Safety and Efficacy of Fluoxetine in Pulmonary Arterial Hypertension

Idiopathic pulmonary arterial hypertension (PAH) is a life-threatening disorder of uncertain
cause that leads to progressive right heart failure and death. Average survival has
improved from about 2.8 years in the early 1990s to approximately 5-7 years with current
treatments, but most patients will still die of their disease. Two classes of oral
medications are approved for use in PAH: endothelin-1 antagonists, and phosphodiesterase-5
inhibitors. Both improve walk distance and symptoms in PAH, but most patients still have
continued dyspnea, fatigue and significant elevations in pulmonary pressures. Those who
remain severely impaired are generally started on a continuous intravenous prostacyclin.
For those who are less ill but still symptomatic, few options are available.

Primary endpoint: the primary endpoint will be change in pulmonary vascular resistance (PVR)
measured by right heart catheterization after three months of therapy.

Secondary endpoints

Efficacy:

- Other three month catheterization variables: right atrial pressure, pulmonary arterial
pressure, Fick cardiac output, pulmonary arterial oxygen saturation, pulmonary
capillary wedge pressure

- Six minute walk distance

- WHO functional class

- Brain natriuretic peptide

Safety and tolerability endpoints will include change between baseline and three month
QIDS-SR depression scale, systolic and diastolic blood pressure (systemic) and tabulation of
adverse events to include but not limited to:

- Death

- Hospitalization

- Symptomatic hypotension

- Gastrointestinal side effects

- Depression

Inclusion Criteria:

1. Signed informed consent prior to any study-mandated procedure

2. PAH of the following subtypes: idiopathic PAH WHO functional class II-III

3. Catheterization within one week showing mPAP >=25, wedge or LV end diastolic pressure
≤15, and PVR > 4 wood units, and baseline fick cardiac output results available

4. Age 16-75

5. Able to complete a six minute walk distance

6. Women of childbearing potential*: negative serum pre-treatment pregnancy test +
consistently and correctly uses a reliable method of contraception** Oral approved
PAH therapy for >3 months with no change in dose for > 1 month

Exclusion Criteria:

1. PAH with connective tissue disease, congenital heart disease, portal hypertension,
glycogen storage disease, Gaucher's disease, hereditary hemorrhagic telangiectasia,
hemoglobinopathy, myeloproliferative disorders.

2. Moderate to severe obstructive or restrictive lung disease: forced expiratory volume
in 1 second/forced vital capacity (FEV1/FVC) < 70% and FEV1 < 60% of predicted value
after bronchodilator administration. -or- total lung capacity (TLC) < 60% of
predicted.

3. Systemic systolic blood pressure <100 mmHg Breastfeeding

4. Significant liver, renal or other medical disease preventing completion of the study
procedures or with life expectancy <12 months, or any other acute or chronic physical
impairment (other than dyspnea), limiting the ability to comply with study
requirements