Spironolactone for Single Ventricle Heart Condition

Overseen By Cassandra L Giner, MS

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

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 All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

120 Participants Needed

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}

Research Team

Mark Fogel, MD

Principal Investigator

Children's Hospital of Philadelphia

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.

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

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

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

Spironolactone, traditionally used for hyperaldosteronism and as a diuretic, has been found to significantly reduce the risk of death in heart failure patients by 30%, as shown in the RALES clinical trial involving heart failure patients.

Beyond its effects on aldosterone receptors, spironolactone also improves heart function and vascular health by reducing fibrosis, improving endothelial function, and potentially treating conditions like left ventricular hypertrophy and acne, indicating its versatile therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The spironolactone renaissance. Doggrell, SA., Brown, L.[2019]

Spironolactone (SPIR) effectively reduces the production of proinflammatory cytokines like TNF-alpha, IL-6, and IFN-gamma in human immune cells, which may help improve outcomes in patients with congestive heart failure (CHF).

The inhibition of these cytokines occurs at the transcriptional level and does not rely on SPIR's known mineralocorticoid or antiandrogen effects, suggesting a novel mechanism contributing to its therapeutic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spironolactone inhibits production of proinflammatory cytokines by human mononuclear cells. Hansen, PR., Rieneck, K., Bendtzen, K.[2013]

In a study of 125 elderly patients with severe congestive heart failure (CHF) treated with spironolactone (SPL), adverse effects such as hyperkalemia and impaired renal function were found to be more common than previously reported, with 36% experiencing elevated potassium levels and 55% showing significant increases in serum creatinine.

The study highlights the need for careful monitoring and management of SPL treatment, especially in patients with an LVEF <20%, and suggests discontinuing potassium supplements and adjusting diuretic doses to mitigate risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How prevalent is hyperkalemia and renal dysfunction during treatment with spironolactone in patients with congestive heart failure? Svensson, M., Gustafsson, F., Galatius, S., et al.[2019]

Spironolactone (SP) encapsulated in nanostructured lipid carriers (NLCs) showed improved cell viability in rat heart cells (H9C2) at a concentration of 25 μM, while free SP was cytotoxic at the same concentration.

The study suggests that SP-NLCs can enhance cardiac tissue regeneration due to their sustained release profile, making them a promising approach for cardiac remodeling therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fabrication and Evaluation of Spironolactone-Loaded Nanostructured Lipid Carries for Cardiac Tissue Regeneration. Falak, M., Mehdikhani, M., Varshosaz, J., et al.[2022]

In a pilot study involving 25 dogs with compensated myxomatous mitral valve disease (MMVD), spironolactone did not significantly prevent the progression of heart disease compared to placebo, as measured by changes in left atrial to aortic ratio and left ventricular internal diameter.

Despite the lack of significant differences in disease progression, the study suggests that a larger clinical trial is warranted to further evaluate the effects of spironolactone in dogs with preclinical MMVD, as preliminary data indicate potential benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of dogs with compensated myxomatous mitral valve disease with spironolactone-a pilot study. Hezzell, MJ., Boswood, A., López-Alvarez, J., et al.[2018]

Spironolactone, at doses of 100 mg to 200 mg daily, is effective in treating androgen-excess conditions like severe hirsutism, especially when combined with oral contraceptives or dexamethasone.

While side effects are generally transient, spironolactone should be avoided during pregnancy and in women with a family history of breast cancer, despite no proven link to breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of spironolactone in treatment of hirsutism. Cumming, DC.[2019]

SC 23992 is a new spirolactone that shows two to eight times greater potency as an anti-aldosterone agent in vivo compared to Aldactone, although it has only about 10% potency in vitro.

This new compound may offer a safer alternative for patients, as it appears to have fewer antiandrogen side effects compared to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SC 23992: radioreceptor assays for therapeutic and side effects. Funder, JW., Mercer, J., Hood, J.[2019]

Spironolactone (Aldactone) has been effectively used in pediatric cardiology, showing good clinical results when combined with digitalis, particularly in cases of secondary hyperaldosteronism.

The recommended dosages for spironolactone vary by age, with careful monitoring for hyperkalemia, as treatment should be paused if serum potassium levels exceed 6 mval.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Experiences with aldactone in pediatric cardiology (author's transl)]. Wimmer, M., Bachl, G., Schlemmer, M., et al.[2013]

In a study of 25 mildly symptomatic patients with idiopathic dilated cardiomyopathy, treatment with spironolactone for 12 months improved left ventricular (LV) diastolic function and reduced chamber stiffness, particularly in patients with higher myocardial collagen accumulation.

The beneficial effects of spironolactone were associated with a reduction in myocardial fibrosis, as indicated by changes in collagen markers, suggesting that its efficacy may be more pronounced in patients with significant collagen buildup.

NCBI (Pubmed)

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. Izawa, H., Murohara, T., Nagata, K., et al.[2013]

Spironolactone is effective in managing both essential and hyperaldosterone-induced hypertension, whether used alone or in combination with other blood pressure medications.

At lower doses (less than 150 mg/d), spironolactone's adverse effects are generally manageable, making it a safe option for treating conditions like hypertension, cirrhosis, and congestive heart failure, while also serving as an antiandrogenic treatment for hirsutism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spironolactone: a re-examination. Skluth, HA., Gums, JG.[2019]

References

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

The spironolactone renaissance. [2019]

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

Spironolactone inhibits production of proinflammatory cytokines by human mononuclear cells. [2013]

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]

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

Fabrication and Evaluation of Spironolactone-Loaded Nanostructured Lipid Carries for Cardiac Tissue Regeneration. [2022]

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

Treatment of dogs with compensated myxomatous mitral valve disease with spironolactone-a pilot study. [2018]

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

Use of spironolactone in treatment of hirsutism. [2019]

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

SC 23992: radioreceptor assays for therapeutic and side effects. [2019]

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

[Experiences with aldactone in pediatric cardiology (author's transl)]. [2013]

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]

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

Spironolactone: a re-examination. [2019]