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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests bumetanide, a water pill commonly used for swelling and high blood pressure, to determine its potential benefits for people with Alzheimer's disease (AD). Researchers aim to assess whether bumetanide is safe and can improve symptoms in individuals with mild memory problems or early-stage AD. Participants will receive either a low dose, high dose, or a placebo for six months. Ideal candidates have mild cognitive issues due to AD, are stable on their current AD medications, and can complete all study tests. As a Phase 2 trial, this research measures bumetanide's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that bumetanide, a drug used to treat swelling and high blood pressure, might be safe for people with Alzheimer's disease. Studies have found that those who took bumetanide had a lower risk of developing Alzheimer's, suggesting potential benefits.

Since bumetanide is already approved for other uses, doctors are familiar with its side effects and how most people tolerate it. However, studying each new use of a drug is crucial to ensure safety in different situations.

In past studies, bumetanide was linked to a 35%–70% lower risk of Alzheimer's in older adults. While this does not directly prove safety, it supports the idea that the drug might be beneficial without major safety concerns. Always consult a doctor before considering joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Alzheimer's?

Unlike the standard treatments for Alzheimer's disease, which often focus on managing symptoms with medications like donepezil or memantine, bumetanide offers a fresh approach by targeting the underlying mechanisms of the condition. Researchers are excited about bumetanide primarily because it is a diuretic that may reduce levels of certain proteins linked to Alzheimer's, potentially altering the disease's progression rather than just alleviating symptoms. This drug is being tested in both low and high doses, providing insights into its optimal efficacy and safety, and offering hope for a more effective intervention.

What evidence suggests that bumetanide might be an effective treatment for Alzheimer's disease?

Research has shown that bumetanide, a medication typically used to treat swelling and high blood pressure, might reduce the risk of Alzheimer's disease. Studies using health records found that people over 65 who took bumetanide had a lower rate of Alzheimer's. In lab tests with mice and cells, bumetanide changed certain genetic patterns related to Alzheimer's. Some research also found that bumetanide improved memory and brain function in animals. This trial will evaluate bumetanide's potential as a treatment for Alzheimer's, with participants receiving either a low or high dose of bumetanide, or a placebo. Early evidence suggests bumetanide could be a promising treatment for Alzheimer's, but more research is needed to confirm its effects in people. ^{1 2 4 6 7}

Who Is on the Research Team?

Kyan Younes, MD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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).

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11350022/

Pharmacoepidemiology evaluation of bumetanide as a ... Cross‐sectional analyses of electronic health records suggest that bumetanide is associated with decreased prevalence of AD; however, ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06052163

Bumetanide in Patients With Alzheimer's Disease (BumxAD) This study aims to investigate bumetanide in patients with biologically confirmed Alzheimer's disease (AD). Bumetanide is a potent diuretic administered ...

3. frontiersin.org frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1190402/full

Evaluation of bumetanide as a potential therapeutic agent ... In models of ischemic stroke, bumetanide at the doses of 0.3 and 0.5 mg/kg by daily ip for 3–4 weeks resulted in improved memory and brain outcomes (Wang et al.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10002844/

Bumetanide Exposure Association with Alzheimer's Disease ... Our study replicates in an independent sample that history of bumetanide exposure is associated with reduced risk of AD.

5. alz-journals.onlinelibrary.wiley.com alz-journals.onlinelibrary.wiley.com/doi/pdf/10.1002/alz.13872

Pharmacoepidemiology evaluation of bumetanide as a ... We conducted a retrospective cohort study of claims data from a 5% random sample of Medicare beneficiaries to overcome limitations of previous ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10436590/

Evaluation of bumetanide as a potential therapeutic agent for ... Electronic health record data revealed that patients exposed to bumetanide have lower incidences of AD by 35%–70%. In the brain, bumetanide has been proposed to ...

7. alz-journals.onlinelibrary.wiley.com alz-journals.onlinelibrary.wiley.com/doi/abs/10.1002/alz.079378

Bumetanide Exposure Association with Alzheimer's Disease ... Our study replicates in an independent sample that a history of bumetanide exposure is associated with reduced AD risk.