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

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ClinicalTrials.gov Identifier: NCT03344159
Recruitment Status : Recruiting
First Posted : November 17, 2017
Last Update Posted : April 18, 2019
Sponsor:
Information provided by (Responsible Party):
Lisa Mielniczuk, Ottawa Heart Institute Research Corporation

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.

Condition or disease Intervention/treatment Phase
Chronic Right-Sided Heart Failure Pulmonary Arterial Hypertension Pulmonary Hypertension, Primary, 2 Pulmonary Hypertension, Primary, 3 Pulmonary Hypertension, Primary, 4 Cardiomyopathy Right Ventricular 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) Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes 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.
Primary Purpose: Treatment
Official Title: Spironolactone Therapy in Chronic Stable Right HF Trial
Actual Study Start Date : April 1, 2018
Estimated Primary Completion Date : January 1, 2020
Estimated Study Completion Date : December 30, 2021


Arm Intervention/treatment
Experimental: Spironolactone
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
Spironolactone 12.5mg daily up to a maximum dose of 50 mg daily if tolerated for a total 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.

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




Primary Outcome Measures :
  1. Change in Ventricular Wall Stress [ Time Frame: Baseline and 12 weeks ]
    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 :
  1. Change in Cardiac Sympathetic Nervous System Activity [ Time Frame: Baseline to 12 weeks ]
    Changes in cardiac sympathetic activity, as assessed by an increase in 11[C]-hydroxy-ephedrine (HED) retention by cardiac PET imaging.

  2. Change in Cardiac Autonomic Nervous System Function [ Time Frame: Baseline to 12 weeks ]
    Heart rate variability

  3. Change in Systemic Sympathetic Activation [ Time Frame: Baseline to 12 weeks ]
    Changes in plasma levels of epinephrine and norepinephrine

  4. Change in Right Ventricle Structure [ Time Frame: Baseline to 12 weeks ]
    Changes in RV end-diastolic and end-systolic size.

  5. Change in Right Ventricle Function [ Time Frame: Baseline to 12 weeks ]
    Changes in RV ejection fraction

  6. Change in Right Ventricle areas of fibrosis [ Time Frame: Baseline to 12 weeks ]
    Changes in RV areas of fibrosis assessed with T1 weighted MR imaging.

  7. Number of participants with treatment-related adverse events. [ Time Frame: number of adverse events from baseline to 12 weeks. ]
    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)

  8. Change in Biomarkers of Fibrosis [ Time Frame: Baseline to 12 weeks ]
    Changes in biomarkers of fibrosis (ST2, PIINP, CITB, TIMP1, MMP-9)


Other Outcome Measures:
  1. Change in Serum Aldosterone [ Time Frame: Baseline to 12 weeks ]
    changes in plasma levels of aldosterone

  2. Change in Six Minute walk test [ Time Frame: Baseline, 6 weeks, 12 weeks ]
    Distance a participant can walk in a period of 6 walks.

  3. Change in NYHA function class [ Time Frame: baseline to 12 weeks ]
    changes in NYHA functional class.

  4. Change in Right heart failure Severity [ Time Frame: Baseline to 12 weeks ]
    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

  5. Clinical Outcomes [ Time Frame: 12 weeks ]
    Hospitalization and/or all cause mortality



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03344159


Contacts
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Contact: Rosemary Dunne, RN 613 696 7000 ext 19295 rdunne@ottawaheart.ca
Contact: Jason Zelt, MSc 613 696 7000 ext 19744 jzelt@ottawaheart.ca

Locations
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Canada, Ontario
University of Ottawa Heart Institute Recruiting
Ottawa, Ontario, Canada, K1Y4W7
Contact: Lisa Mielniczuk, MD    613 696 7274    lmielniczuk@ottawaheart.ca   
Contact: Rosemary Dunne, RN    613 696 7000 ext 19295    rdunne@ottawaheart.ca   
Principal Investigator: Lisa Mielniczuk, MD         
Sub-Investigator: Rob Beanlands, MD         
Sub-Investigator: George Wells, PhD         
Sub-Investigator: Peter Liu, MD         
Sub-Investigator: Rob DeKemp, PhD         
Sub-Investigator: Elena Pena, MD         
Sub-Investigator: George Chandy, MD         
Sub-Investigator: Vladimir Contreras, MD         
Sub-Investigator: Rebecca Thornhill, PhD         
Sub-Investigator: Jason Zelt, MSc         
Sponsors and Collaborators
Ottawa Heart Institute Research Corporation
Investigators
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Principal Investigator: Lisa Mielniczuk, MD Ottawa Heart Institute Research Corporation

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Responsible Party: Lisa Mielniczuk, Director, Heart Failure Program, Medical Co-Director, Pulmonary Hypertension Program, Ottawa Heart Institute Research Corporation
ClinicalTrials.gov Identifier: NCT03344159     History of Changes
Other Study ID Numbers: 20170694
First Posted: November 17, 2017    Key Record Dates
Last Update Posted: April 18, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is no plan to share individual participant data with researchers outside of Dr. Mielniczuk's research team.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Lisa Mielniczuk, Ottawa Heart Institute Research Corporation:
Mineralocorticoid receptor antagonist
Brain natriuretic peptide (BNP)
Sympathetic Nervous System
Positron Emissions Tomography
Additional relevant MeSH terms:
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Mineralocorticoid Receptor Antagonists
Hypertension, Pulmonary
Familial Primary Pulmonary Hypertension
Hypertension
Heart Failure
Cardiomyopathies
Dextrocardia
Vascular Diseases
Cardiovascular Diseases
Heart Diseases
Lung Diseases
Respiratory Tract Diseases
Heart Defects, Congenital
Cardiovascular Abnormalities
Congenital Abnormalities
Situs Inversus
Spironolactone
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents