A 48-week Study of the Effect of Dual Therapy (Inhaled Treprostinil and Tadafafil) Versus Monotherapy (Tadalafil), 2 FDA Approved Pulmonary Hypertension Medications

Inclusion criteria:

1. Age 18 and < 75 years at baseline visit.

2. Diagnosis of Idiopathic PAH, Heritable PAH (including Hereditary Hemorrhagic
Telangiectasia), Associated PAH (including collagen vascular disorders, drug+toxin
exposure, repaired congenital heart disease repaired > 5 years, portopulmonary
disease, and human immunodeficiency virus (HIV) infection not on protease inhibitor).

3. PAH treatment naïve including any prostacycline, endothelin receptor antagonist, or
phosphodiesterase inhibitors within 12 months prior to enrollment.

4. Previous Right Heart Catheterization that documented:

1. Mean PAP; 25 mmHg.

2. Pulmonary capillary wedge pressure < 15 mmHg.

3. Pulmonary Vascular Resistance; 3.0 Wood units or 240 dynes/sec/cm5 5.6MW
distances; 150 m and < 450 meters.

6. WHO functional class II or III as judged by principal investigators.

Exclusion Criteria:

Exclusion criteria:

1. Group II - V pulmonary hypertension.

2. PAH with unrepaired congenital heart defect.

3. Current or prior PAH treatments within the last 6-12 months including experimental
PAH therapies (including but not limited to tyrosine kinase inhibitors, rho-kinase
inhibitors, phosphodiesterase inhibitors, prostacycline, or cGMP modulators).

4. TLC < 60% predicted; if TLC b/w 60 and 70% predicted, high resolution computed
tomography must be available to exclude significant interstitial lung disease.

5. FEV1 / FVC < 70% predicted and FEV1 < 60% predicted

6. Significant left-sided heart disease (based on pre-trial Echocardiogram):

1. Significant aortic or mitral valve disease

2. Diastolic dysfunction ; Grade II C.LV systolic function < 45%

d. Pericardial constriction e. Restrictive cardiomyopathy f. Significant coronary
disease with demonstrable ischemia

7. Chronic renal insufficiency defined as an estimated creatinine clearance < 30 ml/min
(by MDRD equation)

8. Current atrial arrhythmias

9. Uncontrolled systemic hypertension: SBP > 160 mm or DBP > 100mm

10. Severe hypotension: SBP < 80 mmHg.

11. Pregnant or breast-feeding

12. Psychiatric, addictive, or other disorder that compromises patient's ability to
provide informed consent, follow study protocol, and adhere to treatment instructions

13. Co-morbid conditions that would impair a patient's exercise performance and ability
to assess WHO functional class, including but not limited to chronic low-back pain or
peripheral musculoskeletal problems.

14. Contraindications for magnetic resonance imaging, including significant
claustrophobia, implanted metallic objects, or others as per Appendix X).

15. Known allergy to treprostinil or tadalafil.

16. Active oral nitrate use.

17. Diabetes mellitus.

18. Planned initiation of cardiac or pulmonary rehabilitation during period of study.