Dapagliflozin In Alzheimer's Disease

Randomized Controlled Pilot Trial Of Dapagliflozin In Alzheimer's Disease

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03801642

Enrollment

Registered

2019-01-11

Start date

2019-01-29

Completion date

2022-07-07

Last updated

2024-06-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Alzheimer Disease

Brief 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.

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).

Interventions

DRUGDapagliflozin

10 mg oral tablets taken once daily for 12 weeks

OTHERPlacebo

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

50 Years to 85 Years

Healthy volunteers

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.

Design outcomes

Primary

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

Other

Measure	Time frame	Description
Systemic NAA Levels	12 weeks	NAA concentration levels in blood and urine using UPLC-MS/MS method
FDG PET Metabolism (Standard Uptake Value Ratio)	12 weeks	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.
Total Cholesterol	12 weeks	Total cholesterol level
LDL Cholesterol	12 weeks	LDL cholesterol level
HDL Cholesterol	12 weeks	HDL cholesterol level
Plasma Beta-hydroxybutyrate	12 weeks	Plasma beta-hydroxybuteryate levels (ketones)
Hemoglobin A1C	12 weeks	Hemoglobin A1C
Glucose Area Under the Curve	12 weeks	Glucose area under the curve will be calculated based on glucose levels during a 120 minute oral glucose tolerance test.
Insulin Area Under the Curve	12 weeks	Insulin area under the curve will be calculated based on insulin levels during a 120 minute oral glucose tolerance test.
Activated AKT Levels	12 weeks	Activated AKT will be measured in lymphocytes immunochemically.
MTOR Phosphorylation	12 weeks	MTOR phosphorylation will be measured in lymphocytes
Platelet Cytochrome Oxidase Activity	12 weeks	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
Monocyte Chemotactic Protein 1 (MCP-1)	12 weeks	MCP-1, a measure of inflammation, will be measured in platelet free plasma using ELISA.
Eotaxin-1	12 weeks	Eotaxin-1, a measure of inflammation, will be measured in platelet free plasma using ELISA.
Tumor Necrosis Factor (TNF) - Alpha	12 weeks	TNF-alpha, a measure of inflammation, will be measured in platelet free plasma using ELISA.
C-Reactive Protein (CRP)	12 weeks	CRP, a measure of inflammation, will be measured in platelet free plasma using ELISA.
Total Fat Mass	12 weeks	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
Total Lean Mass	12 weeks	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
Resting Metabolic Rate	12 weeks	Resting metabolic rate will be assessed using indirect calorimetry which measures CO2 production and O2 consumption to calculate total energy produced.
ADAS-Cog 14	12 weeks	Cognitive performance as measured by total score on the ADAS-cog 14.
Trailmaking B	12 weeks	Cognitive performance as measured by Trailmaking B
Stroop Word Color Test	12 weeks	Cognitive performance on the Stroop Word Color test.
Logical Memory II	12 weeks	Memory performance as measured by the Logical Memory II test.
Number of Adverse Events	14 weeks	Total number of adverse events considered related to the study medication
Number of Discontinuations Due to Adverse Events	14 weeks	Number of participants who stop taking the study medication due to adverse events

Countries

United States

Participant flow

Participants by arm

Arm	Count
Dapagliflozin 10 mg dapagliflozin oral tablet taken once daily for 12 weeks Dapagliflozin: 10 mg oral tablets taken once daily for 12 weeks	30
Matching Placebo Placebo oral tablet taken once daily for 12 weeks Placebo: Placebo tablet (matched in size and color to active tablet) taken once daily for 12 weeks	16
Total	46

Baseline characteristics

Characteristic	Matching Placebo	Total	Dapagliflozin
Age, Continuous	71.8 years STANDARD_DEVIATION 8.1	71.1 years STANDARD_DEVIATION 8	69.8 years STANDARD_DEVIATION 7.9
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	2 Participants	2 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	13 Participants	37 Participants	24 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	3 Participants	7 Participants	4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Black or African American	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	16 Participants	44 Participants	28 Participants
Sex: Female, Male Female	4 Participants	16 Participants	12 Participants
Sex: Female, Male Male	12 Participants	30 Participants	18 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 30	0 / 16
other Total, other adverse events	13 / 30	8 / 16
serious Total, serious adverse events	0 / 30	0 / 16

Outcome results

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.

Time frame: 12 weeks

Population: All participants completing MRI spectroscopy at baseline and week-12, where data for both scans passed the data quality criteria.

Arm	Measure	Value (MEAN)	Dispersion
Dapagliflozin	Ratio of Cerebral N Acetyl-Aspartate (NAA) / Cerebral Creatine	1.49 Ratio	Standard Deviation 0.11
Matching Placebo	Ratio of Cerebral N Acetyl-Aspartate (NAA) / Cerebral Creatine	1.42 Ratio	Standard Deviation 0.09

Conditions

Brief summary

Detailed description

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Other

Countries

Participant flow

Participants by arm

Baseline characteristics

Adverse events

Outcome results

Ratio of Cerebral N Acetyl-Aspartate (NAA) / Cerebral Creatine

Activated AKT Levels

ADAS-Cog 14

C-Reactive Protein (CRP)

Eotaxin-1

FDG PET Metabolism (Standard Uptake Value Ratio)

Glucose Area Under the Curve

HDL Cholesterol

Hemoglobin A1C

Insulin Area Under the Curve

LDL Cholesterol

Logical Memory II

Monocyte Chemotactic Protein 1 (MCP-1)

MTOR Phosphorylation

Number of Adverse Events

Number of Discontinuations Due to Adverse Events

Plasma Beta-hydroxybutyrate

Platelet Cytochrome Oxidase Activity

Resting Metabolic Rate

Stroop Word Color Test

Systemic NAA Levels

Total Cholesterol

Total Fat Mass

Total Lean Mass

Trailmaking B

Tumor Necrosis Factor (TNF) - Alpha