Fluoxetine in Pulmonary Arterial Hypertension (PAH) Trial

Study Overview
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Brief Summary
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This protocol describes an open-label phase 2 clinical trial of fluoxetine in PAH looking at change in pulmonary vascular resistance (PVR) as the primary endpoint. In this open-label clinical trial, 18 patients with pulmonary arterial hypertension will be given fluoxetine for 24 weeks. A Right Heart Catheterization will be performed at baseline and 24 weeks. Change in PVR will be the primary endpoint; other hemodynamic endpoints, quality of life, QIDS-SR depression scale, functional class and six-minute walk distance will also be evaluated. Primary Hypothesis: Fluoxetine treatment for 24 weeks will lead to significantly lower pulmonary vascular resistance in 18 patients with PAH in patients treated in an open-label clinical trial.

Official Title
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A Phase 2, Open-label, Clinical Trial of Fluoxetine, a Selective Serotonin Reuptake Inhibitor, in the Treatment of Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Fluoxetine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: WHO Group I PAH subtypes of idiopathic PAH and PAH associated with drugs / toxins, connective tissue disease, repaired congenital heart disease and unrepaired atrial septal defect Age 16-80 WHO Functional Class II or III Right Heart Catheterization within 3 weeks of study entry with mPAP ≥ 25 mmHg, wedge ≤ 15 mmHg, and PVR ≥ 3 Wood units. Contraception use, (-) urine pregnancy test, not breast feeding (women of childbearing potential) One or more approved PAH therapies for ≥ 3 months, no change in dose for 1 month (endothelin-1 antagonist, phosphodiesterase-5 inhibitor, prostacyclin / prostacyclin analog). Novel approved therapies in one of the three existing classes will also be acceptable as background therapy if they become available during the course of the study; other medication classes are excluded Exclusion Criteria: WHO Functional Class IV or listed for lung transplant Moderate or greater obstructive lung disease: FEV1/FVC <70% and FEV1 <60% Moderate or greater restrictive lung disease: TLC or FVC <60% (if 50-60%: OK if TLC or FVC ≥50% + PFT stable x1 year + CT with no more than mild lung disease) Other cause for pulmonary hypertension: all other WHO group I diseases (including but not limited to liver disease, HIV), and WHO Groups II-V (i.e. left heart disease, lung disease, chronic PE and miscellaneous causes)24. High probability VQ or positive CTA Left ventricular ejection fraction <40% Depression Severe liver, renal or other medical or physical disease preventing completion of the study procedures Use of antidepressants within 3 months

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Fluoxetine<br>Dosing will be Week 1-4: 20 mg daily Week 5-8: 40 mg daily Week 9-12: 60 mg daily Week 13-24: 80 mg daily | Drug: Fluoxetine<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary Vascular Resistance (PVR) | Change in PVR between baseline and follow-up will be utilized. PVR is calculated as [(Pulmonary Artery mean - wedge) / Fick Cardiac Output]. Fick CO will be used in computing PVR over thermodilution because Fick appears to have greater precision (but not accuracy). The calculation of PVR above is measured in woods unit. Change is derived by getting the difference between baseline and week 24 PVR (Week 24 minus Baseline). mean is then computed by getting the average of the change | Baseline and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-HIAA (HYDROXYINDOLE ACETIC ACID) Level | Urine for spot urine 5-HIAA will be collected at baseline and Week 24. Subjects will be on diet restriction 72 hours prior to urine collection. Sample will be the first morning urine on the visit day. Sample will be brought to site and then sent to affiliate outside laboratory for processing. 5HIAA results are expressed as a ratio to creatinine excretion in the unit mg/g creatinine Change 5-HIAA is derived by getting the difference between baseline and week 24 5HIAA results (Week 24 minus Baseline). mean is then computed by getting the average of the change | Baseline and Week 24 |