Carvedilol PAH A Pilot Study of Efficacy and Safety

Study Overview
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Brief Summary
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Estimate the effect of chronic beta-adrenergic receptor blockade with carvedilol on RV function in patients with PAH. Assess the safety and tolerability of chronic carvedilol therapy in patients with PAH

Detailed Description
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This is a prospective, open label, uncontrolled, pilot study examining the safety and efficacy of beta-blocker therapy with carvedilol on RV function in stable PAH Patients with World Health Organization (WHO) functional class II or III symptoms and RV ejection fraction (EF) < 40%. Twenty-five evaluable patients will be enrolled at the University of Minnesota. Specific Aims: 1.1 Primary Efficacy Endpoint: Adult males and females on a stable dose of an approved PAH medication will undergo cardiac magnetic resonance imaging (MRI), right heart catheterization (RHC), echocardiogram, 6-minute walk test (6-MWT), measurement of plasma NT-ProBNP and serum catecholamine, and quality of life assessment. Patients will receive carvedilol (3.25 mg/kg bid escalating to 25 mg/kg bid over 3 months). Testing is repeated at the end of the study (month 6). RVEF measured by cardiac MRI is the primary efficacy endpoint. We define a 5% increase in RVEF as a meaningful change.

Official Title
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Beta Blockers in Pulmonary Arterial Hypertension (PAH) A Pilot Study of Efficacy and Safety

Conditions
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Pulmonary Hypertension, Cardiac MRI <40

Intervention / Treatment
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* Drug: Carvedilol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects will be eligible to participate in the study if all of the following conditions exist: Age > 18 years WHO category 1 pulmonary arterial hypertension (Dana Point 2008) WHO functional class II-III RVEF by cardiac MRI < 40% Mean pulmonary artery pressure > 40 mm Hg 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: 1. Subjects will be excluded from participation in the study if any of the following conditions exist: 2. Significant persistent bradycardia (resting heart rate < 60 bpm) without a permanent pacemaker 3. Second or third degree AV block without a permanent pacemaker 4. Significant sinus tachycardia (resting heart rate > 100 bpm) 5. Use of anti-arrhythmic drugs 6. Hypotension defined as systolic blood pressure < 100 mmHg at the time of enrollment 7. Significant illness in the past 30 days requiring hospitalization 8. Acute decompensated right heart failure within past 30 days 9. Known allergy or intolerance to carvedilol or other β blockers 10. Cardiac index < 2 l/min/m2 or right atrial pressure > 15 mm Hg 11. Asthma

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carvedilol<br>Carvedilol 0-3.125 mg daily Escalating to 6.25 twice a day | Drug: Carvedilol<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in RVEF | 1. The primary efficacy outcome is the mean change in RVEF as measured by cardiac MRI before and after 6 months of carvedilol treatment. An improvement of 5% will be considered to be clinically significant. Assessment of the RV is challenging due to its complex geometry. Cardiac MRI offers the ability to acquire 3-dimensional datasets that do not require geometric modeling. In addition to being highly reproducible40, RVEF measured by cardiac MRI can be used to identify PAH patients that are likely to have clinical worsening41. The prognostic ability of cardiac MRI-measurements of RVEF is similar to that as mean pulmonary artery pressure and exercise capacity | Baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absence of Adverse Events | The primary safety outcome is the absence of adverse events associated with carvedilol including hypotension (<90 mm Hg), bradycardia (<50 bpm or advanced atrioventricular nodal block), bronchospam, or acute decompensated right heart failure requiring hospitalization. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypertension, PAH