Beraprost-314d Added-on to Tyvaso® (BEAT)

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.