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Spironolactone Therapy in Chronic Stable Right HF Trial (STAR-HF)

Primary Purpose

Chronic Right-Sided Heart Failure, Pulmonary Arterial Hypertension, Pulmonary Hypertension, Primary, 2

Status
Completed
Phase
Phase 4
Locations
Canada
Study Type
Interventional
Intervention
Spironolactone
Placebo
PET/CT Scan: Two PET scans using 1. C-11 HED and 2. N-13 Ammonia or rubidium-82
Cardiac MRI (Gadolinium enhanced)
Sponsored by
Ottawa Heart Institute Research Corporation
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Right-Sided Heart Failure focused on measuring Mineralocorticoid receptor antagonist, Brain natriuretic peptide (BNP), Sympathetic Nervous System, Positron Emissions Tomography

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Ottawa Heart Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Spironolactone

Placebo

Arm Description

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.

Participants with chronic right-sided heart failure will receive placebo daily for a total duration of 12 weeks.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
Change in Cardiac Autonomic Nervous System Function
Heart rate variability
Change in Systemic Sympathetic Activation
Changes in plasma levels of epinephrine and norepinephrine
Change in Right Ventricle Structure
Changes in RV end-diastolic and end-systolic size.
Change in Right Ventricle Function
Changes in RV ejection fraction
Change in Right Ventricle areas of fibrosis
Changes in RV areas of fibrosis assessed with T1 weighted MR imaging.
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)
Change in Biomarkers of Fibrosis
Changes in biomarkers of fibrosis (ST2, PIINP, CITB, TIMP1, MMP-9)

Full Information

First Posted
September 28, 2017
Last Updated
January 5, 2023
Sponsor
Ottawa Heart Institute Research Corporation
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1. Study Identification

Unique Protocol Identification Number
NCT03344159
Brief Title
Spironolactone Therapy in Chronic Stable Right HF Trial
Acronym
STAR-HF
Official Title
Spironolactone Therapy in Chronic Stable Right HF Trial
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Completed
Study Start Date
April 1, 2018 (Actual)
Primary Completion Date
August 30, 2022 (Actual)
Study Completion Date
November 30, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Ottawa Heart Institute Research Corporation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief 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.
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Right-Sided Heart Failure, Pulmonary Arterial Hypertension, Pulmonary Hypertension, Primary, 2, Pulmonary Hypertension, Primary, 3, Pulmonary Hypertension, Primary, 4, Cardiomyopathy Right Ventricular
Keywords
Mineralocorticoid receptor antagonist, Brain natriuretic peptide (BNP), Sympathetic Nervous System, Positron Emissions Tomography

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Patients will be blinded to study treatment for the duration of the study. Clinicians will also be blinded to study drug assignment. Evaluation of all study results will be done blinded to treatment randomization. Because of the double-blind design, safety laboratory tests, and monitoring of potential side effects will be performed for each participant for the duration of the trial, regardless of the treatment arm.
Allocation
Randomized
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Spironolactone
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Participants with chronic right-sided heart failure will receive placebo daily for a total duration of 12 weeks.
Intervention Type
Drug
Intervention Name(s)
Spironolactone
Intervention Description
Spironolactone 12.5mg daily up to a maximum dose of 50 mg daily if tolerated for a total duration of 12 weeks.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo daily for a total of duration of 12 weeks
Intervention Type
Radiation
Intervention Name(s)
PET/CT Scan: Two PET scans using 1. C-11 HED and 2. N-13 Ammonia or rubidium-82
Intervention Description
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.
Intervention Type
Diagnostic Test
Intervention Name(s)
Cardiac MRI (Gadolinium enhanced)
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change in Ventricular Wall Stress
Description
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.
Time Frame
Baseline and 12 weeks
Secondary Outcome Measure Information:
Title
Change in Cardiac Sympathetic Nervous System Activity
Description
Changes in cardiac sympathetic activity, as assessed by an increase in 11[C]-hydroxy-ephedrine (HED) retention by cardiac PET imaging.
Time Frame
Baseline to 12 weeks
Title
Change in Cardiac Autonomic Nervous System Function
Description
Heart rate variability
Time Frame
Baseline to 12 weeks
Title
Change in Systemic Sympathetic Activation
Description
Changes in plasma levels of epinephrine and norepinephrine
Time Frame
Baseline to 12 weeks
Title
Change in Right Ventricle Structure
Description
Changes in RV end-diastolic and end-systolic size.
Time Frame
Baseline to 12 weeks
Title
Change in Right Ventricle Function
Description
Changes in RV ejection fraction
Time Frame
Baseline to 12 weeks
Title
Change in Right Ventricle areas of fibrosis
Description
Changes in RV areas of fibrosis assessed with T1 weighted MR imaging.
Time Frame
Baseline to 12 weeks
Title
Number of participants with treatment-related adverse events.
Description
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)
Time Frame
number of adverse events from baseline to 12 weeks.
Title
Change in Biomarkers of Fibrosis
Description
Changes in biomarkers of fibrosis (ST2, PIINP, CITB, TIMP1, MMP-9)
Time Frame
Baseline to 12 weeks
Other Pre-specified Outcome Measures:
Title
Change in Serum Aldosterone
Description
changes in plasma levels of aldosterone
Time Frame
Baseline to 12 weeks
Title
Change in Six Minute walk test
Description
Distance a participant can walk in a period of 6 walks.
Time Frame
Baseline, 6 weeks, 12 weeks
Title
Change in NYHA function class
Description
changes in NYHA functional class.
Time Frame
baseline to 12 weeks
Title
Change in Right heart failure Severity
Description
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
Time Frame
Baseline to 12 weeks
Title
Clinical Outcomes
Description
Hospitalization and/or all cause mortality
Time Frame
12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lisa Mielniczuk, MD
Organizational Affiliation
Ottawa Heart Institute Research Corporation
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Ottawa Heart Institute
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1Y4W7
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
There is no plan to share individual participant data with researchers outside of Dr. Mielniczuk's research team.

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Spironolactone Therapy in Chronic Stable Right HF Trial

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