Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Sodium-glucose Co Transporter 2 (sGLT2) Inhibitor and Endogenous Ketone Production

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: NCT03852901
Recruitment Status : Recruiting
First Posted : February 25, 2019
Last Update Posted : November 1, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute on Aging (NIA) )

Tracking Information
First Submitted Date  ICMJE February 22, 2019
First Posted Date  ICMJE February 25, 2019
Last Update Posted Date November 1, 2019
Actual Study Start Date  ICMJE March 28, 2019
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 22, 2019)
Elevating ketone bodies may bolster neuronal health and delay onset and progression of cognitive impairment. [ Time Frame: One year ]
The expected outcome of this study is that we will see an increase in circulating levels of ketones, glucagon and fatty acids, an increased expression of receptors and mediators of ketone metabolism in plasma exosomes and a change in Magnetic Resonance Spectroscopy (RS) brain metabolism measures.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03852901 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Sodium-glucose Co Transporter 2 (sGLT2) Inhibitor and Endogenous Ketone Production
Official Title  ICMJE Sodium-Glucose CoTransporter 2 (sGLT2) Inhibitor and Endogenous Ketone Production
Brief Summary

Background:

The drug Jardiance treats diabetes. It lowers blood sugar by increasing glucose the kidneys excrete. This increases levels of ketones formed in the blood. The body makes ketones when it does not have enough glucose for fuel. The brains of many people with age-related diseases like Alzheimer s do not use glucose well. Brain use of ketones might improve mental ability. Researchers want to see how Jardiance affects ketone levels, which could lead to ways to improve brain health as people age.

Objectives:

To study how taking Jardiance affects ketone levels in people without diabetes.

Eligibility:

Adults at least 55 years old without diabetes

Design:

Participants will fast before all visits and sometimes during visits. Snacks or meals will be provided.

Participants will be screened with medical history, physical exam, and blood tests.

At 3 study visits over about 4 weeks, participants will:

Have a thin plastic tube inserted in an arm vein for frequent blood samples

Have their urine collected throughout the visit

Write what they eat and when in a diary

Answer questions about symptoms

Have an MRI/MRS scan. A strong magnetic field and radio waves will take pictures of the brain and measure its blood flow and function. Participants will lie on a table that slides into the scanner. They will wear a plastic device on their head and earplugs.

Participants will take the study drug once a day for 2 weeks.

Participants will get an activity monitor and walk about 2,000 steps most evenings.

A small sensor will be inserted in participants upper arm for 4 weeks to measure blood glucose.

Participants will have a follow-up phone call.

Detailed Description

Objective and Specific Aims: The objective of this proof-of-concept study is to demonstrate in non-diabetic men and women age > 55 years that a sGLT2 inhibitor will increase ketone bodies and metabolites used for gluconeogenesis. We also hypothesize that sGLT2 inhibitor (empagliflozin) will increase circulating glucagon and fatty acids, decrease circulating amino acids, increase expression of receptors and mediators of ketone metabolism in plasma exosomes and change Magnetic Resonance Spectroscopy (MRS) brain metabolism measures.

Experimental Design and Methods: 10 men and 10 women will be recruited for this pilot study. Each eligible participant will have a screen visit (Visit 0) and three additional 2-day study visits (Visit 1-3). On Visits 1, 2 and 3, frequent blood sampling for Beta-hydroxybutyrate butyrate (Beta-OHB), acetoacetate, fatty and amino acids, glucagon, insulin and glucose levels will be carried out; these visits will also include blood work for exosome markers and brain MRS. In addition, placement of a continuous glucose monitor (CGM) along with a 34-hour urine collection will be carried out. On Visits 1 and 2 the participants will wear the CGM until they return for their next visit. On Visit 3 the CGM will be removed at the end of the study visit. On Visit 1, no empagliflozin will be administered. Participants will return in 13 +/- 2 days for Visit 2. Visit 2 is the same as Visit 1 except empagliflozin 25 mg will be administered both mornings, at least 30 minutes before eating breakfast and participants will continue empagliflozin 25 mg once every morning, at least 30 minutes before eating breakfast, at home until they return in 13 +/- 2 days for Visit 3. At the end of Visit 3, empagliflozin will be stopped.

Medical Relevance and Expected Outcome: Elevating ketone bodies may bolster neuronal health and delay onset and progression of cognitive impairment. The expected outcome of this study is that we will see an increase in circulating levels of ketones, glucagon and fatty acids, an increased expression of receptors and mediators of ketone metabolism in plasma exosomes and a change in Magnetic Resonance Spectroscopy (MRS) brain metabolism measures, in subjects taking a sGLT2 inhibitor. We expect circulating amino acid levels will decrease, especially during the overnight hours. This study will aid in deciding whether this class of compound may be used in a larger study to improve cognitive function in patients with diagnosis consistent with declining cognitive function. We require that empagliflozin be taken for up to 2 weeks before returning for Visit 3, because we need to fully understand the homeostatic adaptations that may occur in the metabolite response to empagliflozin due to prolonged (up to 2 weeks) sGLT2 inhibition. It is our goal in the future to use the information gathered in this pilot study to design a long-term study in people who actually suffer from mild cognitive impairment/AD and therefore a Visit 2 (34-hour acute study) only, as outlined above, would not give us the full picture of the metabolic changes that might occur with prolonged use, especially in a non-diabetic population.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE
  • Aging
  • Cognitive
  • Ketones
  • Blood Sugar
Intervention  ICMJE Drug: Jardiance 25 mg
This study involves a screening visit (Visit 0) and 3 study visits (Visits 1, 2 and 3) to the NIA Clinical Unit. In this pilot study, each enrolled participant will have a baseline visit (Visit 1)
Study Arms  ICMJE Experimental: Single Arm
Single group
Intervention: Drug: Jardiance 25 mg
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 22, 2019)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:
  • Age 55 years and older.
  • Healthy (see exclusion criteria below).
  • Able to understand the study risks and procedures, and consent to participate in the study.
  • Able to read and speak English.

EXCLUSION CRITERIA (SCREENING VISIT):

  • History of diabetes (requiring any medical treatment other than diet and exercise) or fasting plasma glucose > 126 mg/dl or HbA1c> 6.5 %.
  • History of hypoglycemia.
  • BMI > 35 kg/m(2).
  • Creatinine clearance less than 60 ml/min as measured by GFR.
  • Glucosuria
  • History of anemia within the past 6 months or Hgb <11.0 mg/dL for women and Hgb <12.5 mg/dL for men.
  • Current steroid use or steroid use within 90 days of screening, excluding eye drops.
  • Currently taking loop diuretics (Lasix, for example).
  • Participant presently following a calorie restriction diet, low carb/high fat diet.
  • HIV virus infection
  • Hepatitis B infection, as evidenced by a positive HBsAG at screen visit.
  • Hepatitis C infection that has not been treated. (The screen blood work must show HCV RNA quantitative is not detectable).
  • Active infection/fever that may cause changes in glucose metabolism.
  • Known allergy to sGLT2 inhibitors in the past.
  • Thyroid dysfunction that is not controlled or treated. This will be determined by Free T3, T4, Free T4 or TSH not within MedStar Harbor Hospital laboratory normal ranges for this pilot study.
  • Adrenal dysfunction as determined by a cortisol level not within the normal range for MedStar Harbor Hospital Laboratory for this pilot study.
  • Kidney or liver disease, (GFR < 60 mL/min/1.73 m(2) and/or liver enzymes not within normal ranges for MedStar Harbor Hospital Laboratory for this pilot study.
  • Severe gastrointestinal diseases such as Crohn s disease or ulcerative colitis requiring continuous treatment.
  • History of severe pulmonary disease such as chronic obstructive pulmonary disease (COPD) or asthma requiring continuous medication use.
  • Patients with known, or evidence of, peripheral vascular disease.
  • History of chronic urinary tract infections.
  • History of recurrent or recent dehydration in the past year.
  • History of recurrent or recent vaginal yeast infection.
  • Alcohol intake greater than 30 grams (drink more than 2 beers OR equivalent per day).
  • History of severe psychiatric conditions associated with behavioral problems or requiring chronic medical treatment.
  • Poor venous access.
  • Inability to walk 2,000 steps
  • Donation or loss of 400 mL or more of blood within 56 days prior to and subsequent to screening.
  • Participation in another study in the past 30 days, in which a study drug was administered.
  • Currently participating in another study unless the investigator feels it would not interfere with the study.
  • History of a medical condition or any other reason that, in the opinion of the investigator, will make participation in this study unsafe.
  • Blood work or urine tests that are not considered by the study physician to be in an acceptable range for the study.
  • Metal implants and devices incompatible with 3T Magnetic Resonance Imaging (MRI), or another contraindication to MRI.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 55 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Denise L Melvin, R.N. (410) 350-3924 dm381j@nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03852901
Other Study ID Numbers  ICMJE 190060
19-AG-0060
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute on Aging (NIA) )
Study Sponsor  ICMJE National Institute on Aging (NIA)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Josephine M Earley, M.D. National Institute on Aging (NIA)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date October 25, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP