Bumetanide for Alzheimer's Disease

(BumxAD Trial)

Overseen By Mina L Kim

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Stanford University

Must not be taking: Lithium, Ototoxic drugs

Disqualifiers: Chronic liver disease, Renal insufficiency, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This study aims to investigate bumetanide in patients with biologically confirmed Alzheimer's disease (AD). Bumetanide is a potent diuretic administered orally and is FDA approved for the treatment of edema and hypertension. Repurposing bumetanide as a medication for AD has been proposed based on data that demonstrated its ability to "flip" the APOE genotype-dependent transcriptomic signatures in AD mouse and cell culture models. Critically, this discovery was subsequently explored in Electronic Health Record cohorts, which revealed that among individuals over the age of 65, bumetanide exposure was significantly associated with a lower prevalence of AD in three independent datasets. Primary Objective: To evaluate the safety and tolerability of bumetanide when administered to participants with biomarker-confirmed Alzheimer's disease. Secondary Objective: To evaluate the clinical and biomarker effects of bumetanide in participants with mild cognitive impairment or mild dementia due to Alzheimer's disease.

Will I have to stop taking my current medications?

The trial requires that your Alzheimer's disease medications stay the same throughout the study. However, if you are taking lithium, certain drugs that can harm the ears or kidneys, probenecid, or indomethacin, you may need to stop those before participating.

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

Research suggests that bumetanide, a drug typically used to treat high blood pressure and fluid retention, may help improve memory deficits in Alzheimer's disease, especially in patients with a specific genetic risk factor (APOE4). Studies have shown that people taking bumetanide have a lower incidence of Alzheimer's disease by 35%-70%, indicating its potential as a repurposed treatment for this condition. ^{1 2 3 4 5}

How is the drug Bumetanide unique for treating Alzheimer's disease?

Bumetanide is unique for Alzheimer's disease treatment because it is primarily a diuretic (a drug that helps remove excess fluid from the body) used for conditions like heart failure and high blood pressure, and its use in Alzheimer's is novel compared to other treatments that focus on reducing amyloid-beta proteins or using immunotherapy. ^{2 6 7 8 9}

Research Team

Kyan Younes, MD

Principal Investigator

Stanford University

Eligibility Criteria

This trial is for adults with mild cognitive impairment or early-stage Alzheimer's disease who are stable on their current Alzheimer's medications. They must be able to complete tests and an MRI. People can't join if they have significant lab test abnormalities, chronic liver disease, kidney issues, uncontrolled high blood pressure, or take certain drugs like lithium.

Inclusion Criteria

I have mild memory loss or mild dementia because of Alzheimer's.

I am willing and able to complete all study requirements, including tests and MRI.

My Alzheimer's medications will not change during the study.

Exclusion Criteria

My high blood pressure is not well-controlled.

I have a long-term liver condition.

I am not taking lithium, ototoxic, nephrotoxic drugs, probenecid, or indomethacin.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either placebo or bumetanide (low or high dose) orally for 6 months and are evaluated on cognitive and functional tests.

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse events and changes in cognitive assessments.

4 weeks

Treatment Details

Interventions

• Bumetanide

Trial Overview The study is testing bumetanide—a diuretic approved for edema and hypertension—to see if it's safe and tolerable for Alzheimer's patients. It also looks at whether bumetanide affects symptoms or biomarkers of the disease compared to a placebo (a substance with no therapeutic effect).

Participant Groups

Group I: Bumetanide low dose Active Control 1 Intervention

15 participants will take bumetanide low dose orally for 6 months and will be evaluated on cognitive and functional tests. Participants blood samples will be tested for levels of proteins involved in Alzheimer's disease.

Group II: Bumetanide high dose Active Control 1 Intervention

15 participants will take bumetanide high dose orally for 6 months and will be evaluated on cognitive and functional tests. Participants blood samples will be tested for levels of proteins involved in Alzheimer's disease.

Group III: Placebo Placebo Group 1 Intervention

10 participants will take placebo orally for 6 months and will be evaluated on cognitive and functional tests. Participants blood samples will be tested for levels of proteins involved in Alzheimer's disease.

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

Approved in United States as Bumetanide for:

• Edema secondary to cardiac failure
• Edema secondary to hepatic disease
• Edema secondary to renal disease
• Nephrotic syndrome
• Hypertension

Approved in European Union as Bumetanide for:

• Oedema associated with congestive heart failure
• Oedema associated with hepatic cirrhosis
• Oedema associated with a nephrotic syndrome
• Hypertension

Approved in Canada as Bumetanide for:

• Edema secondary to congestive heart failure
• Edema secondary to hepatic cirrhosis
• Edema secondary to nephrotic syndrome
• Hypertension

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Findings from Research

Alzheimer's disease (AD) treatment often involves managing multiple health conditions, leading to a high risk of adverse drug reactions and drug-drug interactions, as over 90% of patients require multifactorial treatments.

Pharmacogenetic studies indicate that the effectiveness of AD medications can vary significantly based on genetic factors, suggesting that personalized medicine approaches could optimize treatment strategies for the majority of patients who carry multiple pathogenic gene variants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacogenomics of Alzheimer's Disease: Novel Strategies for Drug Utilization and Development. Cacabelos, R., Naidoo, V., Martínez-Iglesias, O., et al.[2023]

In a study involving 1,052 patients with mild-to-moderate Alzheimer's disease, tramiprosate showed a significant reduction in hippocampus volume loss compared to placebo, suggesting potential disease-modifying effects.

While the primary analyses did not demonstrate a significant cognitive improvement, post-hoc analyses indicated a trend towards cognitive benefits, highlighting the need for further investigation into tramiprosate's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Aisen, PS., Gauthier, S., Ferris, SH., et al.[2021]

A six-month study involving 50 patients with mild to moderate Alzheimer's disease found that both original memantine and the generic version (memantal) showed similar efficacy in improving cognitive functions and neuropsychiatric symptoms.

There were no significant differences in safety or effectiveness between the two medications, indicating that the generic memantal is a viable alternative to the original memantine for treating dementia in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A comparison of the efficacy and safety of memantal and original memantine in the treatment of mild and moderate dementia in Alzheimer's disease]. Shiryaev, OY., Shapovalov, DL., Polozova, TM., et al.[2018]

Bumetanide, a drug originally used for treating hypertension, has been identified as a promising candidate for Alzheimer's disease (AD) treatment, particularly for patients with the APOE4 risk allele, showing potential to reverse harmful brain signatures and improve memory in animal models.

Patients taking bumetanide have shown a 35%-70% lower incidence of Alzheimer's disease, suggesting that it may have protective effects against the disease, possibly through mechanisms beyond its known action on the NKCC1 transporter in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of bumetanide as a potential therapeutic agent for Alzheimer's disease. Boyarko, B., Podvin, S., Greenberg, B., et al.[2023]

Cholinesterase inhibitors are currently the only approved drugs for treating Alzheimer's Disease (AD) in the USA and Europe, showing significant clinical efficacy and safety based on studies involving over 8,000 patients.

These drugs can stabilize cognitive function and improve behavioral symptoms for six to twelve months, with some long-term benefits reported up to two years, suggesting potential for use in other types of dementia as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Present and future of Alzheimer therapy. Giacobini, E.[2019]

In a phase I trial involving 24 healthy Japanese adults, the BACE1 inhibitor verubecestat was found to be well tolerated at both single and multiple doses, indicating a favorable safety profile.

Verubecestat effectively reduced levels of β-amyloid proteins in cerebrospinal fluid, showing similar pharmacodynamics in both Japanese and non-Japanese subjects, which supports its potential as a treatment for Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Pharmacodynamics of the BACE1 Inhibitor Verubecestat (MK-8931) in Healthy Japanese Adults: A Randomized, Placebo-Controlled Study. Chris Min, K., Dockendorf, MF., Palcza, J., et al.[2020]

Amino-2H-imidazoles represent a new class of BACE-1 inhibitors that show promise for treating Alzheimer's disease, particularly compound (S)-1m, which demonstrated high potency in reducing amyloid-beta (Aβ) levels.

In guinea pigs, compound (S)-1m led to a significant decrease of 40-50% in brain Aβ levels within 1.5 hours after oral administration, indicating its potential effectiveness and favorable profile for central nervous system exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New aminoimidazoles as β-secretase (BACE-1) inhibitors showing amyloid-β (Aβ) lowering in brain. Gravenfors, Y., Viklund, J., Blid, J., et al.[2013]

In a double-blind, randomized, placebo-controlled trial involving subjects with multiple sclerosis and cognitive impairment, memantine did not show any significant improvement in cognitive performance compared to placebo, as measured by the PASAT and CVLT-II tests.

While memantine was generally safe with no serious adverse events reported, it was associated with increased fatigue and neurological side effects, and family members reported less cognitive improvement and more neuropsychiatric symptoms in those taking memantine compared to those on placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. Lovera, JF., Frohman, E., Brown, TR., et al.[2021]

Immunotherapy, particularly monoclonal antibodies targeting amyloid-beta (Aβ), shows promise in treating Alzheimer's disease, with recent trials indicating potential for slowing cognitive decline, especially in early-stage patients.

The monoclonal antibody BAN2401, which targets toxic Aβ protofibrils, has entered clinical trials without the safety issues seen in earlier treatments, suggesting a safer and more effective approach to Alzheimer's therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perspectives on future Alzheimer therapies: amyloid-β protofibrils - a new target for immunotherapy with BAN2401 in Alzheimer's disease. Lannfelt, L., Möller, C., Basun, H., et al.[2021]

References

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

Pharmacogenomics of Alzheimer's Disease: Novel Strategies for Drug Utilization and Development. [2023]

2. Poland pubmed.ncbi.nlm.nih.gov

Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). [2021]

3. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[A comparison of the efficacy and safety of memantal and original memantine in the treatment of mild and moderate dementia in Alzheimer's disease]. [2018]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Evaluation of bumetanide as a potential therapeutic agent for Alzheimer's disease. [2023]

5. Austria pubmed.ncbi.nlm.nih.gov

Present and future of Alzheimer therapy. [2019]

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

Pharmacokinetics and Pharmacodynamics of the BACE1 Inhibitor Verubecestat (MK-8931) in Healthy Japanese Adults: A Randomized, Placebo-Controlled Study. [2020]

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

New aminoimidazoles as β-secretase (BACE-1) inhibitors showing amyloid-β (Aβ) lowering in brain. [2013]

8. England pubmed.ncbi.nlm.nih.gov

Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. [2021]

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

Perspectives on future Alzheimer therapies: amyloid-β protofibrils - a new target for immunotherapy with BAN2401 in Alzheimer's disease. [2021]