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Ketone Ester Effects on Biomarkers of Brain Metabolism and Cognitive Performance in Cognitively Intact Adults 55 Years Old or Older

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: NCT04421014
Recruitment Status : Recruiting
First Posted : June 9, 2020
Last Update Posted : July 8, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute on Aging (NIA) )

Brief Summary:

Background:

In Alzheimer s disease (AD) the brain cannot use glucose as a fuel. The brain can use ketones as a fuel instead of glucose. Researchers want to test a supplement, HVNM Ketone Ester (KE). It may improve brain metabolic function and cognition in normal people and, perhaps, down the road, in patients with AD.

Objective:

To study the change in brain ketone levels in people after 28 days of taking HVMN KE compared with baseline and placebo. Also, to study changes in cognitive performance.

Eligibility:

People 55 years old or older with metabolic syndrome and no cognitive impairment

Design:

Participants will have 4 visits.

Participants will be screened at Visit 1 with:

Medical history

Physical exam

Blood and urine tests

Cognitive testing

Participants will be randomly assigned to receive either the study supplement or a placebo with same amount of calories. Neither they nor the researchers will know which they receive.

Visit 2 will include repeats of some screening tests. It will also include:

Stool sample (brought from home)

MRI/MRS: Participants will lie on a table that slides in and out of a scanner. A coil will be placed over their head. They may be asked to perform leg exercises.

First dose of study supplement or placebo

About 2 weeks after Visit 2, Visit 3 will include blood and urine tests and a questionnaire.

About 2 weeks after Visit 3, Visit 4 will include repeats of the Visit 2 tests.

Participants will drink the study supplement or placebo 3 times per day during the study. They will keep a daily log of each dose. They will bring the log to Visits 3 and 4.

Participants will by contacted by phone once per week during the study to see how they are doing.


Condition or disease Intervention/treatment Phase
Metabolic Syndrome Normal Cognition Dietary Supplement: HVMN Ketone Esther drink Dietary Supplement: Placebo: isocaloric dextrose drink Not Applicable

Detailed Description:
We hypothesize that supplementation with a ketone ester drink [HVMN Ketone Ester (KE)] compared to placebo, in cognitively intact adults 55 years old with Metabolic Syndrome (Mets), will (i) increase peripheral and brain ketone levels [primarily f3-hydroxybutyrate (BHB) and secondarily acetoacetate (AcAc)], (ii) improve neuronal/astrocytic insulin resistance (IR) and induce a change in neuronal/astrocytic metabolism as reflected on blood Extracellular Vesicle (EV) biomarkers, (iii) improve cognitive performance, (iv) boost mitochondrial function in muscle, and (v) change gut microbiome. These effects will be examined acutely, after single (NotEqual) dose administration, and chronically, after 28 days on the supplement x 3 times per day. The changes in EV biomarkers and cognition will be associated with the elevation of ketones in brain. The study will involve a Screening Visit and three additional Visits to assess acute effects, compliance and chronic effects, respectively.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Ketone Ester Effects on Biomarkers of Brain Metabolism and Cognitive Performance in Cognitively Intact Adults More Than or Equal to 55 Years Old or Older. A Double-Blinded Randomized Controlled Clinical Trial.
Estimated Study Start Date : July 13, 2020
Estimated Primary Completion Date : September 1, 2021
Estimated Study Completion Date : April 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: HVMN Ketone Ester/ Arm 1
25 participants
Dietary Supplement: HVMN Ketone Esther drink
The main ingredient of HVMN Ketone Ester [(R)-3- hydroxybutyl (R)-3- hydroxybutyrate)] is regulated as GRAS (Generally Recognized as Safe) substance by the FDA (https://www.accessdata .fda.gov/ scripts/ fdcc/index.cfmset=GRASNotices&id=515). The HVMN KE compound is already being sold in the market as a ketogenic supplement and is especially popular among athletes, such as cyclists (sold by the official website of the company (https://hvmn.com/ketone-ester) and in a popular selling website (https://www.amazon.com/HVMN (NotEqual)Ketone-Pocket-Sized (NotEqual)Sugar-Free (NotEqual)Performance/dp/ B07CTP3XST). The dose and formulation (25 g of KE contained in 65 ml of the drink HVMN KE), daily scheme (3 times daily) and total duration (28 days) are identical to a previous safety human study.

Placebo Comparator: Placebo/ Arm 2
25 participants
Dietary Supplement: Placebo: isocaloric dextrose drink
The main content of the Placebo will be an aqueous solution containing ~ 35 g of dextrose. To better match the taste of the placebo to that of the HVMN KE, we will add a fruity flavor powder (provided by HVMN) and stevia. We will also add Denatonium Benzoate (Bittrex) to match the bitterness of HVMN KE. The placebo will be prepared and dispensed by the NIA Pharmacist.




Primary Outcome Measures :
  1. Brain concentration of BHB using brain Magnetic Resonance Spectroscopy [ Time Frame: 28 days - outcome assessed at Visit 2 (baseline measurement before the first dose and after 75 min); Visit 4 (before and after 75 min from last dose). ]
    To detect with brain MRS, a significant change in the concentration of BHB, after 28 days of supplementation with the HVMN KE compared to baseline and placebo.



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.


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Ages Eligible for Study:   55 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

  1. Ability to provide informed consent and willingness to sign a written informed consent document
  2. Male or female, age >=55 years old
  3. Cognitively intact status ascertained during screening (defined as absence of significant memory or cognitive changes in the last 2 years by subjective report, Clinical Dementia Rating (CDR) of 0, and Montreal Cognitive Assessment (MoCA) > 26)
  4. Ability to take oral medications
  5. Willingness to adhere to all study procedures including having MRI/MRS.
  6. Presence of Metabolic Syndrome (MetS). Specifically, they should meet three of the five following MetS diagnostic criteria to be eligible:

    • Receive drug treatment for elevated triglycerides (TGs) or have serum TGs >=150mg/dL (1.7 mmol/L)
    • Receive drug treatment for low HDL-cholesterol or have serum HDL-cholesterol<40 mg/dL (1.0 mmol/L) in males; <50 mg/dL (1.3 mmol/L) in females
    • Receive drug treatment for high Blood Pressure (BP) or have BP>=130/85 mmHg
    • Receive drug treatment for high blood glucose or have fasting plasma glucose>=mg/dL
    • Central obesity, defined as a waist circumference cm (40 in) in men and>=88cm (35 in) in women.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

  1. Previously diagnosed with a condition causing clinically significant cognitive impairment, such as MCI, AD or other type of dementia (such as vascular dementia, Lewy body dementia and frontotemporal dementia).
  2. History of clinically significant brain disorders, such as stroke, multiple sclerosis, Parkinson s disease or other movement disorders, brain tumors, history of meningitis or encephalitis, history of moderate or severe traumatic brain injury (defined as Glasgow Coma Scale of 12 or less), epilepsy. Certain common neurological disorders not considered relevant (e.g. migraine, essential tremor) or incidental neuroimaging findings that are common and of uncertain clinical significance (e.g. mild-moderate microvascular changes on MRI) may be allowed.
  3. Chronic and significant psychiatric conditions (e.g. history of bipolar disorder, schizophrenia, PTSD, moderate to severe depression or treatment-resistant depression. Unipolar depression or anxiety disorder may be allowed if mild or if successfully treated with single anti-depressant or anti-anxiety agents.
  4. Positive urine drug screen (and no prescription medication accounting for the positive test).
  5. Positive HIV, HBV or HCV status during screening.
  6. Contraindications for MRI (pregnancy, pacemakers or other implanted devices, ferrous metal implants or shrapnel in or around the head etc.).
  7. Anemia (defined as HGB < 12 for men or < 11 g/dl for women)
  8. Poor venous access.
  9. Lactation or Pregnancy (positive urine pregnancy test. Pregnancy tests will not be done on post-menopausal women defined as one of the below criteria:

    1. prior bilateral oophorectomy
    2. Amenorrhea for 12 months or more
  10. Known severe allergic reactions to the HVMN KE or other ketogenic supplement or stevia products.
  11. Following high fat/low carb diet (ketogenic) diet or very low calorie (<500 calories) diet or taking other ketogenic supplements (such as Medium Chain Triglycerides (MCTs), Ketone Salts) or fasting intermittently and unwilling to stop it while on the HVMN KE/Placebo.
  12. Very high or severe hypertriglyceridemia >=886mg/dL or 10.0 mmol/L)
  13. Severe Hypertension (systolic blood pressure >=180mmHg and/or diastolic blood pressure >=120mmHg)
  14. Weight >=300 lbs (MRI scanner weight limit)
  15. Diabetes Mellitus (type 1 or 2)
  16. Taking the drug metformin.
  17. Non-English speakers (given staffing constraints for cognitive testing administration and need for decreased variability in testing procedures for a small N study).
  18. Participant has any concurrent medical condition, so that participation in the clinical study would not be in her/his best interest, in the PI s judgement.
  19. To be eligible to consent for optional thigh MRI: Individuals with joint replacements that may be affected by the defined exercise protocol or which may prevent MRI analysis or any condition, in the opinion of the investigator, that would prevent successful completion of the exercise protocol such as, but not limited to reported osteoarthritis, rheumatoid arthritis and/or fibromyalgia.

5.3 INCLUSION OF VULNERABLE PARTICIPANTS

  • Children: No inclusion is planned. This study aims to investigate the effects of aging 55 years old) on brain metabolism, therefore inclusion of children is inappropriate with respect to the purpose of the research.
  • Pregnant Women, Fetuses, or Neonates: No inclusion is planned. We will exclude women, fetuses or neonates with respect to the health of participants, specifically, due to the risk associated with the MRI procedure and the unknown effects of the ketone ester supplement.
  • Prisoners: No inclusion is planned. This study involves several visits to the NIA Clinical Unit, which prisoners are unable to perform. Therefore, inclusion of prisoners is inappropriate with respect to the purpose of the research.
  • Decisionally Impaired Adults: No inclusion is planned. Cognitive intact status will be ascertained at baseline based on Clinical Dementia Rating (CDR) of 0, and Montreal Cognitive Assessment (MoCA) > 26, since the main objective of the study is to study a population of cognitively intact individuals. Therefore, inclusion of decisionally impaired adults is inappropriate with respect to the purpose of the research. Moreover, participants are not expected to become decisionally impaired over the course of the study.
  • NIH Employees: We intend to include NIH staff (to include NIH contractors and special volunteers, guest researchers and trainees) in this study. The staff will be invited to participate through standard recruitment efforts. Participation will be voluntary and neither participation nor refusal to participate will have an effect, either beneficial or adverse, on the participant s employment or position at NIH. We will follow the Guidelines for the Inclusion of Employees in NIH Research Studies and will give each employee a copy of the NIH information sheet on Staff Research Participation per NIH OHSRP SOP 14F.4: Research Involving NIH Staff as Subjects.
  • Neither participation nor refusal to participate will have an effect, either beneficial or adverse, on the participant s employment or work situation.
  • The NIH information sheet regarding NIH employee research participation will be distributed to all potential subjects who are NIH employees.
  • The employee subject s privacy and confidentiality will be preserved in accordance with NIH Intramural policies, which define the scope and limitations of the protections.
  • Subjects that are employees/staff will be consented in the usual manner. The inclusion of employees or staff is not anticipated to affect the research outcome; therefore, if the subject is a co-worker (including a supervisor, subordinate or coworker) the subject may be consented by another co-worker and/or subordinate.The study PI will not be involved in the consenting of employees or staff.
  • Other vulnerable populations: No inclusion is planned.

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): NCT04421014


Contacts
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Contact: Dimitrios I Kapogiannis, M.D. (410) 350-3953 kapogiannisd@mail.nih.gov

Locations
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United States, Maryland
National Institute of Aging, Clinical Research Unit Recruiting
Baltimore, Maryland, United States, 21224
Contact: Dimitrios Kapogiannis, M.D.    410-350-3953    kapogiannisd@mail.nih.gov   
Sponsors and Collaborators
National Institute on Aging (NIA)
Investigators
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Principal Investigator: Dimitrios I Kapogiannis, M.D. National Institute on Aging (NIA)
Publications:
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Responsible Party: National Institute on Aging (NIA)
ClinicalTrials.gov Identifier: NCT04421014    
Other Study ID Numbers: 999920087
20-AG-N087
First Posted: June 9, 2020    Key Record Dates
Last Update Posted: July 8, 2020
Last Verified: May 27, 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute on Aging (NIA) ):
Ketogenic
Brain Metabolism
BETA-HYDROXYBUTYRATE
Dietary Supplement
Alzheimer's Disease
Additional relevant MeSH terms:
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Metabolic Syndrome
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases