A Multi-Center, Open-Label, Multiple Dose, Dose Finding Study Exploring the Safety and Tolerability of Beraprost Sodium Modified Release in PAH Patients

This study is an international, open-label, multi-center, Phase II, multiple dose, dose-finding study to investigate the safety, tolerability and pharmacokinetic characteristics of BPS-MR tablets in male and female patients with PAH.

Patients who meet the inclusion/exclusion criteria will enter the Treatment Phase at a Baseline visit. Patients will begin taking one BPS-MR tablet (60µg) twice daily (b.i.d.) escalating by one tablet b.i.d. each week to a maximum dose of 600µg (ten tablets) b.i.d or until the patient reaches their MTD. Following the achievement of the MTD, patients will be down-titrated off BPS-MR in weekly one tablet b.i.d. decrements. Patients may, alternatively, elect to continue taking the study drug at their MTD in a separate open-label extension study.

This study is an international, open-label, multi-center, Phase II, multiple dose, dose-finding study to investigate the safety, tolerability and pharmacokinetic characteristics of BPS-MR tablets in male and female patients with PAH. All patients will be receiving background therapy with either a phosphodiesterase (PDE-5) inhibitor, endothelin receptor antagonist (ERA), or the combination of these two.

The study is divided into two phases:

1. The Treatment Phase and
2. The Down-Titration Phase

Screening will be conducted on an outpatient basis within 21 days prior to the Baseline visit. Patients meeting the inclusion/exclusion criteria at the Baseline visit will enter the Treatment Phase and begin taking one BPS-MR tablet (60µg) b.i.d. and escalating by one tablet b.i.d. each week to a maximum dose of 600µg (ten tablets) b.i.d. or until the patient reaches an intolerable dose.

Patients who reach an intolerable dose will be instructed to continue treatment at the previous dose, which will be considered as their individual MTD. For example, if a patient attains a full week of six BPS-MR tablets b.i.d. (360µg) but is unable to tolerate seven tablets (420µg) then the patient will return to using six tablets of BPS-MR b.i.d. (360µg) for up to an additional week of treatment. In this scenario, BPS-MR 360µg b.i.d. is the patient's MTD. Patients who do not reach an intolerable dose and tolerate the full ten weeks of BPS-MR dosing will be considered to have their individual MTD as BPS-MR 600µg b.i.d.

When patients reach their individual MTD (either at 10 weeks or earlier) they will return to the site 3-7 days after for an End of Treatment Phase assessment to be evaluated for safety and, optionally, a PK assessment. Subsequent to the End of Treatment Phase visit patients will be instructed to begin down-titration off of BPS-MR in weekly increments. However, patients may alternatively elect to continue taking BPS-MR at their MTD in a separate open-label extension study.

Eligibility Criteria:
Inclusion Criteria:

1. Is male or female between the ages of 18 and 75 years of age, inclusive;
2. Has either idiopathic or familial PAH, PAH associated with collagen vascular disease, or PAH induced by anorexigens;
3. Is clinically stable, as determined by the investigator;
4. Has previously undergone a cardiac catheterization which is consistent with PAH, specifically PAPm ≥25 mmHg (at rest), PCWP (or left ventricular end diastolic pressure) ≤15 mmHg, and PVR \>3 wood units;
5. Has been on a course of an endothelin receptor antagonist (ERA) or phosphodiesterase inhibitor (PDE-5) or the combination for at least 90 days at the time of the Baseline visit;
6. Has an unencouraged six-minute walk distance (6MWD) between 300 and 600 meters at the Screening visit;
7. Is able to communicate effectively with study personnel;
8. Is considered to be reliable, willing, cooperative and compliant with the study protocol requirements;
9. Provides voluntary, written informed consent before participating in the study;
10. Is, if female, physiologically incapable of childbearing or is practicing an acceptable method of birth control (i.e., surgical sterilization, approved hormonal contraceptives, barrier methods \[such as a condom or diaphragm\] used with a spermicide, or an intrauterine device).

Exclusion Criteria:

1. Has pulmonary venous hypertension, pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis, severe chronic obstructive pulmonary disease, pulmonary hypertension related to congenital heart disease, or chronic thromboembolic pulmonary hypertension;
2. Is pregnant or lactating;
3. Has a known intolerance to beraprost sodium or prostanoids;
4. Has a pre-existing condition that could interfere with the absorption, distribution, metabolism, or excretion of drugs;
5. Current use of tobacco products;
6. Known history of syncope;
7. Has, in the opinion of the Investigator, any concomitant disease other than those accepted as part of the inclusion criteria that would compromise the patient or the study;
8. Has had a change in or discontinued any PAH medication (with the exception of anticoagulants) within 30 days prior to the Baseline visit;
9. Has received any prostanoid therapy within the 30 days prior to the Baseline visit or be scheduled to receive additional prostanoid therapy during the study except for acute vasodilatory testing;
10. Has received any investigational medication within 30 days prior to the Baseline visit or be scheduled to receive another investigational drug during the course of this study;
11. In the opinion of the investigator, may be unable to comply with the study protocol;
12. Has any preexisting disease known to cause pulmonary hypertension (e.g., obstructive lung disease, parasitic disease affecting the pulmonary system, sickle cell anemia, mitral valve stenosis, portal hypertension) other than those listed in the inclusion criteria;
13. Has donated blood or plasma or has lost a volume of blood \>450 mL within six weeks prior to the Baseline visit.
14. Has an ongoing hemorrhagic condition (e.g. upper digestive track hemorrhage, hemoptysis, etc.) or has a pre-existing condition that, in the investigator's judgement, may increase the risk for developing hemorrhage during the study (e.g. hemophilia). However, transient hemorrhage (e.g. epistaxis, normal menstrual bleeding, gingival bleeding, hemorrhoidal hemorrhage, etc.) would not preclude enrollment