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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding spironolactone, a medication for high blood pressure, to standard treatments more effectively lowers blood pressure in stroke recovery patients. Two groups participate: one receives spironolactone with their usual medication, while the other continues with their regular treatment. Individuals who have experienced a stroke and have symptoms lasting more than a day may be suitable for this study. Participants must follow study procedures and be available for the trial's duration. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that spironolactone is likely to be safe for humans?

Research shows that spironolactone is usually safe and well-tolerated by many people. One study found that spironolactone reduced deaths by 30% in people with heart conditions compared to those not taking it. However, some discontinued spironolactone due to concerns about side effects like low blood pressure and high potassium levels.

In another study, about 16% of patients with heart failure taking spironolactone experienced these side effects. This suggests that while spironolactone is often safe, it can have some side effects. Discussing these potential risks with a healthcare provider is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for stroke recovery?

Spironolactone is unique for stroke recovery because, unlike typical blood pressure treatments, it acts as an aldosterone antagonist. Most standard treatments focus on lowering blood pressure directly, but Spironolactone works by blocking the effects of aldosterone, a hormone that can negatively affect blood vessels and the heart. Researchers are excited about its potential to not only manage blood pressure but also offer additional benefits in repairing and protecting the brain post-stroke, which could enhance recovery outcomes.

What evidence suggests that spironolactone might be an effective treatment for stroke recovery?

Research has shown that spironolactone can help manage blood pressure, which is crucial for stroke recovery. In this trial, participants in the Spironolactone arm will receive spironolactone alongside their regular blood pressure treatment. Studies have found that spironolactone lowers the risk of various types of strokes, including those caused by blockages and bleeding. In animal studies, spironolactone improved brain health in rats prone to strokes, suggesting potential benefits for stroke survivors. Additionally, spironolactone has proven more effective when combined with other treatments for difficult-to-control high blood pressure. These findings suggest that spironolactone could aid in managing blood pressure in stroke survivors, possibly enhancing their recovery. ^{1 6 7 8 9}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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, 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, 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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04760717

Study Details | NCT04760717 | Regulating Blood Pressure ... The purpose of this research study is to determine whether blood pressure treatment regimens with spironolactone are better than blood pressure treatment ...

2. withpower.com withpower.com/trial/phase-3-cerebral-hemorrhage-2-2021-14f5c

Spironolactone for Stroke Recovery (REDUCE Trial) Chronic treatment with spironolactone in male spontaneously hypertensive stroke-prone rats (SHRSP) for 6 weeks improved the structure of the middle cerebral ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9861555/

Association between Use of Spironolactone and Risk ... The use of spironolactone was statistically significant in reducing total stroke events, ischemic stroke events, and hemorrhagic stroke events according to ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10238046/

Cohort study of add-on antihypertensives for treatment of ... The effectiveness of spironolactone in TRH observed in our study was higher than efficacy reported by key randomized clinical trials. In a ...

5. nephjc.com nephjc.com/news/achieve

In ESRD is spironolactone an overACHIEVEr? After reviewing interim data, which included 508 reported primary outcome events (78% of the total expected), the external safety and efficacy ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04760717

Study Details | NCT04760717 | Regulating Blood Pressure ... The purpose of this research study is to determine whether blood pressure treatment regimens with spironolactone are better than blood pressure treatment ...

7. nejm.org nejm.org/doi/full/10.1056/NEJMoa2405923

Routine Spironolactone in Acute Myocardial Infarction All-cause mortality (the primary outcome) was 30% lower in the spironolactone group than in the placebo group, and the frequency of ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38415888/

Effectiveness and safety of early treatment with ... Safety outcomes were hypotension and hyperkalemia at 90 days. Results: Among 2318 HFrEF patients, 368 (15.9%) were treated with spironolactone ...

9. nature.com nature.com/articles/s41591-024-03263-5

Low-dose spironolactone and cardiovascular outcomes in ... We found that spironolactone was frequently discontinued due to safety concerns, with no evidence that it reduced cardiovascular outcomes in people with stage ...