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

NCT04421014 | Completed Results

• 2 other identifiers: 20008720-AG-0087
• Study Type: interventional
• Target: 99
• Locations: 1 country
• Sites: 1

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, 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 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. ...

Conditions

Metabolic Syndrome; Normal Cognition

Keywords

Ketogenic; Brain Metabolism; BETA-HYDROXYBUTYRATE; Dietary Supplement; Alzheimer's Disease

Outcome Measures

Primary Outcomes (1)

• Change in β-hydroxybutyrate in the Posteromedial Cortex Measured by ¹H-MRS (PRESS)

  β-hydroxybutyrate (BHB) was quantified in the posteromedial cortex (PMC) using ¹H-MRS (PRESS). Acute and acute-on-chronic responses were defined as the within-visit ratios of \~75 minutes post-drink to pre-drink (post/pre) at Weeks 0 and 4, respectively. The chronic effect was defined as the ratio of pre-drink BHB at Week 4 to pre-drink at Week 0 (Week 4 pre / Week 0 pre). BHB values were derived from spectral fitting with predefined quality-control criteria.

  Week 0 and Week 4 (pre-drink and ~75 minutes post-drink)

Secondary Outcomes (36)

• Change in Serum β-hydroxybutyrate

  Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)

• Change in Serum Acetoacetate

  Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)

• Change in Serum Non-Esterified Fatty Acids

  Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)

• Change in Body Mass Index

  Week 0, Week 4

• Change in Waist Circumference

  Week 0, Week 4

Study Arms (2)

Ketone Ester drink/ Arm 1

ACTIVE COMPARATOR

25 participants

Dietary Supplement: Ketone Ester drink

Placebo/ Arm 2

PLACEBO COMPARATOR

25 participants

Dietary Supplement: Placebo: isocaloric dextrose drink

Interventions

Ketone Ester drink DIETARY_SUPPLEMENT

The main ingredient of the Ketone Ester drink \[(R)-3-hydroxybutyl (R)-3-hydroxybutyrate)\] is regulated as GRAS (Generally Recognized as Safe) substance by the FDA (https://www.accessdata.fda.gov/scripts/fdcc/index.cfm?set=GRASNotices\&id=515). The Ketone Ester 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 TdeltaS(R) Global (https://www.deltagketones.com/products/g-ketone-performance). The dose and formulation (25 g of KE contained in 59 ml of a drink), daily scheme (3 times daily) and total duration (28 days) are identical to a previous safety human study. The Ketone Ester drink provided by DeltaG will be repackaged by the NIA Pharmacist into new bottles identical to the ones that will be used for the placebo to ensure the blinding of participants and researchers to the drink.

Ketone Ester drink/ Arm 1

Placebo: isocaloric dextrose drink DIETARY_SUPPLEMENT

The main content of the Placebo will be an aqueous solution containing approximately 35 g of dextrose, a fruity flavor powder and stevia. We will also add Denatonium Benzoate (Bittrex) to match the bitterness of the Ketone Ester drink. The placebo will be prepared and dispensed by the NIA Pharmacist.

Placebo/ Arm 2

Eligibility Criteria

• Age: 55 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to be eligible to participate in this study, an individual must meet all of the following criteria:
• Ability to provide informed consent and willingness to sign a written informed consent document
• Male or female, age \>=55 years old
• 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)
• Ability to take oral medications
• Willingness to adhere to all study procedures including having MRI/MRS.
• 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 \>=150 mg/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 \>=100 mg/dL
• Central obesity, defined as a waist circumference \>=102 cm (40 in) in men and \>=88 cm (35 in) in women.

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this study:
• 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).
• 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.
• 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.
• Positive urine drug screen (and no prescription medication accounting for the positive test).
• Positive HIV, HBV or HCV status during screening.
• Contraindications for MRI (pregnancy, pacemakers or other implanted devices, ferrous metal implants or shrapnel in or around the head etc.).
• Anemia (defined as HGB \< 12 for men or \< 11 g/dl for women)
• Poor venous access.
• Lactation or Pregnancy (positive urine pregnancy test. Pregnancy tests will not be done on post-menopausal women defined as one of the below criteria:
• prior bilateral oophorectomy
• Amenorrhea for 12 months or more
• Known severe allergic reactions to the KE drinks or other ketogenic supplement or stevia products.
• 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 KE drink/Placebo.
• Very high or severe hypertriglyceridemia (\>=886 mg/dL or 10.0 mmol/L)

Sponsors & Collaborators

• National Institute on Aging (NIA): lead

Study Sites (1)

National Institute of Aging, Clinical Research Unit

Baltimore, Maryland, 21224, United States

Location

Related Publications (3)

• Fortier M, Castellano CA, Croteau E, Langlois F, Bocti C, St-Pierre V, Vandenberghe C, Bernier M, Roy M, Descoteaux M, Whittingstall K, Lepage M, Turcotte EE, Fulop T, Cunnane SC. A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. Alzheimers Dement. 2019 May;15(5):625-634. doi: 10.1016/j.jalz.2018.12.017. Epub 2019 Apr 23.

  PMID: 31027873 BACKGROUND

• Soto-Mota A, Vansant H, Evans RD, Clarke K. Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. Regul Toxicol Pharmacol. 2019 Dec;109:104506. doi: 10.1016/j.yrtph.2019.104506. Epub 2019 Oct 23.

  PMID: 31655093 BACKGROUND

• Cunnane SC, Courchesne-Loyer A, Vandenberghe C, St-Pierre V, Fortier M, Hennebelle M, Croteau E, Bocti C, Fulop T, Castellano CA. Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer's Disease. Front Mol Neurosci. 2016 Jul 8;9:53. doi: 10.3389/fnmol.2016.00053. eCollection 2016.

  PMID: 27458340 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Metabolic Syndrome; Alzheimer Disease

Condition Hierarchy (Ancestors)

Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Results Point of Contact

• Title: Dimitrios Kapogiannis
• Organization: National Institute on Aging, NIH

kapogiannisd@nih.mail.gov

+1-202-290-0433

Study Officials

• Dimitrios I Kapogiannis, M.D.

  National Institute on Aging (NIA)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 5, 2020
• First Posted: June 9, 2020
• Study Start: June 24, 2021
• Primary Completion: June 2, 2025
• Study Completion: June 2, 2025
• Last Updated: April 2, 2026
• Results First Posted: April 2, 2026

Record last verified: 2026-03

Locations

US (1)