Bumetanide in Patients With Alzheimer's Disease

Study Overview
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Brief Summary
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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.

Official Title
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Phase IIa, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Safety and Tolerability of Bumetanide in Patients With Alzheimer's Disease.

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: Bumetanide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Mild cognitive impairment or mild dementia due to Alzheimer's disease. Alzheimer's disease medications are planned to remain stable throughout. Willingness and ability to complete all aspects of the study including assessments, neuropsychological testing, and MRI. Exclusion Criteria: Clinically significant abnormalities in screening laboratory tests Chronic liver disease Renal insufficiency Poorly managed hypertension Participants taking the following concomitant medications, based on the current Prescribing Information for bumetanide: lithium, drugs with ototoxic potential, drugs with nephrotoxic potential, probenecid, and indomethacin.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Bumetanide low dose, 15 participants Bumetanide high dose, 15 participants Placebo, 10 participants
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Bumetanide low dose<br>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. | Drug: Bumetanide<br>* Bumetanide is an FDA approved loop diuretic that has been used for more than three decades to treat edema, congestive heart failure, and hypertension across the life span. It has a well-known side effect profile. Most importantly it can cause dehydration and electrolyte imbalance especially at higher doses. This medication is given to individuals at the similar age group as Alzheimer's disease patients and Alzheimer's disease or cognitive impairment do not preclude its use in patients who need it for its FDA indications. At low doses and when titrated carefully, the medication is well tolerated. However, it has not been studied specifically in Alzheimer's disease patients.<br>* Other names: Bumex;|
| Active Comparator: Bumetanide high dose<br>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. | Drug: Bumetanide<br>* Bumetanide is an FDA approved loop diuretic that has been used for more than three decades to treat edema, congestive heart failure, and hypertension across the life span. It has a well-known side effect profile. Most importantly it can cause dehydration and electrolyte imbalance especially at higher doses. This medication is given to individuals at the similar age group as Alzheimer's disease patients and Alzheimer's disease or cognitive impairment do not preclude its use in patients who need it for its FDA indications. At low doses and when titrated carefully, the medication is well tolerated. However, it has not been studied specifically in Alzheimer's disease patients.<br>* Other names: Bumex;|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* A placebo has no active properties and is taken orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Related Adverse Events | Number of participants with adverse events including clinical signs and symptoms, change in vital signs, ECGs, laboratory safety tests, and suicidality assessments. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in The Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog13) | The ADAS-Cog evaluates cognition and is scored from 0 to 90 points with a score of 0 indicating no impairment, and a score of 90 indicating maximum impairment | 6 months | 
| Changed from baseline in the clinical dementia rating scale sum of boxes (CDR-SoB) | CDR-SoB evaluates function with total possible score of 0 to 18 with higher scores indicating more impairment | 6 months |