Beta-blockers in Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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The investigators will conduct a, randomized, phase 2, placebo-controlled, double-blinded, crossover trial of carvedilol in 26 PAH patients with World Health Organization functional class II or III symptoms and RV ejection fraction (EF) < 45% for 6 months.

Detailed Description
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Adult PAH patients on a stable dose of an approved PAH medication will undergo the following baseline assessments: cardiac magnetic resonance imaging (MRI), right heart catheterization (RHC), echocardiogram, 6-minute walk test (6-MWT), plasma NT-ProBNP (biomarkers of RV function) and serum catecholamine (measure of sympathetic activation), and quality of life. Patients will be randomized to carvedilol (3.125 mg bid and escalated to 9.375 mg bid, as tolerated, over 3 months) or placebo in a 1:1 fashion. After 6 months, testing is repeated and patients are crossed over to the alternate treatment. Testing is repeated at the end of the study (month 13).

Official Title
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Beta-blockers in Pulmonary Arterial Hypertension - A Phase 2 Double-Blind, Placebo-Controlled, Crossover Study Evaluating the Efficacy, and Safety of Carvedilol for Right Ventricular Dysfunction in Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Carvedilol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years WHO category 1 pulmonary arterial hypertension (Nice 2013) WHO functional class II-III RVEF by cardiac MRI < 45% Stable on PAH-specific therapy as defined by no change in PAH-specific treatment and functional class in the past 3 months. Patient can be on either mono or combination PAH-specific therapy Exclusion Criteria: Subjects will be excluded from participation in the study if any of the following conditions exist: Significant persistent bradycardia (resting heart rate < 60 bpm) without a permanent pacemaker Second or third degree AV block without a permanent pacemaker Significant sinus tachycardia (resting heart rate > 110 bpm) Use of anti-arrhythmic drugs Hypotension defined as systolic blood pressure < 100 mmHg at the time of enrollment Significant illness in the past 30 days requiring hospitalization Acute decompensated right heart failure within past 30 days Known allergy or intolerance to carvedilol or other β blockers Cardiac index < 2 l/min/m2 or right atrial pressure > 15 mm Hg by right heart catheterization within last 3 months Asthma Positive pregnancy test in patients of child bearing-potential

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carvedilol First<br>Crossover Design: Participants receive Carvedilol first and placebo second | Drug: Carvedilol<br>* Beta-adrenergic receptor blocker<br>* Other names: Beta-blockers;Drug: Placebo<br>* Placebo<br>|
| Placebo Comparator: Placebo First<br>Crossover Design: Participants receive placebo first and Carvedilol second | Drug: Carvedilol<br>* Beta-adrenergic receptor blocker<br>* Other names: Beta-blockers;Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Right Ventricular Ejection Fraction as Measured by Cardiac MRI |  | 6 months |