Study of Macitentan (ACT-064992) on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension Clinical Trial

— SERAPHIN  

Official title:

A Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group, Event-driven, Phase III Study to Assess the Effects of Macitentan (ACT-064992) on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00660179
• Other study ID #: AC-055-302
• Status: Completed
• Phase: Phase 3
• First received: April 14, 2008
• Last updated: September 10, 2015
• Start date: May 2008
• Est. completion date: April 2012

Study information

• Verified date: August 2015
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Health authority: China: Food and Drug AdministrationUnited States: Food and Drug AdministrationChile: Instituto de Salud Pública de ChileSlovakia: State Institute for Drug ControlFinland: Finnish Medicines AgencyRussia: Ministry of Health of the Russian FederationGermany: Federal Institute for Drugs and Medical DevicesSouth Africa: Medicines Control CouncilAustria: Federal Ministry for Health and WomenUkraine: Ministry of HealthFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Mexico: Ministry of HealthAustralia: Department of Health and Ageing Therapeutic Goods AdministrationIsrael: Ministry of HealthBelgium: Federal Agency for Medicinal Products and Health ProductsItaly: The Italian Medicines AgencyBelarus: Ministry of HealthUnited States: Institutional Review BoardTaiwan: Department of HealthNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)United Kingdom: Medicines and Healthcare Products Regulatory AgencyCanada: Health Canada
• Study type: Interventional

Clinical Trial Summary

The AC-055-302/SERAPHIN study will be an event-driven Phase III study, comparing two different doses of macitentan (ACT-064992) (3 and 10 mg) vs placebo in patients with symptomatic PAH. The main study objective is to demonstrate that macitentan (ACT-064992) prolongs time to the first morbidity or mortality event, and to evaluate the benefit/risk profile of macitentan (ACT-064992) in the treatment of patients with symptomatic PAH.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 742
• Est. completion date: April 2012
• Est. primary completion date: March 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years and older

Eligibility

Inclusion Criteria:

1. Signed informed consent prior to initiation of any study mandated procedure.

2. Patients with symptomatic pulmonary arterial hypertension (PAH) in modified World Health Organization (WHO) functional class II to IV.

3. Patients with the following types of pulmonary arterial hypertension (PAH) belonging to groups 1.1 to 1.3 of the Venice classification:

• Idiopathic (IPAH);

• Familial (FPAH); or

• Related to:

• Collagen vascular disease;

• Simple, congenital systemic-to-pulmonary shunts at least 1 year post surgical repair;

• Human immunodeficiency virus (HIV) infection; or

• Drugs and toxins.

4. PAH diagnosis confirmed by hemodynamic evaluation performed prior to randomization and showing all of the following:

• Mean pulmonary artery pressure (mPAP) > 25 mmHg at rest;

• Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) < 15 mmHg; and

• Pulmonary vascular resistance (PVR) at rest >= 320 dyn×sec/cm^5.

5. 6-minute walk distance (6MWD) >= 50 m.

6. Men or women > 12 years of age (women of childbearing potential must have a negative pre-treatment serum pregnancy test and must use a reliable method of contraception).

Exclusion Criteria:

1. PAH associated with portal hypertension, thyroid disorders, glycogen storage disease, Gaucher''s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy.

2. PAH associated with non corrected simple congenital systemic-to-pulmonary shunts, and combined and complex systemic-to-pulmonary shunts, corrected or non corrected.

3. PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg), known pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis.

4. Persistent pulmonary hypertension of the newborn.

5. Pulmonary Hypertension belonging to groups 2 to 5 of the Venice classification.

6. Moderate to severe obstructive lung disease: forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 70% and FEV1 < 65% of predicted value after bronchodilator administration.

7. Moderate to severe restrictive lung disease: total lung capacity (TLC) < 60% of predicted value.

8. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.

9. Estimated creatinine clearance < 30 mL/min

10. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal.

11. Hemoglobin < 75% of the lower limit of the normal range.

12. Systolic blood pressure < 100 mmHg.

13. Acute or chronic physical impairment (other than dyspnea), limiting the ability to comply with study requirements.

14. Pregnant or breast-feeding.

15. Known concomitant life-threatening disease with a life expectancy < 12 months.

16. Body weight < 40 kg.

17. Any condition that prevents compliance with the protocol or adherence to therapy.

18. Recently started (< 8 weeks prior to randomization) or planned cardio-pulmonary rehabilitation program based on exercise.

19. Treatment with endothelin receptor antagonists (ERAs) within 3 months prior to randomization.

20. Systemic treatment within 4 week prior to randomization with cyclosporine A or tacrolimus, everolimus, sirolimus (calcineurin or mammalian target of rapamycin (mTOR) inhibitors).

21. Treatment with cytochrome P3A (CYP3A) inducers within 4 weeks prior to randomization

22. Known hypersensitivity to drugs of the same class as the study drug, or any of their excipients.

23. Planned treatment, or treatment, with another investigational drug within 1 month prior to randomization.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• macitentan (ACT-064992)
Tablet, 3 mg dosage, once daily
• macitentan (ACT-064992)
Tablet, 10 mg dosage, once daily
• placebo
Matching placebo, once daily

Locations

Country	Name	City	State
Argentina	Fundacion Favaloro	Buenos Aires
Argentina	Hospital Britanico	Buenos Aires
Argentina	Sanatorio MITRE	Buenos Aires
Argentina	SANATORIO OTAMENDI y MIROLI	Buenos Aires
Argentina	Htal Italiano Cordoba	Cordoba
Argentina	Htla privado de Cordoba	Cordoba
Argentina	Instituto Cardiologia Corrientes	Corrientes
Argentina	'Hospital Italiano - Garibaldi de Rosario	Santa Fe
Australia	St. Vincent's Hospital	Darlinghurst, NSW
Australia	The Alfred Hospital	Melbourne, VIC
Australia	Royal Brisbane Hospital	Sunshine Coast
Austria	Medical University of Vienna/ Department of Internal Medicine II, Division of Cardiology	Vienna
Belarus	Minsk Regional Clinical Hospital	Minsk
Belarus	Republican reserach - Pratical Centre of Cardilogy	Minsk
Belarus	Vitebsk Regional Clinical Hospital	Vitebsk
Belgium	University Hospital Gasthuisberg / Kliniekhoofd, Interne Geneeskunde - I.G. Pneumologie	Leuven
Bulgaria	Specialized Hospital for Active Treatment of Cardio-Vascular Diseases / Department of Pediatric Cardiology	Sofia
Canada	Peter Lougheed Centre	Calgary
Canada	London Health Sciences Centre / Victoria Hospital	London	Ontario
Canada	L'Hopital Laval	Saint-Foy	Quebec
Canada	Toronto General Hospital	Toronto
Canada	Vancouver General Hospital	Vancouver
Chile	Hospital San Juan de Dios	Santiago
Chile	'Pontificia Universidad Catolica de Chile	Santiago de Chile
Chile	Hospital del Torax	Santiago de Chile
China	Beijing Anzhen Hospital of the Capital University of Medical Sciences, Cardiology Department	Beijing
China	Chinese PLA General Hospital (301 Hospital), Cardiology Department	Beijing
China	Peking Union Medcical College Hospital, Rheumatology Department	Beijing
China	Guangdong General Hospital, Cardiology Department	Guangzhou	Guangdong
China	Jiangsu Province Hospital - Pneumology Department	Nanjing	Jiangsu
China	Renji Hospital, Cardiology Dept	Shanghai
China	Renji Hospital, Rheumatology Dept	Shanghai
China	Shanghai Pulmonary Hospital, Dept of Pulmonary Circulation	Shanghai
China	Zhongshan Hospital Fudan University, Cardiology Dept	Shanghai
Colombia	Fundación Clínica Shaio	Bogota
Colombia	'Fundacion Cardiovascular de Colombia	Floridablanca, Santander
Croatia	Clinical Hospital Center	Rijeka
France	Hôpital Antoine Béclère / Service de Pneumologie	Clamart
France	Hôpital Arnaud de Villeneuve Service des Maladies Respiratoires	Montpellier Cedex 5
France	Hopital Haut-Leveque - Maison du Haut-Leveque	Pessac
Germany	Unfallkrankenhaus Berlin, Klinik für Innere Medizin	Berlin
Germany	Medizinische Klinik und Poliklinik I Universitätsklinikum Carl Gustav Carus	Dresden
Germany	Universitätsklinikums Gießen und Marburg GmbH / Medizinische Klinik und Poliklinik II, Innere Med.	Giessen
Germany	Universität Greifswald / Klinik für Innere Medizin B,	Greifswald
Germany	Universitätsklinikum Hamburg-Eppendorf / Onkologie, Hämatologie und Knochenmarktransplantation mit Sektion Pneumologie	Hamburg
Germany	Thoraxklinik am Universitätsklinikum Heidelberg	Heidelberg
Germany	Universitätskliniken des Saarlandes / Medizinische Klinik und Poliklinik, Innere Medizin V	Homburg/Saar
Germany	Universität zu Köln, Medizinische Klinik III, Abteilung Kardiologie	Koln
Germany	Universtätsklinik Leipzig	Leipzig
Germany	Klinikum der Johannes Gutenberg-Universität / II. Medizinische Klinik und Poliklinik	Mainz
Germany	Medizinische Klinik und Poliklinik I der Ludwig-Maximilians-Universität München / Klinikum Großhadern, Schwerpunkt Pneumologie	Munich
Germany	Universitätsklinikum Regensburg / Innere Medizin II	Regensburg
Hong Kong	Prince of Wales Hospital/ Division of Rheumatology, Department of Medicine & Therapeutics	Hong Kong
Hong Kong	Queen Mary Hospital / Division of Cardiology, Department of Medicine	Hong Kong
Hungary	Gottsegen György Országos Kardiológiai Intézet (Hungarian Institute of Cardiology)	Budapest
Hungary	Semmelweis University, Pulmonolgy Clinic	Budapest
Hungary	University of Szeged Albert Szent-Györgyi Medical and Pharmaceutical Center, Faculty of General Medicine, II. Internal Medicine Clinic, Cardiology Center	Szeged
India	Life Care Institute of Medical Science & Research, Ahmedabad	Ahmedabad
India	G B Pant Hospital & Maulana Azad Medical College	Delhi
India	Care Hospital	Hyderabad
India	King Edward VII Memorial Hospital (KEM) Hospital	Mumbai
India	P D Hinduja National Hospital and Medical Research Centre/ Pulmunory Medicine	Mumbai
India	Deenanath Mangeshkar Hospital and Research Centre	Pune
Israel	Lady Davis Carmel Medical Center / Department of Cardiovascular Medicine, Pulmonary Division	Haifa
Israel	Rabin Medical Center - Belinson campus - Pulmonary Institute	Petach - Tikvah
Israel	Pulmonary Institute, Kaplan Medical Center	Rehovot
Israel	The pulmonary institute Sheba Medical centre	Tel Hashomer
Israel	Sourasky Medical Center - Division of Pulmonary Medicine and Allergy	Tel-Aviv
Italy	Policlinico Umberto I, Cardiologia	Roma
Malaysia	Institut Jantung Negara (National Heart Institute)	Kuala Lumpur
Mexico	'Instituto Nacional de Cardiología (INC) Ignacio Chávez	Mexico City
Mexico	Unidad de Investigación Clinica en Medicina, SC	Monterrey Nuevo León
Netherlands	St. Antonius ziekenhuis	Nieuwegein
Norway	Aker University Dept of Cardilogy	Oslo
Peru	Hospital Alberto Sabogal Sologuren - EsSALUD	Lima
Peru	IInstituto de Enfermedades Respiratorias, Clinica San Gabriel	Lima
Poland	Klinika Chorob Serca i Naczyn Instytut Kardiologii Collegium Medicum UJ	Krakow
Poland	Klinika Chorób Wewnetrznych Klatki Piersiowej	Warszawa
Poland	III Katedra i Oddzial Kliniczny Kardiologii Slaskiego Uniwersytetu Medycznego	Zabrze
Romania	Institutul de boli cardiovasculare / Clinica de Cardiologie	Bucharest
Romania	Institutul de Pneumologie "Marius Nasta" / I. Clinica de Pneumoftiziologie	Bucharest
Russian Federation	Sverdlovsk Regional Clinical Hospital # 1/ Cardiology Department (2nd Therapy Department)	Ekaterinburg
Russian Federation	Municipal Health Care Institution "Kemerovo Cardiology Dispensary"	Kemerovo
Russian Federation	Federal State Institution "Russian Cardiology Scientific and Production Complex of Rosmedtechnology"	Moscow
Russian Federation	Federal State Institution "Scientific Research Institute of Pulmonology of Roszdrav"	Moscow
Russian Federation	State Health Care Institution of Moscow "City Clinical Hospital #1 named after N. I. Pirogov"	Moscow
Russian Federation	Federal State Institution "Federal Center of Heart, Blood and Endocrinology named after V.A. Almazov" of Rosmedtechnology	St. Petersburg
Russian Federation	State Educational Institution of High Professional Education	St. Petersburg
Russian Federation	State Institution "Scientific Research Institute of Cardiology" of Tomsk Scientific Center of RAMS, Siberian branch	Tomsk
Russian Federation	Tomsk Regional Clinical Hospital / Pulmonology Unit	Tomsk
Russian Federation	Municipal Health Care Institution "Clinical Hospital of Emergency Care named after N.V. Soloviov"	Yaroslavl
Serbia	University Children's Hospital (UNIVERZITETSKA DECJA KLINIKA)	Belgrade
Serbia	University Clinical Center of Serbia / Institute for Lung Diseases and Tuberculosis	Belgrade
Serbia	Zemun Clinical Hospital (Klinicko-bolnicki centar "Zemun" ) / Department of Cardiology	Belgrade
Singapore	National University Hospital/ The Heart Institute	Singapore
Singapore	Singapore General Hospital	Singapore
Slovakia	National Institute of Cardiovascular Diseases (Národný ústav srdcových a cievnych chorôb, a.s. - NÚSCH) / Department of Heart Transplantation	Bratislava
Slovakia	Slovak Medical University (Slovenská zdravotnícka univerzita) / Faculty of Medical Speciality Studies (Fakulta zdravotníckych špecializacných štúdií), Department of Cardiology and Angiology	Bratislava
South Africa	Chris Hani Baragwanath Hospital, Department of Cardiology	Johannesburg
South Africa	Netcare Milpark Hospital,Center for Chest Disease	Johannesburg
South Africa	Tread Research	Parow
South Africa	Block 4, Vergelegen Medi-Clinic	Somerset West
Spain	Hospital Juan Canalejo Servicio de Neumología	A Coruna
Spain	Hospital Clínico I Provincial, Servicio de Neumología.	Barcelona
Spain	Hospital Universitario Vall d'Hebron, Pneumology Unit, Planta Baja Hospital General	Barcelona
Spain	Hospital 12 Octubre/ Cardiology department Planta 5a.	Madrid
Spain	Hospital Clínico Virgen de la Victoria / Pneumology Unit,	Malaga
Spain	Hospital Montecelo, Servicio de Neumología	Pontevedra
Sweden	University Hospital in Lund, Heart and Lung Division	Lund
Sweden	Servicio de Medicina Interna, Unidad de Hipertensión Pulmonar	Uppsala
Taiwan	Taichung Veterans General Hospital / Division of Allergy, Immunology and Rheumatology	Taichung
Taiwan	National Taiwan University Hospital/ Thoracic Surgical Division, Surgical Department	Taipei
Thailand	Ramathibodi Hospital, Mahidol University, Cardiology Unit, Department of Medicine,	Bangkok
Thailand	Siriraj Hospital/ Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University	Bangkok
Thailand	Chiang Mai Hospital / Division of Rheumatology, Department of Medicine, Faculty of Medicine, Chiang Mai University	Chiang Mai
Thailand	Srinagarind Hospital/Division of Rheumatology, Department of Medicine, Faculty of Medicine, Khon Kaen University	Khon Kaen
Turkey	Istanbul University Cardiology Institure	Istanbul
Ukraine	Dnipropetrovsk State Medical Academy / Regional Diagnostic Center, Department of electrophysiologic researches and anaesthesiologic aid	Dnepropetrovsk
Ukraine	Danylo Halytskyi Lviv State Medical University	Lviv
United Kingdom	Royal Free Hospital	London
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University Hospital - McKelvey Center for Lung Transplantation & Pulmonary Vascular Disease	Atlanta	Georgia
United States	Pulmonary & Critical Care of Atlanta	Atlanta	Georgia
United States	University of Maryland School of Medicine	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Boston University School of Medicine	Boston	Massachusetts
United States	Pulmonary/Critical Care Division/Tufts New England Medical Center	Boston	Massachusetts
United States	University of Chicago Hospitals	Chicago	Illinois
United States	University of Cincinnati Ohio Heart Health Center	Cincinnati	Ohio
United States	Ohio State University	Columbus	Ohio
United States	University of Texas Medical Center - St. Paul University	Dallas	Texas
United States	Southeastern Lung Care	Decatur	Georgia
United States	University of Colorado Health Sciences Center	Denver	Colorado
United States	Duke University Medical Center	Durham	North Carolina
United States	Baylor College of Medicine and the Methodist Hospital	Houston	Texas
United States	University of Iowa	Iowa City	Iowa
United States	Mayo Clinic, Jacksonville	Jacksonville	Florida
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	GLVA Healthcare Center	Los Angeles	California
United States	Kentuckiana Pulmonary Associate, PLLC	Louisville	Kentucky
United States	Comprehensive Cardiovascular Care Group	Milwaukee	Wisconsin
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	University of NJ - Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Medical Center of Louisiana at New Orleans	New Orleans	Louisiana
United States	Columbia University Medical Center - Pediatric Cardiology	New York	New York
United States	Sentara Hospital T/A Sentara Cardiovascular Research Institute	Norfolk	Virginia
United States	Arizona Pulmonary Specialists	Pheonix	Arizona
United States	Maine Medical Center	Portland	Maine
United States	Dept. of Pulmonary Medicine - Latter Day Saints Hospital	Salt Lake City	Utah
United States	University of California, San Diego	San Diego	California
United States	Santa Barbara Cottage Hospital	Santa Barbara	California
United States	Washington University School of Medicine	St. Louis	Missouri
United States	Liu Center for Pulmonary Hypertension	Torrance	California

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belarus,  Belgium,  Bulgaria,  Canada,  Chile,  China,  Colombia,  Croatia,  France,  Germany,  Hong Kong,  Hungary,  India,  Israel,  Italy,  Malaysia,  Mexico,  Netherlands,  Norway,  Peru,  Poland,  Romania,  Russian Federation,  Serbia,  Singapore,  Slovakia,  South Africa,  Spain,  Sweden,  Taiwan,  Thailand,  Turkey,  Ukraine,  United Kingdom, 

References & Publications (1)

Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani HA, Jansa P, Jing ZC, Le Brun FO, Mehta S, Mittelholzer CM, Perchenet L, Sastry BK, Sitbon O, Souza R, Torbicki A, Zeng X, Rubin LJ, Simonneau G; SERAPHIN Investigators. Macitentan and morb — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Summary of the First Causes of Morbidity or Mortality	Morbidity or mortality events were defined as: a) Death; b) Atrial septostomy; c) Lung transplantation; d) Initiation of intravenous (i.v.) or subcutaneous prostanoids, or; e) Other worsening of pulmonary arterial hypertension (PAH).; Other worsening of PAH was defined by the combined occurrence of all the following 3 events: At least 15% decrease in the 6 minute walk distance from baseline, confirmed by 2 tests performed on separate days, within 2 weeks.; AND worsening of PAH symptoms including at least one of the following: a) Increase in WHO Functional Class (WHO FC), or no change in patients in WHO FC IV at baseline; b) Appearance or worsening of signs of right heart failure that did not respond to optimized oral diuretic therapy; AND need for new treatment(s) for PAH that included the following: a) Oral or inhaled prostanoids; b) Oral phosphodiesterase inhibitors; c) Endothelin receptor antagonists (only after discontinuation of study treatment; d) i.v. diuretics	Up to end of treatment (Up to 36 months)	No
Primary	Time to First Confirmed Morbidity or Mortality Event up to the End of Treatment (Kaplan-Meier Estimate of Patients Without a Morbidity or Mortality Event)	Morbidity or mortality events were defined as: a) Death; b) Atrial septostomy; c) Lung transplantation; d) Initiation of intravenous (i.v.) or subcutaneous prostanoids, or; e) Other worsening of pulmonary arterial hypertension (PAH).; Other worsening of PAH was defined by the combined occurrence of all the following 3 events: At least 15% decrease in the 6 minute walk distance from baseline, confirmed by 2 tests performed on separate days, within 2 weeks.; AND worsening of PAH symptoms including at least one of the following: a) Increase in WHO Functional Class (WHO FC), or no change in patients in WHO FC IV at baseline; b) Appearance or worsening of signs of right heart failure that did not respond to optimized oral diuretic therapy; AND need for new treatment(s) for PAH that included the following: a) Oral or inhaled prostanoids; b) Oral phosphodiesterase inhibitors; c) Endothelin receptor antagonists (only after discontinuation of study treatment; d) i.v. diuretics	Up to end of treatment (data presented up to month 36)	No
Secondary	Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event)	Events of PAH or hospitalization for PAH up to the end of treatment included: death due to PAH, or onset of a treatment-emergent adverse event with a fatal outcome due to PAH occurring up to 4 weeks after the end of treatment, or hospitalisation for PAH up to the end of treatment.	Up to end of treatment (data presented up to month 36)	No
Secondary	Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event)	Events of death due to any cause up to the end of treatment (plus 7 days)	Up to end of treatment (data presented up to month 36)	No
Secondary	Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event)	Events of death due to any cause up to the end of study (EOS). The initiation of EOS procedure occurred when the target of 285 events was expected to have been achieved (30 January 2012).	Up to end of study (data presented up to month 36)	No
Secondary	Change From Baseline to Month 6 in 6-minute Walk Distance	The 6-minute walk test (6MWT) is a non-encouraged test, performed in a 30 m long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. These guidelines were provided to all sites. For patients who had never performed a 6MWT previously, a training test was required before the qualifying tests for inclusion were performed.	Baseline to month 6	No
Secondary	Number of Patients With Improvements in World Health Organization Functional Class From Baseline to Month 6	Class I: no limitation of usual physical activity (PA) which does not increase dyspnea, fatigue, chest pain, or presyncope.; Class II: mild limitation of PA. No discomfort at rest. Normal PA increases dyspnea, fatigue, chest pain, or presyncope.; Class III: marked limitation of PA. No discomfort at rest. Less than ordinary activity increases dyspnea, fatigue, chest pain, or presyncope.; Class IV: unable to perform any PA and who may have signs of right ventricular failure. Dyspnea and/or fatigue may be present at rest and symptoms are increased by almost any PA.	Baseline to month 6	No
Secondary	Pulmonary Vascular Resistance at Baseline and Month 6	In a sub-study, hemodynamic variables were assessed at baseline and Month 6. If the patient had undergone a right heart catheterization during the 3 months prior to randomization, these results were to be used as baseline values, if the background therapy had not changed during the intervening period.	Baseline to month 6	No
Secondary	Cardiac Index at Baseline and Month 6	In a sub-study, hemodynamic variables were assessed at baseline and Month 6. If the patient had undergone a right heart catheterization during the 3 months prior to randomization, these results were to be used as baseline values, if the background therapy had not changed during the intervening period.	Baseline to month 6	No