Spironolactone for Single Ventricle Heart Condition

Recruiting in Palo Alto (17 mi)

Overseen by Mark Fogel, MD

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Children's Hospital of Philadelphia

Must be taking: Spironolactone

Must not be taking: Eplerenone, Enalapril

Disqualifiers: Pacemaker, Hyperkalemia, Severe renal insufficiency, others

No Placebo Group

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

The purpose of this study is to non-invasively characterize the fibrotic consequences of single ventricle physiology, its possible solution and effect on lymphatics. This project investigates the response to acute imposition of Fontan hemodynamics by examining the interrelationship between liver and cardiac fibrosis/dysfunction and lymphatic congestion along with a pilot trial of the antifibrotic agent, spironolactone, to prevent these consequences and to determine if MRI can discern these differences. The combination of serum biomarkers and MRI form a powerful non-invasive tool in putting together this complicated web of dysfunction.

Will I have to stop taking my current medications?

If you are currently taking spironolactone, eplerenone, or certain blood pressure medications like enalapril, you may need to stop these before joining the trial. The protocol does not specify other medications, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Spironolactone for treating heart conditions?

Spironolactone has been shown to reduce the risk of death by 30% in patients with heart failure, improve heart function, and reduce hospitalizations. It also helps in reducing inflammation and improving heart tissue health, which may be beneficial for heart conditions. ^{1 2 3 4 5}

Is spironolactone generally safe for use in humans?

Spironolactone is generally well-tolerated in humans, with studies showing it is safe for treating conditions like heart failure and hirsutism. However, it can cause high potassium levels, so monitoring is important, especially in patients with heart conditions. ^{1 3 6 7 8}

How is the drug spironolactone unique for treating single ventricle heart condition?

Spironolactone is unique because it not only acts as a diuretic but also has direct effects on the heart, such as reducing cardiac fibrosis (scarring of heart tissue) and improving heart function, which may benefit patients with single ventricle heart conditions by potentially aiding in cardiac tissue regeneration and remodeling. ^{1 4 5 9 10}

Eligibility Criteria

This trial is for children aged 1 to less than 6 with a single ventricle heart defect, scheduled for Fontan surgery at CHOP. It includes those who agree to MRI scans under sedation and whose parents consent. Excluded are kids already on spironolactone or similar drugs, with severe kidney issues, hyperkalemia, Addison disease, or conditions making the trial harmful.

Inclusion Criteria

I am between 1 and 6 years old, scheduled for a Fontan operation at CHOP, and my parents have agreed.

I am between 1 and 6 years old, with a specific heart condition, and planning to have a Fontan operation at CHOP.

I am between 1 and 6 years old, scheduled for a Fontan operation at CHOP, and my parents have agreed.

Exclusion Criteria

Cohort 2 (Study Drug Group - Spironolactone): Subjects with any condition judged by the patient's physician that would cause this trial to be detrimental to the patient. Any contradiction to a sedated CMR (i.e. presence of a pacemaker). Patient currently taking spironolactone or eplerenone. Subjects with hyperkalemia or Addison disease. Subjects on enalapril or other angiotensin receptor blockers. Subjects with a history of hypersensitivity to spironolactone suspension or any component of the formulation. Subjects with a clinically documented diagnosis of severe renal insufficiency (implying estimated glomerular filtration rate (eGFR) <30 mL/minute/1.73 m2). Subjects in any study that would preclude participation in the study by altering results.

Cohort 1A (formerly part of study drug group who wish continued participation in the observational group): Subjects with any condition judged by the patient's physician that would cause this trial to be detrimental to the patient. Any contradiction to a sedated CMR (i.e. presence of a pacemaker). Subjects in any study that would preclude participation in the current study.

My doctor thinks this trial is not safe for me or I have a pacemaker, or I am on specific heart medications.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Fontan Assessment

Characterization and measurement of liver and cardiac fibrosis with MRI and CMR as well as serum biomarkers immediately prior to the Fontan operation

1-2 weeks

1 visit (in-person)

Post-Fontan Treatment

Administration of spironolactone and follow-up assessments including MRI and CMR to evaluate fibrosis and lymphatic function

1 year

Multiple visits (in-person) over 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment, including evaluation of liver and cardiac fibrosis and lymphatic function

4 weeks

Treatment Details

Interventions

• Spironolactone (Mineralocorticoid Receptor Antagonist)

Trial Overview The study tests if spironolactone can prevent heart and liver fibrosis in kids with single ventricle hearts facing Fontan surgery. It uses MRIs and blood markers to track changes non-invasively. Participants will be observed before and after starting the medication.

Participant Groups

Group I: Spironolactone Experimental Treatment 1 Intervention

Children will undergo characterization and measurement of liver and cardiac fibrosis with MRI and cardiac magnetic resonance (CMR) as well as serum biomarkers immediately prior to the Fontan operation. All SV children will undergo characterization and measurement of liver and cardiac fibrosis with MRI and cardiac magnetic resonance (CMR) as well as serum biomarkers \~1 year after the Fontan operation. Spironolactone is a mild diuretic. Drug dosage will be those used clinically and per the CHOP formulary: 3 mg/kg/day in divided doses every 6-24 hours; the drug will be weight adjusted every \~0.5 kg with a maximum dosage of 200 mg/24 hours. Maximum single dose is 100 mg. Spironolactone administration will begin after the Fontan procedure in the hospital prior to discharge or at the first outpatient visit \~ 2 weeks after discharge.

Group II: Observational Active Control 1 Intervention

Children will undergo characterization and measurement of liver and cardiac fibrosis with MRI and cardiac magnetic resonance (CMR) as well as serum biomarkers immediately prior to the Fontan operation. All SV children, whether they received spironolactone or not, will undergo characterization and measurement of liver and cardiac fibrosis with MRI and cardiac magnetic resonance (CMR) as well as serum biomarkers \~1 year after the Fontan operation. Demographics and medical history will be collected again along with adverse events. Children will also undergo CMR for evaluation of hemodynamics, ventricular function (including strain), computational modeling and lymphatic abnormalities. A few of these patients will be undergoing CMR for clinical reasons and study CMR related and study MRI related imaging and blood draws will be performed in coordination with their clinical care (ie these sequences will be added on to their clinical sequences).

Group III: Control Active Control 1 Intervention

The purpose of this study is to non-invasively characterize the fibrotic consequences of SV physiology, its possible solution and effect on lymphatics. This project investigates the response to acute imposition of Fontan hemodynamics by examining the interrelationship between liver and cardiac fibrosis/dysfunction and lymphatic congestion (figure 1) along with a pilot trial of the antifibrotic agent, spironolactone, to prevent these consequences and to determine if MRI can discern these differences. The combination of serum biomarkers and MRI form a powerful non-invasive tool in putting together this complicated web of dysfunction. Control subjects who are non-SV patients but who have normal heart function who are undergoing CMR for evaluation (eg patients undergoing CMR for vascular ring evaluation, family history of congenital heart disease but found to be normal, etc) will have study related MRI and CMR sequences performed.

Group IV: Observational - 1A Active Control 1 Intervention

Subjects who were enrolled in this study in Spironolactone arm and patient's family would like to continue participation. All SV children, whether they received spironolactone or not, will undergo characterization and measurement of liver and cardiac fibrosis with MRI and cardiac magnetic resonance (CMR) as well as serum biomarkers \~1 year after the Fontan operation. Demographics and medical history will be collected again along with adverse events. Children will also undergo CMR for evaluation of hemodynamics, ventricular function (including strain), computational modeling and lymphatic abnormalities. A few of these patients will be undergoing CMR for clinical reasons and study CMR related and study MRI related imaging and blood draws will be performed in coordination with their clinical care (ie these sequences will be added on to their clinical sequences).

Group V: Observational - 1B Active Control 1 Intervention

Subjects who were enrolled in other studies with intervention. All SV children, whether they received spironolactone or not, will undergo characterization and measurement of liver and cardiac fibrosis with MRI and cardiac magnetic resonance (CMR) as well as serum biomarkers \~1 year after the Fontan operation. Demographics and medical history will be collected again along with adverse events. Children will also undergo CMR for evaluation of hemodynamics, ventricular function (including strain), computational modeling and lymphatic abnormalities. A few of these patients will be undergoing CMR for clinical reasons and study CMR related and study MRI related imaging and blood draws will be performed in coordination with their clinical care (ie these sequences will be added on to their clinical sequences).

Spironolactone is already approved in United States, European Union for the following indications:

🇺🇸 Approved in United States as Aldactone for:

• High blood pressure
• Heart failure
• Liver scarring
• Kidney disease
• Low blood potassium
• Early puberty in boys
• Acne
• Excessive hair growth in women

🇪🇺 Approved in European Union as Aldactone for:

• Fluid retention due to heart failure
• Liver scarring
• Kidney disease
• High blood pressure
• Low blood potassium

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Children's Hospital of Philadelphia Philadelphia, PA

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia Lead Sponsor

National Heart, Lung, and Blood Institute (NHLBI) Collaborator

References

1. England pubmed.ncbi.nlm.nih.gov

The spironolactone renaissance. [2019] Until recently, spironolactone was considered only as an antagonist at the aldosterone receptors of the epithelial cells of the kidney and was used clinically in the treatment of hyperaldosteronism and, occasionally, as a K(+)-sparing diuretic. The spironolactone renaissance started with the experimental finding that spironolactone reversed aldosterone-induced cardiac fibrosis by a cardiac action. Experimentally, spironolactone also has direct effects on blood vessels. Spironolactone reduces vascular fibrosis and injury, inhibits angiogenesis, reduces vascular tone and reduces portal hypertension. The rationale for the Randomized Aldactone Evaluation Study (RALES) of spironolactone in heart failure was that 'aldosterone escape' occurred through non-angiotensin II mechanisms. The RALES clinical trial was stopped early when it was shown that there was a 30% reduction in risk of death among the spironolactone patients. In RALES, spironolactone also reduced hospitalisation for worsening heart failure and improved the symptoms of heart failure. Other recent clinical trials have shown that spironolactone reduces cardiac and vascular collagen turnover, improves heart variability, reduces ventricular arrhythmias, improves endothelial dysfunction and dilates blood vessels in human heart failure and these effects probably all contribute to the increased survival in heart failure. Spironolactone may also be useful in the treatment of left ventricular hypertrophy, portal hypertension and cirrhosis. There have also been some recent small clinical trials of spironolactone as an anti-androgen showing potential in acne, hirsutism and precocious puberty.

2. Netherlands pubmed.ncbi.nlm.nih.gov

Spironolactone inhibits production of proinflammatory cytokines by human mononuclear cells. [2013] The mineralocorticoid receptor antagonist spironolactone (SPIR) reduces the mortality and morbidity in patients with congestive heart failure (CHF). Overexpression of proinflammatory cytokines contribute to the development and progression of CHF.

3. United States pubmed.ncbi.nlm.nih.gov

How prevalent is hyperkalemia and renal dysfunction during treatment with spironolactone in patients with congestive heart failure? [2019] Treatment with spironolactone (SPL) is beneficial in patients with severe congestive heart failure (CHF). In the Randomized Aldactone Evaluation Study SPL was well tolerated, particularly with regard to renal function and serum K(+) levels. Our aim was to investigate whether the reported low frequency of adverse effects during SPL treatment in a heart failure study population could be confirmed in an unselected heart failure outpatient cohort and to identify potential predictors of harmful effects.

4. India pubmed.ncbi.nlm.nih.gov

Fabrication and Evaluation of Spironolactone-Loaded Nanostructured Lipid Carries for Cardiac Tissue Regeneration. [2022] Spironolactone (SP) is a lipophilic aldosterone receptor antagonist that few studies have reported its effect on cardiac remodeling. In addition, fewer researches have considered its influence on cardiomyocyte viability and potential benefits for myocardial tissue remodeling.

5. Netherlands pubmed.ncbi.nlm.nih.gov

Treatment of dogs with compensated myxomatous mitral valve disease with spironolactone-a pilot study. [2018] Spironolactone improves outcome in dogs with advanced myxomatous mitral valve disease (MMVD). Its efficacy in preclinical MMVD is unknown. The hypothesis was the administration of spironolactone to dogs with compensated MMVD demonstrating risk factors for poorer prognosis will decrease the rate of disease progression. The aim was to provide pilot data to evaluate preliminary effects and sample size calculation for a definitive clinical trial.

6. United States pubmed.ncbi.nlm.nih.gov

Use of spironolactone in treatment of hirsutism. [2019] Spironolactone (Aldactone), 100 mg to 200 mg daily, has antiandrogenic effects that may enhance treatment of androgen-excess syndromes, particularly severe hirsutism. Combination therapy with an oral contraceptive or with dexamethasone appears to have a beneficial effect. Side effects are transient. The drug should be avoided during pregnancy and in women who have a family history of breast cancer, although there is no proven association between spironolactone and breast malignancy.

7. England pubmed.ncbi.nlm.nih.gov

SC 23992: radioreceptor assays for therapeutic and side effects. [2019] 1. A new spirolactone (SC 23992) has been assayed in vitro to determine its affinity for mineralocorticoid and androgen receptors. 2. Although two to eight times as potent as anti-aldosterone agent as Aldactone in vivo, SC 23992 has only approximately 10% the potency in vitro. 3. This discrepancy between potency in vivo and in vitro appears to be explained on radioreceptor assay of the principal metabolites of Aldactone SC 23992. 4. SC 23992 may represent an antimineralocorticoid with less antiandrogen side effects.

8. Austria pubmed.ncbi.nlm.nih.gov

[Experiences with aldactone in pediatric cardiology (author's transl)]. [2013] In Pediatric Cardiology for many years the usage of spironolactone (Aldactone) and Canreonat-K+ (Aldactone pro injectione) had been experienced. The efficiency of aldactone was controlled by clinical parameters, electrolytes, discontinuity of the drug and in some cases by radioimmunologic measurement of the plasma aldosterone concentration. The treatment with aldactone in combination with digitalis gave good clinical results in cases with and without signs of secondary hyperaldosteronism. The recommended dosage i. v. and orally was for infancy 2--3 mg/kg/die the first 2--4 days and afterwards 1,5--2 mg/kg/die, for later childhood 4--5 mg/kg/die for 3--5 days and afterwards 2--3 mg/kg/die. Special attention should be paid to hyperkaliemia, over 6 mval serum K+ the aldactone administration was interrupted.

9. United States pubmed.ncbi.nlm.nih.gov

Mineralocorticoid receptor antagonism ameliorates left ventricular diastolic dysfunction and myocardial fibrosis in mildly symptomatic patients with idiopathic dilated cardiomyopathy: a pilot study. [2013] Mineralocorticoid receptor antagonism reduces mortality associated with heart failure by mechanisms that remain unclear. The effects of the mineralocorticoid receptor antagonist spironolactone on left ventricular (LV) function and chamber stiffness associated with myocardial fibrosis were investigated in mildly symptomatic patients with idiopathic dilated cardiomyopathy (DCM).

10. United States pubmed.ncbi.nlm.nih.gov

Spironolactone: a re-examination. [2019] A review of the aldosterone antagonist spironolactone is presented. It is effective both as monotherapy and in combination with other hypotensive agents in the control of both essential and hyperaldosterone-induced hypertension. It is useful as a diuretic in conditions such as cirrhosis and congestive heart failure, and is most commonly employed because of its potassium- and magnesium-sparing qualities. Spironolactone also has been used as an antiandrogenic agent in managing hirsutism. Its adverse effect profile, considered somewhat prohibitive in the past, is generally not significant when reasonably low doses (less than 150 mg/d) are used.