Spironolactone Therapy in Chronic Stable Right HF Trial

Pulmonary Arterial Hypertension Clinical Trial

— STAR-HF  

Official title:

Spironolactone Therapy in Chronic Stable Right HF Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03344159
• Other study ID #: 20170694
• Status: Completed
• Phase: Phase 4
• Start date: April 1, 2018
• Est. completion date: November 30, 2022

Study information

• Verified date: January 2023
• Source: Ottawa Heart Institute Research Corporation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: November 30, 2022
• Est. primary completion date: August 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

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

Intervention

Drug:
• Spironolactone
Spironolactone 12.5mg daily up to a maximum dose of 50 mg daily if tolerated for a total duration of 12 weeks.
• Placebo
Placebo daily for a total of duration of 12 weeks

Radiation:
• PET/CT Scan: Two PET scans using 1. C-11 HED and 2. N-13 Ammonia or rubidium-82
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.

Diagnostic Test:
• Cardiac MRI (Gadolinium enhanced)
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.

Locations

Country	Name	City	State
Canada	University of Ottawa Heart Institute	Ottawa	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
Ottawa Heart Institute Research Corporation

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in Serum Aldosterone	changes in plasma levels of aldosterone	Baseline to 12 weeks
Other	Change in Six Minute walk test	Distance a participant can walk in a period of 6 walks.	Baseline, 6 weeks, 12 weeks
Other	Change in NYHA function class	changes in NYHA functional class.	baseline to 12 weeks
Other	Change in Right heart failure Severity	Worsening right HF- defined as need for increase in diuretic dose or open-label initiation of a potassium sparing diuretic, or hospitalization or need for IV diuretics	Baseline to 12 weeks
Other	Clinical Outcomes	Hospitalization and/or all cause mortality	12 weeks
Primary	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	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
Secondary	Change in Cardiac Autonomic Nervous System Function	Heart rate variability	Baseline to 12 weeks
Secondary	Change in Systemic Sympathetic Activation	Changes in plasma levels of epinephrine and norepinephrine	Baseline to 12 weeks
Secondary	Change in Right Ventricle Structure	Changes in RV end-diastolic and end-systolic size.	Baseline to 12 weeks
Secondary	Change in Right Ventricle Function	Changes in RV ejection fraction	Baseline to 12 weeks
Secondary	Change in Right Ventricle areas of fibrosis	Changes in RV areas of fibrosis assessed with T1 weighted MR imaging.	Baseline to 12 weeks
Secondary	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.
Secondary	Change in Biomarkers of Fibrosis	Changes in biomarkers of fibrosis (ST2, PIINP, CITB, TIMP1, MMP-9)	Baseline to 12 weeks