Selexipag (ACT-293987) in Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension Clinical Trial

— GRIPHON  

Official title:

A Multicenter, Double-blind, Placebo-controlled Phase 3 Study Assessing the Safety and Efficacy of Selexipag on Morbidity and Mortality in Patients With Pulmonary Arterial Hypertension

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01106014
• Other study ID #: AC-065A302
• Status: Completed
• Phase: Phase 3
• First received: April 2, 2010
• Last updated: December 13, 2017
• Start date: December 1, 2009
• Est. completion date: October 1, 2014

Study information

• Verified date: December 2017
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The AC-065A302 (GRIPHON) study is an event-driven Phase 3 study to demonstrate the effect of selexipag on time to first morbidity or mortality event in patients with pulmonary arterial hypertension.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1156
• Est. completion date: October 1, 2014
• Est. primary completion date: April 1, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Male and female patients 18-75 years old, with symptomatic PAH

• PAH belonging to the following subgroups of the updated Dana Point Clinical Classification Group 1 (Idiopathic, or Heritable, or Drug or toxin induced, or Associated (APAH) with Connective tissue disease, Congenital heart disease with simple systemic-to-pulmonary shunt at least 1 year after surgical repair, or HIV infection)

• Documented hemodynamic diagnosis of PAH by right heart catheterization, performed at any time prior to Screening

• Six minute walk distance (6MWD) between 50 and 450 m at Screening within 2 weeks prior to the Baseline Visit

• Signed informed consent

Exclusion Criteria:

• Patients with pulmonary hypertension (PH) in the Updated Dana Point Classification Groups 2-5, and PAH Group 1 subgroups that are not covered by the inclusion criteria

• Patients who have received prostacyclin or its analogs within 1 month before Baseline Visit, or are scheduled to receive any of these compounds during the trial

• Patients with moderate or severe obstructive lung disease

• Patients with moderate or severe restrictive lung disease

• Patients with moderate or severe hepatic impairment (Child-Pugh B and C)

• Patients with documented left ventricular dysfunction

• Patients with severe renal insufficiency

• Patients with BMI <18.5 Kg/m2

• Patients who are receiving or have been receiving any investigational drugs within 1 month before the Baseline Visit

• Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements, in particular with 6MWT

• Recently conducted or planned cardio-pulmonary rehabilitation program based on exercise training

• Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements

• Life expectancy less than 12 months

• Females who are lactating or pregnant or plan to become pregnant during the study

• Known hypersensitivity to any of the excipients of the drug formulations

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• Selexipag
Selexipag 200 µg tablets
• Placebo
Placebo tablets matching selexipag

Locations

Country	Name	City	State
Argentina	Centro de Investigacion y Prevencion Cardiovascular (CIPREC)	Buenos Aires
Argentina	Hospital Britanico-Pneumology	Buenos Aires
Argentina	Sanatorio Otamendi y Miroli S.A.	Buenos Aires
Argentina	Sanatorio San Jose	Buenos Aires
Argentina	Hospital Privado Centro Medico de Cordoba S.A.	Cordoba
Argentina	Instituto De Cardiologia de Corrientes	Corrientes
Australia	Royal Adelaide Hospital, Cardiovascular Investigation Unit (CVIU)	Adelaide	South Australia
Australia	Flinders Medical Centre, Pulmonary Hypertension, c/- Cardiology	Bedford Park	South Australia
Australia	Prince Charles Hospital Lung Transplant, Thoracic Department	Chermside	Queensland
Australia	St. Vincent's Hospital / Heart and Lung Transplant Unit	Darlinghurst	New South Wales
Australia	St Vincent's Hospital	Fitzroy	Victoria
Australia	Royal Hobart Hospital, Centre for Clinical Research	Hobart
Australia	John Hunter Hospital Autoimmune Resource and Research Centre	New Lambton
Australia	Royal Melbourne Hospital, Department of Respiratory and Sleep Medicine	Parkville
Australia	Royal Perth Hospital	Perth
Austria	Medizinische Universität Graz	Graz
Austria	Medical University of Vienna and AKH Cardiology	Vienna
Belarus	Minsk City Hospital No. 9	Minsk
Belarus	Minsk Regional Clinical Hospital of the Red Banner of Labour	Minsk
Belarus	The Republican Scientific-Practical Center "Cardiology"	Minsk
Belgium	Ulb Erasme, Cardiology	Brussels
Belgium	University Hospital Gasthuisberg - Pneumologie	Leuven
Canada	University of Alberta Hospital - Children's Centre	Edmonton	Alberta
Canada	Hopital General Juif (Jewish General Hospital)	Montreal	Quebec
Canada	University of Ottawa Heart Institute	Ottawa	Ontario
Canada	Institut Universitaire de Cardiologie et de Pneumologie de Quebec	Quebec City	Quebec
Canada	University Health Network	Toronto	Ontario
Canada	Vancouver General Hospital	Vancouver	British Columbia
Canada	Health Sciences Centre	Winnipeg	Manitoba
Chile	Clinica Tabancura- Cardiology Unit	Santiago
Chile	Instituto Nacional del Torax Teaching Dept	Santiago
Chile	Pontificia Universidad Catolica de Chile-Departmento De Enfermedades Cardiovasculares	Santiago
China	Beijing Shijitan Hospital	Beijing
China	Cardiovascular Institute & Fuwai Hospital-Pulmonary Vascular Center	Beijing
China	Peking Union Medical College Hospital, Rheumatology Department	Beijing
China	Guangdong General Hospital, Cardiology Department	Guangzhou
China	Renji Hospital, Cardiology Department	Shanghai
China	Renji Hospital, Rheumatology Department	Shanghai
China	Shanghai Pulmonary Hospital, Department of Pulmonary Circulation	Shanghai
Colombia	Fundacion Cardio Infantil	Bogota
Colombia	Fundacion Clinica Shaio	Bogota
Czechia	Gen Faculty Hosp Prague Cardiology Clin	Praha 2
Denmark	Aarhus University Hospital , Cardiology	Arhus
Denmark	Rigshospitalet, Hjertemedicinsk klinik - Cardiology	Copenhagen
France	Hosp Pradel Lyon - Dpt Pneumology	Bron cedex
France	Hosp Cote de Nacre - Dpt Pneumology	Caen Cedex
France	Hosp A. Beclere - Dept Pulmo & Resp Intensive Care	Clamart
France	Hosp Huriez - Dpt Internal Medecine	Lille Cedex
France	Hosp Civil - Dpt Pneumology	Strasbourg
France	Hosp Larrey - Dpt Pneumology	Toulouse Cedex 9
Germany	DRK Kliniken Köpenick	Berlin
Germany	Universitätsklinikum Carl Gustav Carus, Medizinische Klinik1-Pneumologie/MK1-A13	Dresden
Germany	"Justus-Liebig-Universität Gießen Zentrum für Innere Medizin Medizinische Klinik II"	Giessen
Germany	Universität Greifswald / Klinik für Innere Medizin B	Greifswald
Germany	Medizinische Hochschule Hannover / Klinik für Pneumologie	Hannover
Germany	Thoraxklinik am Universitätsklinikum Heidelberg	Heidelberg
Germany	"Universitätsklinikum Köln Herzzentrum / Klinik III für Innere Medizin (Kardiologie, Pneumologie, Angiologie und Intensivmedizin)"	Köln
Germany	Praxis für Pneumologie und Allergologie	Leipzig
Germany	Klinik Löwenstein gGmbH, Medizinische Klinik 1, Pneumologie - Kardiologie	Löwenstein
Germany	Universitätsklinkum Regensburg / Innere Medizin II	Regensburg
Greece	Onasseio Cardiosurgical Hospital	Athens
Hungary	"Gottsegen György Országos Kardiológiai Intézet, Felnott kardiológiai osztály"	Budapest
Hungary	"Semmelweis Egyetem, Pulmonológiai Klinika"	Budapest
Hungary	Egészségügyi Járóbeteg Központ Kardiológiai Intézete - Debrecen	Debrecen
Hungary	"Pécsi Tudományegyetem Klinikai Központ,	Pécs
Hungary	"Szegedi Tudományegyetem ÁOK Szent-Györgyi Albert Klinikai Központ, II. sz. Belgyógyászati klinika és Kardiológiai központ"	Szeged
India	Sanjivani Hospitals - Department of Cardiology	Ahmedabad
India	Apollo Hospitals, Chennai	Chennai
India	Frontier Lifeline Hospitals, Dr KM Cherian Heart Foundation, Chennai	Chennai
India	CARE Hospitals Nampally, Cardiology Dep. Hyderabad	Hyderabad
India	Apollo Indraprastha Hospitals	New Delhi
Ireland	Mater Miscordiae University Hospital	Dublin
Israel	Carmel Medical Center, Pulmonary Unit	Haifa
Israel	Pulmonology Institute, Hadassah University Hospital at Ein Karem	Jerusalem
Israel	Rabin Medical Centre - Pulmonology	Petach Tikvah
Israel	Kaplan Medical - Pulmonary Institute	Rehovot
Israel	The Chaim Sheba Med Ctr -Pulmonology	Tel-Hashomer
Italy	Policlinico S. Orsola-Malpighi - Dipartimento Cardio-Toraco-Vascolare	Bologna
Italy	Seconda Università Degli Studi di Napoli - Azienda Universitaria Policlinico - Dipartimento Assistenziale di medicina Generale, Angiologia, Endocrinologia, Epatogastroenterologia e Reumatologia - Unità Operativa di Reumatologia	Napoli
Italy	ISMETT - Istituto Mediterraneo Trapianti e Terapie ad Alta Specializzazione - Dipartimento di Medicina - Divisione di Pneumologia	Palermo
Korea, Republic of	Gil Medical Centre	Incheon
Korea, Republic of	"The Catholic University of Korea, Seoul St. Mary's Hospital Department of Cardiology"	Seoul
Korea, Republic of	Samsung Medical Center, Division of Cardiology	Seoul
Korea, Republic of	Seoul Nathional University Hospital	Seoul
Korea, Republic of	Yonsei University Health System Dept of Cardiology	Seoul
Malaysia	Institut Jantung Negara (National Heart Institute)	Kuala Lumpur
Mexico	Instituto Nacional de Cardiologia (INC) Ignacio Chavez	Mexico City
Mexico	Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubrian	Mexico City
Netherlands	VU Medisch Centrum / Afdeling longziekten, secretariaat 4A 48	Amsterdam
Netherlands	Academisch Ziekenhuis Maastricht / Department of Pulmonary Diseases	Maastricht
Netherlands	St. Antonius Ziekenhuis afdeling Longziekten	Nieuwegein
Netherlands	Erasmus Medisch Centrum Rotterdam afdeling longziekten	Rotterdam
Peru	Hospital Nacional Edgardo Rebagliati / Unidad de Investigacion Cardiologia 2	Lima
Peru	Instituto de Enfermedades Respiratorias Clinica San Gabriel	Lima
Poland	"Uniwersyteckie Centrum Kliniczne II Klinika Kardiologii i Elektroterapii Serca"	Gdansk
Poland	"Instytut Kardiologii Collegium Medium UJ Krakowski Szpital Specjalistyczny im Jana Pawla II Klinika Chorób Serca i Naczyn"	Krakow
Poland	"Wojewódzki Specjalistyczny Szpital im. dr Wladyslawa Bieganskiego Oddzial Kardiologiczny, II Katedra i Klinika Kardiologii UM"	Lódz
Poland	"Instytut Gruzlicy i Chorób Pluc Klinika Chorób Wewnetrznych Klatki Piersiowej"	Warszawa
Romania	"Institutul de Pneumologie "Marius Nasta", I. Clinica de Pneumoftiziologie"	Bucharest
Romania	"Spitalul Clinic de Pneumoftiziologie Iasi Sectia Clinica I de Pneumoftiziologie"	Iasi
Russian Federation	Municipal Medical Institution City Hospital #5	Barnaul
Russian Federation	Regional Clinical Hospital # 1	Ekaterinburg
Russian Federation	Kemerovo Cardiology Dispensary / Kemerovo Regional Hospital	Kemerovo
Russian Federation	Scientific Research Institute of Pulmonology of the Federal Medical and Biological Agency of Russia	Moscow
Russian Federation	State Institution, "Institute fo Rheumatology of RAMS"	Moscow
Russian Federation	The Institution of the Clinical Cardiology named after A. L. Myaskinov	Moscow
Russian Federation	Limited liability company, Consultative diagnostic centre Healthy Joints	Novosibirsk
Russian Federation	V. A. Almazov Institute of Cardiology, Russian Ministry of Healthcare and Social Development / Medical Treatment and Rehabilitation Complex	St Petersburg
Russian Federation	Cardiology Scientific Research Institute of Tomsk Scientific Center of RAMs, Siberian Branch / Cardiovascular Surgery Department	Tomsk
Russian Federation	Tomsk Regional Clinical Hospital/ Pulmonology Unit	Tomsk
Serbia	"Klinicki Centar Srbije, Klinika za pulmologiju"	Belgrade
Serbia	"Klinicko-bolnicki centar Zemun, Kardiološko odeljenje"	Belgrade
Singapore	National Heart Centre (NHC) Singapore	Singapore
Slovakia	Národný ústav srdcových a cievnych chorôb, a.s. - NÚSCH a.s.	Bratislava
Spain	Clinic-Barcelona	Barcelona
Spain	Hosp Vall D'Hebron - Barcelona - Pneumology	Barcelona
Spain	Hospital 12 Octubre	Madrid
Sweden	Sahlgrenska Universitetssjukhuset, Kardiologi	Goteborg
Sweden	Linköping University Hospital, Cardiology	Linköping
Sweden	Umeå University Hospital, Cardiology (Umeå)	Umea
Sweden	Uppsala Akademiska Sjukhuset, Kardiologkliniken 50F	Uppsala
Switzerland	University Hospital Basel Division of Pneumology	Basel
Switzerland	Universitätsspital Bern, Clinic for Pneumology (Inselspital)	Bern
Switzerland	HUG Hôpitaux Universitaires de Genève; Pneumology, PAH	Genève 14
Switzerland	Kantonsspital St. Gallen Klinik für Pneumologie	St. Gallen
Taiwan	Kaohsiung Veterans General Hospital (KVGH)	Kaohsiung
Taiwan	National Taiwan University Hospital / Department of Surgery	Taipei
Thailand	Srinagarind Hospital, Khon Kaen University, Division of Allergy-Immunology and Rheumatology, Department of Medicine	Khon Kaen
Turkey	Çukurova Üniversitesi Tip Fakültesi Kardiyoloji Anabilim Dali	Adana
Turkey	Istanbul Üniversitesi Kardiyoloji Enstitisü	Istanbul
Turkey	Marmara Üniversitesi Tip Fakultesi Kardiyoloji Anabilim Dali	Istanbul
Turkey	Dokuz Eylül Üniversitesi Tip Fakültesi Kardiyoloji Anabilim Dali	Izmir
Ukraine	"Dnipropetrovsk State Medical Academy, Municipal Institution ""Dnipropetrovsk Regional Clinic Diagnostic Center""	Dnipropetrovsk
Ukraine	Health Care Municipal Institution, City Clinical Hospital #13	Kharkiv
Ukraine	Public Institution "F.H. Yanovski Phthisiology and Pulmonology National Institute Under Ukrainian Academy of Medical Sciences"	Kyiv
Ukraine	Lviv Regional Clinical Hospital	Lviv
United Kingdom	Golden Jubilee - Pulm Vascular Unit	Glasgow
United Kingdom	Hammersmith	London
United Kingdom	Royal Free & Ucms Rheumatology Unit	London
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University School of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine	Atlanta	Georgia
United States	Georgia Health Sciences University	Augusta	Georgia
United States	Georgia Clinical Research	Austell	Georgia
United States	Johns Hopkins University School of Medicine	Baltimore	Maryland
United States	Boston University School of Medicine / Boston University Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital - Pulmonary Critical Care Unit	Boston	Massachusetts
United States	Massachusetts General Hospital-Pulmonary Critical Care Unit	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Montefiore Medical Center, Weiler Division	Bronx	New York
United States	Clarian North Hospital	Carmel	Indiana
United States	The Lindner Clinical Trial Center	Cincinnati	Ohio
United States	University of Cincinnati	Cincinnati	Ohio
United States	University Hospitals Case Medical Center	Cleveland	Ohio
United States	The Ohio State University Medical Center	Columbus	Ohio
United States	UT Southwestern Medical Center at Dallas	Dallas	Texas
United States	Henry Ford Hospital	Detroit	Michigan
United States	Central Bucks Specialists	Doylestown	Pennsylvania
United States	Duke University Medical Center	Durham	North Carolina
United States	Baylor College of Medicine	Houston	Texas
United States	University of Texas-Houston Health Center Department of Pulmonary & Critical Care	Houston	Texas
United States	University of Iowa Hospitals & Clinics	Iowa City	Iowa
United States	University of California San Diego Medical Center (La Jolla)	La Jolla	California
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	GLVA Healthcare Center	Los Angeles	California
United States	Kentuckiana Pulmonary Associates	Louisville	Kentucky
United States	University of Wisconsin Hospital-Department of Medicine	Madison	Wisconsin
United States	Froedtert Hospital - Medical College of Wisconsin	Milwaukee	Wisconsin
United States	St. Luke's Medical Center	Milwaukee	Wisconsin
United States	University of South Alabama	Mobile	Alabama
United States	Vanderbilt Medical Center	Nashville	Tennessee
United States	LSU Health Science Center - New Orleans	New Orleans	Louisiana
United States	Columbia University Medical Center, Pediatric Cardiology	New York	New York
United States	Lung Health & Sleep Emhancement Center, LLC	Newark	Delaware
United States	Newark Beth Isreal Medical Center-Department of Pulmonary Medicine	Newark	New Jersey
United States	Penn Presbyterian Medical Center	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Oregon Pulmonary Associates, PC	Portland	Oregon
United States	University of California, Davis, UC Davis Medical Center	Sacramento	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	LIU Center for Pulmonary Hypertension	Torrance	California
United States	Beaumont Hospital	Troy	Michigan
United States	The University of Arizona, Clinical and Translational Science (CATS) Research Center	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belarus,  Belgium,  Canada,  Chile,  China,  Colombia,  Czechia,  Denmark,  France,  Germany,  Greece,  Hungary,  India,  Ireland,  Israel,  Italy,  Korea, Republic of,  Malaysia,  Mexico,  Netherlands,  Peru,  Poland,  Romania,  Russian Federation,  Serbia,  Singapore,  Slovakia,  Spain,  Sweden,  Switzerland,  Taiwan,  Thailand,  Turkey,  Ukraine,  United Kingdom, 

References & Publications (1)

Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galiè N, Ghofrani HA, Hoeper MM, Lang IM, Preiss R, Rubin LJ, Di Scala L, Tapson V, Adzerikho I, Liu J, Moiseeva O, Zeng X, Simonneau G, McLaughlin VV; GRIPHON Investigators. Selexipag for the Treatment of P — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time From Randomization to the First Morbidity Event or Death (All Causes) up to 7 Days After the Last Study Drug Intake	Time from randomization to the first occurrence of a morbidity event or death (all causes) was analyzed with the Kaplan-Meier method (event-free KM estimates at different time points).; Morbidity event was defined as any of the following events confirmed by the Critical Event committee: Hospitalization for worsening of pulmonary arterial hypertension (PAH),; Worsening of PAH resulting in need for lung transplantation or balloon atrial septostomy,; Initiation of parenteral prostanoid therapy or chronic oxygen therapy due to worsening of PAH,; Disease progression which was defined by a decrease in 6-minute walk distance from baseline (>=15%, confirmed by a 2nd test on a different day) combined with worsening of WHO FC for patients belonging to WHO FC II/III at baseline, or combined with the need for additional PAH-specific therapy for patients belonging to WHO FC III/IV at baseline.; Note: The number of patients at risk decreased over time but this cannot be captured below	Up to 7 days after end of double-blind treatment (maximum: 4.3 years)
Secondary	Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD) at Trough	The 6-minute walk distance test (6MWD) 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. If the patient was used to taking bronchodilators before a walk, he/she was given them 5 to 30 min before the test. Also if the patient was on chronic oxygen therapy, oxygen was given at their standard rate during the test. Absolute change from baseline to Week 26 in 6MWD was measured at trough, i.e., either on the next day after the last study drug administration or at least 12 hours after study drug administration if on the same day.	Week 26
Secondary	Absence of Worsening From Baseline to Week 26 in Modified NYHA/WHO Functional Class (WHO FC)		Week 26