Bumetanide in Patients With Alzheimer's Disease (BumxAD)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: Bumetanide; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Mina L Kim; Phone Number: (650) 387-1559; Email: minakim@stanford.edu

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Recruiting
      • Stanford University
      • Principal Investigator: Kyan Younes, MD
      • Contact: Mina L Kim; Phone Number: 650-387-1559; Email: mina.kmiecik@stanford.edu
      • Contact: Stanford Memory Disorders research; Email: memoryresearch@stanford.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Bumetanide low dose; 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; 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.; Other Names: Bumex
Active Comparator: Bumetanide high dose; 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; 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.; Other Names: Bumex
Placebo Comparator: Placebo; 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; A placebo has no active properties and is taken orally.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: Kyan Younes, MD, Stanford University

Publications and helpful links

General Publications

• Taubes A, Nova P, Zalocusky KA, Kosti I, Bicak M, Zilberter MY, Hao Y, Yoon SY, Oskotsky T, Pineda S, Chen B, Jones EAA, Choudhary K, Grone B, Balestra ME, Chaudhry F, Paranjpe I, De Freitas J, Koutsodendris N, Chen N, Wang C, Chang W, An A, Glicksberg BS, Sirota M, Huang Y. Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer's disease. Nat Aging. 2021 Oct;1(10):932-947. doi: 10.1038/s43587-021-00122-7. Epub 2021 Oct 11. Erratum In: Nat Aging. 2021 Dec;1(12):1202.
• Graber-Naidich A, Lee J, Younes K, Greicius MD, Le Guen Y, He Z. Bumetanide Exposure Association with Alzheimer's Disease Risk. Res Sq [Preprint]. 2023 Feb 28:rs.3.rs-2574215. doi: 10.21203/rs.3.rs-2574215/v1.

Helpful Links

• Stanford Neurology & Neurological Sciences Clinical Trials
• Stanford Alzheimer's Disease Research Center Clinical Trials and Research Studies

Study record dates

Study Major Dates

• Study Start (Actual): April 10, 2023
• Primary Completion (Estimated): April 15, 2025
• Study Completion (Estimated): April 15, 2025

Study Registration Dates

• First Submitted: September 18, 2023
• First Submitted That Met QC Criteria: September 18, 2023
• First Posted (Actual): September 25, 2023

Study Record Updates

• Last Update Posted (Actual): April 12, 2024
• Last Update Submitted That Met QC Criteria: April 10, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Potassium Chloride Symporter Inhibitors; Bumetanide
• Other Study ID Numbers: IRB-69153

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No