Dose-response Study of the Safety and Efficacy of Beraprost Sodium Modified Release (BPS-MR) in Patients With Pulmonary Arterial Hypertension (PAH)
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: Beraprost Sodium Modified Release
Intervention description: 60µg Tablets, twice a day for 12 weeks
Intervention MeSH terms: Beraprost
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 36.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: PAH

Summary:

      This is a 12-week, international, multicenter, double-blind, three-group, dose-response study
      to assess the safety and efficacy of BPS-MR in patients with PAH. Eligible patients will have
      been previously diagnosed with PAH and will be on a stable course of an ERA and/or PDE-5
      inhibitor for at least 60 days prior to Baseline.

      Patients will be randomized to 1 of 3 treatment groups in a 1:1:1 ratio and will be
      stratified by PAH background therapy (Endothelium Receptor Antagonist (ERA),
      Phosphodiesterase-5 (PDE-5), and both). The treatment groups consist of one Maximum Tolerated
      Dose (MTD) and two Fixed Dose (FD) groups. Following randomization, patients will begin
      taking active drug (60µg) orally twice daily. Patients will visit their investigational site
      at Week 6 and Week 12 for study evaluations.
    

Eligibility criteria:

        Inclusion Criteria:

          1. IRB approved written informed consent has been obtained.

          2. Male or female, age 18 to 75 years (inclusive).

          3. Established diagnosis of pulmonary arterial hypertension that is either idiopathic or
             familial PAH, collagen vascular disease associated PAH, PAH induced by anorexigens, or
             PAH associated with repaired congenital systemic-to-pulmonary shunts (repaired ≥5
             years).

          4. Clinically stable PAH as determined by the Investigator.

          5. Able to walk unassisted.

          6. Has a complete, unencouraged 6MWT distance of 150 to 450 meters (inclusive) at
             Screening.

          7. Previous (at any time) right heart cardiac catheterization 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. Previous (at any time) chest radiograph consistent with the diagnosis of PAH.

          9. Has been on a stable course of an ERA or/and PDE-5 inhibitor for a minimum of 60 days
             prior to Baseline.

         10. Women of child-bearing potential (defined as less than 1 year post-menopausal or not
             surgically sterile) must be using an acceptable method of birth control or practicing
             abstinence. If sexually active, female patients must use a double barrier method of
             birth control, such as a condom and spermicidal. Patient must have a negative
             pregnancy test at the Screening and Baseline visits.

         11. Willing and able to comply with study requirements and restrictions.

        Exclusion Criteria:

          1. Has pulmonary venous hypertension, pulmonary veno-occlusive disease, pulmonary
             capillary hemangiomatosis, or chronic thromboembolic pulmonary hypertension.

          2. Has a history of interstitial lung disease, unless:

               -  Pulmonary Function Testing conducted within 6 months of the Baseline visit
                  demonstrates a Total Lung Capacity ≥ 70 % of predicted.

          3. Has a history of obstructive lung disease, unless:

               -  Pulmonary Function Testing conducted within 6 months of the Baseline visit
                  demonstrates a forced expiratory volume in 1 second/forced vital capacity
                  (FEV1/FVC) ratio of ≥ 50%.

          4. Is pregnant and/or lactating.

          5. Changed or discontinued any PAH medication within 60 days prior to the Baseline visit
             including, but not limited to, an ERA, PDE-5 inhibitor, or calcium channel blocker
             (with the exception of anticoagulants).

          6. 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 hemorrhage, etc.) will not preclude enrollment.

          7. Has donated blood or plasma, or has lost a volume of blood >450mL within 6-weeks of
             the Baseline visit.

          8. Has received any investigational medication, 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 received any prostanoid therapy at any time.

         10. Has any preexisting disease known to cause pulmonary hypertension other than collagen
             vascular disease.

         11. Has any musculoskeletal disease or any other disease that would limit ambulation.

         12. Has any form of unrepaired or recently repaired (< 5 years) congenital
             systemic-to-pulmonary shunt other than patent foramen ovale.

         13. History of pulmonary embolism or deep venous thrombosis.

         14. History of ischemic heart disease, including previous myocardial infarction, or
             symptomatic coronary artery disease, or 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 patients 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.

         15. Presence of atrial fibrillation (determined from 12-lead ECG at Screening).

         16. Any other clinically significant illness that, in the opinion of the Investigator,
             might put the patient at risk of harm during the study or might adversely affect the
             interpretation of the study data.