A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients

Hypertension Clinical Trial

Official title:

A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Ralinepag When Added to PAH Standard of Care or PAH Specific Background Therapy in Subjects With WHO Group 1 PAH

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03626688
• Other study ID #: ROR-PH-301
• Secondary ID: APD811-301
• Status: Recruiting
• Phase: Phase 3
• Start date: August 30, 2018
• Est. completion date: December 2024

Study information

• Verified date: March 2024
• Source: United Therapeutics
• Contact: United Therapeutics Global Medical Information
• Phone: 919-485-8350
• Email: clinicaltrials[@]unither.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Study ROR-PH-301, ADVANCE OUTCOMES, is designed to assess the efficacy and safety of ralinepag when added to pulmonary arterial hypertension (PAH) standard of care or PAH-specific background therapy in subjects with World Health Organization (WHO) Group 1 PAH.

Description:

Study ROR-PH-301 is a multicenter, randomized, double-blind, placebo-controlled study. Subjects who meet entry criteria will be randomly allocated 1:1 to receive ralinepag or placebo, in addition to their standard of care or PAH-specific background therapy, as applicable. The primary endpoint is the time (in days) from randomization to the first adjudicated protocol-defined clinical worsening event. All primary endpoint events will be adjudicated by an independent Clinical Event Committee (CEC) in a blinded fashion. Subjects who have a confirmed primary endpoint event adjudicated by the CEC at any time during the study and all subjects on treatment at the conclusion of the study who have completed the Week 28 Visit (after the target number of confirmed events is achieved) will have the option to enroll in an open-label extension (OLE) study. Subjects who do not choose to participate in the OLE study will discontinue study drug and should remain in the study for long-term follow-up of survival status and will receive standard of care PAH treatment, at the discretion of the treating physician.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1000
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. At least 18 years of age.

2. Evidence of a personally signed and dated informed consent form indicating that the subject has been informed of all pertinent aspects of the study prior to initiation of any study-related procedures.

3. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures

4. Primary diagnosis of symptomatic PAH.

5. Has had a right heart catheterization (RHC) performed at or within 3 years prior to Screening (RHC will be performed during Screening if not available) that is consistent with the diagnosis of PAH.

6. Has WHO/ NYHA functional class II to IV symptoms.

7. If on PAH-specific background oral therapy, subject is on stable therapy with either an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 inhibitor (PDE5-I) or a soluble guanylate cyclase (sGC) stimulator.

8. Has a 6MWD of =150 meters.

9. If taking concomitant medications that may affect the clinical manifestations of PAH (eg, calcium channel blockers, diuretics, digoxin, or L arginine supplementation, beta blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers), must be on a stable dose for at least 30 days prior to the Baseline Visit and the dosage maintained throughout the study. The exception is that the dose of diuretics must be stable for at least the 10 days prior to Baseline.

10. Both male and female subjects agree to use a highly effective method of birth control throughout the entire study period from informed consent through to the 30-Day Follow-up Visit, if the possibility of conception exists. Eligible male and female subjects must also agree not to participate in a conception process during the study and for 30 days after the last dose of IMP. Eligible male subjects must agree not to participate in sperm donation for 90 days after the last dose of IMP.

Exclusion Criteria:

1. For subjects with known HIV-associated PAH, a cluster designation 4 (CD4+) T-cell count <200/mm3 within 90 days of Baseline.

2. Must not have 3 or more left ventricular dysfunction risk factors as defined in the study protocol.

3. Has evidence of more than mild lung disease on pulmonary function tests performed within 180 days prior to, or during Screening.

4. Has evidence of thromboembolic disease as determined by a V/Q lung scan or local standard of care diagnostic evaluation at or after diagnosis of PAH.

5. Current diagnosis of ongoing and clinically significant sleep apnea as defined by the Investigator.

6. Male subjects with a corrected QT interval using Fridericia's formula (QTcF) >450 msec and female subjects with a QTcF >470 msec on ECG recorded at Screening and analyzed by the central ECG laboratory. Subjects with evidence of intraventricular conduction delay, defined as a QRS interval greater than 110 msec, will be excluded if the QTcF is >500 msec for both males and females.

7. Severe chronic liver disease (ie, Child-Pugh Class C), portal hypertension, cirrhosis or complications of cirrhosis/portal hypertension (eg, history of variceal hemorrhage, encephalopathy).

8. Confirmed active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).

9. Subjects with alanine aminotransferase or aspartate aminotransferase =3 times the upper limit of normal (ULN) or total bilirubin =2 × ULN at Screening.

10. Chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL or requiring dialysis at Screening.

11. Hemoglobin concentration <9 g/dL at Screening.

12. Subjects treated with an IV or SC prostacyclin pathway agent (eg, epoprostenol, treprostinil, or iloprost) for PAH at any time prior to Baseline (use in vasoreactive testing is permitted).

13. Subjects currently on or who were treated with an inhaled or oral prostacyclin pathway agent (iloprost, treprostinil, beraprost, or selexipag) for >6 months or within 90 days prior to Baseline.

14. Subject has pulmonary veno-occlusive disease.

15. Malignancy diagnosed and/or treated within 5 years prior to Screening, with the exception of localized non-metastatic basal cell or squamous cell carcinoma of the skin or in-situ carcinoma of the cervix excised with curative intent.

16. Subject tests positive for amphetamine, cocaine, methamphetamine, methylenedioxymethamphetamine or phencyclidine in urine drug screen performed at Screening, or has a recent history (6 months) of alcohol or drug abuse. A subject will not be excluded due to a positive drug screen caused by prescribed medications.

17. Initiation or discontinuation of a cardio-pulmonary rehabilitation program based upon exercise within 90 days prior to Screening and/or planned during study participation.

18. Prior participation in any study of ralinepag or participation in another interventional clinical study with medicinal products within 30 days prior to Screening. Concurrent participation in registry or observational studies is allowed, as long as the subject can fulfill all other entry criteria and comply with all study procedures.

19. Any reason that, in the opinion of the Investigator or Medical Monitor, precludes the subject from participating in the study (eg, any previous or intercurrent medical condition) that may increase the risk associated with study participation or that would confound study analysis or impair study participation or cooperation.

20. Known hypersensitivity to ralinepag or any of the excipients.

21. Life expectancy <12 months based on the Investigator's opinion.

22. Women who are pregnant, lactating or breast-feeding.

Related Conditions & MeSH terms

• Cardiovascular Diseases
• Connective Tissue Diseases
• Familial Primary Pulmonary Hypertension
• Hypertension
• Hypertension, Pulmonary
• Lung Diseases
• PAH
• Pulmonary Arterial Hypertension
• Pulmonary Hypertension
• Respiratory Tract Disease
• Respiratory Tract Diseases
• Vascular Diseases

Intervention

Drug:
• Ralinepag
Active
• Placebo
Placebo

Locations

Country	Name	City	State
Argentina	Sanatorio de la Trinidad Mitre	Buenos Aires
Argentina	Cardiologia Palmero	Caba
Argentina	Fundacion Favaloro	Ciudad Autonoma Buenos Aires
Argentina	Fundacion Respirar	Ciudad Autonoma Buenos Aires
Argentina	Hospital Britanico de Buenos Aires	Ciudad Autonoma Buenos Aires
Argentina	Hospital Italiano	Ciudad Autonoma Buenos Aires	Buenos Aires
Argentina	Hospital Italiano de Cordoba	Cordoba
Argentina	Hospital Privado Centro Medico de Cordoba S.A	Cordoba
Argentina	Instituto de Cardiologia de Corrientes	Corrientes
Argentina	Instituto de Investigaciones Clinicas Mar del Plata	Mar Del Plata	Buenos Aires
Argentina	Sanatorio Parque S.A.	Rosario	Santa Fe
Argentina	Hospital PROVINCIAL "Dr. Jose Maria Cullen"	Santa Fe
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	The Prince Charles Hospital	Chermside	Queensland
Australia	St Vincent's Hospital Sydney	Darlinghurst	New South Wales
Australia	St Vincent's Hospital Melbourne	Fitzroy	Victoria
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Nepean Hospital	Kingswood	New South Wales
Australia	Macquarie University	Macquarie	New South Wales
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Australia	Westmead Hospital	Sydney	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Austria	Medizinische Universität Innsbruck	Innsbruck
Austria	Ordensklinikum Linz GmbH - Elisabethinen, Fadingerstrasse 1	Linz
Austria	AKH Wien, Innere Med. II, Kardiologie, Währingergürtel 18-20	Vienna
Belgium	Cliniques Universitaires de Bruxelles Hopital Erasme	Bruxelles
Belgium	UZ Leuven, UZ Leuven Campus Gasthuisberg, Herestraat 49	Leuven
Brazil	Instituto das Pequenas Missionárias de Maria Imaculada - Hospital Madre Teresa	Belo Horizonte	MG
Brazil	UNESP-Faculdade de Medicina da Universidade Estadual Paulista Campus Botucatu	Botucatu	Sao Paulo
Brazil	HC-UFG - Hospital das Clínicas da Universidade Federal de Goiás	Goiânia	Goias
Brazil	Hospital Sao Lucas da PUC-RS	Porto Alegre	R.S
Brazil	Irmandade da Santa Casa de Misericórdia de Porto Alegre	Porto Alegre	RS
Brazil	Hospital Sao Paulo	Sao Paulo	SP
Brazil	Instituto do Coracao	Sao Paulo	SP
Bulgaria	MHAT "Sveta Anna" Sofia AD	Sofia
Bulgaria	MHAT - "National Heart Hospital" EAD, 65, Konyovitza Str.	Sofia
Canada	Peter Lougheed Centre	Calgary	Alberta
Canada	LHSC - Victoria Hospital	London	Ontario
Canada	SMBD Jewish General Hospital d/b/a Jewish General Hospital	Montreal	Quebec
Canada	Institut Universitaire de Cardiologie et de Pneumologie de Quebec	Québec	Quebec
Canada	University Health Network-Toronto General Hospital	Toronto	Ontario
Chile	Instiuto Nacional del Torax	Providencia	Santiago De Chile
China	Beijing Shijitan Hospital, Capital Medical University	Beijing	Beijing
China	Fuwai Hospital, Chinese Academy of Medical Sciences	Beijing
China	Xiangya Hospital Central South University	Changsha	Hunan
China	Guangdong Provincial People's Hospital	Guangzhou	Guangdong
China	Shanghai Pulmonary Hospital	Shanghai	Shanghai
China	Fuwai Central China Cardiovascular Hospital	Zhengzhou
Croatia	Clinical Hospital Dubrava Zagreb, Avenija G.Šuška 6	Zagreb
Croatia	University Clinic for Pulmonary Diseases, Jordanovac 104	Zagreb
Czechia	Vseobecna fakultni nemocnice v Praze, II. interni klinika kardiologie a angiologie VFN a 1. LF UK, U nemocnice 2	Praha 2
Denmark	Århus Universitetshospital	Århus
Denmark	Copenhagen University Hospital (Rigshospitalet)	Copenhagen
France	CHU Besançon - Hôpital Jean Minjoz	Besançon Cedex
France	CHU de Brest - Hôpital de la Cavale Blanche	Brest cedex 2
France	CHU Lyon - Hôpital Cardio-Vasculaire et Pneumologique Louis Pradel, Service de Pneumologie, 59 Boulevard Pinel	Bron cedex	Rhone
France	CHU de Grenoble - Hôpital Albert Michallon, Clinique de Cardiologie, Boulevrad de la Chantourne	Grenoble	Isere
France	Groupement Hospitalier Sud - Hôpital Bicêtre	Le Kremlin-Bicêtre	Val De Marne
France	CHRU de Lille - Hopital Cardiologique	Lille Cedex
France	Hôpital Nord - CHU Marseille	Marseille
France	CHU de Rouen - Hôpital Charles Nicolle	Rouen cedex	Seine Maritime
France	CHU de Saint-Etienne - Hopital Nord, Service de Medecine vasculaire et therapeutique, 81 Avenue A. Raimond	Saint-Étienne	Loire
France	CHU de Strasbourg - Nouvel Hôpital Civil, Ctre de competence Hypertension Arterielle Pulmona, 1 place de l Hopital	Strasbourg	Bas Rhin
France	CHU Nancy - Hôpital de Brabois Adultes, Pneumologie- Oncologie Médicale, Rue du Morvan	Vandoeuvre les Nancy	Meurthe Et Moselle
Germany	Schwarzwald-Baar Klinikum	Donaueschingen
Germany	Universitaetsklinikum Carl Gustav Carus TU Dresden	Dresden
Germany	Universitätsmedizin Greifswald	Greifswald	Mecklenburg-Vorpommern
Germany	Universitaetsklinikum Hamburg-Eppendorf	Hamburg
Germany	Thoraxklinik-Heidelberg Zentrum für Pulmonale Hypertonie	Heidelberg	Baden-Württemberg
Germany	Universitaetsklinikum des Saarlandes, Innere Medizin V, IMED, Kirrberger Strasse 100, Gebäude 41	Homburg	Saarland
Germany	Universitätsklinikum Leipzig, Medizinische Klinik II, Pneumologie	Leipzig	Sachsen
Germany	Universitaetsmedizin der Johannes-Gutenberg-Universitaet Mainz, Zentrum für Kardiologie I, Centrum für Thrombose und Hämostase (CTH), Langenbeckstrasse 1	Mainz	Rheinland Pfalz
Greece	University General Hospital of Alexandroupolis	Alexandroupolis
Greece	"Onasseio" Cardiosurgery Hospital, Hemodynamic Research and Interventional Cardiology Dept., 356, Syggrou Avenue	Athens	Kallithea
Greece	University General Hospital Attikon	Chaidari
Greece	AHEPA General Hospital of Thessaloniki, A' Cardiology Clinic, 1 St. Kyriakidi Street	Thessaloniki
Hungary	Gottsegen György Országos Kardiovaszkuláris Intézet	Budapest
Hungary	Pecsi Tudomanyegyetem, Szivgyogyaszati Klinika, Ifjusag u. 13.	Pecs
Hungary	Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ Családorvosi Intézet és Rendelo	Szeged	Csongrád-Csanád
Israel	The Lady Davis Carmel Medical Center, 7 Michal st.	Haifa
Israel	Hadassah Ein Kerem Medical Center, Kiryat Hadassah	Jerusalem
Israel	Meir Medical Center, 59 Tshernichovski st.	Kfar- Sava
Israel	Rabin Medical Center-Beilinson Campus, Pulmonary Institute, 39 Jabotinsky St Ground floor	Petach Tikva
Israel	Tel Aviv Sourasky Medical Center, 6 Weizmann St.	Tel Aviv
Italy	Azienda Ospedaliero Universitaria Ospedali Riuniti di Foggia, S.C. di Cardiologia, Viale Luigi Pinto, 1	Foggia
Italy	IRCC Ospedale Policlinico San Martino	Genova
Italy	Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35	Milano
Italy	Azienda Socio Sanitaria Territoriale di Monza (Presidio San Gerardo)	Monza
Italy	Istituto Mediterraneo Trapianti e Terapie a Alta Specializzazione (IRCCS-ISMETT)	Palermo	PA
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Italy	Azienda Ospedaliera Universitaria Policlinico Umberto I - Università di Roma La Sapienza, Viale del Policlinico, 155	Roma
Korea, Republic of	Gachon University Hospital Gil Medical Center	Incheon	Namdong-gu
Korea, Republic of	Samsung Medical Center	Seoul	Gangnam-gu
Korea, Republic of	Seoul National University Hospital	Seoul	Jongno-gu
Mexico	CICUM San Miguel	Guadalajara	Jalisco
Mexico	Instituto Nacional de Cardiologia Dr Ignacio Chavez Rivera	Mexico	Distrito Federal
Mexico	Instituto Nacional de Ciencias Médicas y Nutricion Dr. Salvador Zubiran	Mexico	Distrito Federal
Mexico	Unidad de Investigacion Clinica en Medicina, S.C.	Monterrey	N.l.
Netherlands	VU Medisch Centrum, De Boelelaan 1117	Amsterdam
Poland	Uniwersytecki Szpital Kliniczny w Bialymstoku, Klinika Kardiologii z Oddzialem Intensywnego Nazdoru Kardiologicznego, M. Sklodowskiej 24a	Bialystok
Poland	Krakowski Szpital Specjalistyczny im. Jana Pawla II, Oddzial Kliniczny Chorób Serca i Naczyn z Pododdzialem Intensywnego Nadzoru Kardiologicznego, Pradnicka 80	Krakow
Poland	NZOZ Europejskie Centrum Zdrowia, ul. Borowa 14/18	Otwock
Poland	Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu, Oddzial Kardiologii - F, ul. Dluga 1/2	Poznan
Poland	Premium Clinic Wroclaw CM, Podwale 83/17	Wroclaw
Portugal	Hospital Garcia de Orta, E.P.E	Almada
Portugal	Centro Hospitalar e Universitário de Coimbra, E.P.E.	Coimbra
Portugal	Centro Hospitalar Universitário Lisboa Norte, E.P.E. Hospital Pulido Valente	Lisboa
Portugal	Centro Hospitalar de Santo António E.P.E.	Porto
Romania	Institutul de Urgenta pentru Boli Cardiovasculare "Prof. Dr. C.C. Iliescu", Sos. Fundeni nr. 258	Bucharest
Romania	Institutul de Pneumoftiziologie "Marius Nasta", Sos. Viilor nr. 90, Sector 5	Bucuresti
Romania	Institutul Inimii "Niculae Stancioiu" Cluj-Napoca, Cardiologie, Str. Motilor nr. 19-21	Cluj-Napoca
Romania	Spitalul Clinic de Boli Infectioase si Pneumoftiziologie "Dr. Victor Babes" Timisoara, Str. Gheorghe Adam nr. 13	Timisoara
Serbia	Clinical Center of Serbia, Koste Todorovica 8	Belgrade
Serbia	Clinical Center Zemun. Clinic for internal medicine, Department of Cardiology	Belgrade
Serbia	Institute for Pulmonary Diseases of Vojvodina, Put Dr Goldmana 4	Sremska Kamenica
Singapore	National Heart Centre	Singapore
Singapore	National University Hospital	Singapore
Spain	Hospital Clinic de Barcelona, C/ Villarroel, 170	Barcelona
Spain	Hospital Universitari Vall d'Hebron, Respiratory Dept., Passeig Vall d'Hebron,119-129, Neumologia	Barcelona
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospoital Universitari i Politecnic La Fe	Valencia
Sweden	Sahlgrenska Universitetssjukhuset	Göteborg
Sweden	Linköping Universitetssjukhuset	Linköping
Sweden	Norrlands Universitetssjukhus, Hjärtcentrum	Umeå
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	National Taiwan University Hospital	Taipei
Turkey	Balcali, Çukurova Üniversitesi Kardiyoloji ABD	Adana	Saricam
Turkey	Gazi University Medical Faculty Hospital	Ankara
Turkey	Uludag Universitesi Tip Fakültesi, Gorukle Kampusu	Bursa
Turkey	Osmangazi Uni Medical Faculty	Eskisehir	Odunpazari
Turkey	Marmara Universitesi Istanbul Pendik Egitim ve Arastirma Hastanesi, Fevzi Cakmak Mahallesi Muhsin Yazicioglu Cad. No: 10	Istanbul
Turkey	Dokuz Eylul Universitesi Tip Fakultesi, Mithatpasa caddesi Inciralti Balcova	Izmir
Turkey	Mersin Üniversitesi Tip Fakültesi Ciftlikköy Kampüsü	Mersin	Yenisehir
Ukraine	CE Dniprop RCC&C Center of Dniprop RC Dept of Card SI DMA of MOHU, Chair of Internal Medicine 3, 28, Knyazya Volodymyra Velykogo St.	Dnipro
Ukraine	SI F.H.Yanovskyi National Institute of Phthisiology and Pulmonology of NAMSU, Clinical and Functional Dept, 10, Amosova St.	Kyiv
Ukraine	Communal Noncommercial Enterprise of Lviv Regional Council Lviv Clinical Hospital, Dept of Cardiology, D.Halytskyi Lviv NMU, Ch of Internal Medicine #1, 7, Chernihivska str.	Lviv
United Kingdom	Golden Jubilee National Hospital	Glasgow	West Dunbartonshire
United Kingdom	Imperial College Healthcare NHS Trust	London
United Kingdom	Royal Brompton Hospital	London
United Kingdom	Royal Free London NHS Foundation Trust, Pond Street	London	Greater London
United Kingdom	The Newcastle upon Tyne Hospitals NHS Foundation Trust, Sir William Leech Lung Research Centre, Freeman Hospital	Newcastle upon Tyne	Tyne & Wear
United States	University of New Mexico	Albuquerque	New Mexico
United States	Emory University Hospital	Atlanta	Georgia
United States	University of Colorado Hospital	Aurora	Colorado
United States	Piedmont Healthcare Pulmonary and Critical Care Research	Austell	Georgia
United States	Ascension Texas Cardiovascular	Austin	Texas
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Boston University Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	University of Virginia Medical Center	Charlottesville	Virginia
United States	University of Chicago Medical Center	Chicago	Illinois
United States	University of Cincinnati-Medical Science Building	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	Vermont Lung Center	Colchester	Vermont
United States	The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	UT Southwestern Medical Center	Dallas	Texas
United States	National Jewish Health	Denver	Colorado
United States	Duke University Medical Center	Durham	North Carolina
United States	Ascension Alexian Brothers	Elk Grove Village	Illinois
United States	University of Florida	Gainesville	Florida
United States	Spectrum Health Medical Group	Grand Rapids	Michigan
United States	East Carolina University	Greenville	North Carolina
United States	Memorial Hermann Hospital	Houston	Texas
United States	The Methodist Hospital Research Institute	Houston	Texas
United States	Community Health Network Cancer Center North	Indianapolis	Indiana
United States	Indiana University School of Medicine	Indianapolis	Indiana
United States	St. Vincent Medical Group, Inc.	Indianapolis	Indiana
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	Mayo Clinic Florida	Jacksonville	Florida
United States	Statcare Pulmonary Consultants	Knoxville	Tennessee
United States	UCSD Health Sciences	La Jolla	California
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California
United States	Keck Hospital of USC	Los Angeles	California
United States	Ronald Reagan UCLA Medical Center	Los Angeles	California
United States	VA Greater Los Angeles Healthcare System	Los Angeles	California
United States	Kentuckiana Pulmonary Research Center	Louisville	Kentucky
United States	University of Miami	Miami	Florida
United States	Medical College of Wisconsin/Froedtert Hospital	Milwaukee	Wisconsin
United States	Winthrop Hospital	Mineola	New York
United States	Ochsner Medical Center	New Orleans	Louisiana
United States	Mount Sinai School of Medicine	New York	New York
United States	NYU Langone Medical Center	New York	New York
United States	Weill-Cornell-New York Presbyterian Hospital	New York	New York
United States	Sentara Cardiovascular Research Institute	Norfolk	Virginia
United States	Integris Baptist Medical Center	Oklahoma City	Oklahoma
United States	Nebraska Medical Center	Omaha	Nebraska
United States	University of California, Irvine	Orange	California
United States	AdventHealth Orlando	Orlando	Florida
United States	Central Florida Pulmonary Group	Orlando	Florida
United States	Temple University	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	St. Joseph's Hospital and Medical Center	Phoenix	Arizona
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	Oregon Clinic-Pulmonary West	Portland	Oregon
United States	Oregon Health & Science University	Portland	Oregon
United States	Carilion Clinic Pulmonary and Sleep Medicine	Roanoke	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	University of California Davis Medical Center	Sacramento	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	SBPA Research LLC	Santa Barbara	California
United States	Mayo Clinic Scottsdale	Scottsdale	Arizona
United States	Chest Medicine Associates	South Portland	Maine
United States	Stanford Healthcare	Stanford	California
United States	LA Biomedical Research Institute Harbor-UCLA Medical Center	Torrance	California
United States	University of Arizona	Tucson	Arizona
United States	Cleveland Clinic Florida	Weston	Florida

Sponsors (1)

Lead Sponsor	Collaborator
United Therapeutics

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Bulgaria,  Canada,  Chile,  China,  Croatia,  Czechia,  Denmark,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Korea, Republic of,  Mexico,  Netherlands,  Poland,  Portugal,  Romania,  Serbia,  Singapore,  Spain,  Sweden,  Taiwan,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time from randomization to the first adjudicated protocol-defined clinical worsening event	Clinical worsening events are defined as death, nonelective hospital admission for worsening PAH (further defined in clinical study protocol), initiation of parenteral or inhaled prostacyclin pathway agent for treatment of worsening PAH, disease progression (further defined in clinical study protocol), or unsatisfactory long-term clinical response (further defined in clinical study protocol).	The study duration was event-based. This parameter was assessed from randomization until the conclusion of the study, up to 3 years
Secondary	Change from Baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP)	NT-proBNP was measured at Baseline (prior to starting study drug) and Week 4, 8, 12, and 16, then every 12 weeks thereafter including the End of Study/Early Termination Visit.	Baseline to Week 28
Secondary	Change from Baseline in 6-minute walk distance (6MWD)	6MWD was measured at Baseline (prior to starting study drug) and Week 4, 8, 12, and 16, then every 12 weeks thereafter including the End of Study/Early Termination Visit.	Baseline to Week 28
Secondary	Change from Baseline in WHO/New York Heart Association (NYHA) Functional Class	The severity of PAH was graded according to the functional status of the subject and assessed at every visit.	Baseline to Week 28
Secondary	Shift and proportion of subjects who attain all 3 of the following: NT-proBNP level <300 pg/mL, 6MWD >440 meters, and WHO/NYHA Functional Class I or II	Data from NT-proBNP, 6MWD, and WHO/NYHA functional class assessment were compiled as a composite endpoint at visits through Week 28.	Baseline to Week 28
Secondary	Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) risk score	Data from NT-proBNP, 6MWD, WHO/NYHA functional class, systolic blood pressure, heart rate, and estimated glomerular filtration rate values collected at visits through Week 28 were used to calculate the composite REVEAL risk score.	Baseline to Week 28
Secondary	Clinical improvement as defined by the absence of clinical worsening and fulfillment of at least 2 of the 3 of the following: increase in 6MWD =10% or =30 m, improvement to or maintenance of WHO FC I or II, and decrease in NT-proBNP by at least 30%.	Data from 6MWD, WHO/NYHA functional class assessment, and NT-proBNP were compiled as a composite endpoint at visits through Week 28.	Baseline to Week 28
Secondary	Change from Baseline in health-related quality of life as measured by patient-reported outcomes.	Quality of life was assessed using patient-reported outcomes at Baseline (prior to starting study drug) and Week 16, then every 12 weeks thereafter including the End of Study/Early Termination Visit.	Baseline to Week 28
Secondary	Time to first all-cause nonelective hospitalization	All nonelective hopsitalizations during the study period were collected.	The study duration was event-based. This parameter was assessed from randomization until the conclusion of the study (when the target number of adjudicated events was achieved, as defined in the study protocol).
Secondary	Time to all-cause mortality	All deaths during the study period were collected.	The study duration was event-based. This parameter was assessed from randomization until the conclusion of the study (when the target number of adjudicated events was achieved, as defined in the study protocol).
Secondary	Change from Baseline in heart rate recovery (HRR) following completion of the 6MWT	HRR was measured at Baseline (prior to starting study drug) and Week 4, 8, 12, and 16, then every 12 weeks thereafter including the End of Study/Early Termination Visit.	Baseline to Week 28
Secondary	Safety and tolerability of ralinepag in subjects with PAH	Safety and tolerability were assessed by adverse events.	Baseline to Week 28