Clinical trial NCT01908699: Beraprost-314d Added-on to Tyvaso® (BEAT)
Official title: A Multicenter, Double-blind, Randomized, Placebo-controlled, Phase 3 Study to Assess the Efficacy and Safety of Oral BPS-314d-MR added-on to Treprostinil, Inhaled (Tyvaso®) in Subjects With Pulmonary Arterial Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Lead sponsor: Lung Biotechnology PBC
Sponsor class: INDUSTRY
First posted: 2013-07-26
Enrollment: 273
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multicenter, double-blind, randomized, placebo-controlled Phase 3 study, to assess the efficacy and safety of BPS-314d-MR when added-on to inhaled treprostinil (Tyvaso®)in patients with pulmonary arterial hypertension.

Patients new to Tyvaso, will enter a run-in period on inhaled treprostinil until 90 days of experience is achieved to ensure drug tolerability before enrolling in the study.

Treatment groups consist of one active and one placebo group. Subjects will be randomly allocated in a 1:1 ratio to one of the two treatment groups.


Eligibility criteria: Inclusion Criteria

The following are inclusion criteria to be enrolled in this study:

1. Male or female, age 18 to 80 years (inclusive).
2. Established diagnosis of pulmonary arterial hypertension that is either idiopathic or familial PAH, collagen vascular disease associated PAH, PAH associated with HIV infection, PAH induced by anorexigens/toxins, or PAH associated with repaired congenital systemic-to-pulmonary shunts (repaired ≥1 years).
3. If HIV positive, has a CD4 lymphocyte count ≥200 cells/mm3 within 30 days of Baseline Visit and is receiving current standard of care antiretroviral or other effective medication.
4. At the Screening Visit, WHO functional class III or IV and who have declining or unsatisfactory clinical response to current PAH therapy.
5. At the Baseline Visit, WHO functional class III or IV and who have declining or unsatisfactory clinical response to inhaled treprostinil therapy.
6. Able to walk unassisted (oxygen use allowed).
7. A 6-Minute Walk distance (6MWD) of ≥ 100 meters at the Screening Visit.
8. Previous (within five years prior to the Baseline Visit) right heart cardiac catheterization (RHC) with findings consistent with PAH, specifically mean Pulmonary Arterial Pressure (PAPm) ≥25 mmHg (at rest), Pulmonary Capillary Wedge Pressure (PCWP) (or left ventricular end diastolic pressure) ≤15 mmHg, and Pulmonary Vascular Resistance (PVR) \>3 mmHg/L/min.
9. Echocardiography excluding any clinically significant left heart disease (e.g. left sided valve disease, wall motion abnormality suggesting of myocardial infarction, left ventricular hypertrophy, etc).
10. Pulmonary function tests conducted within 12 months before or during the Screening period to confirm the following:

    1. Total lung capacity (TLC) is at least 60% (predicted value) and
    2. Forced expiratory volume at one second (FEV1) of at least 50% (predicted value).
11. Subjects receiving additional FDA approved PAH therapies must be stable on their current dose for at least 30 days prior to the Baseline Visit, apart from modification of anticoagulant or diuretic dosages.
12. Must have completed 90 days of uninterrupted inhaled treprostinil treatment and received a stable dose of inhaled treprostinil for at least 30 days prior to Baseline to be eligible for randomization into the study.
13. Women of child-bearing potential (defined as less than 1 year post-menopausal and not surgically sterile) must be practicing abstinence or using two highly effective methods of contraception (defined as a method of birth control that result in a low failure rate, i.e., less than 1% per year, such as approved hormonal contraceptives, barrier methods \[such as a condom or diaphragm\] used with a spermicide, or an intrauterine device). Subject must have a negative pregnancy test at the Screening and Baseline Visits.
14. Willing and able to comply with study requirements and restrictions.

Exclusion Criteria

Patients who meet any of the following criteria will be excluded from the study:

1. Pregnant or lactating.
2. Has previous experience with beraprost or BPS-314d (i.e., BPS-IR, BPS-MR or BPS-314d- MR).
3. PAH related to any condition not covered under inclusion criteria, including but not limited to pulmonary venous hypertension, pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis, or chronic thromboembolic pulmonary hypertension.
4. History of interstitial lung disease, unless subject has collagen vascular disease and has had pulmonary function testing conducted within 12 months of the Baseline Visit demonstrating a total lung capacity ≥60% of predicted.
5. Has active hemorrhagic condition (e.g., upper digestive tract hemorrhage, hemoptysis, etc), or has a pre-existing condition that, in the Investigator's judgment, may increase the risk for developing hemorrhage during the study (e.g., hemophilia). Transient hemorrhage (e.g., epistaxis, normal menstrual bleeding, gingival bleeding, hemorrhoidal bleeding, etc) will not preclude enrollment.
6. Has received any investigational drug, device or therapy within 30 days prior to the Baseline Visit or is scheduled to receive another investigational drug, device or therapy during the course of the study.
7. Has any musculoskeletal disease or any other disease that would significantly limit ambulation.
8. Has any form of unrepaired or recently repaired (\< 1 year) congenital systemic-to-pulmonary shunt other than patent foramen ovale.
9. Evidence of significant coronary arterial disease with symptoms, such as angina.
10. Left sided myocardial disease as evidenced by left ventricular ejection fraction \< 40%, or shortening fraction \<22%.
11. Has creatinine clearance \<30 (using the Cockroft-Gault formula) or requires hemodialysis.
12. Has Childs-Pugh class C liver cirrhosis.
13. Has had previous atrial septostomy.
14. Any other clinically significant illness or abnormal laboratory values (measured during the Screening period) that, in the opinion of the Investigator, might put the subject at risk of harm during the study or might adversely affect the interpretation of the study data.
15. Anticipated survival less than 1 year due to concomitant disease.

The Sponsor recognizes that the pulmonary hypertension population is complex and diverse. In order to facilitate enrollment of appropriate subjects to this pivotal trial, Investigators are strongly encouraged to contact the medical director or study team to discuss potential study subjects who have comorbid conditions before enrollment into this study. See Appendix 9 for additional details.

No waivers to entry criteria are allowable in this study. Subjects who are initially ineligible for this study may be reassessed for eligibility after consultation with the Sponsor.

Primary outcomes:
measure: Number of Participants That Experienced Clinical Worsening
timeFrame: up to 144 weeks
Secondary outcomes:
measure: Mean Change From Baseline in Borg Dyspnea Score at Week 24
timeFrame: Baseline and Week 24
measure: Mean Change From Baseline in NT-pro-BNP Levels at Week 24
timeFrame: Baseline and Week 24
measure: Change in WHO Functional Class From Baseline to Week 24
timeFrame: Baseline and Week 24
measure: Mean Change From Baseline in Six Minutes Walk Distance (6MWD) at Week 24
timeFrame: Baseline and Week 24
measure: Number of Participants With TEAEs, Serious TEAEs, Investigations SOC TEAEs, and Serious Investigations SOC TEAEs
timeFrame: up to 144 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Beverly Hills
country: United States
facility: Cedars-Sinai Medical Center Heart Institute
state: California
city: Fountain Valley
country: United States
facility: Allianz Research Institute Inc.
state: California
city: Fresno
country: United States
facility: University of California San Francisco - Fresno
state: California
city: La Jolla
country: United States
facility: University of California - San Diego
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Los Angeles
country: United States
facility: Keck Medical Center of USC
state: California
city: Los Angeles
country: United States
facility: Veterans Affairs Greater Los Angeles Healthcare System
state: California
city: Rancho Mirage
country: United States
facility: Center for Advanced Pulmonary Medicine
state: California
city: San Francisco
country: United States
facility: University of California - San Francisco
state: California
city: Santa Barbara
country: United States
facility: Cottage Pulmonary Hypertension Center
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Denver
country: United States
facility: Aurora Denver Cardiology Associates
state: Colorado
city: Littleton
country: United States
facility: South Denver Cardiology Associates P.C.
state: Colorado
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
city: Brandon
country: United States
facility: Bay Area Cardiology Associates, P.A.
state: Florida
city: Celebration
country: United States
facility: Florida Lung, Asthma, and Sleep Institute
state: Florida
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Jacksonville
country: United States
facility: University of Florida College of Medicine
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Orlando
country: United States
facility: Florida Hospital
state: Florida
city: Orlando
country: United States
facility: Orlando Health Heart Institute
state: Florida
city: South Miami
country: United States
facility: South Miami Heart Specialists
state: Florida
city: Weston
country: United States
facility: Cleveland Clinic Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Atlanta
country: United States
facility: Pulmonary & Critical Care of Atlanta
state: Georgia
city: Austell
country: United States
facility: Georgia Clinical Research
state: Georgia
city: Lawrenceville
country: United States
facility: Gwinnett Biomedical Research
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medicine
state: Illinois
city: Oakbrook Terrace
country: United States
facility: Advocate Health and Hospitals Corporation
state: Illinois
city: Carmel
country: United States
facility: Indiana University - Health Physicians
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Louisville
country: United States
facility: Kentuckiana Pulmonary Associates
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville Department of Medicine
state: Kentucky
city: New Orleans
country: United States
facility: John Ochsner Heart & Vascular Institute
state: Louisiana
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Troy
country: United States
facility: Beaumont Health Systems
state: Michigan
city: Newark
country: United States
facility: Rutgers University Hospital
state: New Jersey
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: Mineola
country: United States
facility: Winthrop University Hospital
state: New York
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Syracuse
country: United States
facility: Pulmonary Health Physicians, PC
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina, Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Toledo
country: United States
facility: University of Toledo Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Presbyterian Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Anderson
country: United States
facility: Anderson Pharmaceutical Research
state: South Carolina
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: San Antonio
country: United States
facility: Methodist Healthcare Clinical Trials Office
state: Texas
city: Temple
country: United States
facility: Scott & White Memorial Hospital
state: Texas
city: Norfolk
country: United States
facility: Sentara Norfolk General Hospital
state: Virginia
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Beer-sheva
country: Israel
facility: Soroka Medical Center
city: Haifa
country: Israel
facility: The Lady Davis Carmel Medical Center
city: Jerusalem
country: Israel
facility: Hadassah University Hospital - Ein Kerem
city: Petach Tikva
country: Israel
facility: Rabin Medical Center-Beilinson Campus
city: Ramat-Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Rechovot
country: Israel
facility: Kaplan Medical Center
Study officials:
References: