Spironolactone Therapy in Chronic Stable Right HF Trial

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability and mechanistic effects of spironolactone, an aldosterone receptor antagonist, on sympathetic nervous system activity and right heart function and remodeling in patients with chronic right heart failure.

Detailed Description
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This study is a phase 4, single center, randomized, double blind, placebo-controlled trial evaluating the safety, tolerability and mechanistic effects of spironolactone, an aldosterone antagonist, on neurohormonal activity and remodeling in patients with chronic right heart failure (RHF). RHF is one of the most important predictors of prognosis in many cardiac disease states including pulmonary hypertension (PH), and left heart failure. Sympathetic nervous system activation plays an important role in the development and progression of heart failure. It remains to be determined whether there is a role for neurohormonal therapy in chronic right HF, but evidence points to the role of sympathetic nervous system stimulation and activation of the renin-angiotensin and aldosterone system as a contributor to progressive right heart failure. The study will determine if treatment with spironolactone is associated with reduction in right ventricular wall stress. In addition, the study aims to evaluate the effects of spironolactone on cardiac sympathetic activity assessed by HED(11 C-hydroxy-ephedrine) retention on PET(positron emission tomography) imaging, and global autonomic function assessed by heart rate variability. Approximately 30 patients with RHF will be randomized to receive either spironolactone daily or placebo.

Official Title
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Spironolactone Therapy in Chronic Stable Right HF Trial

Conditions
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Chronic Right-Sided Heart Failure, Pulmonary Arterial Hypertension, Pulmonary Hypertension, Primary, 2, Pulmonary Hypertension, Primary, 3, Pulmonary Hypertension, Primary, 4, Cardiomyopathy Right Ventricular

Intervention / Treatment
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* Drug: Spironolactone
* Drug: Placebo
* Radiation: PET/CT Scan: Two PET scans using 1. C-11 HED and 2. N-13 Ammonia or rubidium-82
* Diagnostic Test: Cardiac MRI (Gadolinium enhanced)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide a personally signed and dated inform consent form. Male or female ≥ 18 years. Able to comply with all study procedures. History of right heart failure (RHF) secondary to either: i) WHO, group 1 pulmonary arterial hypertension PAH OR ii) WHO group II PH with normal LV systolic function OR iii) WHO group III or IV PH OR iv) primary RV cardiomyopathy. Current NYHA II-IV RV dysfunction as measured by 2D echocardiogram: i)defined as a tricuspid annular plane systolic excursion (TAPSE) <16 mm ii) and /or a two dimensional fractional area change <35% on screening echo plus NT-proBNP>400 pg/ml Chronic use of diuretics Clinical stability: defined as no need for increased diuretics, hospitalization or emergency room visit 3 months prior to enrollment Exclusion Criteria: Patients on chronic MRA therapy or other potassium sparing diuretics. Baseline serum potassium>5 ummol/l. Estimated glomerular filtration rate <30 ml/min. LV ejection fraction <45%, Moderate or severe LV diastolic function, Moderate or severe aortic or valvular disease. Patients requiring augmentation of diuretics or otherwise not meeting definition for clinical stability. Severe Liver Failure (Child-Pugh Class C) Claustrophobia or inability lie still in a supine position Patients with contraindications to either PET or CMR imaging Pregnancy or lactation. Unable to provide consent and comply with follow up visits.

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: Parallel Assignment
Interventional Model Description: STAR-HF is a phase 4 single center, randomized, placebo controlled trial comparing spironolactone 12.5mg daily up to a maximum dose of 50 mg daily if tolerated to matching placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Spironolactone<br>Participants with chronic right-sided heart failure will receive spironolactone 12.5mg daily up to a maximum dose of 50 mg daily for a total duration of 12 weeks. | Drug: Spironolactone<br>* Spironolactone 12.5mg daily up to a maximum dose of 50 mg daily if tolerated for a total duration of 12 weeks.<br>Radiation: PET/CT Scan: Two PET scans using 1. C-11 HED and 2. N-13 Ammonia or rubidium-82<br>* At baseline and 12 weeks, all participants will undergo rest perfusion PET imaging according to standard protocols with either 82-Rb or N-13 NH3, followed by C-11 HED PET.<br>Diagnostic Test: Cardiac MRI (Gadolinium enhanced)<br>* At baseline and 12 weeks all participants will undergo cMR to assess RV function and structure. We will acquire precontrast T2 and native T1 maps, and post gadolinium T1 maps.<br>|
| Placebo Comparator: Placebo<br>Participants with chronic right-sided heart failure will receive placebo daily for a total duration of 12 weeks. | Drug: Placebo<br>* Placebo daily for a total of duration of 12 weeks<br>Radiation: PET/CT Scan: Two PET scans using 1. C-11 HED and 2. N-13 Ammonia or rubidium-82<br>* At baseline and 12 weeks, all participants will undergo rest perfusion PET imaging according to standard protocols with either 82-Rb or N-13 NH3, followed by C-11 HED PET.<br>Diagnostic Test: Cardiac MRI (Gadolinium enhanced)<br>* At baseline and 12 weeks all participants will undergo cMR to assess RV function and structure. We will acquire precontrast T2 and native T1 maps, and post gadolinium T1 maps.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Ventricular Wall Stress | To determine if treatment with spironolactone is associated with a significant reduction in RV ventricular wall stress, as reflected by a reduction in serum NT-proBNP, in patients with chronic stable right HF when compared to placebo. | Baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cardiac Sympathetic Nervous System Activity | Changes in cardiac sympathetic activity, as assessed by an increase in 11[C]-hydroxy-ephedrine (HED) retention by cardiac PET imaging. | Baseline to 12 weeks | 
| Change in Cardiac Autonomic Nervous System Function | Heart rate variability | Baseline to 12 weeks | 
| Change in Systemic Sympathetic Activation | Changes in plasma levels of epinephrine and norepinephrine | Baseline to 12 weeks | 
| Change in Right Ventricle Structure | Changes in RV end-diastolic and end-systolic size. | Baseline to 12 weeks | 
| Change in Right Ventricle Function | Changes in RV ejection fraction | Baseline to 12 weeks | 
| Change in Right Ventricle areas of fibrosis | Changes in RV areas of fibrosis assessed with T1 weighted MR imaging. | Baseline to 12 weeks | 
| Number of participants with treatment-related adverse events. | 1. incidence of worsening renal function (defined as a change in estimated glomerular filtration rate>30%). 2. Incidence of hyperkalemia (>4.5, 5 or 5.5 mmol/L) | number of adverse events from baseline to 12 weeks. | 
| Change in Biomarkers of Fibrosis | Changes in biomarkers of fibrosis (ST2, PIINP, CITB, TIMP1, MMP-9) | Baseline to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mineralocorticoid receptor antagonist, Brain natriuretic peptide (BNP), Sympathetic Nervous System, Positron Emissions Tomography