Phase III Clinical Worsening Study of UT-15C in Subjects With PAH Receiving Background Oral Monotherapy
FREEDOM-EV
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
1 other identifier
interventional
690
22 countries
153
Brief Summary
This is an international, multicenter, randomized, double-blind, placebo-controlled, event driven study in subjects with pulmonary arterial hypertension.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3
Started Jun 2012
Longer than P75 for phase_3
153 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
March 9, 2012
CompletedFirst Posted
Study publicly available on registry
March 22, 2012
CompletedStudy Start
First participant enrolled
June 26, 2012
CompletedPrimary Completion
Last participant's last visit for primary outcome
June 24, 2018
CompletedStudy Completion
Last participant's last visit for all outcomes
June 24, 2018
CompletedResults Posted
Study results publicly available
February 13, 2020
CompletedFebruary 13, 2020
February 1, 2020
6 years
March 9, 2012
November 20, 2019
February 12, 2020
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Time to First Clinical Worsening Event
Clinical worsening was assessed continuously from randomization until the subject's last study visit. Clinical worsening events were defined as death (all causes), hospitalizations due to worsening pulmonary arterial hypertension (PAH), initiation of an inhaled or infused prostacyclin (PGI2) for the treatment of worsening PAH, disease progression, or unsatisfactory long-term clinical response. All clinical worsening events reported by the study sites were reviewed by the Sponsor Medical Monitors. Once a clinical worsening event occurred, it was entered in the eCRF and a narrative was submitted for review by the Sponsor's Medical Monitor within 48 hours after the event became known to the Investigator or designee. Subsequently, the narratives for subjects with the reported clinical worsening events were sent to an independent adjudication committee. The independent adjudication committee reviewed and adjudicated all clinical worsening events throughout the study.
From randomization to approximately 4 years
Secondary Outcomes (3)
Change in 6-Minute Walk Distance
From Baseline to Week 24
Change in Plasma N-Terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 24
From Baseline to Week 24
Change in World Health Organization Functional Class (WHO FC) From Baseline to Week 48
Baseline to Week 48
Study Arms (2)
UT-15C
EXPERIMENTALTreprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID
Placebo
PLACEBO COMPARATORMatching placebo tablets (oral)
Interventions
Eligibility Criteria
You may qualify if:
- Voluntarily gave informed consent to participate in the study.
- Are 18 to 75 years of age (inclusive) at Screening.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Have pulmonary function tests conducted within 6 months before Screening or during the Screening Period to confirm the following:
- Total lung capacity is at least 60%
- Forced expiratory volume at 1 second is at least 50%
- +1 more criteria
You may not qualify if:
- Is pregnant or lactating.
- Have previously received oral treprostinil.
- 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.
- 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.
- 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.
- 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.
- Have a current diagnosis of uncontrolled sleep apnea as defined by their physician.
- 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.
- Have uncontrolled systemic hypertension as evidenced by systolic blood pressure (BP) greater than 160 mmHg or diastolic BP greater than 100 mmHg.
- 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.
- Have any other disease or condition that would interfere with the interpretation of study assessments.
- 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.
- 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.
- 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.
- Have chronic renal insufficiency as defined by either a Screening creatinine value greater than 2.5 mg/dL or the requirement for dialysis.
- +5 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (155)
Arizona Pulmonary Specialists, Ltd.
Phoenix, Arizona, 85012, United States
University of Arizona
Tucson, Arizona, 85724, United States
University of California, San Francisco-Fresno
Fresno, California, 93721, United States
Cedars-Sinai Medical Center
Los Angeles, California, 90211, United States
University of California-Davis Medical Group, Advanced Lung Disease/Transplant Program
Sacramento, California, 95817, United States
David Geffen School of Medicine
Torrance, California, 90502, United States
University of Colorado Hospital
Aurora, Colorado, 80045, United States
University of Florida
Gainesville, Florida, 32610, United States
University of Florida College of Medicine Jacksonville- Division of Pulmonary & Critical Medicine
Jacksonville, Florida, 32209, United States
University of Florida College of Medicine Jacksonville
Jacksonville, Florida, 32209, United States
University of Florida College of Medicine, Jacksonville
Jacksonville, Florida, 32209, United States
Cleveland Clinic Florida
Weston, Florida, 33331, United States
Emory University Hospital
Atlanta, Georgia, 30322, United States
Augusta University
Augusta, Georgia, 30912, United States
Piedmont - Georgia Lung Associates
Austell, Georgia, 30106, United States
HeartCare Midwest
Peoria, Illinois, 61614, United States
Indiana University Hospital
Carmel, Indiana, 46032, United States
University of Iowa Hospitals and Clinics
Iowa City, Iowa, 55242, United States
Kentuckiana Pulmonary Associates
Louisville, Kentucky, 40202, United States
University of Maryland
Baltimore, Maryland, 21201, United States
Tufts Medical Center
Boston, Massachusetts, 02111, United States
Massachusetts General Hospital
Boston, Massachusetts, 02114, United States
Henry Ford Health System
Detroit, Michigan, 48202, United States
Beaumont Health
Troy, Michigan, 48085, United States
Nebraska Medical Center
Omaha, Nebraska, 68198-5990, United States
Newark Beth Israel Medical Center
Newark, New Jersey, 07112, United States
University of Rochester
Rochester, New York, 14642, United States
Asheville Cardiology Associates
Asheville, North Carolina, 28803, United States
University of Cincinnati
Cincinnati, Ohio, 45267-0564, United States
University Hospital
Cleveland, Ohio, 44106, United States
The Ohio State University
Columbus, Ohio, 43321, United States
Oregon Health and Science University
Portland, Oregon, 97201-3098, United States
Legacy Research Institute
Portland, Oregon, 97210, United States
Perelman Center for Advanced Medicine; University of Pennsylvania
Philadelphia, Pennsylvania, 19104, United States
University of Pittsburgh Medical Center - Presbyterian Cardiovascular Institute
Pittsburgh, Pennsylvania, 15213, United States
Rhode Island Hospital
Providence, Rhode Island, 02903, United States
The University of Texas Health Science Center at Houston
Houston, Texas, 77030, United States
Sentara Cardiovascular Research Institute
Norfolk, Virginia, 23507, United States
Virginia Commonwealth University
Richmond, Virginia, 23298, United States
Aurora Saint Luke's Medical Center
Milwaukee, Wisconsin, 53215, United States
Sanatorio San José
CABA, Buenos Aires, C1425DUH, Argentina
Hospital Italiano de Buenos Aires
Buenos Aires, Distrito Federal, C1181ACH, Argentina
Hospital Italiano Garibaldi
Rosario, Santa Fe Province, S2001OAD, Argentina
Sanatorio de la Trinidad Mitre
Buenos Aires, Argentina
Hospital Dr. José María Cullen
Santa Fe, S3000EOY, Argentina
Royal Prince Alfred Hospital
Camperdown, New South Wales, 2050, Australia
Nepean Hospital
Kingswood, New South Wales, 2751, Australia
Saint Vincents Hospital
Sydney, New South Wales, 2010, Australia
Macquarie University
Sydney, New South Wales, 2109, Australia
Prince Charles Hospital
Chermside, Queensland, 4032, Australia
Royal Hobart Hospital
Hobart, Tasmania, 7000, Australia
The Alfred Hospital
Melbourne, Victoria, 3004, Australia
Royal Melbourne Hospital
Parkville, Victoria, 3052, Australia
Krankenhaus Elisabethinen Linz
Linz, Upper Austria, 4020, Austria
Medizinische Universität Wien
Vienna, 1090, Austria
Hospital das Clinicas da Universidade Federal de Goias
Goiânia, Goiás, 74605-050, Brazil
Hospital das Clínicas da Universidade Federal de Minas Gerais
Belo Horizonte, Minas Gerais, 30130-100, Brazil
Hospital Madre Teresa
Belo Horizonte, Minas Gerais, 30380-090, Brazil
Complexo Hospitalar Santa Casa de Porto Alegre
Porto Alegre, Rio Grande do Sul, 90020-090, Brazil
Hospital das Clínicas da Faculdade de Medicina de Botucatu- UNESP
Botucatu, São Paulo, 18618-970, Brazil
Hospital da Clínicas da Faculdade de Medicina da Universidade de São Paulo
São Paulo, São Paulo, 05403-000, Brazil
Escola Paulista de Medicina, Universidade Federal de São Paulo
São Paulo, São Paulo, Brazil
Hospital Alemão Oswaldo Cruz
São Paulo, 01323-020, Brazil
Respiratory Research Foundation
Calgary, Alberta, T1Y 6J4, Canada
University of Alberta Hospital
Edmonton, Alberta, T6G 2B7, Canada
Vancouver Coastal Health
Vancouver, British Columbia, V5Z 1M9, Canada
Lawson Health Research Institute
London, Ontario, N6A 5A5, Canada
Centro de Investigaciones TASOL
Santiago, Santiago Metropolitan, 7500710, Chile
Clínica Tabancura
Vitacura, Santiago Metropolitan, 7650018, Chile
Beijing Chao-Yang Hospital
Beijing, Beijing Municipality, 100020, China
Guangdong General Hospital
Guangzhou, Guangdong, 510080, China
Wuhan Asia Heart Hospital
Wuhan, Hubei, 430022, China
Xiangya Hospital
Changsha, Hunan, 410008, China
The First Affiliated Hospital of Nanjing Medical University
Nanjing, Jiangsu, 210029, China
The Second Affiliated Hospital of Nanchang Medical University
Nanchang, Jiangxi, 330006, China
Zhongshan Hospital Fudan University
Shanghai, Shanghai Municipality, 200032, China
Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Shanghai, Shanghai Municipality, 200120, China
West China Hospital
Chengdu, Sichuan, 610047, China
Peking Union Medical College Hospital
Beijing, 100005, China
Beijing Shijitan Hospital
Beijing, 100038, China
Chinese PLA General Hospital
Beijing, 100853, China
The Affiliated Hospital of Qingdao University
Qingdao, 26603, China
Renji Hospital of Shanghai Jiaotong University
Shanghai, 200001, China
Shanghai Pulmonary Hospital of Tongji University
Shanghai, 200433, China
Shenyang General Hospital of Shenyang Military Command
Shenyang, 110015, China
Aarhus Universitetshospital, Skejby
Aarhus, 8200, Denmark
Rigshospitalet-Copenhagen University Hospital
Copenhagen, 2100, Denmark
Hopital Haut-Leveque, CHU Bordeaux
Pessac, Aquitaine, 33064, France
Hopital Jean Minjoz Centre Hospitalier Universitaire Besancon
Besançon, Franche-comte, 25030, France
Centre Hospitalier Régional Universitaire de Lille - Hôpital Claude Huriez
Lille, Hauts-de-France, 59037, France
CHU de Montpellier
Montpellier, Languedoc-roussillon, 34295, France
Hopital Brabois
Vandœuvre-lès-Nancy, Limousin, Lorraine, 54500, France
Centre Hospitalier Universitaire Hopital Nord
Marseille, Provence-Alpes-Côte d'Azur Region, 13015, France
Thoraxklinik am Universitätsklinikum Heidelberg
Heidelberg, Baden-Wurttemberg, 69126, Germany
Ludwig-Maximilians-Universitat Munchen
München, Bavaria, 81377, Germany
Universitätsklinikum Regensburg
Regensburg, Bavaria, 93053, Germany
Missionsarztliche Klinik Wurzburg gGmbH
Würzburg, Bavaria, 97074, Germany
Universitätsmedizin Greifswald
Greifswald, Mecklenburg-Vorpommern, 17475, Germany
Bergmannsheil Berufsgenossenschaftliche Universitätsklinik GmbH
Bochum, North Rhine-Westphalia, 44789, Germany
Universitätsklinikum Köln
Cologne, North Rhine-Westphalia, 50937, Germany
Herzzentrum Duisburg
Duisburg, North Rhine-Westphalia, 47137, Germany
Universitätsmedizin der Johannes Gutenberg Universität
Mainz, Rhineland-Palatinate, 55131, Germany
Universitätsklinikum des Saarlandes
Homburg, Saarland, 66424, Germany
Technische Universität Dresden
Dresden, Saxony, 01307, Germany
Universitätsklinikum Leipzig
Leipzig, Saxony, 04103, Germany
Universitätskrankenhaus Hamburg-Eppendorf
Hamburg, 20246, Germany
Technische Universität Dresden
Sachsen, 01307, Germany
University General Hospital of Attikon
Athens, Attica, 12462, Greece
General Hospital of Thessaloniki, "G.Papanikolaou"
Thessaloniki, Macedoni, 57010, Greece
CARE Hospital
Hyderabad, Andhra Pradesh, 500 001, India
Mediciti Hospital
Hyderabad, Andhra Pradesh, 500 063, India
Care Institute Medical Sciences
Ahmedabad, Gujarat, 38006, India
Apollo Hospitals International, Ltd.
Gandhinagar, Gujarat, 382428, India
Medanta - The Medicity
Gurgaon, Haryana, 122 001, India
Narayana Institute of Cardiac Sciences
Bangalore, Karnataka, 560 099, India
KEM Hospital
Mumbai, Maharashtra, 400012, India
Ruby Hall Clinic
Pune, Maharashtra, 411 001, India
Sir Ganga Ram Hospital
New Delhi, National Capital Territory of Delhi, 110060, India
Indraprastha Apollo Hospital
New Delhi, National Capital Territory of Delhi, 110076, India
Apollo Hospital
Chennai, Tamil Nadu, 600006, India
G. Kuppuswamy Naidu Memorial Hospital
Coimbatore, Tamil Nadu, 641037, India
Rabin Medical Center
Petach Tikvah, Petah Tiqwa, 49100, Israel
The Chaim Sheba Medical Center at Tel Hashomer
Tel Litwinsky, Tel Aviv, 52621, Israel
Rambam Health Corp.
Haifa, 31096, Israel
Carmel Medical Center
Haifa, 34362, Israel
Hadassah Medical Center
Jerusalem, 91120, Israel
Azienda Ospedaliera Universitaria
Napoli, Italy
Istituto Mediterraneo Trapianti e Terapia Alta Specializzazione (ISMETT)
Palermo, 90127, Italy
Fondazione IRCCS Policlinico S. Matteo
Pavia, 27100, Italy
Azienda Policlinico Umberto I di Roma
Roma, 00161, Italy
Instituto Nacional de Cardiologia Ignacio Chavez
Tlalpan, Mexico City, 14080, Mexico
Unidad de Investigacion Clinica en Medicina S.C.
Monterrey, Nuevo León, 64718, Mexico
Universitair Medisch Centrum Sint Radboud
Nijmegen, Gelderland, 6525 GA, Netherlands
Vrije Universiteit Medisch Centrum
Amsterdam, North Holland, 1081 HV, Netherlands
Uniwersytecki Szpital Kliniczny w Bialymstoku
Bialystok, 15276, Poland
Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im K. Marcinkowskiego w Poznaniu
Krakow, 61848, Poland
Krakowski Szpital Specjalistyczny im. Jana Pawla II
Małogoskie, 31202, Poland
Europejskie Centrum Zdrowia Otwock, Szpital im. Fryderyka Chopina
Otwock, Poland
National University Hospital
Singapore, 119228, Singapore
National Heart Centre Singapore
Singapore, 168 752, Singapore
Gachon University Gil Medical Center
Incheon, 405-760, South Korea
Seoul National University Hospital
Seoul, 110-744, South Korea
Severance Hospital, Yonsei University Health System
Seoul, 120-752, South Korea
Samsung Medical Center
Seoul, 135-710, South Korea
Asan Medical Center
Seoul, 138-736, South Korea
Sahlgrenska University Hospital
Gothenburg, Västra Götaland County, 413 45, Sweden
Karolinska University Hospital Solna
Stockholm, 171 76, Sweden
National Cheng Kung University Hospital
Tainan, Tainan CITY, 70403, Taiwan
Veterans General Hospital-Kaohsiung
Kaohsiung City, 81362, Taiwan
Taichung Veterans General Hospital
Taichung, 40705, Taiwan
National Taiwan University Hospital
Taipei, 10002, Taiwan
Papworth Hospital
Papworth Everard, Cambridgshire, CB3 8RE, United Kingdom
Royal Free Hospital
London, England, NW3 2QG, United Kingdom
Freeman Hospital
Newcastle upon Tyne, England, NE7 7DN, United Kingdom
Royal Hallamshire Hospital
Sheffield, England, S10 2JF, United Kingdom
Related Publications (1)
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.
PMID: 31765604DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Results Point of Contact
- Title
- Louis Holdstock
- Organization
- United Therapeutics
Study Officials
- PRINCIPAL INVESTIGATOR
James White, MD, PhD
Mary M. Parkes Center
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
March 9, 2012
First Posted
March 22, 2012
Study Start
June 26, 2012
Primary Completion
June 24, 2018
Study Completion
June 24, 2018
Last Updated
February 13, 2020
Results First Posted
February 13, 2020
Record last verified: 2020-02