Clinical trial NCT01560624: Phase III Clinical Worsening Study of UT-15C in Subjects With PAH Receiving Background Oral Monotherapy
Official title: A Phase III, International, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Clinical Worsening Study of UT-15C in Subjects With Pulmonary Arterial Hypertension Receiving Background Oral Monotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Keywords: Pulmonary arterial hypertension (PAH)
Pulmonary hypertension (PH)
Clinical Worsening
Freedom
Freedom-EV
Treprostinil
UT-15C
6 Minute walk test
Lead sponsor: United Therapeutics
Sponsor class: INDUSTRY
First posted: 2012-03-22
Enrollment: 690
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is an international, multicenter, randomized, double-blind, placebo-controlled, event driven study in subjects with pulmonary arterial hypertension.

Detailed description: Study TDE-PH-310 is an international, multicenter, randomized (1:1 oral treprostinil (UT-15C): placebo), double-blind, placebo-controlled study in subjects with pulmonary arterial hypertension (PAH) who are receiving background oral monotherapy for PAH for at least 30 days at randomization. Subjects are randomly allocated to receive oral treprostinil extended-release tablets or placebo by a stratified randomization by type of background therapy (Strata 1: phosphodiesterase type 5 inhibitor \[PDE5-I\] or soluble guanylate cyclase \[sGC\] stimulator; Strata 2: endothelin receptor antagonist \[ERA\]. Subjects are also stratified by baseline 6-minute walk distance (6MWD) less than or equal to 350 m or greater than 350 m. Subjects receive their first dose of study drug (0.125 mg) or matching placebo on the day of randomization. Oral dosing of study drug is continued at 0.125 mg 3 times daily (TID; every 6 to 8 hours) with food. The dose (or matching placebo) is titrated throughout the study up to a maximum dose of 12 mg TID to reach and maintain a tolerated dosing regimen that provided optimal clinical benefit. Once randomized, subjects return for study visits every 4 weeks for the first 12 weeks, then every 12 weeks for the duration of the study. Subjects continue in the study until experiencing clinical worsening, the number of adjudicated events necessary for study closure occurr, or prematurely discontinue participation in the study for any reason other than protocol-specified clinical worsening. At each scheduled visit, subjects undergo efficacy assessments for clinical worsening, exercise capacity (6MWD and Borg dyspnea score), WHO functional class (FC), and plasma N-Terminal pro-brain natriuretic peptide (NT-proBNP). Subjects could participate in an optional hemodynamic sub-study (assessed by RHC). Safety assessments consist of adverse events (AEs), physical examinations, vital signs, 12-lead electrocardiograms (ECGs), and clinical laboratory parameters. Patients who complete all required assessments are eligible to enter a long-term, open-label, extension study (TDE-PH-311).

Eligibility criteria: Subject Inclusion Criteria:

1. Voluntarily gave informed consent to participate in the study.
2. Are 18 to 75 years of age (inclusive) at Screening.
3. Women of childbearing potential must practice abstinence from intercourse when in line with their preferred and usual lifestyle, or use 2 different forms of highly effective contraception for the duration of the study, and for at least 30 days after discontinuing study medication. A negative urine pregnancy test is required at Screening and Baseline prior to initiating study medication.
4. Male subjects must consent to use a condom during intercourse for the duration of the study, and for at least 48 hours after discontinuing study medication.
5. Have a diagnosis of symptomatic idiopathic or heritable PAH, PAH associated with connective tissue disease (CTD), PAH associated with HIV infection, PAH associated with repaired congenital systemic-to-pulmonary shunt, or PAH associated with appetite suppressant or toxin use.
6. If known to be positive for HIV infection, have a CD4 lymphocyte count of at least 200 cells/mm\^3 assessed at Screening and are receiving current standard of care anti retroviral or other effective medication for the treatment of HIV infection.
7. Have a baseline 6MWD greater than or equal to 150 m in the absence of a concurrent injury, illness, or other confounding factor including, but not limited to, use of an aid for ambulation or connection to a nonportable machine, that would have prevented the accurate assessment of the subject's exercise capacity.
8. Are optimally treated with conventional pulmonary hypertension therapy with no additions, discontinuations, or dose changes for a minimum of 10 days prior to randomization. The exceptions are the discontinuation or dose changes of anticoagulants and/or dose change of diuretics.
9. Are receiving a PAH-approved oral monotherapy at a minimum dose that complies with the approved prescribing information for the product for at least 30 days prior to randomization and are receiving a stable dose for at least 10 days prior to randomization.
10. Have had previously undergone a cardiac catheterization within 3 years prior to the start of Screening or during the Screening Period, and the most recent assessment documented a pulmonary artery pressure mean of at least 25 mmHg, a pulmonary capillary wedge pressure (PCWP) (or in the event a PCWP could not be reliably obtained, a left ventricular end diastolic pressure \[LVEDP\]) less than or equal to 15 mmHg, and absence of unrepaired congenital heart disease (other than patent foramen ovale). If a reliable PCWP or LVEDP are unable to be obtained during cardiac catheterization, subjects with clinically normal left heart function and absence of clinically relevant mitral valve disease on echocardiography are eligible for enrollment.
11. Undergo echocardiography with evidence of clinically normal systolic and diastolic left ventricular function and absence of any clinically significant left sided heart disease (eg, mitral valve disease). Subjects with clinically insignificant left ventricular diastolic dysfunction due to the effects of right ventricular overload (ie, right ventricular hypertrophy and/or dilatation) are eligible.
12. Have a previous ventilation perfusion lung scan, high-resolution computerized tomography scan of the chest, and/or pulmonary angiography that are consistent with the diagnosis of PAH.
13. Have pulmonary function tests conducted within 6 months before Screening or during the Screening Period to confirm the following:

    1. Total lung capacity is at least 60%
    2. Forced expiratory volume at 1 second is at least 50%
14. In the opinion of the Principal Investigator, is able to communicate effectively with study personnel and is considered reliable, willing, and likely to cooperate with protocol requirements, including attending all study visits.

Subject Exclusion Criteria:

1. Is pregnant or lactating.
2. Have previously received oral treprostinil.
3. Have received a PGI2 (except if used during acute vasoreactivity testing) within 30 days prior to randomization or have previous intolerance or significant lack of efficacy to any PGI2 or PGI2 analogue that resulted in discontinuation or inability to titrate that therapy effectively.
4. Have any background conventional therapies for PAH added, removed, or dose-adjusted within 10 days prior to randomization. The exceptions are removal or dose adjustments of anticoagulants and/or dose adjustments of diuretics.
5. Receive their first dose of a PAH-approved oral monotherapy less than 30 days prior to randomization, or have their PAH-approved oral monotherapy dose changed within 10 days prior to randomization, or the subject discontinues any PAH approved therapy within 30 days prior to Screening, or the subject has previously received 2 PAH approved oral therapies at the same time (specifically, a PDE5-I, an ERA, or a sGC stimulator) concomitantly for more than 90 days cumulatively.
6. Have any disease associated with PAH other than CTD, HIV infection, repaired (for at least 1 year) congenital systemic-to-pulmonary shunt, PAH associated with appetite suppressant/toxin use, or have an atrial septostomy.
7. Have a current diagnosis of uncontrolled sleep apnea as defined by their physician.
8. Have a history of ischemic heart disease, including a previous myocardial infarction or symptomatic coronary artery disease within 6 months prior to Screening or a history of left-sided myocardial disease as evidenced by a mean PCWP (or a LVEDP) greater than 15 mmHg or left ventricular ejection fraction less than 40% as assessed by either multigated angiogram, angiography, or echocardiography.
9. Have uncontrolled systemic hypertension as evidenced by systolic blood pressure (BP) greater than 160 mmHg or diastolic BP greater than 100 mmHg.
10. Have alanine aminotransferase or aspartate aminotransferase levels at least 3 times greater than the upper limit of normal, clinically significant liver disease/dysfunction, or known Child-Pugh Class C hepatic disease at Screening.
11. Have any other disease or condition that would interfere with the interpretation of study assessments.
12. Have a musculoskeletal disorder, is using a device to assist walking, or any disease that is likely to limit ambulation, or is connected to a machine that is nonportable.
13. Have an unstable psychiatric condition or is mentally incapable of understanding the objectives, nature, or consequences of the study, or has any condition which in the Investigator's opinion would constitute an unacceptable risk to the subject's safety.
14. Is receiving an investigational drug, have an investigational device in place, or have participated in an investigational drug or device study within 30 days prior to Screening.
15. Have chronic renal insufficiency as defined by either a Screening creatinine value greater than 2.5 mg/dL or the requirement for dialysis.
16. Does not have 3 or more of the following left ventricular disease/dysfunction risk factors:

    1. Body mass index at least 30 kg/m\^2
    2. History of essential hypertension
    3. Diabetes mellitus (any type)
    4. Historical evidence of significant coronary artery disease established by any 1 of the following: history of myocardial infarction, percutaneous coronary intervention, or angiographic evidence of coronary artery disease; positive stress test with imaging; previous coronary artery bypass graft; or stable angina.

Primary outcomes:
measure: Time to First Clinical Worsening Event
timeFrame: From randomization to approximately 4 years
Secondary outcomes:
measure: Change in 6-Minute Walk Distance
timeFrame: From Baseline to Week 24
measure: Change in Plasma N-Terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 24
timeFrame: From Baseline to Week 24
measure: Change in World Health Organization Functional Class (WHO FC) From Baseline to Week 48
timeFrame: Baseline to Week 48
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Arizona Pulmonary Specialists, Ltd.
state: Arizona
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Fresno
country: United States
facility: University of California, San Francisco-Fresno
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Sacramento
country: United States
facility: University of California-Davis Medical Group, Advanced Lung Disease/Transplant Program
state: California
city: Torrance
country: United States
facility: David Geffen School of Medicine
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Jacksonville
country: United States
facility: University of Florida College of Medicine Jacksonville- Division of Pulmonary & Critical Medicine
state: Florida
city: Jacksonville
country: United States
facility: University of Florida College of Medicine Jacksonville
state: Florida
city: Jacksonville
country: United States
facility: University of Florida College of Medicine, Jacksonville
state: Florida
city: Weston
country: United States
facility: Cleveland Clinic Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Augusta
country: United States
facility: Augusta University
state: Georgia
city: Austell
country: United States
facility: Piedmont - Georgia Lung Associates
state: Georgia
city: Peoria
country: United States
facility: HeartCare Midwest
state: Illinois
city: Carmel
country: United States
facility: Indiana University Hospital
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Louisville
country: United States
facility: Kentuckiana Pulmonary Associates
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Troy
country: United States
facility: Beaumont Health
state: Michigan
city: Omaha
country: United States
facility: Nebraska Medical Center
state: Nebraska
city: Newark
country: United States
facility: Newark Beth Israel Medical Center
state: New Jersey
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Asheville
country: United States
facility: Asheville Cardiology Associates
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: University Hospital
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Portland
country: United States
facility: Legacy Research Institute
state: Oregon
city: Philadelphia
country: United States
facility: Perelman Center for Advanced Medicine; University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center - Presbyterian Cardiovascular Institute
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Houston
country: United States
facility: The University of Texas Health Science Center at Houston
state: Texas
city: Norfolk
country: United States
facility: Sentara Cardiovascular Research Institute
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Milwaukee
country: United States
facility: Aurora Saint Luke's Medical Center
state: Wisconsin
city: Caba
country: Argentina
facility: Sanatorio San José
state: Buenos Aires
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires
state: Distrito Federal
city: Rosario
country: Argentina
facility: Hospital Italiano Garibaldi
state: Santa Fe
city: Buenos Aires
country: Argentina
facility: Sanatorio de la Trinidad Mitre
city: Santa Fe
country: Argentina
facility: Hospital Dr. José María Cullen
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Kingswood
country: Australia
facility: Nepean Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Saint Vincents Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Macquarie University
state: New South Wales
city: Chermside
country: Australia
facility: Prince Charles Hospital
state: Queensland
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Linz
country: Austria
facility: Krankenhaus Elisabethinen Linz
state: Upper Austria
city: Wien
country: Austria
facility: Medizinische Universität Wien
city: Goiania
country: Brazil
facility: Hospital das Clinicas da Universidade Federal de Goias
state: Goias
city: Belo Horizonte
country: Brazil
facility: Hospital das Clínicas da Universidade Federal de Minas Gerais
state: Minas Gerais
city: Belo Horizonte
country: Brazil
facility: Hospital Madre Teresa
state: Minas Gerais
city: Porto Alegre
country: Brazil
facility: Complexo Hospitalar Santa Casa de Porto Alegre
state: RIO Grande DO SUL
city: Botucatu
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina de Botucatu- UNESP
state: SAO Paulo
city: São Paulo
country: Brazil
facility: Hospital da Clínicas da Faculdade de Medicina da Universidade de São Paulo
state: SAO Paulo
city: São Paulo
country: Brazil
facility: Escola Paulista de Medicina, Universidade Federal de São Paulo
state: SAO Paulo
city: São Paulo
country: Brazil
facility: Hospital Alemão Oswaldo Cruz
city: Calgary
country: Canada
facility: Respiratory Research Foundation
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver Coastal Health
state: British Columbia
city: London
country: Canada
facility: Lawson Health Research Institute
state: Ontario
city: Santiago
country: Chile
facility: Centro de Investigaciones TASOL
state: Region Metropolitana
city: Vitacura
country: Chile
facility: Clínica Tabancura
state: Santiago
city: Beijing
country: China
facility: Beijing Chao-Yang Hospital
state: Beijing
city: Guangzhou
country: China
facility: Guangdong General Hospital
state: Guangdong
city: Wuhan
country: China
facility: Wuhan Asia Heart Hospital
state: Hubei
city: Changsha
country: China
facility: Xiangya Hospital
state: Hunan
city: Nanjing
country: China
facility: The First Affiliated Hospital of Nanjing Medical University
state: Jiangsu
city: Nanchang
country: China
facility: The Second Affiliated Hospital of Nanchang Medical University
state: Jiangxi
city: Shanghai
country: China
facility: Zhongshan Hospital Fudan University
state: Shanghai
city: Shanghai
country: China
facility: Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
state: Shanghai
city: Chengdu
country: China
facility: West China Hospital
state: Sichuan
city: Beijing
country: China
facility: Peking Union Medical College Hospital
city: Beijing
country: China
facility: Beijing Shijitan Hospital
city: Beijing
country: China
facility: Chinese PLA General Hospital
city: Qingdao
country: China
facility: The Affiliated Hospital of Qingdao University
city: Shanghai
country: China
facility: Renji Hospital of Shanghai Jiaotong University
city: Shanghai
country: China
facility: Shanghai Pulmonary Hospital of Tongji University
city: Shenyang
country: China
facility: Shenyang General Hospital of Shenyang Military Command
city: Aarhus
country: Denmark
facility: Aarhus Universitetshospital, Skejby
city: Copenhagen
country: Denmark
facility: Rigshospitalet-Copenhagen University Hospital
city: Pessac
country: France
facility: Hopital Haut-Leveque, CHU Bordeaux
state: Aquitaine
city: Besancon
country: France
facility: Hopital Jean Minjoz Centre Hospitalier Universitaire Besancon
state: Franche-comte
city: Montpellier Cedex 5
country: France
facility: CHU de Montpellier
state: Languedoc-roussillon
city: Vandoeuvre-Les-Nancy
country: France
facility: Hopital Brabois
state: Limousin, Lorraine
city: Lille
country: France
facility: Centre Hospitalier Régional Universitaire de Lille - Hôpital Claude Huriez
state: NORD Pas-de-calais
city: Marseille
country: France
facility: Centre Hospitalier Universitaire Hopital Nord
state: Provence Alpes COTE D'azur
city: Heidelberg
country: Germany
facility: Thoraxklinik am Universitätsklinikum Heidelberg
state: Baden-wuerttemberg
city: Munchen
country: Germany
facility: Ludwig-Maximilians-Universitat Munchen
state: Bayern
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
state: Bayern
city: Wurzburg
country: Germany
facility: Missionsarztliche Klinik Wurzburg gGmbH
state: Bayern
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald
state: Mecklenburg-vorpommern
city: Bochum
country: Germany
facility: Bergmannsheil Berufsgenossenschaftliche Universitätsklinik GmbH
state: Nordrhein-westfalen
city: Duisburg
country: Germany
facility: Herzzentrum Duisburg
state: Nordrhein-westfalen
city: Köln
country: Germany
facility: Universitätsklinikum Köln
state: Nordrhein-westfalen
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg Universität
state: Rheinland-pfalz
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes
state: Saarland
city: Dresden
country: Germany
facility: Technische Universität Dresden
state: Sachsen
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
state: Sachsen
city: Hamburg
country: Germany
facility: Universitätskrankenhaus Hamburg-Eppendorf
city: Sachsen
country: Germany
facility: Technische Universität Dresden
city: Athens
country: Greece
facility: University General Hospital of Attikon
state: Attica
city: Thessaloniki
country: Greece
facility: General Hospital of Thessaloniki, "G.Papanikolaou"
state: Macedoni
city: Hyderabad
country: India
facility: CARE Hospital
state: Andhra Pradesh
city: Hyderabad
country: India
facility: Mediciti Hospital
state: Andhra Pradesh
city: New Delhi
country: India
facility: Sir Ganga Ram Hospital
state: Delhi
city: New Delhi
country: India
facility: Indraprastha Apollo Hospital
state: Delhi
city: Ahmedabad
country: India
facility: Care Institute Medical Sciences
state: Gujarat
city: Gandhinagar
country: India
facility: Apollo Hospitals International, Ltd.
state: Gujarat
city: Gurgaon
country: India
facility: Medanta - The Medicity
state: Haryana
city: Bangalore
country: India
facility: Narayana Institute of Cardiac Sciences
state: Karnataka
city: Mumbai
country: India
facility: KEM Hospital
state: Maharashtra
city: Pune
country: India
facility: Ruby Hall Clinic
state: Maharashtra
city: Chennai
country: India
facility: Apollo Hospital
state: Tamil NADU
city: Coimbatore
country: India
facility: G. Kuppuswamy Naidu Memorial Hospital
state: Tamil NADU
city: Petach Tikvah
country: Israel
facility: Rabin Medical Center
state: Petah Tiqwa
city: Tel Hashomer
country: Israel
facility: The Chaim Sheba Medical Center at Tel Hashomer
state: Tel Aviv
city: Haifa
country: Israel
facility: Rambam Health Corp.
city: Haifa
country: Israel
facility: Carmel Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria
city: Palermo
country: Italy
facility: Istituto Mediterraneo Trapianti e Terapia Alta Specializzazione (ISMETT)
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico S. Matteo
city: Roma
country: Italy
facility: Azienda Policlinico Umberto I di Roma
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Tlalpan
country: Mexico
facility: Instituto Nacional de Cardiologia Ignacio Chavez
state: Distrito Federal
city: Monterrey
country: Mexico
facility: Unidad de Investigacion Clinica en Medicina S.C.
state: Nuevo LEON
city: Nijmegen
country: Netherlands
facility: Universitair Medisch Centrum Sint Radboud
state: Gelderland
city: Amsterdam
country: Netherlands
facility: Vrije Universiteit Medisch Centrum
state: Noord-holland
city: Bialystok
country: Poland
facility: Uniwersytecki Szpital Kliniczny w Bialymstoku
city: Krakow
country: Poland
facility: Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im K. Marcinkowskiego w Poznaniu
city: Malogoskie
country: Poland
facility: Krakowski Szpital Specjalistyczny im. Jana Pawla II
city: Otwock
country: Poland
facility: Europejskie Centrum Zdrowia Otwock, Szpital im. Fryderyka Chopina
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: National Heart Centre Singapore
city: Göteborg
country: Sweden
facility: Sahlgrenska University Hospital
state: Vastra Gotaland
city: Stockholm
country: Sweden
facility: Karolinska University Hospital Solna
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
state: Tainan CITY
city: Kaohsiung
country: Taiwan
facility: Veterans General Hospital-Kaohsiung
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Papworth Everard
country: United Kingdom
facility: Papworth Hospital
state: Cambridgshire
city: London
country: United Kingdom
facility: Royal Free Hospital
state: England
city: Newcastle upon Tyne
country: United Kingdom
facility: Freeman Hospital
state: England
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
state: England
Study officials:
affiliation: Mary M. Parkes Center
name: James White, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: White RJ, Jerjes-Sanchez C, Bohns Meyer GM, Pulido T, Sepulveda P, Wang KY, Grunig E, Hiremath S, Yu Z, Gangcheng Z, Yip WLJ, Zhang S, Khan A, Deng CQ, Grover R, Tapson VF; FREEDOM-EV Investigators. Combination Therapy with Oral Treprostinil for Pulmonary Arterial Hypertension. A Double-Blind Placebo-controlled Clinical Trial. Am J Respir Crit Care Med. 2020 Mar 15;201(6):707-717. doi: 10.1164/rccm.201908-1640OC.