Dapagliflozin In Alzheimer's Disease

Randomized Controlled Pilot Trial Of Dapagliflozin In Alzheimer's Disease

This is a pilot randomized controlled trial in individuals with probable Alzheimer's disease testing the effects of 10 mg dapagliflozin, taken daily for 12 weeks, on cerebral n-acetyl aspartate (NAA) levels using magnetic resonance spectroscopy (MRS). The investigators will also examine the safety and tolerability of dapagliflozin and explore the effects on systemic NAA levels in blood and urine, cerebral metabolism (fluorodeoxyglucose [FDG] PET), systemic metabolic biomarkers that indicate and quantify secondary metabolic effects, and cognitive performance.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: Dapagliflozin; Other: Placebo

Detailed Description

This is a double-blind, randomized, placebo-controlled, parallel group, 12-week study performed at a single site (University of Kansas Alzheimer's Disease Center) to investigate the effect of dapagliflozin in participants with probable AD (MMSE 15-26 inclusive). A total of 48 participants will be enrolled with 2:1 randomization to 10mg dapagliflozin once daily (n=32) for 12 weeks vs matching placebo (n=16).

The primary objective of the study is to assess the effect of 12 weeks of 10mg dapagliflozin once daily on cerebral NAA (a proxy measure of mitochondrial mass) in participants with AD.

Procedures will include phlebotomy, urine collection, MRI/MRS, FDG-PET, cognitive testing, DEXA scanning, and indirect calorimetry at baseline and 12 weeks to assess these outcomes:

• N Acetyl-Aspartate (NAA): Cerebral NAA (as measured by MRS) and Systemic NAA levels (in blood and urine)
• Cerebral metabolism (by FDG PET)
• Systemic metabolic effects: Lipids (total cholesterol, LDL, HDL), Plasma beta-hydroxybutyrate, Insulin resistance (Hemoglobin A1c, glucose and insulin during tolerance testing), Catabolic/Anabolic state [activated AKT and MTOR], Mitochondrial function measures [platelet cytochrome oxidase and citrate synthase], Inflammatory mechanisms [MCP-1, eotaxin, TNF alpha, CRP], Body composition (DEXA scanning for fat and lean mass), Resting metabolic rate (indirect calorimetry),
• Cognitive effects will be assessed at baseline and week 12 using the Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14) and individual tests of Logical Memory I and II, Trailmaking A and B, and Stroop Word Color Test.
• 12 participants will be enrolled in an optional MRI/MRS sub-study with repeat MRI/MRS prior to randomization to assess scan-rescan reliability of the NAA measure.

Safety and tolerability of dapagliflozin (10mg daily) will be monitored throughout the study and formally at every study visit to assess the incidence and severity of AEs and the rate of discontinuations due to AEs. Safety assessments will include measuring vital signs and body weight, safety labs (including a comprehensive metabolic panel [CMP] and complete blood count [CBC] with differential) and physical and neurological examinations at screening and at end of treatment (EOT).

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 46 years to 81 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures.
2. Have a diagnosis of probable AD per McKhann et al. criteria
3. Have a body mass index (BMI) ≥23
4. Age 50-85
5. Have a Mini Mental Status Exam (MMSE) score of 15-26 (inclusive) at screening visit
6. Have a reliable and competent study partner who is willing to accompany the participant to all study visits, monitor compliance of study medication administration, and observe/report any changes in the participant's health throughout the study duration
7. Are on stable doses of concurrent medications for at least 4 weeks prior to the screening visit
8. Speaks English as his/her primary language.
9. Females of child-bearing potential (i.e., pre-menopausal) must have a negative urine pregnancy test at the screening visit and must agree to use of contraception throughout the trial and for 30 days after the last dose of study medication. The approved methods of contraception are abstinence, the consistent use of an approved oral contraceptive (birth control pill or "the pill"), an intrauterine device (IUD), hormonal implants, contraceptive injection, double barrier method (diaphragm with spermicidal gel or condom with contraceptive foam).

Exclusion Criteria:

1. Received an investigational product in another clinical study during the last 4 weeks prior to screening
2. Diagnosis of Type 1 diabetes
3. Diagnosis of Type 2 diabetes treated with insulin, sulfonylureas, glucagon like peptide1 receptor agonists (GLP-1), thiazolidinedione (TZD) or SGLT2 inhibitors (metformin monotherapy is allowed).
4. Estimated Glomerular Filtration Rate (eGFR; MDRD) <45 mL/min at screening or unstable renal disease.
5. Any condition when MRI is contraindicated such as, but not limited to, having a pacemaker or claustrophobia.
6. Severe hepatic injury and/or significant abnormal liver function defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN. Total bilirubin >2.0 mg/dL (34.2 μmol/L)
7. Intolerance or allergy to dapaglifozin or any other SGLT2 inhibitor or any other substance in the tablets.
8. Dementia due to causes other than AD
9. History of recurrent urinary tract infection
10. Active mycotic genital infection
11. History of bladder cancer
12. History of diabetic ketoacidosis

13. Potentially confounding, serious, or unstable medical conditions such as:

    1. cancer within the past 3 years (except basal cell, squamous cell, or localized prostate cancer)
    2. a recent cardiac event (i.e. heart attack, angioplasty, etc. within the 3 months prior to screening visit)
    3. other conditions that pose a potential safety risk or confounding factor in the investigator's opinion
14. Any abnormal physical examination assessment or vital sign assessment at the screening visit that is deemed to be clinically significant by the principal investigator.
15. Any abnormal clinical laboratory test result at the screening visit that is deemed to be clinically significant by the principal investigator.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dapagliflozin; 10 mg dapagliflozin oral tablet taken once daily for 12 weeks	Drug: Dapagliflozin; 10 mg oral tablets taken once daily for 12 weeks; Other Names: Farxiga
Placebo Comparator: Matching placebo; Placebo oral tablet taken once daily for 12 weeks	Other: Placebo; Placebo tablet (matched in size and color to active tablet) taken once daily for 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ratio of Cerebral N Acetyl-Aspartate (NAA) / Cerebral Creatine	Estimated mean change from baseline in the ratio of cerebral NAA/ cerebral Creatine as measured by MRI Spectroscopy.	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
FDG PET Metabolism (Standard Uptake Value Ratio)	FDG PET measures reflecting cerebral metabolism standardized to the uptake value of the cerebellum and standardized uptake value ratios (SUVR) will be calculated from native-space ROIs.	12 weeks
Total Cholesterol	Total cholesterol level	12 weeks
LDL Cholesterol	LDL cholesterol level	12 weeks
HDL Cholesterol	HDL cholesterol level	12 weeks
Hemoglobin A1C	Hemoglobin A1C	12 weeks
Glucose Area Under the Curve	Glucose area under the curve will be calculated based on glucose levels during a 120 minute oral glucose tolerance test.	12 weeks
Insulin Area Under the Curve	Insulin area under the curve will be calculated based on insulin levels during a 120 minute oral glucose tolerance test.	12 weeks
MTOR Phosphorylation	MTOR phosphorylation will be measured in lymphocytes	12 weeks
Monocyte Chemotactic Protein 1 (MCP-1)	MCP-1, a measure of inflammation, will be measured in platelet free plasma using ELISA.	12 weeks
Eotaxin-1	Eotaxin-1, a measure of inflammation, will be measured in platelet free plasma using ELISA.	12 weeks
C-Reactive Protein (CRP)	CRP, a measure of inflammation, will be measured in platelet free plasma using ELISA.	12 weeks
Resting Metabolic Rate	Resting metabolic rate will be assessed using indirect calorimetry which measures CO2 production and O2 consumption to calculate total energy produced.	12 weeks
ADAS-Cog 14	Cognitive performance as measured by total score on the ADAS-cog 14.	12 weeks
Trailmaking B	Cognitive performance as measured by Trailmaking B	12 weeks
Stroop Word Color Test	Cognitive performance on the Stroop Word Color test.	12 weeks
Logical Memory II	Memory performance as measured by the Logical Memory II test.	12 weeks
Number of Adverse Events	Total number of adverse events considered related to the study medication	14 weeks
Systemic NAA Levels	NAA concentration levels in blood and urine using UPLC-MS/MS method	12 weeks
Plasma Beta-hydroxybutyrate	Plasma beta-hydroxybuteryate levels (ketones)	12 weeks
Activated AKT Levels	Activated AKT will be measured in lymphocytes immunochemically.	12 weeks
Platelet Cytochrome Oxidase Activity	Cytochrome Oxidase Vmax activity is determined as a pseudo first order-rate constant (sec-1/mg protein) by measuring the oxidation of reduced cytochrome c at 550 nm	12 weeks
Tumor Necrosis Factor (TNF) - Alpha	TNF-alpha, a measure of inflammation, will be measured in platelet free plasma using ELISA.	12 weeks
Total Fat Mass	Body composition will be assessed using dual energy x-ray absorptiometry (GE Lunar iDEXA) to determine fat-free mass, fat mass, and percent body fat at baseline, and week 12	12 weeks
Total Lean Mass	Body composition will be assessed using dual energy x-ray absorptiometry (GE Lunar iDEXA) to determine fat-free mass, fat mass, and percent body fat at baseline, and week 12	12 weeks
Number of Discontinuations Due to Adverse Events	Number of participants who stop taking the study medication due to adverse events	14 weeks

Collaborators and Investigators

• Sponsor: Jeff Burns, MD
• Investigators: Principal Investigator: Jeffrey Burns, MD, University of Kansas Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2019
• Primary Completion (Actual): July 7, 2022
• Study Completion (Actual): July 7, 2022

Study Registration Dates

• First Submitted: December 21, 2018
• First Submitted That Met QC Criteria: January 10, 2019
• First Posted (Actual): January 11, 2019

Study Record Updates

• Last Update Posted (Actual): June 13, 2024
• Last Update Submitted That Met QC Criteria: May 20, 2024
• Last Verified: May 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; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: Dapa in AD

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
• product manufactured in and exported from the U.S.: No