Metabolic SyndromeNCT04421014
Ketone Ester Effects on Biomarkers of Brain Metabolism and Cognitive Performance in Cognitively Intact Adults 55 Years Old or Older
A study testing Ketone Ester drink in people with Metabolic Syndrome and Normal Cognition, run by National Institute on Aging (NIA) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 55 years and older
- Conditions the study is for
- Metabolic Syndrome, Normal Cognition
- What is being tested?
- Ketone Ester drink
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 99 participants
- Where
- 1 siteUnited States
- Study dates
- 24 Jun 2021to 2 Jun 2025
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 55 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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)
- Severe Hypertension (systolic blood pressure >=180 mmHg and/or diastolic blood pressure >=120 mmHg)
- Weight >= 300 lbs (MRI scanner weight limit)
- Diabetes Mellitus (type 1 or 2)
- Taking the drug metformin.
- Non-English speakers (given staffing constraints for cognitive testing administration and need for decreased variability in testing procedures for a small N study).
- 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.
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institute of Aging, Clinical Research Unit
Baltimore, Maryland, 21224
About this study
Official title: Ketone Ester Effects on Biomarkers of Brain Metabolism and Cognitive Performance in Cognitively Intact Adults >= 55 Years Old. A Double-Blinded Randomized Controlled Clinical Trial.
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.
Read more
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.
...
Read the detailed description
Study Description:
We hypothesize that supplementation with a ketone ester drink [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 beta-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-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, and a follow-up visit to obtain DNA.
Objectives:
Primary: To investigate the change in brain concentration BHB, using brain Magnetic Resonance Spectroscopy, after 28 days of supplementation with the KE, compared to baseline and placebo.
Secondary: To test the hypothesis that genetic factors may affect the response to the KE supplement.
Endpoints: Primary: To detect with brain MRS, a significant change in the concentration of BHB, after 28 days of supplementation with the KE compared to baseline and placebo
Secondary: To assess whether genetic factors modulate the response to the KE supplement.
- Conditions
- Metabolic Syndrome, Normal Cognition
- Being tested
- Ketone Ester drink, Placebo: isocaloric dextrose drink
- Keywords
- Ketogenic, Brain Metabolism, BETA-HYDROXYBUTYRATE, Dietary Supplement, Alzheimer's Disease
- Medical subject headings
- Metabolic Syndrome, Alzheimer Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ketone Ester drinkDietary 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.
Placebo: isocaloric dextrose drinkDietary 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.
| Study group | Role | What they receive |
|---|---|---|
| Ketone Ester drink/ Arm 1 | Active comparator | 25 participants Receives: Dietary Supplement: Ketone Ester drink |
| Placebo/ Arm 2 | Placebo comparator | 25 participants Receives: Dietary Supplement: Placebo: isocaloric dextrose drink |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Week 0 and Week 4 (pre-drink and ~75 minutes post-drink)
Secondary outcomes (36)
Change in Serum β-hydroxybutyrate
Measured: Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)
Change in Serum Acetoacetate
Measured: Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)
Change in Serum Non-Esterified Fatty Acids
Measured: Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)
Change in Body Mass Index
Measured: Week 0, Week 4
Change in Waist Circumference
Measured: Week 0, Week 4
Change in Fasting Glucose
Measured: Week 0, Week 4
Change in Fasting Insulin
Measured: Week 0, Week 4
Change in Total Cholesterol
Measured: Week 0, Week 4
Change in Glucose in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Glucose was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a glucose-to-creatine (Glucose/Cr) ratio. The chronic response was defined as the ratio of pre-drink Glucose/Cr at Week 4 to pre-drink Glucose/Cr at Week 0 (Week 4 pre / Week 0 pre). Glucose/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in N-acetyl-aspartate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
N-acetyl-aspartate was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a N-acetyl-aspartate-to-creatine (N-acetyl-aspartate/Cr) ratio. The chronic response was defined as the ratio of pre-drink N-acetyl-aspartate/Cr at Week 4 to pre-drink N-acetyl-aspartate/Cr at Week 0 (Week 4 pre / Week 0 pre). N-acetyl-aspartate/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Lactate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Lactate was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Lactate-to-creatine (Lactate/Cr) ratio. The chronic response was defined as the ratio of pre-drink Lactate/Cr at Week 4 to pre-drink Lactate/Cr at Week 0 (Week 4 pre / Week 0 pre). Lactate/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Glycine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Glycine was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Glycine-to-creatine (Glycine/Cr) ratio. The chronic response was defined as the ratio of pre-drink Glycine/Cr at Week 4 to pre-drink Glycine/Cr at Week 0 (Week 4 pre / Week 0 pre). Glycine/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Glutamate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Glutamate was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Glutamate-to-creatine (Glutamate/Cr) ratio. The chronic response was defined as the ratio of pre-drink Glutamate/Cr at Week 4 to pre-drink Glutamate/Cr at Week 0 (Week 4 pre / Week 0 pre). Glutamate/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Gamma-aminobutyric Acid in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Gamma-aminobutyric acid was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Gamma-aminobutyric acid-to-creatine (Gamma-aminobutyric acid/Cr) ratio. The chronic response was defined as the ratio of pre-drink Gamma-aminobutyric acid/Cr at Week 4 to pre-drink Gamma-aminobutyric acid/Cr at Week 0 (Week 4 pre / Week 0 pre). Gamma-aminobutyric acid/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Glutamine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Glutamine was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Glutamine-to-creatine (Glutamine/Cr) ratio. The chronic response was defined as the ratio of pre-drink Glutamine/Cr at Week 4 to pre-drink Glutamine/Cr at Week 0 (Week 4 pre / Week 0 pre). Glutamine/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Glutathione in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Glutathione was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Glutathione-to-creatine (Glutathione/Cr) ratio. The chronic response was defined as the ratio of pre-drink Glutathione/Cr at Week 4 to pre-drink Glutathione/Cr at Week 0 (Week 4 pre / Week 0 pre). Glutathione/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Myo-inositol in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Myo-inositol was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Myo-inositol-to-creatine (Myo-inositol/Cr) ratio. The chronic response was defined as the ratio of pre-drink Myo-inositol/Cr at Week 4 to pre-drink Myo-inositol/Cr at Week 0 (Week 4 pre / Week 0 pre). Myo-inositol/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in N-acetyl-aspartyl-glutamate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
N-acetyl-aspartyl-glutamate was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a N-acetyl-aspartyl-glutamate-to-creatine (N-acetyl-aspartyl-glutamate/Cr) ratio. The chronic response was defined as the ratio of pre-drink N-acetyl-aspartyl-glutamate/Cr at Week 4 to pre-drink N-acetyl-aspartyl-glutamate/Cr at Week 0 (Week 4 pre / Week 0 pre). N-acetyl-aspartyl-glutamate/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Aspartate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Aspartate was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as an Aspartate-to-creatine (Aspartate/Cr) ratio. The chronic response was defined as the ratio of pre-drink Aspartate/Cr at Week 4 to pre-drink Aspartate/Cr at Week 0 (Week 4 pre / Week 0 pre). Aspartate/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Ascorbate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ascorbate was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as an Ascorbate-to-creatine (Ascorbate/Cr) ratio. The chronic response was defined as the ratio of pre-drink Ascorbate/Cr at Week 4 to pre-drink Ascorbate/Cr at Week 0 (Week 4 pre / Week 0 pre). Ascorbate/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Alanine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Alanine was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as an Alanine-to-creatine (Alanine/Cr) ratio. The chronic response was defined as the ratio of pre-drink Alanine/Cr at Week 4 to pre-drink Alanine/Cr at Week 0 (Week 4 pre / Week 0 pre). Alanine/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Scyllo-inositol in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Scyllo-inositol was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Scyllo-inositol-to-creatine (Scyllo-inositol/Cr) ratio. The chronic response was defined as the ratio of pre-drink Scyllo-inositol/Cr at Week 4 to pre-drink Scyllo-inositol/Cr at Week 0 (Week 4 pre / Week 0 pre). Scyllo-inositol/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Phosphocholine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Phosphocholine was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Phosphocholine-to-creatine (Phosphocholine/Cr) ratio. The chronic response was defined as the ratio of pre-drink Phosphocholine/Cr at Week 4 to pre-drink Phosphocholine/Cr at Week 0 (Week 4 pre / Week 0 pre). Phosphocholine/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Glycerophosphocholine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Glycerophosphocholine was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Glycerophosphocholine-to-creatine (Glycerophosphocholine/Cr) ratio. The chronic response was defined as the ratio of pre-drink Glycerophosphocholine/Cr at Week 4 to pre-drink Glycerophosphocholine/Cr at Week 0 (Week 4 pre / Week 0 pre). Glycerophosphocholine/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Phosphoethanolamine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Phosphoethanolamine was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Phosphoethanolamine-to-creatine (Phosphoethanolamine/Cr) ratio. The chronic response was defined as the ratio of pre-drink Phosphoethanolamine/Cr at Week 4 to pre-drink Phosphoethanolamine/Cr at Week 0 (Week 4 pre / Week 0 pre). Phosphoethanolamine/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Taurine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Taurine was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Taurine-to-creatine (Taurine/Cr) ratio. The chronic response was defined as the ratio of pre-drink Taurine/Cr at Week 4 to pre-drink Taurine/Cr at Week 0 (Week 4 pre / Week 0 pre). Taurine/Cr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Post-exercise Phosphocreatine (PCr) Recovery Time Constant (τPCr) Measured by Thigh ³¹P-MRS
Post-exercise phosphocreatine (PCr) recovery time constant (τPCr) was measured by thigh ³¹P-MRS at pre-drink assessments. The chronic response was defined as the ratio of pre-drink τPCr at Week 4 to pre-drink τPCr at Week 0 (Week 4 pre / Week 0 pre). τPCr values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Phosphocreatine (PCr) Depletion Area During Exercise (PCr Drop Area) Measured by Thigh ³¹P-MRS
Phosphocreatine (PCr) depletion area during exercise (PCr drop area) was measured by thigh ³¹P-MRS at pre-drink assessments. The chronic response was defined as the ratio of pre-drink PCr drop area at Week 4 to pre-drink PCr drop area at Week 0 (Week 4 pre / Week 0 pre). PCr drop area values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Intramuscular Minimum pH During Exercise Measured by Thigh ³¹P-MRS
Intramuscular minimum pH during exercise was measured by thigh ³¹P-MRS at pre-drink assessments. The chronic response was defined as the difference between pre-drink PCr drop area at Week 4 and pre-drink PCr drop area at Week 0 (Week 4 pre - Week 0 pre). Intramuscular minimum pH values were derived from spectral fitting with predefined quality-control criteria.
Measured: Week 0 and Week 4 (pre-drink)
Change in Global Brain-age Gap (G-BrainAGE) Measured by Brain MRI (T1-weighted MP-RAGE)
G-BrainAGE was derived from pre-drink 3D T1-weighted MP-RAGE brain MRI using FreeSurfer (longitudinal pipeline) features processed through the CentileBrain platform with sex-specific pretrained models. G-BrainAGE represents the difference between the model-predicted brain age and chronological age (predicted age - chronological age), with higher values indicating an "older-appearing" brain relative to age and lower values indicating a "younger-appearing" brain. The chronic effect was assessed as the change in G-BrainAGE from Week 0 to Week 4.
Measured: Week 0 and Week 4 (pre-drink)
Change in Logical Memory Test
The Logical Memory test assesses verbal episodic memory for short stories. Participants recall two stories immediately and after a 20-30 minute delay. Outcomes include immediate and delayed recall subscores, each ranging from 0 to 50 (25 units/story × 2 stories), with higher scores indicating better performance. Verbatim subscores reflect exact recall; gist subscores reflect recall of essential elements.
Measured: Week 0, Week 4
Change in Montreal Cognitive Assessment (MoCA)
MoCA is a brief assessment of global cognitive function across multiple domains (e.g., attention, executive function, memory, language, visuospatial abilities, and orientation). Total scores range from 0 to 30, with higher scores indicating better cognitive performance.
Measured: Week 0, Week 4
Change in Eriksen Flanker
The Eriksen flanker task assesses selective attention and inhibitory control by requiring responses to a target stimulus while ignoring distracting flankers. The outcome is a composite score integrating response accuracy and response time into a single performance metric. Composite scores range from 0 to 10, with higher scores indicating better performance.
Measured: Week 0, Week 4
Change in Dimensional Set Shifting
The Dimensional Set Shifting task assesses cognitive flexibility (ability to shift between rules or stimulus dimensions). The outcome is a task-derived composite performance score; scores range from 0 to 10, with higher scores indicating better performance.
Measured: Week 0, Week 4
Change in Digit Symbol Substitution Test (DSST)
The Digit Symbol Substitution Test (DSST) assesses processing speed, attention, and visuomotor coordination by requiring participants to match symbols to digits using a provided key within a fixed time. The outcome is the total number of correct symbol-digit matches. Total scores range from 0 to 93, with higher scores indicating better performance.
Measured: Week 0, Week 4
Change in Free and Cued Selective Reminding Test (FCSRT)
The Free and Cued Selective Reminding Test (FCSRT) assesses verbal episodic memory using controlled learning and recall of a 16-word list with semantic cues. Total Free Recall (TFR) is the sum of freely recalled words across three learning trials (range 0 to 48). Total Delayed Free Recall (TDFR) is the number of freely recalled words after a delay (range 0 to 16). Higher scores indicate better memory performance.
Measured: Week 0, Week 4
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jun 2020
- Study start24 Jun 2021
- Primary completion2 Jun 2025
- Study completion2 Jun 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Metabolic SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 99 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institute on Aging (NIA)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Dimitrios I Kapogiannis, M.D., Principal investigator, National Institute on Aging (NIA)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04421014
- Sponsor's protocol ID
- 200087
- Other IDs
- 20-AG-0087
- Status last verified
- Mar 2026
- First submitted
- 5 Jun 2020
- Last updated
- 2 Apr 2026
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: There is ongoing discussion within the NIA IRP and a plan has not been finalized yet.
Publications
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.
PubMed 31027873Soto-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.
PubMed 31655093Cunnane 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.
PubMed 27458340
Study at a glance
From the registry record, last updated by the sponsor on 2 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Ketone Ester Effects on Biomarkers of Brain Metabolism and Cognitive Performance in Cognitively Intact Adults >= 55 Years Old. A Double-Blinded Randomized Controlled Clinical Trial.
- ClinicalTrials.gov ID
- NCT04421014
- Acronym / sponsor ID
- 200087
- Conditions
- Metabolic Syndrome, Normal Cognition
- Keywords
- Ketogenic, Brain Metabolism, BETA-HYDROXYBUTYRATE, Dietary Supplement, Alzheimer's Disease
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 99 participants (actual)
- Lead sponsor
- National Institute on Aging (NIA)US National Institutes of Health
- Study start
- 24 Jun 2021 (actual)
- Primary completion
- 2 Jun 2025 (actual)
- Study completion
- 2 Jun 2025 (actual)
- First posted
- 9 Jun 2020 (actual)
- Results
- Posted 2 Apr 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
...
Detailed description
Study Description:
We hypothesize that supplementation with a ketone ester drink [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 beta-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-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, and a follow-up visit to obtain DNA.
Objectives:
Primary: To investigate the change in brain concentration BHB, using brain Magnetic Resonance Spectroscopy, after 28 days of supplementation with the KE, compared to baseline and placebo.
Secondary: To test the hypothesis that genetic factors may affect the response to the KE supplement.
Endpoints: Primary: To detect with brain MRS, a significant change in the concentration of BHB, after 28 days of supplementation with the KE compared to baseline and placebo
Secondary: To assess whether genetic factors modulate the response to the KE supplement.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Ketone Ester drink/ Arm 1 | Active comparator | Dietary Supplement: Ketone Ester drink25 participants |
| Placebo/ Arm 2 | Placebo comparator | Dietary Supplement: Placebo: isocaloric dextrose drink25 participants |
Who may qualify
- Ages
- 55 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- 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
Key exclusion criteria (22 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ketone Ester drinkThe 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. | Dietary supplement | Ketone Ester drink/ Arm 1 |
| Placebo: isocaloric dextrose drinkThe 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. | Dietary supplement | Placebo/ Arm 2 |
Primary outcome
Change in β-hydroxybutyrate in the Posteromedial Cortex Measured by ¹H-MRS (PRESS)
Time frame: Week 0 and Week 4 (pre-drink and ~75 minutes post-drink)
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.
36 secondary outcomes
Change in Serum β-hydroxybutyrate
Time frame: Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)
Change in Serum Acetoacetate
Time frame: Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)
Change in Serum Non-Esterified Fatty Acids
Time frame: Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)
Change in Body Mass Index
Time frame: Week 0, Week 4
Change in Waist Circumference
Time frame: Week 0, Week 4
Change in Fasting Glucose
Time frame: Week 0, Week 4
Change in Fasting Insulin
Time frame: Week 0, Week 4
Change in Total Cholesterol
Time frame: Week 0, Week 4
Change in Glucose in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in N-acetyl-aspartate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in Lactate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in Glycine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in Glutamate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in Gamma-aminobutyric Acid in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in Glutamine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in Glutathione in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in Myo-inositol in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in N-acetyl-aspartyl-glutamate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in Aspartate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in Ascorbate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in Alanine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in Scyllo-inositol in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in Phosphocholine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in Glycerophosphocholine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in Phosphoethanolamine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in Taurine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Time frame: Week 0 and Week 4 (pre-drink)
Change in Post-exercise Phosphocreatine (PCr) Recovery Time Constant (τPCr) Measured by Thigh ³¹P-MRS
Time frame: Week 0 and Week 4 (pre-drink)
Change in Phosphocreatine (PCr) Depletion Area During Exercise (PCr Drop Area) Measured by Thigh ³¹P-MRS
Time frame: Week 0 and Week 4 (pre-drink)
Change in Intramuscular Minimum pH During Exercise Measured by Thigh ³¹P-MRS
Time frame: Week 0 and Week 4 (pre-drink)
Change in Global Brain-age Gap (G-BrainAGE) Measured by Brain MRI (T1-weighted MP-RAGE)
Time frame: Week 0 and Week 4 (pre-drink)
Change in Logical Memory Test
Time frame: Week 0, Week 4
Change in Montreal Cognitive Assessment (MoCA)
Time frame: Week 0, Week 4
Change in Eriksen Flanker
Time frame: Week 0, Week 4
Change in Dimensional Set Shifting
Time frame: Week 0, Week 4
Change in Digit Symbol Substitution Test (DSST)
Time frame: Week 0, Week 4
Change in Free and Cued Selective Reminding Test (FCSRT)
Time frame: Week 0, Week 4
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Apr 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 31027873Fortier 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.
- Background: PubMed 31655093Soto-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.
- Background: PubMed 27458340Cunnane 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.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: Undecided. There is ongoing discussion within the NIA IRP and a plan has not been finalized yet.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Dimitrios I Kapogiannis, M.D. principal investigator
National Institute on Aging (NIA)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Ketone Ester drink in people with Metabolic Syndrome and Normal Cognition, run by National Institute on Aging (NIA) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Apr 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in β-hydroxybutyrate in the Posteromedial Cortex Measured by ¹H-MRS (PRESS) (time frame: Week 0 and Week 4 (pre-drink and ~75 minutes post-drink)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04421014, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Apr 2026.