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

NCT ID: NCT01560624

Last Updated: 2020-02-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 690 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-06-26
• Study Completion Date: 2018-06-24

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).

Conditions

Pulmonary Arterial Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

UT-15C

Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID

Group Type: EXPERIMENTAL

Treprostinil Diolamine

Intervention Type: DRUG

Active

Placebo

Matching placebo tablets (oral)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo

Interventions

Treprostinil Diolamine

Active

Intervention Type: DRUG

Placebo

Placebo

Intervention Type: DRUG

Other Intervention Names

UT--15C

Eligibility Criteria

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.

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

United Therapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

James White, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Mary M. Parkes Center

Locations

Arizona Pulmonary Specialists, Ltd.

Phoenix, Arizona, United States

University of Arizona

Tucson, Arizona, United States

University of California, San Francisco-Fresno

Fresno, California, United States

Cedars-Sinai Medical Center

Los Angeles, California, 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

University of Colorado Hospital

Aurora, Colorado, United States

University of Florida

Gainesville, 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

University of Florida College of Medicine, Jacksonville

Jacksonville, Florida, United States

Cleveland Clinic Florida

Weston, Florida, United States

Emory University Hospital

Atlanta, Georgia, United States

Augusta University

Augusta, Georgia, United States

Piedmont - Georgia Lung Associates

Austell, Georgia, United States

HeartCare Midwest

Peoria, Illinois, United States

Indiana University Hospital

Carmel, Indiana, United States

University of Iowa Hospitals and Clinics

Iowa City, Iowa, United States

Kentuckiana Pulmonary Associates

Louisville, Kentucky, United States

University of Maryland

Baltimore, Maryland, United States

Tufts Medical Center

Boston, Massachusetts, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Henry Ford Health System

Detroit, Michigan, United States

Beaumont Health

Troy, Michigan, United States

Nebraska Medical Center

Omaha, Nebraska, United States

Newark Beth Israel Medical Center

Newark, New Jersey, United States

University of Rochester

Rochester, New York, United States

Asheville Cardiology Associates

Asheville, North Carolina, United States

University of Cincinnati

Cincinnati, Ohio, United States

University Hospital

Cleveland, Ohio, United States

The Ohio State University

Columbus, Ohio, United States

Oregon Health and Science University

Portland, Oregon, United States

Legacy Research Institute

Portland, Oregon, United States

Perelman Center for Advanced Medicine; University of Pennsylvania

Philadelphia, Pennsylvania, United States

University of Pittsburgh Medical Center - Presbyterian Cardiovascular Institute

Pittsburgh, Pennsylvania, United States

Rhode Island Hospital

Providence, Rhode Island, United States

The University of Texas Health Science Center at Houston

Houston, Texas, United States

Sentara Cardiovascular Research Institute

Norfolk, Virginia, United States

Virginia Commonwealth University

Richmond, Virginia, United States

Aurora Saint Luke's Medical Center

Milwaukee, Wisconsin, United States

Sanatorio San José

CABA, Buenos Aires, Argentina

Hospital Italiano de Buenos Aires

Buenos Aires, Distrito Federal, Argentina

Hospital Italiano Garibaldi

Rosario, Santa Fe Province, Argentina

Sanatorio de la Trinidad Mitre

Buenos Aires, , Argentina

Hospital Dr. José María Cullen

Santa Fe, , Argentina

Royal Prince Alfred Hospital

Camperdown, New South Wales, Australia

Nepean Hospital

Kingswood, New South Wales, Australia

Saint Vincents Hospital

Sydney, New South Wales, Australia

Macquarie University

Sydney, New South Wales, Australia

Prince Charles Hospital

Chermside, Queensland, Australia

Royal Hobart Hospital

Hobart, Tasmania, Australia

The Alfred Hospital

Melbourne, Victoria, Australia

Royal Melbourne Hospital

Parkville, Victoria, Australia

Krankenhaus Elisabethinen Linz

Linz, Upper Austria, Austria

Medizinische Universität Wien

Vienna, , Austria

Hospital das Clinicas da Universidade Federal de Goias

Goiânia, Goiás, Brazil

Hospital das Clínicas da Universidade Federal de Minas Gerais

Belo Horizonte, Minas Gerais, Brazil

Hospital Madre Teresa

Belo Horizonte, Minas Gerais, Brazil

Complexo Hospitalar Santa Casa de Porto Alegre

Porto Alegre, Rio Grande do Sul, Brazil

Hospital das Clínicas da Faculdade de Medicina de Botucatu- UNESP

Botucatu, São Paulo, Brazil

Hospital da Clínicas da Faculdade de Medicina da Universidade de São Paulo

São Paulo, São Paulo, Brazil

Escola Paulista de Medicina, Universidade Federal de São Paulo

São Paulo, São Paulo, Brazil

Hospital Alemão Oswaldo Cruz

São Paulo, , Brazil

Respiratory Research Foundation

Calgary, Alberta, Canada

University of Alberta Hospital

Edmonton, Alberta, Canada

Vancouver Coastal Health

Vancouver, British Columbia, Canada

Lawson Health Research Institute

London, Ontario, Canada

Centro de Investigaciones TASOL

Santiago, Santiago Metropolitan, Chile

Clínica Tabancura

Vitacura, Santiago Metropolitan, Chile

Beijing Chao-Yang Hospital

Beijing, Beijing Municipality, China

Guangdong General Hospital

Guangzhou, Guangdong, China

Wuhan Asia Heart Hospital

Wuhan, Hubei, China

Xiangya Hospital

Changsha, Hunan, China

The First Affiliated Hospital of Nanjing Medical University

Nanjing, Jiangsu, China

The Second Affiliated Hospital of Nanchang Medical University

Nanchang, Jiangxi, China

Zhongshan Hospital Fudan University

Shanghai, Shanghai Municipality, China

Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

Shanghai, Shanghai Municipality, China

West China Hospital

Chengdu, Sichuan, China

Peking Union Medical College Hospital

Beijing, , China

Beijing Shijitan Hospital

Beijing, , China

Chinese PLA General Hospital

Beijing, , China

The Affiliated Hospital of Qingdao University

Qingdao, , China

Renji Hospital of Shanghai Jiaotong University

Shanghai, , China

Shanghai Pulmonary Hospital of Tongji University

Shanghai, , China

Shenyang General Hospital of Shenyang Military Command

Shenyang, , China

Aarhus Universitetshospital, Skejby

Aarhus, , Denmark

Rigshospitalet-Copenhagen University Hospital

Copenhagen, , Denmark

Hopital Haut-Leveque, CHU Bordeaux

Pessac, Aquitaine, France

Hopital Jean Minjoz Centre Hospitalier Universitaire Besancon

Besançon, Franche-comte, France

Centre Hospitalier Régional Universitaire de Lille - Hôpital Claude Huriez

Lille, Hauts-de-France, France

CHU de Montpellier

Montpellier, Languedoc-roussillon, France

Hopital Brabois

Vandœuvre-lès-Nancy, Limousin, Lorraine, France

Centre Hospitalier Universitaire Hopital Nord

Marseille, Provence-Alpes-Côte d'Azur Region, France

Thoraxklinik am Universitätsklinikum Heidelberg

Heidelberg, Baden-Wurttemberg, Germany

Ludwig-Maximilians-Universitat Munchen

München, Bavaria, Germany

Universitätsklinikum Regensburg

Regensburg, Bavaria, Germany

Missionsarztliche Klinik Wurzburg gGmbH

Würzburg, Bavaria, Germany

Universitätsmedizin Greifswald

Greifswald, Mecklenburg-Vorpommern, Germany

Bergmannsheil Berufsgenossenschaftliche Universitätsklinik GmbH

Bochum, North Rhine-Westphalia, Germany

Universitätsklinikum Köln

Cologne, North Rhine-Westphalia, Germany

Herzzentrum Duisburg

Duisburg, North Rhine-Westphalia, Germany

Universitätsmedizin der Johannes Gutenberg Universität

Mainz, Rhineland-Palatinate, Germany

Universitätsklinikum des Saarlandes

Homburg, Saarland, Germany

Technische Universität Dresden

Dresden, Saxony, Germany

Universitätsklinikum Leipzig

Leipzig, Saxony, Germany

Universitätskrankenhaus Hamburg-Eppendorf

Hamburg, , Germany

Technische Universität Dresden

Sachsen, , Germany

University General Hospital of Attikon

Athens, Attica, Greece

General Hospital of Thessaloniki, "G.Papanikolaou"

Thessaloniki, Macedoni, Greece

CARE Hospital

Hyderabad, Andhra Pradesh, India

Mediciti Hospital

Hyderabad, Andhra Pradesh, India

Care Institute Medical Sciences

Ahmedabad, Gujarat, India

Apollo Hospitals International, Ltd.

Gandhinagar, Gujarat, India

Medanta - The Medicity

Gurgaon, Haryana, India

Narayana Institute of Cardiac Sciences

Bangalore, Karnataka, India

KEM Hospital

Mumbai, Maharashtra, India

Ruby Hall Clinic

Pune, Maharashtra, India

Sir Ganga Ram Hospital

New Delhi, National Capital Territory of Delhi, India

Indraprastha Apollo Hospital

New Delhi, National Capital Territory of Delhi, India

Apollo Hospital

Chennai, Tamil Nadu, India

G. Kuppuswamy Naidu Memorial Hospital

Coimbatore, Tamil Nadu, India

Rabin Medical Center

Petach Tikvah, Petah Tiqwa, Israel

The Chaim Sheba Medical Center at Tel Hashomer

Tel Litwinsky, Tel Aviv, Israel

Rambam Health Corp.

Haifa, , Israel

Carmel Medical Center

Haifa, , Israel

Hadassah Medical Center

Jerusalem, , Israel

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, , Italy

Instituto Nacional de Cardiologia Ignacio Chavez

Tlalpan, Mexico City, Mexico

Unidad de Investigacion Clinica en Medicina S.C.

Monterrey, Nuevo León, Mexico

Universitair Medisch Centrum Sint Radboud

Nijmegen, Gelderland, Netherlands

Vrije Universiteit Medisch Centrum

Amsterdam, North Holland, Netherlands

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

Małogoskie, , Poland

Europejskie Centrum Zdrowia Otwock, Szpital im. Fryderyka Chopina

Otwock, , Poland

National University Hospital

Singapore, , Singapore

National Heart Centre Singapore

Singapore, , Singapore

Gachon University Gil Medical Center

Incheon, , South Korea

Seoul National University Hospital

Seoul, , South Korea

Severance Hospital, Yonsei University Health System

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

Sahlgrenska University Hospital

Gothenburg, Västra Götaland County, Sweden

Karolinska University Hospital Solna

Stockholm, , Sweden

National Cheng Kung University Hospital

Tainan City, Tainan CITY, Taiwan

Veterans General Hospital-Kaohsiung

Kaohsiung City, , Taiwan

Taichung Veterans General Hospital

Taichung, , Taiwan

National Taiwan University Hospital

Taipei, , Taiwan

Papworth Hospital

Papworth Everard, Cambridgshire, United Kingdom

Royal Free Hospital

London, England, United Kingdom

Freeman Hospital

Newcastle upon Tyne, England, United Kingdom

Royal Hallamshire Hospital

Sheffield, England, United Kingdom

Countries

United States; Argentina; Australia; Austria; Brazil; Canada; Chile; China; Denmark; France; Germany; Greece; India; Israel; Italy; Mexico; Netherlands; Poland; Singapore; South Korea; Sweden; Taiwan; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 31765604 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

TDE-PH-310

Identifier Type: -

Identifier Source: org_study_id