	382428
98	Care Hospital	Hyderabad		India	500001
99	Seth GS Medical College & King Edward VII Memorial (KEM) Hospital / Department Of Cardiology	Mumbai		India	400012
100	P D Hinduja National Hospital and Medical Research Centre/ Pulmunory Medicine	Mumbai		India	400016
101	G B Pant Hospital & Maulana Azad Medical College	New Delhi		India	110 002
102	Deenanath Mangeshkar Hospital and Research Centre	Pune		India	411 004
103	Rambam Health Care Campus / Division of Medicine, Institute of Pulmonology	Haifa		Israel	31096
104	Lady Davis Carmel Medical Center / Department of Cardiovascular Medicine, Pulmonary Division	Haifa		Israel	34362
105	Rabin Medical Center - Belinson campus - Pulmonary Institute	Petach - Tikvah		Israel	49100
106	Pulmonary Institute, Kaplan Medical Center	Rehovot		Israel	76100
107	The pulmonary institute Sheba Medical centre	Tel Hashomer		Israel	52621
108	Sourasky Medical Center - Division of Pulmonary Medicine and Allergy	Tel-Aviv		Israel	64239
109	IRCCS Policlinico San Matteo Policlinico / Dipartimento di Cardiologia	Pavia		Italy	207100
110	Policlinico Umberto I, Cardiologia	Roma		Italy	00161
111	Institut Jantung Negara (National Heart Institute)	Kuala Lumpur		Malaysia	50400
112	Instituto Nacional de Cardiología (INC) Ignacio Chávez	Mexico City		Mexico	14080
113	Unidad de Investigación Clinica en Medicina	Monterrey		Mexico	64718
114	VU Medisch Centrum, Dept. Pulmonology 4A 48	Amsterdam		Netherlands	1081 HV
115	St. Antonius ziekenhuis	Nieuwegein		Netherlands	3435 CM
116	Hospital Alberto Sabogal Sologuren - EsSALUD	Callao		Peru	Callao 02
117	Clinica Medica Cayetano Heredia	Lima		Peru	31
118	Instituto de Enfermedades Respiratorias	Lima		Peru	32
119	Klinika Chorob Serca i Naczyn Instytut Kardiologii Collegium Medicum UJ	Krakow		Poland	31-202
120	Cardiology Otwock Priv	Otwock		Poland	05-400
121	III Katedra i Oddział Kliniczny Kardiologii Slaskiego Uniwersytetu Medycznego	Zabrze		Poland	41-800
122	Institutul de Pneumologie "Marius Nasta" / I. Clinica de Pneumoftiziologie	Bucharest		Romania	050159
123	Institutul de boli cardiovasculare / Clinica de Cardiologie	Bucuresti		Romania	022328
124	Sverdlovsk Regional Clinical Hospital # 1/ Cardiology Department (2nd Therapy Department)	Ekaterinburg		Russian Federation	620102
125	Municipal Health Care Institution Kemerovo Cardiology Dispensary	Kemerovo		Russian Federation	650002
126	Federal State Institution "State Scientific Research Centre of Preventive Medicine" of Rosmedtechnology	Moscow		Russian Federation	101990
127	Federal State Institution "Scientific Research Institute of Pulmonology of Roszdrav"	Moscow		Russian Federation	105077
128	State Health Care Institution of Moscow "City Clinical Hospital #1 named after N. I. Pirogov"	Moscow		Russian Federation	117049
129	Federal State Institution "Russian Cardiology Scientific and Production Complex of Rosmedtechnology"	Moscow		Russian Federation	121552
130	State Educational Institution "St Petersburg Medical Academy of Postgraduate Education" of Federal Agency of Public Health and Social Development	St Petersburg		Russian Federation	193015
131	State Educational Institution of High Professional Education "St Petersburg State Medical	St Petersburg		Russian Federation	197 022
132	Federal State Institution "Federal Center of Heart, Blood and Endocrinology named after V.A. Almazov" of Rosmedtechnology	St. Petersburg		Russian Federation	197341
133	State Institution "Scientific Research Institute of Cardiology" of Tomsk Scientific Center of RAMS, Siberian branch	Tomsk		Russian Federation	634012
134	Tomsk Regional Clinical Hospital / Pulmonology Unit	Tomsk		Russian Federation	634063
135	Municipal Health Care Institution "Clinical Hospital of Emergency Care named after N.V. Soloviov"	Yaroslavl		Russian Federation	150 003
136	University Children's Hospital (UNIVERZITETSKA DECJA KLINKIKA)	Belgrade		Serbia	11000
137	University Clinical Center of Serbia/ Institute for Lung Diseases and Tuberculosis	Belgrade		Serbia	11000
138	Zemun Clinical Hospital (Klinicko-bolnicki centar Zemun) / Department of Cardiology	Belgrade		Serbia	11080
139	National University Hospital/ The Heart Institute	Singapore		Singapore	119228
140	National Heart Centre (Nhc) Singapore	Singapore		Singapore	169609
141	National Institute of Cardiovascular Diseases (Slovenska zdravotnicka univerzita) / Faculty of Medical Specialty Studies (Fakulta zdravotnickych speci	Bratislava		Slovakia	833 48
142	Slovak Medical University (Slovenská zdravotnícka univerzita) / Faculty of Medical Speciality Studies (Fakulta zdravotníckych špecializačných štúdií)	Bratislava		Slovakia	833 48
143	Tread Research	Cape Town		South Africa	7505
144	Chris Hani Baragwanath Hospital, Department of Cardiology	Johannesburg		South Africa	2013
145	Netcare Milpark Hospital,Center for Chest Disease	Johannesburg		South Africa	2193
146	Block 4, Vergelegen Medi-Clinic	Somerset West		South Africa	7130
147	University Hospital of Lund, Dept. of Cardiology	Lund		Sweden	221 85
148	Uppsala University Hospital, Cardiology	Uppsala		Sweden	751 85
149	Taichung Veterans General Hospital	Taichung		Taiwan	40705
150	National Taiwan University Hospital/ Thoracic Surgical Division, Surgical Department	Taipei		Taiwan	100
151	Ramathibodi Hospital, Mahidol University, Cardiology Unit, Department of Medicine,	Bangkok		Thailand	10400
152	Siriraj Hospital, Mahidol University	Bangkok		Thailand	10700
153	Maharaj Nakorn Chiang Mai Hospital, Division of Rheumatology	Chiang Mai		Thailand	50200
154	Srinagarind Hospital/Division of Rheumatology, Department of Medicine, Faculty of Medicine, Khon Kaen University	Khon Kaen		Thailand	40002
155	Dnipropetrovsk State Medical Academy / Regional Diagnostic Center, Department of electrophysiologic researches and anaesthesiologic aid	Dnepropetrovsk		Ukraine	49060
156	Danylo Galytskyi Lviv State Medical University	Lviv		Ukraine	79010
157	Odessa State Medical University, Military-medical Clinical Center of the South region	Odessa		Ukraine	65044
158	Royal Free Hospital	London		United Kingdom	NW3 2QG

Sponsors and Collaborators

• Actelion

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 17, 2020
• Statistical Analysis Plan - Dec 21, 2020

More Information

Publications

None provided.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT00667823
• Other Study ID Numbers: AC-055-303
• First Posted: Apr 28, 2008
• Last Update Posted: Feb 10, 2022
• Last Verified: Jan 1, 2022

• Keywords provided by Actelion: SERAPHIN; Pulmonary Arterial Hypertension; ACT-064992
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Macitentan

Study Results

Participant Flow

Pre-assignment Detail	Participant flow reported below is up to study closure.

Arm/Group Title	Macitentan 10 mg
Arm/Group Description	Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Period Title: Overall Study
STARTED	550
COMPLETED	334
NOT COMPLETED	216

Baseline Characteristics

Arm/Group Title	Macitentan 10 mg
Arm/Group Description	Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Overall Participants	550
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.7 (15.67)
Sex: Female, Male (Count of Participants)
Female	440 80%
Male	110 20%
Race/Ethnicity, Customized (Count of Participants)
Asian	165 30%
Other	13 2.4%
White	372 67.6%
Region of Enrollment (Count of Participants)
ARGENTINA	32 5.8%
AUSTRALIA	6 1.1%
AUSTRIA	4 0.7%
BELARUS	21 3.8%
BELGIUM	2 0.4%
BULGARIA	4 0.7%
CANADA	12 2.2%
CHILE	24 4.4%
CHINA	74 13.5%
COLOMBIA	7 1.3%
FRANCE	8 1.5%
GERMANY	27 4.9%
HONG KONG	3 0.5%
HUNGARY	4 0.7%
INDIA	30 5.5%
ISRAEL	10 1.8%
ITALY	3 0.5%
MALAYSIA	6 1.1%
MEXICO	33 6%
NETHERLANDS	1 0.2%
PERU	4 0.7%
POLAND	19 3.5%
ROMANIA	12 2.2%
RUSSIAN FEDERATION	54 9.8%
SERBIA	13 2.4%
SINGAPORE	12 2.2%
SLOVAKIA	4 0.7%
SOUTH AFRICA	17 3.1%
SWEDEN	6 1.1%
TAIWAN	14 2.5%
THAILAND	19 3.5%
UKRAINE	12 2.2%
UNITED KINGDOM	4 0.7%
UNITED STATES	49 8.9%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs) up to 28 Days After Study Treatment Discontinuation
Description	An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAE are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline.
Time Frame	Up to 28 days after study treatment discontinuation (Up to 12 years)

Outcome Measure Data

Analysis Population Description

The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).

Arm/Group Title	Macitentan 10 mg
Arm/Group Description	Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Measure Participants	550
Count of Participants [Participants]	527 95.8%

2. Primary Outcome

Title	Number of Participants With Death up to 28 Days After Study Treatment Discontinuation
Description	Number of participants with deaths up to 28 days after study treatment discontinuation were reported.
Time Frame	Up to 28 days after study treatment discontinuation (Up to 12 years)

Outcome Measure Data

Analysis Population Description

The SAF included all participants who received at least 1 dose of macitentan 10 mg.

Arm/Group Title	Macitentan 10 mg
Arm/Group Description	Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Measure Participants	550
Count of Participants [Participants]	175 31.8%

3. Primary Outcome

Title	Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) up to 28 Days After Study Treatment Discontinuation
Description	An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAE are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically significant, or requires intervention to prevent at least one of the outcomes listed above.
Time Frame	Up to 28 days after study treatment discontinuation (Up to 12 years)

Outcome Measure Data

Analysis Population Description

The SAF included all participants who received at least 1 dose of macitentan 10 mg.

Arm/Group Title	Macitentan 10 mg
Arm/Group Description	Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Measure Participants	550
Count of Participants [Participants]	354 64.4%

4. Primary Outcome

Title	Number of Participants With AEs Leading to Permanent Discontinuation of Study Treatment
Description	Number of participants with AEs leading to permanent discontinuation of study treatment were reported. An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.
Time Frame	Up to 28 days after study treatment discontinuation (Up to12 years)

Outcome Measure Data

Analysis Population Description

The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 mg.

Arm/Group Title	Macitentan 10 mg
Arm/Group Description	Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Measure Participants	550
Count of Participants [Participants]	62 11.3%

5. Primary Outcome

Title	Number of Participants With Treatment Emergent Abnormal Liver Tests up to 28 Days After Study Treatment Discontinuation
Description	Number of participants with treatment-emergent abnormal liver tests: Alanine aminotransferase (ALT) greater than (>) 3*upper limit of normal (ULN) or aspartate aminotransferase (AST) >3* ULN, ALT >5* ULN or AST >5*ULN, ALT >8*ULN or AST >8*ULN, total bilirubin (TBIL) >2*ULN, ALT >3*ULN or AST >3*ULN and TBIL >2*ULN at any time were reported.
Time Frame	Up to 28 days after study treatment discontinuation (Up to12 years)

Outcome Measure Data

Analysis Population Description

The SAF included all participants who received at least 1 dose of macitentan 10 mg.

Arm/Group Title	Macitentan 10 mg
Arm/Group Description	Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Measure Participants	550
ALT or AST >3*ULN	45 8.2%
ALT or AST >5*ULN	20 3.6%
ALT or AST >8*ULN	11 2%
TBIL >2*ULN	75 13.6%
ALT or AST >3*ULN and (TBIL>2*ULN at any time)	8 1.5%

6. Primary Outcome

Title	Number of Participants With Treatment Emergent Hemoglobin Abnormality up to 28 Days After Study Treatment Discontinuation
Description	Number of participants with treatment-emergent hemoglobin (HGB) abnormality up to 28 days after study treatment discontinuation were reported. Participants assessed for different categories of HGB were <=80 grams/Liter (g/L), <=100g/L, decrease from baseline >=20 g/L, and decrease from baseline >=50 g/L.
Time Frame	Up to 28 days after treatment discontinuation (Up to 12 years)

Outcome Measure Data

Analysis Population Description

The SAF included all participants who received at least 1 dose of macitentan 10 mg.

Arm/Group Title	Macitentan 10 mg
Arm/Group Description	Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Measure Participants	550
HGB <= 80 gram/Liter (g/L)	33 6%
HGB <= 100 g/L	98 17.8%
HGB decrease from baseline >= 20 g/L	188 34.2%
HGB decrease from baseline >= 50 g/L	29 5.3%

Adverse Events

Time Frame	Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years)
Adverse Event Reporting Description	The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Arm/Group Title	Macitentan 10 mg
Arm/Group Description	Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
All Cause Mortality
	Macitentan 10 mg
	Affected / at Risk (%)	# Events
Total	182/550 (33.1%)
Serious Adverse Events
	Macitentan 10 mg
	Affected / at Risk (%)	# Events
Total	354/550 (64.4%)
Blood and lymphatic system disorders
Anaemia	27/550 (4.9%)
Autoimmune Haemolytic Anaemia	1/550 (0.2%)
Coagulopathy	1/550 (0.2%)
Hypercoagulation	1/550 (0.2%)
Iron Deficiency Anaemia	2/550 (0.4%)
Pancytopenia	3/550 (0.5%)
Cardiac disorders
Acute Coronary Syndrome	1/550 (0.2%)
Acute Myocardial Infarction	2/550 (0.4%)
Acute Right Ventricular Failure	11/550 (2%)
Angina Pectoris	1/550 (0.2%)
Arrhythmia	3/550 (0.5%)
Atrial Fibrillation	7/550 (1.3%)
Atrial Flutter	8/550 (1.5%)
Bradycardia	1/550 (0.2%)
Cardiac Arrest	9/550 (1.6%)
Cardiac Disorder	1/550 (0.2%)
Cardiac Failure	7/550 (1.3%)
Cardiac Failure Acute	2/550 (0.4%)
Cardiac Failure Chronic	1/550 (0.2%)
Cardiac Failure Congestive	6/550 (1.1%)
Cardio-Respiratory Arrest	4/550 (0.7%)
Cardiogenic Shock	9/550 (1.6%)
Cardiopulmonary Failure	2/550 (0.4%)
Cardiorenal Syndrome	1/550 (0.2%)
Chronic Right Ventricular Failure	1/550 (0.2%)
Coronary Artery Disease	1/550 (0.2%)
Cyanosis	1/550 (0.2%)
Left Ventricular Dysfunction	1/550 (0.2%)
Left Ventricular Failure	2/550 (0.4%)
Myocardial Infarction	4/550 (0.7%)
Myocardial Ischaemia	1/550 (0.2%)
Palpitations	3/550 (0.5%)
Pericardial Effusion	1/550 (0.2%)
Right Ventricular Dysfunction	1/550 (0.2%)
Right Ventricular Failure	72/550 (13.1%)
Stress Cardiomyopathy	1/550 (0.2%)
Supraventricular Tachycardia	2/550 (0.4%)
Tachyarrhythmia	1/550 (0.2%)
Ventricular Fibrillation	2/550 (0.4%)
Ventricular Tachycardia	1/550 (0.2%)
Ear and labyrinth disorders
Vertigo Positional	1/550 (0.2%)
Eye disorders
Cataract	1/550 (0.2%)
Gastrointestinal disorders
Abdominal Distension	1/550 (0.2%)
Abdominal Pain	3/550 (0.5%)
Abdominal Pain Upper	1/550 (0.2%)
Anal Fistula	1/550 (0.2%)
Ascites	1/550 (0.2%)
Colitis	2/550 (0.4%)
Diarrhoea	3/550 (0.5%)
Duodenal Perforation	1/550 (0.2%)
Enterocolitis Haemorrhagic	1/550 (0.2%)
Gastritis	2/550 (0.4%)
Gastritis Erosive	1/550 (0.2%)
Gastroduodenitis	1/550 (0.2%)
Gastrointestinal Disorder	1/550 (0.2%)
Gastrointestinal Haemorrhage	3/550 (0.5%)
Gastrointestinal Necrosis	1/550 (0.2%)
Haematemesis	1/550 (0.2%)
Hiatus Hernia	1/550 (0.2%)
Ileus Paralytic	1/550 (0.2%)
Intestinal Pseudo-Obstruction	1/550 (0.2%)
Lower Gastrointestinal Haemorrhage	1/550 (0.2%)
Pancreatitis Acute	2/550 (0.4%)
Pancreatitis Relapsing	1/550 (0.2%)
Peptic Ulcer	1/550 (0.2%)
Rectal Haemorrhage	1/550 (0.2%)
Small Intestinal Obstruction	2/550 (0.4%)
Umbilical Hernia	3/550 (0.5%)
Upper Gastrointestinal Haemorrhage	6/550 (1.1%)
Vomiting	2/550 (0.4%)
General disorders
Cardiac Death	1/550 (0.2%)
Chest Discomfort	3/550 (0.5%)
Chest Pain	11/550 (2%)
Death	5/550 (0.9%)
Drug Ineffective	1/550 (0.2%)
Fatigue	2/550 (0.4%)
General Physical Health Deterioration	1/550 (0.2%)
Influenza Like Illness	1/550 (0.2%)
Infusion Site Pain	1/550 (0.2%)
Multiple Organ Dysfunction Syndrome	4/550 (0.7%)
Oedema Peripheral	2/550 (0.4%)
Peripheral Swelling	2/550 (0.4%)
Pyrexia	4/550 (0.7%)
Sudden Cardiac Death	3/550 (0.5%)
Sudden Death	11/550 (2%)
Vascular Stent Thrombosis	1/550 (0.2%)
Hepatobiliary disorders
Bile Duct Stone	1/550 (0.2%)
Cholecystitis	1/550 (0.2%)
Cholecystitis Acute	1/550 (0.2%)
Cholelithiasis	1/550 (0.2%)
Hepatic Function Abnormal	2/550 (0.4%)
Hepatic Steatosis	1/550 (0.2%)
Immune system disorders
Drug Hypersensitivity	1/550 (0.2%)
Infections and infestations
Abscess Limb	1/550 (0.2%)
Appendicitis	3/550 (0.5%)
Arthritis Bacterial	1/550 (0.2%)
Atypical Pneumonia	1/550 (0.2%)
Bronchitis	9/550 (1.6%)
Bronchitis Viral	1/550 (0.2%)
Candida Sepsis	1/550 (0.2%)
Cellulitis	4/550 (0.7%)
Device Related Infection	1/550 (0.2%)
Endocarditis	1/550 (0.2%)
Erysipelas	1/550 (0.2%)
Gastroenteritis	4/550 (0.7%)
Gastroenteritis Bacterial	1/550 (0.2%)
Gastroenteritis Norovirus	1/550 (0.2%)
Gastroenteritis Salmonella	1/550 (0.2%)
Herpes Zoster	1/550 (0.2%)
Hiv Infection	2/550 (0.4%)
Infected Skin Ulcer	2/550 (0.4%)
Infective Exacerbation of Chronic Obstructive Airways Disease	1/550 (0.2%)
Influenza	5/550 (0.9%)
Joint Tuberculosis	1/550 (0.2%)
Laryngitis Bacterial	1/550 (0.2%)
Localised Infection	1/550 (0.2%)
Lower Respiratory Tract Infection	8/550 (1.5%)
Lung Infection	8/550 (1.5%)
Meningitis	1/550 (0.2%)
Peritonitis	1/550 (0.2%)
Pneumococcal Sepsis	1/550 (0.2%)
Pneumonia	40/550 (7.3%)
Pneumonia Influenzal	1/550 (0.2%)
Pneumonia Klebsiella	1/550 (0.2%)
Pneumonia Streptococcal	1/550 (0.2%)
Postoperative Wound Infection	1/550 (0.2%)
Pulmonary Sepsis	2/550 (0.4%)
Pulmonary Tuberculosis	1/550 (0.2%)
Pyelonephritis	1/550 (0.2%)
Pyelonephritis Acute	2/550 (0.4%)
Respiratory Tract Infection	3/550 (0.5%)
Respiratory Tract Infection Viral	1/550 (0.2%)
Salmonella Sepsis	2/550 (0.4%)
Sepsis	4/550 (0.7%)
Septic Shock	6/550 (1.1%)
Staphylococcal Bacteraemia	1/550 (0.2%)
Subcutaneous Abscess	1/550 (0.2%)
Tuberculosis	2/550 (0.4%)
Upper Respiratory Tract Infection	8/550 (1.5%)
Urinary Tract Infection	3/550 (0.5%)
Urosepsis	1/550 (0.2%)
Viral Upper Respiratory Tract Infection	1/550 (0.2%)
Injury, poisoning and procedural complications
Accidental Overdose	1/550 (0.2%)
Acetabulum Fracture	1/550 (0.2%)
Ankle Fracture	1/550 (0.2%)
Brain Contusion	1/550 (0.2%)
Contusion	1/550 (0.2%)
Fall	5/550 (0.9%)
Femoral Neck Fracture	1/550 (0.2%)
Femur Fracture	2/550 (0.4%)
Foot Fracture	1/550 (0.2%)
Humerus Fracture	2/550 (0.4%)
Perineal Injury	1/550 (0.2%)
Post Procedural Haematoma	1/550 (0.2%)
Post Procedural Haemorrhage	2/550 (0.4%)
Radius Fracture	1/550 (0.2%)
Spinal Compression Fracture	1/550 (0.2%)
Subarachnoid Haemorrhage	3/550 (0.5%)
Subdural Haematoma	2/550 (0.4%)
Thermal Burn	1/550 (0.2%)
Thoracic Vertebral Fracture	2/550 (0.4%)
Toxicity to Various Agents	3/550 (0.5%)
Traumatic Haematoma	1/550 (0.2%)
Traumatic Haemorrhage	1/550 (0.2%)
Ulna Fracture	1/550 (0.2%)
Upper Limb Fracture	1/550 (0.2%)
Investigations
Anticoagulation Drug Level above Therapeutic	1/550 (0.2%)
Blood Bilirubin Increased	1/550 (0.2%)
Catheterisation Cardiac	2/550 (0.4%)
Computerised Tomogram Abnormal	1/550 (0.2%)
International Normalised Ratio Increased	3/550 (0.5%)
Investigation	1/550 (0.2%)
Liver Function Test Increased	3/550 (0.5%)
Oxygen Saturation Decreased	1/550 (0.2%)
Metabolism and nutrition disorders
Dehydration	4/550 (0.7%)
Electrolyte Imbalance	2/550 (0.4%)
Fluid Overload	4/550 (0.7%)
Fluid Retention	1/550 (0.2%)
Gout	2/550 (0.4%)
Hyperkalaemia	1/550 (0.2%)
Hypoglycaemia	4/550 (0.7%)
Hypokalaemia	1/550 (0.2%)
Hyponatraemia	5/550 (0.9%)
Metabolic Acidosis	1/550 (0.2%)
Musculoskeletal and connective tissue disorders
Back Pain	2/550 (0.4%)
Intervertebral Disc Degeneration	1/550 (0.2%)
Intervertebral Disc Protrusion	1/550 (0.2%)
Joint Swelling	1/550 (0.2%)
Mixed Connective Tissue Disease	1/550 (0.2%)
Muscular Weakness	2/550 (0.4%)
Musculoskeletal Pain	1/550 (0.2%)
Osteoporosis	1/550 (0.2%)
Pain in Extremity	2/550 (0.4%)
Polymyositis	1/550 (0.2%)
Rheumatoid Arthritis	1/550 (0.2%)
Scleroderma	3/550 (0.5%)
Spinal Column Stenosis	1/550 (0.2%)
Systemic Lupus Erythematosus	5/550 (0.9%)
Systemic Scleroderma	2/550 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Anogenital Warts	1/550 (0.2%)
Basal Cell Carcinoma	1/550 (0.2%)
Bladder Cancer	1/550 (0.2%)
Brain Neoplasm	1/550 (0.2%)
Cardiac Valve Fibroelastoma	1/550 (0.2%)
Colon Cancer	2/550 (0.4%)
Haemangioma	1/550 (0.2%)
Intraductal Proliferative Breast Lesion	1/550 (0.2%)
Invasive Ductal Breast Carcinoma	2/550 (0.4%)
Metastases to Lung	2/550 (0.4%)
Metastatic Uterine Cancer	1/550 (0.2%)
Nasopharyngeal Cancer	1/550 (0.2%)
Ovarian Adenoma	1/550 (0.2%)
Ovarian Cancer	1/550 (0.2%)
Rectosigmoid Cancer Recurrent	1/550 (0.2%)
Richter's Syndrome	1/550 (0.2%)
Squamous Cell Carcinoma of Lung	1/550 (0.2%)
Squamous Cell Carcinoma of the Cervix	1/550 (0.2%)
Uterine Cancer	1/550 (0.2%)
Uterine Leiomyoma	2/550 (0.4%)
Nervous system disorders
Amnesia	1/550 (0.2%)
Brain Oedema	1/550 (0.2%)
Cerebellar Infarction	1/550 (0.2%)
Cerebrovascular Accident	2/550 (0.4%)
Dizziness	2/550 (0.4%)
Headache	2/550 (0.4%)
Hepatic Encephalopathy	1/550 (0.2%)
Ischaemic Stroke	2/550 (0.4%)
Loss of Consciousness	1/550 (0.2%)
Polyneuropathy	2/550 (0.4%)
Radiculopathy	1/550 (0.2%)
Syncope	20/550 (3.6%)
Pregnancy, puerperium and perinatal conditions
Abortion Missed	1/550 (0.2%)
Abortion Spontaneous	2/550 (0.4%)
Pregnancy	2/550 (0.4%)
Product Issues
Device Dislocation	1/550 (0.2%)
Device Malfunction	1/550 (0.2%)
Psychiatric disorders
Anxiety	1/550 (0.2%)
Anxiety Disorder	1/550 (0.2%)
Completed Suicide	1/550 (0.2%)
Confusional State	1/550 (0.2%)
Depression	1/550 (0.2%)
Mental Status Changes	1/550 (0.2%)
Renal and urinary disorders
Acute Kidney Injury	8/550 (1.5%)
Calculus Urinary	1/550 (0.2%)
Chronic Kidney Disease	1/550 (0.2%)
Cystitis Haemorrhagic	1/550 (0.2%)
Lupus Nephritis	2/550 (0.4%)
Nephrolithiasis	1/550 (0.2%)
Neurogenic Bladder	1/550 (0.2%)
Pollakiuria	1/550 (0.2%)
Prerenal Failure	1/550 (0.2%)
Renal Colic	3/550 (0.5%)
Renal Failure	2/550 (0.4%)
Renal Impairment	2/550 (0.4%)
Ureterolithiasis	1/550 (0.2%)
Reproductive system and breast disorders
Dysmenorrhoea	1/550 (0.2%)
Menometrorrhagia	1/550 (0.2%)
Menorrhagia	2/550 (0.4%)
Metrorrhagia	1/550 (0.2%)
Ovarian Cyst	4/550 (0.7%)
Ovarian Cyst Ruptured	1/550 (0.2%)
Ovarian Cyst Torsion	1/550 (0.2%)
Pelvic Haematoma	1/550 (0.2%)
Prostatitis	1/550 (0.2%)
Uterine Haemorrhage	1/550 (0.2%)
Vaginal Haemorrhage	1/550 (0.2%)
Respiratory, thoracic and mediastinal disorders
Acute Pulmonary Oedema	1/550 (0.2%)
Acute Respiratory Failure	4/550 (0.7%)
Asthma	1/550 (0.2%)
Bronchitis Chronic	1/550 (0.2%)
Bronchospasm	1/550 (0.2%)
Chronic Obstructive Pulmonary Disease	1/550 (0.2%)
Chronic Respiratory Failure	1/550 (0.2%)
Dyspnoea	16/550 (2.9%)
Dyspnoea Exertional	5/550 (0.9%)
Epistaxis	2/550 (0.4%)
Haemoptysis	8/550 (1.5%)
Hypoxia	3/550 (0.5%)
Nasal Polyps	1/550 (0.2%)
Organising Pneumonia	1/550 (0.2%)
Pleural Effusion	3/550 (0.5%)
Pulmonary Arterial Hypertension	123/550 (22.4%)
Pulmonary Congestion	1/550 (0.2%)
Pulmonary Embolism	10/550 (1.8%)
Pulmonary Fibrosis	1/550 (0.2%)
Pulmonary Haemorrhage	1/550 (0.2%)
Pulmonary Hypertension	6/550 (1.1%)
Pulmonary Hypertensive Crisis	2/550 (0.4%)
Pulmonary Oedema	3/550 (0.5%)
Respiratory Failure	5/550 (0.9%)
Respiratory Tract Haemorrhage	1/550 (0.2%)
Skin and subcutaneous tissue disorders
Photosensitivity Reaction	1/550 (0.2%)
Rash Pruritic	1/550 (0.2%)
Surgical and medical procedures
Aortic Surgery	1/550 (0.2%)
Bunion Operation	1/550 (0.2%)
Chemotherapy	1/550 (0.2%)
Cholecystectomy	1/550 (0.2%)
Gastric Polypectomy	1/550 (0.2%)
Hysterectomy	1/550 (0.2%)
Lung Transplant	7/550 (1.3%)
Oophorectomy	1/550 (0.2%)
Osteosynthesis	1/550 (0.2%)
Therapy Cessation	1/550 (0.2%)
Transfusion	1/550 (0.2%)
Vascular disorders
Accelerated Hypertension	1/550 (0.2%)
Aneurysm Ruptured	1/550 (0.2%)
Aortic Aneurysm	1/550 (0.2%)
Aortic Aneurysm Rupture	1/550 (0.2%)
Circulatory Collapse	1/550 (0.2%)
Deep Vein Thrombosis	2/550 (0.4%)
Haematoma	1/550 (0.2%)
Hypertension	1/550 (0.2%)
Hypotension	3/550 (0.5%)
Hypovolaemic Shock	1/550 (0.2%)
Venous Thrombosis Limb	1/550 (0.2%)
Other (Not Including Serious) Adverse Events
	Macitentan 10 mg
	Affected / at Risk (%)	# Events
Total	476/550 (86.5%)
Blood and lymphatic system disorders
Anaemia	80/550 (14.5%)
Iron Deficiency Anaemia	14/550 (2.5%)
Leukopenia	22/550 (4%)
Thrombocytopenia	36/550 (6.5%)
Cardiac disorders
Atrial Fibrillation	24/550 (4.4%)
Palpitations	34/550 (6.2%)
Right Ventricular Failure	24/550 (4.4%)
Tachycardia	22/550 (4%)
Endocrine disorders
Hypothyroidism	21/550 (3.8%)
Gastrointestinal disorders
Abdominal Distension	14/550 (2.5%)
Abdominal Pain	12/550 (2.2%)
Abdominal Pain Upper	22/550 (4%)
Constipation	20/550 (3.6%)
Diarrhoea	59/550 (10.7%)
Dyspepsia	13/550 (2.4%)
Gastritis	11/550 (2%)
Gastrooesophageal Reflux Disease	21/550 (3.8%)
Nausea	28/550 (5.1%)
Vomiting	24/550 (4.4%)
General disorders
Chest Pain	35/550 (6.4%)
Fatigue	19/550 (3.5%)
Oedema Peripheral	105/550 (19.1%)
Pyrexia	25/550 (4.5%)
Hepatobiliary disorders
Hyperbilirubinaemia	26/550 (4.7%)
Infections and infestations
Bronchitis	78/550 (14.2%)
Cellulitis	11/550 (2%)
Cystitis	11/550 (2%)
Gastroenteritis	16/550 (2.9%)
Influenza	17/550 (3.1%)
Laryngitis	11/550 (2%)
Lower Respiratory Tract Infection	12/550 (2.2%)
Nasopharyngitis	105/550 (19.1%)
Pharyngitis	28/550 (5.1%)
Pneumonia	29/550 (5.3%)
Respiratory Tract Infection	31/550 (5.6%)
Respiratory Tract Infection Viral	23/550 (4.2%)
Rhinitis	16/550 (2.9%)
Sinusitis	18/550 (3.3%)
Tooth Abscess	11/550 (2%)
Upper Respiratory Tract Infection	121/550 (22%)
Urinary Tract Infection	46/550 (8.4%)
Injury, poisoning and procedural complications
Ligament Sprain	11/550 (2%)
Investigations
Alanine Aminotransferase Increased	22/550 (4%)
Aspartate Aminotransferase Increased	20/550 (3.6%)
Blood Bilirubin Increased	16/550 (2.9%)
Blood Creatinine Increased	12/550 (2.2%)
Haemoglobin Decreased	13/550 (2.4%)
Liver Function Test Increased	15/550 (2.7%)
Weight Decreased	19/550 (3.5%)
Metabolism and nutrition disorders
Decreased Appetite	18/550 (3.3%)
Gout	16/550 (2.9%)
Hyperglycaemia	11/550 (2%)
Hyperkalaemia	16/550 (2.9%)
Hyperuricaemia	15/550 (2.7%)
Hypokalaemia	39/550 (7.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	33/550 (6%)
Back Pain	33/550 (6%)
Myalgia	15/550 (2.7%)
Osteoarthritis	12/550 (2.2%)
Pain in Extremity	21/550 (3.8%)
Nervous system disorders
Dizziness	55/550 (10%)
Headache	63/550 (11.5%)
Syncope	40/550 (7.3%)
Psychiatric disorders
Anxiety	13/550 (2.4%)
Depression	12/550 (2.2%)
Insomnia	36/550 (6.5%)
Renal and urinary disorders
Acute Kidney Injury	14/550 (2.5%)
Respiratory, thoracic and mediastinal disorders
Cough	74/550 (13.5%)
Dyspnoea	54/550 (9.8%)
Epistaxis	27/550 (4.9%)
Haemoptysis	18/550 (3.3%)
Nasal Congestion	14/550 (2.5%)
Oropharyngeal Pain	18/550 (3.3%)
Pulmonary Arterial Hypertension	47/550 (8.5%)
Skin and subcutaneous tissue disorders
Rash	16/550 (2.9%)
Skin Ulcer	13/550 (2.4%)
Vascular disorders
Hypotension	20/550 (3.6%)

Limitations/Caveats

The limitation of the open-label study design was the open label nature of the trial due to which the number of participants decreased over time to the extent that 10 percent (%) and 2.4% of participants (N=550) remained in the study at Years 7 and 9, respectively.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days.