Spironolactone for Alzheimer's Disease

(STAND Trial)

Overseen By Antoine Trammell, MD, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Emory University

Must not be taking: RAAS modulators

Disqualifiers: Stroke, Renal disease, Hyperkalemia, others

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: 4

Duration: 12 months

30 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial requires that you do not take certain blood pressure medications, specifically those that affect the renin-angiotensin-aldosterone system (RAAS), like angiotensin II receptor blockers, ACE inhibitors, renin inhibitors, or aldosterone antagonists. If you are on these medications, you may need to stop them to participate.

What data supports the effectiveness of the drug spironolactone for Alzheimer's disease?

Research suggests that spironolactone, a mineralocorticoid receptor antagonist, may help reduce cognitive decline in Alzheimer's by increasing brain-derived neurotrophic factor (BDNF) levels, which can enhance learning and memory in animal models. ^{1 2 3 4 5}

How does the drug spironolactone work differently for Alzheimer's disease?

Spironolactone is unique because it may help reduce neuroinflammation (brain inflammation) in Alzheimer's disease by inhibiting microglial activation (a type of immune cell in the brain), although it does not directly improve memory. This anti-inflammatory effect is different from other Alzheimer's treatments that primarily focus on improving memory or reducing amyloid plaques. ^{1 2 3 6 7}

What is the purpose of this trial?

The purpose of this study is to investigate whether a blood pressure medication, spironolactone, can be tolerated by older African American adults that have memory and thinking problems, also called mild cognitive impairment (MCI). This study will also investigate the effect of spironolactone on memory and thinking abilities as measured by performance on cognitive tests, which are tests that measure memory and thinking skills. Participants will take spironolactone or a placebo for one year and will have 4 to 5 study visits during the study period.

Research Team

Antoine Trammell, MD, MPH

Principal Investigator

Emory University

Eligibility Criteria

This trial is for older African American adults with mild cognitive impairment or early Alzheimer's. Participants must be willing to follow the study procedures for a year, have certain blood pressure levels, and score within specific ranges on memory and thinking tests. It excludes those with severe medical issues, women who can become pregnant, recent stroke survivors, uncontrolled hypertension or heart failure.

Inclusion Criteria

Signed and dated informed consent form

I am willing and able to follow all study rules and attend all appointments.

My blood pressure meets the study's specific criteria.

Exclusion Criteria

I do not have kidney disease, high potassium, uncontrolled heart issues, or mental conditions affecting my thinking. My thyroid and vitamin B12 levels are normal.

My blood pressure is not well controlled.

I have difficulty understanding or following instructions.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive spironolactone or placebo for 12 months to assess tolerability and effects on cognitive function

12 months

4 to 5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including cognitive tests and ultrasound assessments

4 weeks

Treatment Details

Interventions

• Placebo
• Spironolactone

Trial Overview The trial is testing if spironolactone, a blood pressure medication, is safe for participants and if it affects their memory and thinking skills. Over one year, they'll take either spironolactone or a placebo while attending 4-5 study visits where their cognitive abilities will be assessed.

Participant Groups

Group I: Spironolactone Experimental Treatment 1 Intervention

Participants with mild cognitive impairment or early Alzheimer's Disease who are randomized to receive spironolactone for 12 months.

Group II: Placebo Placebo Group 1 Intervention

Participants with mild cognitive impairment or early Alzheimer's Disease who are randomized to receive a placebo to match spironolactone for 12 months.

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?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

Alzheimer's Association

Collaborator

Trials

103

Recruited

44,300+

Findings from Research

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]

Allopregnanolone was found to be safe and well tolerated in a trial involving 24 participants with early Alzheimer's disease, with no significant adverse events related to the treatment, indicating its potential as a therapeutic option.

The study established a maximum tolerated dose (MTD) for allopregnanolone, with pharmacokinetic data showing a predictable linear dose-response, supporting further investigation into its efficacy for Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, tolerability, and pharmacokinetics of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: A single and multiple ascending dose phase 1b/2a clinical trial. Hernandez, GD., Solinsky, CM., Mack, WJ., et al.[2022]

The study successfully isolated three known and five new steroidal impurities from spironolactone using various chromatographic methods, enhancing our understanding of the compound's composition.

The structures of the new compounds were elucidated through spectrometric analysis, providing valuable insights into their chemical properties and potential implications for the safety and efficacy of spironolactone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isolation and identification of novel impurities in spironolactone. Chen, H., Wang, YF., Yang, ZD., et al.[2013]

References

1. Iran pubmed.ncbi.nlm.nih.gov

The Effect of Spironolactone on β-amyloid-Induced Memory Impairment in Male Rats: The Role of Microglial Inhibition. [2022]

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

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

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

Mineralocorticoid receptor antagonist-mediated cognitive improvement in a mouse model of Alzheimer's type: possible involvement of BDNF-H2 S-Nrf2 signaling. [2021]

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

Safety, tolerability, and pharmacokinetics of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: A single and multiple ascending dose phase 1b/2a clinical trial. [2022]

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

Synthesis and antimineralocorticoid activities of some 7alpha-cyano and 7alpha-alkoxycarbonylamino steroidal spirolactones. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Isolation and identification of novel impurities in spironolactone. [2013]

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

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