ClinicalTrials.gov
ClinicalTrials.gov Menu

Dapagliflozin In Alzheimer's Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03801642
Recruitment Status : Recruiting
First Posted : January 11, 2019
Last Update Posted : January 11, 2019
Sponsor:
Information provided by (Responsible Party):
Jeff Burns, MD, University of Kansas Medical Center

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.

Condition or disease Intervention/treatment Phase
Alzheimer Disease Drug: Dapagliflozin Other: Placebo Phase 1 Phase 2

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  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Randomized Controlled Pilot Trial Of Dapagliflozin In Alzheimer's Disease
Estimated Study Start Date : February 2019
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : October 2020


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 Name: 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




Primary Outcome Measures :
  1. Cerebral N Acetyl-Aspartate (NAA) [ Time Frame: 12 weeks ]
    Cerebral NAA concentration via Magnetic Resonance Spectroscopy (MRS)


Other Outcome Measures:
  1. Systemic NAA levels [ Time Frame: 12 weeks ]
    NAA concentration levels in blood and urine using UPLC-MS/MS method

  2. FDG PET Metabolism (Standard Uptake Value Ratio) [ Time Frame: 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.

  3. Total Cholesterol [ Time Frame: 12 weeks ]
    Total cholesterol level

  4. LDL Cholesterol [ Time Frame: 12 weeks ]
    LDL cholesterol level

  5. HDL Cholesterol [ Time Frame: 12 weeks ]
    HDL cholesterol level

  6. Plasma beta-hydroxybutyrate [ Time Frame: 12 weeks ]
    Plasma beta-hydroxybuteryate levels (ketones)

  7. Hemoglobin A1C [ Time Frame: 12 weeks ]
    Hemoglobin A1C

  8. Glucose Area Under the Curve [ Time Frame: 12 weeks ]
    Glucose area under the curve will be calculated based on glucose levels during a 120 minute oral glucose tolerance test.

  9. Insulin Area Under the Curve [ Time Frame: 12 weeks ]
    Insulin area under the curve will be calculated based on insulin levels during a 120 minute oral glucose tolerance test.

  10. Activated AKT levels [ Time Frame: 12 weeks ]
    Activated AKT will be measured in lymphocytes immunochemically.

  11. MTOR Phosphorylation [ Time Frame: 12 weeks ]
    MTOR phosphorylation will be measured in lymphocytes

  12. Platelet Cytochrome Oxidase activity [ Time Frame: 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

  13. Monocyte Chemotactic Protein 1 (MCP-1) [ Time Frame: 12 weeks ]
    MCP-1, a measure of inflammation, will be measured in platelet free plasma using ELISA.

  14. Eotaxin-1 [ Time Frame: 12 weeks ]
    Eotaxin-1, a measure of inflammation, will be measured in platelet free plasma using ELISA.

  15. Tumor Necrosis Factor (TNF) - alpha [ Time Frame: 12 weeks ]
    TNF-alpha, a measure of inflammation, will be measured in platelet free plasma using ELISA.

  16. C-Reactive Protein (CRP) [ Time Frame: 12 weeks ]
    CRP, a measure of inflammation, will be measured in platelet free plasma using ELISA.

  17. Total fat mass [ Time Frame: 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

  18. Total lean mass [ Time Frame: 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

  19. Resting Metabolic Rate [ Time Frame: 12 weeks ]
    Resting metabolic rate will be assessed using indirect calorimetry which measures CO2 production and O2 consumption to calculate total energy produced.

  20. ADAS-Cog 14 [ Time Frame: 12 weeks ]
    Cognitive performance as measured by total score on the ADAS-cog 14.

  21. Trailmaking B [ Time Frame: 12 weeks ]
    Cognitive performance as measured by Trailmaking B

  22. Stroop Word Color Test [ Time Frame: 12 weeks ]
    Cognitive performance on the Stroop Word Color test.

  23. Logical Memory II [ Time Frame: 12 weeks ]
    Memory performance as measured by the Logical Memory II test.

  24. Number of Adverse Events [ Time Frame: 14 weeks ]
    Total number of adverse events considered related to the study medication

  25. Number of Discontinuations due to Adverse Events [ Time Frame: 14 weeks ]
    Number of participants who stop taking the study medication due to adverse events



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   50 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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) <60 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 ULN16. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03801642


Contacts
Contact: Erin Schwartz (913) 945-7311 eschwartz@kumc.edu
Contact: Annette Becker (913) 945-7674 abecker@kumc.edu

Locations
United States, Kansas
University of Kansas Medical Center Recruiting
Kansas City, Kansas, United States, 66160
Sponsors and Collaborators
Jeff Burns, MD
Investigators
Principal Investigator: Jeffrey Burns, MD University of Kansas Medical Center

Responsible Party: Jeff Burns, MD, Professor, University of Kansas Medical Center
ClinicalTrials.gov Identifier: NCT03801642     History of Changes
Other Study ID Numbers: Dapa in AD
First Posted: January 11, 2019    Key Record Dates
Last Update Posted: January 11, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Additional relevant MeSH terms:
Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders