Dapagliflozin In Alzheimer's Disease

Alzheimer Disease Clinical Trial

Official title:

Randomized Controlled Pilot Trial Of Dapagliflozin In Alzheimer's Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03801642
• Other study ID #: Dapa in AD
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: January 29, 2019
• Est. completion date: July 7, 2022

Study information

• Verified date: May 2024
• Source: University of Kansas Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 46
• Est. completion date: July 7, 2022
• Est. primary completion date: July 7, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 85 Years

Eligibility

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.

Related Conditions & MeSH terms

• Alzheimer Disease

Intervention

Drug:
• Dapagliflozin
10 mg oral tablets taken once daily for 12 weeks

Other:
• Placebo
Placebo tablet (matched in size and color to active tablet) taken once daily for 12 weeks

Locations

Country	Name	City	State
United States	University of Kansas Medical Center	Kansas City	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Jeff Burns, MD

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Systemic NAA Levels	NAA concentration levels in blood and urine using UPLC-MS/MS method	12 weeks
Other	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
Other	Total Cholesterol	Total cholesterol level	12 weeks
Other	LDL Cholesterol	LDL cholesterol level	12 weeks
Other	HDL Cholesterol	HDL cholesterol level	12 weeks
Other	Plasma Beta-hydroxybutyrate	Plasma beta-hydroxybuteryate levels (ketones)	12 weeks
Other	Hemoglobin A1C	Hemoglobin A1C	12 weeks
Other	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
Other	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
Other	Activated AKT Levels	Activated AKT will be measured in lymphocytes immunochemically.	12 weeks
Other	MTOR Phosphorylation	MTOR phosphorylation will be measured in lymphocytes	12 weeks
Other	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
Other	Monocyte Chemotactic Protein 1 (MCP-1)	MCP-1, a measure of inflammation, will be measured in platelet free plasma using ELISA.	12 weeks
Other	Eotaxin-1	Eotaxin-1, a measure of inflammation, will be measured in platelet free plasma using ELISA.	12 weeks
Other	Tumor Necrosis Factor (TNF) - Alpha	TNF-alpha, a measure of inflammation, will be measured in platelet free plasma using ELISA.	12 weeks
Other	C-Reactive Protein (CRP)	CRP, a measure of inflammation, will be measured in platelet free plasma using ELISA.	12 weeks
Other	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
Other	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
Other	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
Other	ADAS-Cog 14	Cognitive performance as measured by total score on the ADAS-cog 14.	12 weeks
Other	Trailmaking B	Cognitive performance as measured by Trailmaking B	12 weeks
Other	Stroop Word Color Test	Cognitive performance on the Stroop Word Color test.	12 weeks
Other	Logical Memory II	Memory performance as measured by the Logical Memory II test.	12 weeks
Other	Number of Adverse Events	Total number of adverse events considered related to the study medication	14 weeks
Other	Number of Discontinuations Due to Adverse Events	Number of participants who stop taking the study medication due to adverse events	14 weeks
Primary	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