The Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study

A prospective, double blind, placebo-controlled clinical study involving 30 patients with
World Health Organization (WHO) Group 1 pulmonary arterial hypertension being treated with
ambrisentan randomized to receive placebo or spironolactone (50 mg/d) for 90 days using a
cross-over trial design.

Eligible participants will be randomized to receive placebo or spironolactone (50 mg/d) for
90 days (Phase I). At the completion of Phase I, participants will undergo repeat end-point
assessment followed by a 21-day drug washout period. Then, the 90 day crossover phase of the
trial will occur (Phase II), in which participants randomized to placebo in Phase I will be
treated with spironolactone (50 mg/d) in Phase II and vice versa. At the conclusion of Phase
II, end-point measures are reassessed.

Spironolactone is a diuretic used in treatment of PAH patients. Spironolactone is usually
added to medical treatment when doses of Lasix/Torsemide are increased and patients are at
risk for hypokalemia.

Study procedures being done for this research study are the standard procedures performed on
all PAH patients when they are in clinic for follow-up except for the Cardiopulmonary
Exercise Test (CPET) with Innocor.

Inclusion Criteria:

1. Voluntarily gives informed consent to participate in the study.

2. Right heart catheterization demonstrating conventional mean pulmonary artery pressure
(mPAP) >25, pulmonary vascular resistance (PVR) >3.0 Wood Units, pulmonary capillary
wedge pressure (PCWP) <16 mmHg within two years of enrollment

3. Subject is 18 years of age or older at Screening.

4. Diagnosis of symptomatic idiopathic or heritable PAH, PAH associated with Connective
Tissue Disease (CTD), PAH associated with repaired/unrepaired congenital
systemic-to-pulmonary shunt, Portopulmonary hypertension or PAH associated with HIV
infection.

5. New York Heart Association Functional Class II or III

6. Stable therapy with ambrisentan 5 or 10 mg every day for > 90 days.

7. Baseline 6-Minute Walk Distance 50-450m

Exclusion Criteria:

1. Substantial Primary Lung disease

- forced expiratory volume at one second (FEV-1)/forced vital capacity (FVC) <0.6
and FEV-1 <70% predicted

- diffusing capacity of lung for carbon monoxide (DLCO) <30% predicted

- Pulmonary fibrosis

2. Left ventricular ejection fraction < 50%

3. Pulmonary capillary wedge pressure > 16 mm Hg

4. Aortic valve disease

5. Ischemic heart disease

6. Systemic hypotension (SBP <90 mm Hg)

7. Co-existing treatment with other endothelin receptor antagonists or prostacyclin
analogues

8. New York Heart Association Functional Class IV

9. Chronic thromboembolic pulmonary hypertension

10. Known or suspected pulmonary veno-occlusive disease

11. Serum creatinine >2.0 mg/dL in women, Serum creatinine >2.5 mg/dL in men

12. Baseline serum potassium >5.0 milliequivalent (mEq)/L

13. Participation in ongoing drug/intervention-based clinical trial

14. Pregnancy

15. Unable to provide consent