Spironolactone for Stroke Recovery

(REDUCE Trial)

Recruiting at 4 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yale University

Disqualifiers: Pregnancy, eGFR <45, Addison's, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 year

200 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, if you are on mineralocorticoid antagonist therapy, you may need to discontinue it for 3-12 months, depending on the investigator's discretion.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but if you are on a mineralocorticoid antagonist (a type of medication), you may need to stop it for 3-12 months if the investigator decides it's necessary.

What data supports the idea that Spironolactone for Stroke Recovery is an effective drug?

The available research shows that Spironolactone can help reduce the size of brain damage after a stroke in rats. It improves the structure of blood vessels in the brain, which is important for recovery. In mice, Spironolactone also reduces harmful substances in the brain and increases helpful factors that protect brain cells and improve blood flow. This leads to a smaller area of damage in the brain. These findings suggest that Spironolactone may be effective in helping the brain recover after a stroke. ^{1 2 3 4 5}

What evidence supports the effectiveness of the drug spironolactone for stroke recovery?

Research shows that spironolactone can reduce the size of brain damage after a stroke in certain animal models by improving blood vessel structure and promoting brain healing. It also helps protect the brain by reducing harmful substances and encouraging the growth of new blood vessels and brain cells. ^{1 2 3 4 6}

What safety data is available for spironolactone?

Spironolactone has been studied for various conditions, including resistant hypertension, pediatric cardiology, and hirsutism. It is known to have antiandrogenic effects and can cause side effects like hyperkalemia. In pediatric cardiology, careful monitoring of electrolytes is recommended. It should be avoided during pregnancy and in women with a family history of breast cancer. New derivatives like SC 23992 show potential for fewer side effects. ^{4 7 8 9 10}

Is spironolactone generally safe for humans?

Spironolactone has been used safely in humans for conditions like high blood pressure and heart issues, but it can cause side effects like high potassium levels, which need monitoring. It has been studied for its effects on hormones, and newer versions aim to reduce these side effects. ^{4 7 8 9 11}

Is the drug Spironolactone a promising treatment for stroke recovery?

Yes, Spironolactone shows promise for stroke recovery. It helps improve the structure of blood vessels in the brain, reduces damage from strokes, and encourages the growth of new blood vessels and brain cells. This can lead to better blood flow and less brain damage after a stroke. ^{1 2 5 10 12}

How does the drug Spironolactone differ from other treatments for stroke recovery?

Spironolactone is unique in stroke recovery because it blocks mineralocorticoid receptors, reducing harmful superoxide production and promoting the growth of new blood vessels and nerve cells in the brain, which can help reduce brain damage after a stroke. ^{1 2 5 10 12}

What is the purpose of this trial?

The purpose of this research study is to determine whether blood pressure treatment regimens with spironolactone are better than blood pressure treatment regimens without spironolactone at lowering blood pressure in stroke survivors.

Eligibility Criteria

This trial is for adults over 18 who've had a stroke confirmed by CT or MRI, or have persistent symptoms of ischemic injury. They must be able to follow the study plan and not be pregnant, breastfeeding, or planning pregnancy. People with life expectancy under a year, severe kidney issues, high potassium levels, large upper arm circumference (>17 inches), extreme blood pressure values, Addison's disease or allergies to spironolactone can't join.

Inclusion Criteria

Written, informed consent by patient or surrogate

I have had a stroke or brain bleed confirmed by a scan.

Ability to comply with all study procedures and available for the duration of the study

Exclusion Criteria

Pregnancy, planned pregnancy, or breastfeeding

You are not expected to live for more than 1 year.

Your blood test results showed high levels of potassium on two recent tests before joining the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

3 weeks

Treatment

Participants receive either spironolactone-containing antihypertensive regimens or standard antihypertensive regimens for blood pressure control

1 year

Regular assessments for home BP readings

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Treatment Details

Interventions

• Spironolactone

Trial Overview The study is testing if adding the pill spironolactone to regular blood pressure treatments helps better control blood pressure in people recovering from strokes compared to standard treatment without it.

Participant Groups

Group I: Spironolactone Experimental Treatment 1 Intervention

Participants randomized to the Spironolactone arm will be receiving Spironolactone in addition to their normal routine blood pressure treatment.

Group II: Standard Care Active Control 1 Intervention

Participants randomized to the Standard care arm will be receiving their normal routine blood pressure treatment.

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?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

American Heart Association

Collaborator

Trials

352

Recruited

6,196,000+

Findings from Research

Chronic treatment with spironolactone in male spontaneously hypertensive stroke-prone rats (SHRSP) for 6 weeks improved the structure of the middle cerebral artery, leading to increased lumen and outer diameters, which may help reduce ischemic stroke risk.

The effects of spironolactone on cerebral artery structure occurred independently of blood pressure changes, suggesting a direct protective mechanism against ischemic damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spironolactone improves structure and increases tone in the cerebral vasculature of male spontaneously hypertensive stroke-prone rats. Rigsby, CS., Pollock, DM., Dorrance, AM.[2018]

In a mouse model of stroke, mineralocorticoid receptors (MRs) were found to increase significantly in the ischemic brain, particularly in astrocytes, during the acute and subacute phases after cerebral ischemia.

Treatment with the MR antagonist spironolactone not only reduced harmful superoxide production but also enhanced the expression of neuroprotective factors like bFGF and VEGF, leading to reduced apoptosis and a significant decrease in infarct volume, suggesting its potential as a neuroprotective therapy after stroke.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of mineralocorticoid receptor expression in brain remodeling after cerebral ischemia. Oyamada, N., Sone, M., Miyashita, K., et al.[2021]

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, a potassium-sparing diuretic, effectively lowers blood pressure in patients with resistant hypertension, showing an average reduction of 22/10 mm Hg in several studies involving both prospective and retrospective designs.

While spironolactone is beneficial for managing resistant hypertension, it can cause significant side effects such as hyperkalemia, gynecomastia, and renal insufficiency, which require careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spironolactone management of resistant hypertension. Marrs, JC.[2013]

A four-week treatment with high-dose spironolactone (100 mg four times daily) significantly increased the TSH and T3 responses to TRH/LH-RH injections in six women, indicating enhanced pituitary-thyroid function.

Spironolactone did not affect baseline hormone levels (TSH, T3, T4, LH, FSH, prolactin) or sex hormones, suggesting its effects may be due to its antiandrogenic properties, potentially modulating TRH receptor levels in the pituitary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pituitary-thyroid function in spironolactone treated hypertensive women. Smals, AG., Kloppenborg, PW., Hoefnagels, WH., et al.[2019]

A new steroidal compound, the 15 beta,16 beta-methylene derivative 17, was developed and showed twice the aldosterone antagonistic potency compared to the standard drug spironolactone.

This new compound also demonstrated significantly reduced antiandrogenic side effects, suggesting it could be a safer alternative for patients needing aldosterone antagonism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aldosterone antagonists. 3. Synthesis and activities of steroidal 7 alpha-(alkoxycarbonyl)-15,16-methylene spirolactones. Nickisch, K., Bittler, D., Laurent, H., et al.[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]

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, 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]

Spironolactone is effective as an off-label treatment for various dermatological conditions in females, particularly those related to excess androgen production, such as acne, hirsutism, and female pattern hair loss.

The drug works by blocking aldosterone receptors and has antiandrogenic properties, but it is important to monitor for potential adverse effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spironolactone in dermatology: uses in acne and beyond. Searle, TN., Al-Niaimi, F., Ali, FR.[2021]

References

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

Spironolactone improves structure and increases tone in the cerebral vasculature of male spontaneously hypertensive stroke-prone rats. [2018]

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

The role of mineralocorticoid receptor expression in brain remodeling after cerebral ischemia. [2021]

3. England pubmed.ncbi.nlm.nih.gov

The spironolactone renaissance. [2019]

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

Spironolactone management of resistant hypertension. [2013]

5. Denmark pubmed.ncbi.nlm.nih.gov

Pituitary-thyroid function in spironolactone treated hypertensive women. [2019]

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

Intact female stroke-prone hypertensive rats lack responsiveness to mineralocorticoid receptor antagonists. [2020]

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

Aldosterone antagonists. 3. Synthesis and activities of steroidal 7 alpha-(alkoxycarbonyl)-15,16-methylene spirolactones. [2019]

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

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

9. England pubmed.ncbi.nlm.nih.gov

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

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

Use of spironolactone in treatment of hirsutism. [2019]

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

Isolation and identification of a sulfur-containing metabolite of spironolactone from human urine. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Spironolactone in dermatology: uses in acne and beyond. [2021]