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

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

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Placebo; Drug: Treprostinil Diolamine

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).

• Study Type: Interventional
• Enrollment (Actual): 690
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Sanatorio de la Trinidad Mitre
  • Santa Fe, Argentina, S3000EOY
    • Hospital Dr. Jose Maria Cullen
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1425DUH
      • Sanatorio San Jose
  • Distrito Federal
    • Ciudad Autónoma de Buenos Aires, Distrito Federal, Argentina, C1181ACH
      • Hospital Italiano de Buenos Aires
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2001OAD
      • Hospital Italiano Garibaldi
• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
    • Kingswood, New South Wales, Australia, 2751
      • Nepean Hospital
    • Sydney, New South Wales, Australia, 2109
      • Macquarie University
    • Sydney, New South Wales, Australia, 2010
      • Saint Vincents Hospital
  • Queensland
    • Chermside, Queensland, Australia, 4032
      • Prince Charles Hospital
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Royal Hobart Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hospital
    • Parkville, Victoria, Australia, 3052
      • Royal Melbourne Hospital
• Austria
  • Wien, Austria, 1090
    • Medizinische Universität Wien
  • Upper Austria
    • Linz, Upper Austria, Austria, 4020
      • Krankenhaus Elisabethinen Linz
• Brazil
  • São Paulo, Brazil, 01323-020
    • Hospital Alemao Oswaldo Cruz
  • Goias
    • Goiania, Goias, Brazil, 74605-050
      • Hospital das Clínicas da Universidade Federal de Goiás
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30130-100
      • Hospital das Clinicas da Universidade Federal de Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30380-090
      • Hospital Madre Teresa
  • RIO Grande DO SUL
    • Porto Alegre, RIO Grande DO SUL, Brazil, 90020-090
      • Complexo Hospitalar Santa Casa de Porto Alegre
  • SAO Paulo
    • Botucatu, SAO Paulo, Brazil, 18618-970
      • Hospital das Clínicas da Faculdade de Medicina de Botucatu- UNESP
    • São Paulo, SAO Paulo, Brazil, 05403-000
      • Hospital da Clinicas da Faculdade de Medicina da Universidade de São Paulo
    • São Paulo, SAO Paulo, Brazil
      • Escola Paulista de Medicina, Universidade Federal de São Paulo
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T1Y 6J4
      • Respiratory Research Foundation
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Vancouver Coastal Health
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • Lawson Health Research Institute
• Chile
  • Region Metropolitana
    • Santiago, Region Metropolitana, Chile, 7500710
      • Centro de Investigaciones TASOL
  • Santiago
    • Vitacura, Santiago, Chile, 7650018
      • Clinica Tabancura
• China
  • Beijing, China, 100853
    • Chinese PLA General Hospital
  • Beijing, China, 100038
    • Beijing Shijitan Hospital
  • Beijing, China, 100005
    • Peking Union Medical College Hospital
  • Qingdao, China, 26603
    • The Affiliated Hospital of Qingdao University
  • Shanghai, China, 200001
    • Renji Hospital of Shanghai Jiaotong University
  • Shanghai, China, 200433
    • Shanghai Pulmonary Hospital of Tongji University
  • Shenyang, China, 110015
    • Shenyang general hospital of Shenyang military command
  • Beijing
    • Beijing, Beijing, China, 100020
      • Beijing Chao-Yang Hospital
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • Guangdong General Hospital
  • Hubei
    • Wuhan, Hubei, China, 430022
      • Wuhan Asia Heart Hospital
  • Hunan
    • Changsha, Hunan, China, 410008
      • Xiangya Hospital
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • The First Affiliated Hospital of Nanjing Medical University
  • Jiangxi
    • Nanchang, Jiangxi, China, 330006
      • The Second Affiliated Hospital of Nanchang Medical University
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Zhongshan Hospital Fudan University
    • Shanghai, Shanghai, China, 200120
      • Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
  • Sichuan
    • Chengdu, Sichuan, China, 610047
      • West China Hospital
• Denmark
  • Aarhus, Denmark, 8200
    • Aarhus Universitetshospital, Skejby
  • Copenhagen, Denmark, 2100
    • Rigshospitalet-Copenhagen University Hospital
• France
  • Aquitaine
    • Pessac, Aquitaine, France, 33064
      • Hôpital Haut-Lévêque, CHU Bordeaux
  • Franche-comte
    • Besancon, Franche-comte, France, 25030
      • Hopital Jean Minjoz Centre Hospitalier Universitaire Besancon
  • Languedoc-roussillon
    • Montpellier Cedex 5, Languedoc-roussillon, France, 34295
      • CHU de Montpellier
  • Limousin, Lorraine
    • Vandoeuvre-Les-Nancy, Limousin, Lorraine, France, 54500
      • Hôpital Brabois
  • NORD Pas-de-calais
    • Lille, NORD Pas-de-calais, France, 59037
      • Centre Hospitalier Regional Universitaire de Lille - Hopital Claude Huriez
  • Provence Alpes COTE D'azur
    • Marseille, Provence Alpes COTE D'azur, France, 13015
      • Centre Hospitalier Universitaire Hôpital Nord
• Germany
  • Hamburg, Germany, 20246
    • Universitatskrankenhaus Hamburg-Eppendorf
  • Sachsen, Germany, 01307
    • Technische Universität Dresden
  • Baden-wuerttemberg
    • Heidelberg, Baden-wuerttemberg, Germany, 69126
      • Thoraxklinik am Universitätsklinikum Heidelberg
  • Bayern
    • Munchen, Bayern, Germany, 81377
      • Ludwig-Maximilians-Universität München
    • Regensburg, Bayern, Germany, 93053
      • Universitätsklinikum Regensburg
    • Wurzburg, Bayern, Germany, 97074
      • Missionsarztliche Klinik Wurzburg gGmbH
  • Mecklenburg-vorpommern
    • Greifswald, Mecklenburg-vorpommern, Germany, 17475
      • Universitätsmedizin Greifswald
  • Nordrhein-westfalen
    • Bochum, Nordrhein-westfalen, Germany, 44789
      • Bergmannsheil Berufsgenossenschaftliche Universitätsklinik GmbH
    • Duisburg, Nordrhein-westfalen, Germany, 47137
      • Herzzentrum Duisburg
    • Köln, Nordrhein-westfalen, Germany, 50937
      • Universitatsklinikum Koln
  • Rheinland-pfalz
    • Mainz, Rheinland-pfalz, Germany, 55131
      • Universitätsmedizin der Johannes Gutenberg Universität
  • Saarland
    • Homburg, Saarland, Germany, 66424
      • Universitätsklinikum des Saarlandes
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • Technische Universität Dresden
    • Leipzig, Sachsen, Germany, 04103
      • Universitätsklinikum Leipzig
• Greece
  • Attica
    • Athens, Attica, Greece, 12462
      • University General Hospital of Attikon
  • Macedoni
    • Thessaloniki, Macedoni, Greece, 57010
      • General Hospital of Thessaloniki, "G.Papanikolaou"
• India
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500 063
      • Mediciti Hospital
    • Hyderabad, Andhra Pradesh, India, 500 001
      • Care Hospital
  • Delhi
    • New Delhi, Delhi, India, 110060
      • Sir Ganga Ram Hospital
    • New Delhi, Delhi, India, 110076
      • Indraprastha Apollo Hospital
  • Gujarat
    • Ahmedabad, Gujarat, India, 38006
      • Care Institute Medical Sciences
    • Gandhinagar, Gujarat, India, 382428
      • Apollo Hospitals International, Ltd.
  • Haryana
    • Gurgaon, Haryana, India, 122 001
      • Medanta - The Medicity
  • Karnataka
    • Bangalore, Karnataka, India, 560 099
      • Narayana Institute of Cardiac Sciences
  • Maharashtra
    • Mumbai, Maharashtra, India, 400012
      • KEM hospital
    • Pune, Maharashtra, India, 411 001
      • Ruby Hall Clinic
  • Tamil NADU
    • Chennai, Tamil NADU, India, 600006
      • Apollo Hospital
    • Coimbatore, Tamil NADU, India, 641037
      • G. Kuppuswamy Naidu Memorial Hospital
• Israel
  • Haifa, Israel, 34362
    • Carmel Medical Center
  • Haifa, Israel, 31096
    • Rambam Health Corp.
  • Jerusalem, Israel, 91120
    • Hadassah Medical Center
  • Petah Tiqwa
    • Petach Tikvah, Petah Tiqwa, Israel, 49100
      • Rabin Medical Center
  • Tel Aviv
    • Tel Hashomer, Tel Aviv, Israel, 52621
      • The Chaim Sheba Medical Center at Tel HaShomer
• Italy
  • Napoli, Italy
    • Azienda Ospedaliera Universitaria
  • Palermo, Italy, 90127
    • Istituto Mediterraneo Trapianti e Terapia Alta Specializzazione (ISMETT)
  • Pavia, Italy, 27100
    • Fondazione IRCCS Policlinico S. Matteo
  • Roma, Italy, 00161
    • Azienda Policlinico Umberto I di Roma
• Korea, Republic of
  • Incheon, Korea, Republic of, 405-760
    • Gachon University Gil Medical Center
  • Seoul, Korea, Republic of, 135-710
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center
  • Seoul, Korea, Republic of, 110-744
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 120-752
    • Severance Hospital, Yonsei University Health System
• Mexico
  • Distrito Federal
    • Tlalpan, Distrito Federal, Mexico, 14080
      • Instituto Nacional de Cardiologia Ignacio Chavez
  • Nuevo LEON
    • Monterrey, Nuevo LEON, Mexico, 64718
      • Unidad de Investigacion Clinica en Medicina S.C.
• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Universitair Medisch Centrum Sint Radboud
  • Noord-holland
    • Amsterdam, Noord-holland, Netherlands, 1081 HV
      • Vrije Universiteit Medisch Centrum
• Poland
  • Bialystok, Poland, 15276
    • Uniwersytecki Szpital Kliniczny w Bialymstoku
  • Krakow, Poland, 61848
    • Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im K. Marcinkowskiego w Poznaniu
  • Malogoskie, Poland, 31202
    • Krakowski Szpital Specjalistyczny im. Jana Pawla II
  • Otwock, Poland
    • Europejskie Centrum Zdrowia Otwock, Szpital im. Fryderyka Chopina
• Singapore
  • Singapore, Singapore, 119228
    • National University Hospital
  • Singapore, Singapore, 168 752
    • National Heart Centre Singapore
• Sweden
  • Stockholm, Sweden, 171 76
    • Karolinska University Hospital Solna
  • Vastra Gotaland
    • Göteborg, Vastra Gotaland, Sweden, 413 45
      • Sahlgrenska University Hospital
• Taiwan
  • Kaohsiung, Taiwan, 81362
    • Veterans General Hospital-Kaohsiung
  • Taichung, Taiwan, 40705
    • Taichung Veterans General Hospital
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital
  • Tainan CITY
    • Tainan, Tainan CITY, Taiwan, 70403
      • National Cheng Kung University Hospital
• United Kingdom
  • Cambridgshire
    • Papworth Everard, Cambridgshire, United Kingdom, CB3 8RE
      • Papworth Hospital
  • England
    • London, England, United Kingdom, NW3 2QG
      • Royal Free Hospital
    • Newcastle upon Tyne, England, United Kingdom, NE7 7DN
      • Freeman Hospital
    • Sheffield, England, United Kingdom, S10 2JF
      • Royal Hallamshire Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85012
      • Arizona Pulmonary Specialists, Ltd.
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • Fresno, California, United States, 93721
      • University of California, San Francisco-Fresno
    • Los Angeles, California, United States, 90211
      • Cedars-Sinai Medical Center
    • Sacramento, California, United States, 95817
      • University of California-Davis Medical Group, Advanced Lung Disease/Transplant Program
    • Torrance, California, United States, 90502
      • David Geffen School of Medicine
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida College of Medicine Jacksonville
    • Jacksonville, Florida, United States, 32209
      • University of Florida College of Medicine, Jacksonville
    • Jacksonville, Florida, United States, 32209
      • University of Florida College of Medicine Jacksonville- Division of Pulmonary & Critical Medicine
    • Weston, Florida, United States, 33331
      • Cleveland Clinic Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
    • Augusta, Georgia, United States, 30912
      • Augusta University
    • Austell, Georgia, United States, 30106
      • Piedmont - Georgia Lung Associates
  • Illinois
    • Peoria, Illinois, United States, 61614
      • HeartCare Midwest
  • Indiana
    • Carmel, Indiana, United States, 46032
      • Indiana University Hospital
  • Iowa
    • Iowa City, Iowa, United States, 55242
      • University of Iowa Hospitals and Clinics
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kentuckiana Pulmonary Associates
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
    • Troy, Michigan, United States, 48085
      • Beaumont Health
  • Nebraska
    • Omaha, Nebraska, United States, 68198-5990
      • Nebraska Medical Center
  • New Jersey
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Asheville, North Carolina, United States, 28803
      • Asheville Cardiology Associates
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0564
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44106
      • University Hospital
    • Columbus, Ohio, United States, 43321
      • The Ohio State University
  • Oregon
    • Portland, Oregon, United States, 97210
      • Legacy Research Institute
    • Portland, Oregon, United States, 97201-3098
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Perelman Center for Advanced Medicine; University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center - Presbyterian Cardiovascular Institute
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas Health Science Center at Houston
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Sentara Cardiovascular Research Institute
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Aurora Saint Luke's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: UT-15C; Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID	Drug: Treprostinil Diolamine; Active; Other Names: UT--15C
PLACEBO_COMPARATOR: Placebo; Matching placebo tablets (oral)	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 6-Minute Walk Distance	The intent of the 6-Minute Walk Test (6MWT) is to evaluate exercise capacity associated with carrying out activities of daily living. A baseline 6MWT was performed prior to initiation of study drug on the day of randomization. 6MWTs were conducted at Weeks 4, 8, 12, 24, and every 12 weeks thereafter. The change between Baseline and Week 24 is reported.	From Baseline to Week 24
Change in Plasma N-Terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 24	Plasma NT-proBNP concentration is a useful biomarker for the severity of PAH as it is associated with changes in right heart morphology and function. NT-proBNP sample collection occurred at Baseline (prior to starting study drug), Week 12, Week 24, the first Continued Visit, and every other Continued Visit thereafter (ie, Continued Visits 3, 5, 7, etc). NT-proBNP was also assessed at the Study Drug Termination Visit. The change between Baseline and Week 24 is reported.	From Baseline to Week 24
Change in World Health Organization Functional Class (WHO FC) From Baseline to Week 48	The WHO FC for PAH was assessed at Baseline prior to starting study drug, at all subsequent scheduled study visits, and every time the 6MWT was performed for purposes of assessing clinical worsening status.	Baseline to Week 48

Collaborators and Investigators

• Sponsor: United Therapeutics
• Investigators: Principal Investigator: James White, MD, PhD, Mary M. Parkes Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 26, 2012
• Primary Completion (ACTUAL): June 24, 2018
• Study Completion (ACTUAL): June 24, 2018

Study Registration Dates

• First Submitted: March 9, 2012
• First Submitted That Met QC Criteria: March 21, 2012
• First Posted (ESTIMATE): March 22, 2012

Study Record Updates

• Last Update Posted (ACTUAL): February 13, 2020
• Last Update Submitted That Met QC Criteria: February 12, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Treprostinil; Pulmonary hypertension (PH); Pulmonary arterial hypertension (PAH); Clinical Worsening; Freedom; Freedom-EV; UT-15C; 6 Minute walk test
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Antihypertensive Agents; Treprostinil
• Other Study ID Numbers: TDE-PH-310

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No