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
Trial status: Open for Enrollment
Why is this study being done?
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.
Who is eligible to participate?
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-topulmonary shunts (repaired ≥5 years).
3. If HIV positive, has CD4 lymphocyte count ≥200 cells/mm3 within 30 days of Baseline Visit and is receiving current standard of care anti-retroviral or other effective medication.
4. Showing signs of deterioration on inhaled treprostinil or having a less than optimal response to inhaled treprostinil treatment.
5. Able to walk unassisted (oxygen use allowed).
6. A 6-Minute Walk distance (6MWD) of ≥ 100 meters at the Screening Visit.
7. 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.
8. Within five years prior to the Baseline visit, chest radiograph consistent with PAH.
9. Echocardiography with results consistent with PAH and the absence of any clinically significant left heart disease (e.g. mitral valve stenosis, myocardial infarction, etc.).
10. Pulmonary function tests conducted within 6 months before or during the Screening period to confirm the following:
1. Total lung capacity (TLC) is at least 60% (predicted value) assessed by whole body plethysmography
2. Forced expiratory volume at one second (FEV1) of at least 50% (predicted value)
11. WHO functional class III to IV
12. Subjects receiving PAH therapies (i.e. ERAs, PDE-5 inhibitors) must be stable on their current dose for at least 30 days prior to Baseline. Discontinuation or dose changes of anticoagulants and/or dose change of diuretics are allowed.
13. Must have received a stable dose of inhaled treprostinil for at least 30 days prior to Baseline. Those initiating therapy at the time of screening must complete 90 days of inhaled treprostinil treatment and any concurrent background therapies before the Baseline visit to be eligible for randomization into the study.
14. 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.
15. Willing and able to comply with study requirements and restrictions.
1. The subject is pregnant or lactating.
2. The subject previously received beraprost or BPS-314d (i.e., BPS-IR, BPS-MR or BPS-314d-MR)
3. Has pulmonary venous hypertension, pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis, or chronic thromboembolic pulmonary hypertension.
4. Has a positive vasoreactive response (a reduction of pulmonary artery pressure ≥10 Hg mm to ≤ 40 mmHg with increased or unchanged cardiac output) to acute pulmonary vasodilator testing or failure to respond to calcium channel blocker therapy within the past 5 years.
5. Has a history of interstitial lung disease, unless subject has collagen vascular disease and has had pulmonary function testing conducted within 6 months of the Baseline visit demonstrating a total lung capacity ≥70% of predicted.
6. Has a history of obstructive lung disease, unless subject has had pulmonary function testing conducted within 6 months of the Baseline visit demonstrating a forced expiratory volume in 1 second (FEV1) of ≥ 50% of predicted.
7. Has an ongoing 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.
8. 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.
9. Has any musculoskeletal disease or any other disease that would significantly limit ambulation.
10. Has any form of unrepaired or recently repaired (< 5 years) congenital systemic-topulmonary shunt other than patent foramen ovale.
11. Documented history or current evidence of ischemic heart disease.
12. History of left sided myocardial disease as evidenced by a mean PCWP (or a left ventricular end diastolic pressure) > 15 mmHg or left ventricular ejection fraction < 40% as assessed by either multigated angiogram, angiography or echocardiography, or left ventricular shortening fraction <22% as assessed by echocardiography. Note that subjects in whom abnormal left ventricular function is attributed entirely to impaired left ventricular filling due to the effects of right ventricular overload (i.e., right ventricular hypertrophy and/or dilatation) will not be excluded.
13. Has creatinine clearance <30 (using the Crockroft-Gault formula) or requires hemodialysis.
14. Has Childs-Pugh class C liver cirrhosis.
15. Has had previous atrial septostomy.
16. Any other clinically significant illness 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.
No waivers to entry criteria are allowable in this study; however, subjects who are initially ineligible for this study may be reassessed for eligibility after consultation with the Sponsor.