Phase III Clinical Worsening Study of UT-15C in Subjects With PAH Receiving Background Oral Monotherapy

Pulmonary Arterial Hypertension Clinical Trial

— FREEDOM-EV  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01560624
• Other study ID #: TDE-PH-310
• Status: Completed
• Phase: Phase 3
• Start date: June 26, 2012
• Est. completion date: June 24, 2018

Study information

• Verified date: February 2020
• Source: United Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 690
• Est. completion date: June 24, 2018
• Est. primary completion date: June 24, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• Treprostinil Diolamine
Active
• Placebo
Placebo

Locations

Country	Name	City	State
Argentina	Sanatorio de la Trinidad Mitre	Buenos Aires
Argentina	Sanatorio San José	Caba	Buenos Aires
Argentina	Hospital Italiano de Buenos Aires	Ciudad Autónoma de Buenos Aires	Distrito Federal
Argentina	Hospital Italiano Garibaldi	Rosario	Santa Fe
Argentina	Hospital Dr. José María Cullen	Santa Fe
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Prince Charles Hospital	Chermside	Queensland
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Nepean Hospital	Kingswood	New South Wales
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Macquarie University	Sydney	New South Wales
Australia	Saint Vincents Hospital	Sydney	New South Wales
Austria	Krankenhaus Elisabethinen Linz	Linz	Upper Austria
Austria	Medizinische Universität Wien	Wien
Brazil	Hospital das Clínicas da Universidade Federal de Minas Gerais	Belo Horizonte	Minas Gerais
Brazil	Hospital Madre Teresa	Belo Horizonte	Minas Gerais
Brazil	Hospital das Clínicas da Faculdade de Medicina de Botucatu- UNESP	Botucatu	SAO Paulo
Brazil	Hospital das Clinicas da Universidade Federal de Goias	Goiania	Goias
Brazil	Complexo Hospitalar Santa Casa de Porto Alegre	Porto Alegre	RIO Grande DO SUL
Brazil	Escola Paulista de Medicina, Universidade Federal de São Paulo	São Paulo	SAO Paulo
Brazil	Hospital Alemão Oswaldo Cruz	São Paulo
Brazil	Hospital da Clínicas da Faculdade de Medicina da Universidade de São Paulo	São Paulo	SAO Paulo
Canada	Respiratory Research Foundation	Calgary	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Lawson Health Research Institute	London	Ontario
Canada	Vancouver Coastal Health	Vancouver	British Columbia
Chile	Centro de Investigaciones TASOL	Santiago	Region Metropolitana
Chile	Clínica Tabancura	Vitacura	Santiago
China	Beijing Chao-Yang Hospital	Beijing	Beijing
China	Beijing Shijitan Hospital	Beijing
China	Chinese PLA General Hospital	Beijing
China	Peking Union Medical College Hospital	Beijing
China	Xiangya Hospital	Changsha	Hunan
China	West China Hospital	Chengdu	Sichuan
China	Guangdong General Hospital	Guangzhou	Guangdong
China	The Second Affiliated Hospital of Nanchang Medical University	Nanchang	Jiangxi
China	The First Affiliated Hospital of Nanjing Medical University	Nanjing	Jiangsu
China	The Affiliated Hospital of Qingdao University	Qingdao
China	Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine	Shanghai	Shanghai
China	Renji Hospital of Shanghai Jiaotong University	Shanghai
China	Shanghai Pulmonary Hospital of Tongji University	Shanghai
China	Zhongshan Hospital Fudan University	Shanghai	Shanghai
China	Shenyang General Hospital of Shenyang Military Command	Shenyang
China	Wuhan Asia Heart Hospital	Wuhan	Hubei
Denmark	Aarhus Universitetshospital, Skejby	Aarhus
Denmark	Rigshospitalet-Copenhagen University Hospital	Copenhagen
France	Hopital Jean Minjoz Centre Hospitalier Universitaire Besancon	Besancon	Franche-comte
France	Centre Hospitalier Régional Universitaire de Lille - Hôpital Claude Huriez	Lille	NORD Pas-de-calais
France	Centre Hospitalier Universitaire Hopital Nord	Marseille	Provence Alpes COTE D'azur
France	CHU de Montpellier	Montpellier Cedex 5	Languedoc-roussillon
France	Hopital Haut-Leveque, CHU Bordeaux	Pessac	Aquitaine
France	Hopital Brabois	Vandoeuvre-Les-Nancy	Limousin, Lorraine
Germany	Bergmannsheil Berufsgenossenschaftliche Universitätsklinik GmbH	Bochum	Nordrhein-westfalen
Germany	Technische Universität Dresden	Dresden	Sachsen
Germany	Herzzentrum Duisburg	Duisburg	Nordrhein-westfalen
Germany	Universitätsmedizin Greifswald	Greifswald	Mecklenburg-vorpommern
Germany	Universitätskrankenhaus Hamburg-Eppendorf	Hamburg
Germany	Thoraxklinik am Universitätsklinikum Heidelberg	Heidelberg	Baden-wuerttemberg
Germany	Universitätsklinikum des Saarlandes	Homburg	Saarland
Germany	Universitätsklinikum Köln	Köln	Nordrhein-westfalen
Germany	Universitätsklinikum Leipzig	Leipzig	Sachsen
Germany	Universitätsmedizin der Johannes Gutenberg Universität	Mainz	Rheinland-pfalz
Germany	Ludwig-Maximilians-Universitat Munchen	Munchen	Bayern
Germany	Universitätsklinikum Regensburg	Regensburg	Bayern
Germany	Technische Universität Dresden	Sachsen
Germany	Missionsarztliche Klinik Wurzburg gGmbH	Wurzburg	Bayern
Greece	University General Hospital of Attikon	Athens	Attica
Greece	General Hospital of Thessaloniki, "G.Papanikolaou"	Thessaloniki	Macedoni
India	Care Institute Medical Sciences	Ahmedabad	Gujarat
India	Narayana Institute of Cardiac Sciences	Bangalore	Karnataka
India	Apollo Hospital	Chennai	Tamil NADU
India	G. Kuppuswamy Naidu Memorial Hospital	Coimbatore	Tamil NADU
India	Apollo Hospitals International, Ltd.	Gandhinagar	Gujarat
India	Medanta - The Medicity	Gurgaon	Haryana
India	CARE Hospital	Hyderabad	Andhra Pradesh
India	Mediciti Hospital	Hyderabad	Andhra Pradesh
India	KEM Hospital	Mumbai	Maharashtra
India	Indraprastha Apollo Hospital	New Delhi	Delhi
India	Sir Ganga Ram Hospital	New Delhi	Delhi
India	Ruby Hall Clinic	Pune	Maharashtra
Israel	Carmel Medical Center	Haifa
Israel	Rambam Health Corp.	Haifa
Israel	Hadassah Medical Center	Jerusalem
Israel	Rabin Medical Center	Petach Tikvah	Petah Tiqwa
Israel	The Chaim Sheba Medical Center at Tel Hashomer	Tel Hashomer	Tel Aviv
Italy	Azienda Ospedaliera Universitaria	Napoli
Italy	Istituto Mediterraneo Trapianti e Terapia Alta Specializzazione (ISMETT)	Palermo
Italy	Fondazione IRCCS Policlinico S. Matteo	Pavia
Italy	Azienda Policlinico Umberto I di Roma	Roma
Korea, Republic of	Gachon University Gil Medical Center	Incheon
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Mexico	Unidad de Investigacion Clinica en Medicina S.C.	Monterrey	Nuevo LEON
Mexico	Instituto Nacional de Cardiologia Ignacio Chavez	Tlalpan	Distrito Federal
Netherlands	Vrije Universiteit Medisch Centrum	Amsterdam	Noord-holland
Netherlands	Universitair Medisch Centrum Sint Radboud	Nijmegen	Gelderland
Poland	Uniwersytecki Szpital Kliniczny w Bialymstoku	Bialystok
Poland	Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im K. Marcinkowskiego w Poznaniu	Krakow
Poland	Krakowski Szpital Specjalistyczny im. Jana Pawla II	Malogoskie
Poland	Europejskie Centrum Zdrowia Otwock, Szpital im. Fryderyka Chopina	Otwock
Singapore	National Heart Centre Singapore	Singapore
Singapore	National University Hospital	Singapore
Sweden	Sahlgrenska University Hospital	Göteborg	Vastra Gotaland
Sweden	Karolinska University Hospital Solna	Stockholm
Taiwan	Veterans General Hospital-Kaohsiung	Kaohsiung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Cheng Kung University Hospital	Tainan	Tainan CITY
Taiwan	National Taiwan University Hospital	Taipei
United Kingdom	Royal Free Hospital	London	England
United Kingdom	Freeman Hospital	Newcastle upon Tyne	England
United Kingdom	Papworth Hospital	Papworth Everard	Cambridgshire
United Kingdom	Royal Hallamshire Hospital	Sheffield	England
United States	Asheville Cardiology Associates	Asheville	North Carolina
United States	Emory University Hospital	Atlanta	Georgia
United States	Augusta University	Augusta	Georgia
United States	University of Colorado Hospital	Aurora	Colorado
United States	Piedmont - Georgia Lung Associates	Austell	Georgia
United States	University of Maryland	Baltimore	Maryland
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Indiana University Hospital	Carmel	Indiana
United States	University of Cincinnati	Cincinnati	Ohio
United States	University Hospital	Cleveland	Ohio
United States	The Ohio State University	Columbus	Ohio
United States	Henry Ford Health System	Detroit	Michigan
United States	University of California, San Francisco-Fresno	Fresno	California
United States	University of Florida	Gainesville	Florida
United States	The University of Texas Health Science Center at Houston	Houston	Texas
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of Florida College of Medicine Jacksonville	Jacksonville	Florida
United States	University of Florida College of Medicine Jacksonville- Division of Pulmonary & Critical Medicine	Jacksonville	Florida
United States	University of Florida College of Medicine, Jacksonville	Jacksonville	Florida
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Kentuckiana Pulmonary Associates	Louisville	Kentucky
United States	Aurora Saint Luke's Medical Center	Milwaukee	Wisconsin
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Sentara Cardiovascular Research Institute	Norfolk	Virginia
United States	Nebraska Medical Center	Omaha	Nebraska
United States	HeartCare Midwest	Peoria	Illinois
United States	Perelman Center for Advanced Medicine; University of Pennsylvania	Philadelphia	Pennsylvania
United States	Arizona Pulmonary Specialists, Ltd.	Phoenix	Arizona
United States	University of Pittsburgh Medical Center - Presbyterian Cardiovascular Institute	Pittsburgh	Pennsylvania
United States	Legacy Research Institute	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Virginia Commonwealth University	Richmond	Virginia
United States	University of Rochester	Rochester	New York
United States	University of California-Davis Medical Group, Advanced Lung Disease/Transplant Program	Sacramento	California
United States	David Geffen School of Medicine	Torrance	California
United States	Beaumont Health	Troy	Michigan
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,  Brazil,  Canada,  Chile,  China,  Denmark,  France,  Germany,  Greece,  India,  Israel,  Italy,  Korea, Republic of,  Mexico,  Netherlands,  Poland,  Singapore,  Sweden,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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