Study of Intravenous Remodulin in Patients in India With Pulmonary Arterial Hypertension (TRUST-1)

• Borg Dyspnea Score [ Time Frame: Twelve weeks ]
• Dyspnea-Fatigue Index [ Time Frame: Twelve weeks ]
• NYHA Functional Class [ Time Frame: Twelve Weeks ]
• Clinical Worsening [ Time Frame: Twelve weeks ]

Multi-center, double-blind, placebo-controlled, randomized, parallel study comparing continuous intravenous (IV) Remodulin® to placebo in patients with pulmonary arterial hypertension either primary (PPH) or associated with human immunodeficiency virus (HIV) infection or collagen vascular disease).

Inclusion Criteria:Patients Must:

1. Be between 16 years and 75 years of age.
2. Be male or, if female, be physiologically incapable of childbearing or practicing an acceptable method of birth control.

3. Have a current diagnosis of symptom-limited NYHA Functional Class III or IV PAH that is:

   • PPH (“idiopathic” or familial PAH); or
   • PAH associated with collagen vascular disease (confirmed by antinuclear antibody titer or other acceptable test); or
   • PAH associated with HIV infection (confirmed by appropriate serological test).
4. If HIV positive, must have a CD4 lymphocyte count ≥ 200 at baseline and be receiving current standard of care anti-retroviral or other effective medication for HIV infection.
5. Be optimally treated with conventional pulmonary hypertension therapy and clinically stable for at least one month prior to baseline assessments.
6. Have either a ventilation/perfusion scan, contrast-enhanced CT scan, or pulmonary angiogram after the onset of PAH that rules out pulmonary embolism.

7. Have a cardiac catheterization within the last 3 months (or at Baseline) showing:

   • PAPm > 35 mmHg (at rest) and
   • PCWPm (or left ventricular end diastolic pressure) < 16 mmHg and
   • PVR > 5 mmHg/L/min.

8. Have an echocardiogram within the last three months consistent with pulmonary hypertension, specifically:

   • evidence of right ventricular hypertrophy or dilation and
   • evidence of normal left ventricular function and
   • absence of mitral valve stenosis.
9. Have a chest radiograph consistent with pulmonary hypertension performed within the last three months. The radiograph must show clear lung fields or no more than patchy interstitial (not diffuse) infiltrates.
10. Unless contraindicated, be able to receive one of the following anticoagulants: warfarin to achieve an INR between 1.5 and 2.5 or heparin to produce an aPTT between 1.3 to 1.5 times control, unless higher levels are clinically indicated.
11. Be mentally and physically capable of learning to administer Study Drug using an ambulatory intravenous infusion pump and a central venous access, or have an appropriately trained caregiver.
12. If on corticosteroids, be receiving a stable dose of  20 mg/day of prednisone (or an equivalent dose of another steroid) for at least one month prior to entry.

Exclusion Criteria: Patients must not:

1. Be a nursing or pregnant woman (women of childbearing potential must have a negative pregnancy test).
2. Have had a new type of chronic therapy (including but not limited to oxygen, a different category of vasodilator, a diuretic, digoxin) for pulmonary hypertension, except for anticoagulants, added within the last month.
3. Be scheduled for heart-lung transplant.
4. Have any pulmonary hypertension medication except for anticoagulants discontinued within the week prior to study entry.
5. Have received any chronic prostaglandin or prostaglandin analogue therapy (including intravenous/inhaled/oral: epoprostenol, iloprost, beraprost, etc.), any phosphodiesterase inhibitor therapy such as sildenafil, or any endothelin antagonist therapy such as bosentan, within the past 30 days.

6. Have pulmonary hypertension associated with chronic thromboembolic disease; or chronic obstructive lung diseases or hypoxemia; or evidence of significant parenchymal lung disease as evidenced by pulmonary function tests within the last three months as follows (any one of the following ):

   • Total Lung Capacity < 60% (predicted); or a high resolution CT documenting diffuse interstitial fibrosis or alveolitis
   • FEV1/FVC ratio < 50%.
7. Have Portal Hypertension.
8. Have a history of uncontrolled Sleep Apnea, defined as oxygen desaturation to less than 90% at night, within the past three months.

9. Have a history of left-sided heart disease including:

   • Aortic or mitral valve disease or
   • Pericardial constriction or
   • Restrictive or congestive cardiomyopathy; or have evidence of current left-sided heart disease as defined by:
   • PCWPm or left ventricular end diastolic pressure > 16 mmHg or
   • LVEF < 40% by MUGA, angiography or echocardiography or
   • LV Shortening Fraction < 22% by echocardiography or
   • Symptomatic coronary disease (demonstrable ischemia).
10. Have any disease other than HIV or connective tissue disease that is associated with pulmonary hypertension (e.g. sickle cell anemia, schistosomiasis).
11. Have active AIDS or tuberculosis.
12. Have a musculoskeletal disorder (e.g. arthritis, artificial leg, etc.) or any other disease which is thought to limit ambulation, or be connected to a machine which is not portable.
13. Have a baseline exercise capacity of less than 50 meters or greater than 325 meters as measured by the Six-Minute Walk Test.
14. Have uncontrolled systemic hypertension as evidenced by systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg.
15. Have used prescription appetite suppressants within 3 months of study entry.
16. Have chronic renal insufficiency as defined by creatinine greater than 2.5 mg/dL or the requirement for dialysis.
17. Be receiving an investigational drug (other than acute challenge with epoprostenol), have in place an investigational device, or have participated in an investigational drug/device study within the past 30 days.
18. Have the presence of any physiological or mental condition which contraindicates the administration of Remodulin.