Ketone Ester for Frail Elderly

(TAKEOFF Trial)

Recruiting at 2 trial locations

Overseen By Brianna Stubbs, DPhil

Age: 65+

Sex: Any

Trial Phase: Academic

Sponsor: Buck Institute for Research on Aging

Must not be taking: Immunosuppressants, Chemotherapy, Chronic antibiotics, others

Disqualifiers: Non ambulatory, Frailty, Cancer, others

Compensation: Varies

Number of Visits: 6

Duration: 20 weeks

600 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must maintain your usual medication routine during the study.

What data supports the effectiveness of the treatment Ketone Ester for frail elderly?

Research suggests that ketone esters can safely increase blood ketone levels, which may improve physical and cognitive performance. Additionally, ketone bodies have been studied for their potential to target aging mechanisms, which could help reduce frailty in older adults. ^{1 2 3 4 5}

Is ketone ester safe for human use?

Research shows that ketone esters, like (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, are generally safe and well-tolerated in healthy adults, with some mild gastrointestinal effects reported at high doses. Long-term use over 28 days did not affect body weight, blood sugar, cholesterol, or kidney function. ^{2 3 6 7 8}

How is the ketone ester treatment for frail elderly different from other treatments?

Ketone ester treatment is unique because it induces ketosis (a state of increased blood ketone levels) without requiring dietary changes, potentially improving frailty by targeting aging mechanisms through anti-inflammatory and metabolic effects. ^{1 3 5 9 10}

What is the purpose of this trial?

This study aims to find out if a special drink that contains a naturally occurring substance, ketones, can help to improve strength and general wellness in adults at, or over the age of 65 years who are experiencing a slight decline in their physical function. Participation will involve a screening visit and 4 additional study visits over the course of 20 weeks. After being assessed for eligibility, study participants will be sorted into two groups at random and consume either a ketone drink or placebo drink at home every day for 20 weeks. Both study drinks can cause gastro-intestinal side effects in some individuals. At all study visits, subjects will provide blood samples. At three study visits, subjects will be asked to complete physical performance tests, provide blood, stool and urine samples. They will also complete questionnaires during three study visits to assess physical function, markers of inflammation, and other aspects of general well-being.

Research Team

John Newman, MD, PhD

Principal Investigator

Buck Institute

Jeff Volek, Phd

Principal Investigator

Ohio State University

Jenna Bartley, PhD

Principal Investigator

University of Connecticut

Eligibility Criteria

This trial is for adults aged 65 or older who are experiencing a decline in physical function. Participants must be able to attend five study visits over 20 weeks and provide blood, stool, and urine samples. The key exclusion criteria have not been provided.

Inclusion Criteria

I am 65 years old or older.

I can walk at a required speed.

I weigh at least 50 kg.

Exclusion Criteria

I cannot walk by myself.

I am considered very frail according to a clinical assessment.

I was in the hospital within the last 30 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person), phone screening

Baseline

Baseline assessments including medical history, physical assessment, and cognitive and physical function testing

1 day

1 visit (in-person)

Treatment

Participants consume either a ketone drink or placebo daily for 20 weeks, with regular assessments and sample collections

20 weeks

4 visits (in-person), bi-weekly phone check-ins

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ketone Ester
• Placebo Comparator

Trial Overview The study tests if a ketone ester drink can improve strength and wellness in frail elderly individuals compared to a non-ketone placebo drink. Participants will consume their assigned drink daily for 20 weeks with random assignment into two groups.

Participant Groups

Group I: Ketone ester Active Control 1 Intervention

Ketone ester (KE) (Chemical name: Bis-octanoyl-(R)-1,3-butanediol, Common name: C8 ketone di-ester) formulated in a tropical flavored beverage . KE 12.5 g in 37.5 mL per day for 1 week KE 25 g/day in 75 mL per day for 1 week KE 37.5g/day in 112.5 mL per day for 1 week KE 50 g/day in 150 mL per day for 17 weeks (37.5 mL of study beverage contains 12.5 g of KE)

Group II: Non-ketone placebo Placebo Group 1 Intervention

Placebo (non-ketogenic canola oil) formulated in a tropical flavored beverage * 37.5 mL tropical flavored beverage containing 12.5 g/day of canola oil will be consumed for the first 7 days, with the first meal of the day. * 75 mL tropical flavored beverage containing 25 g/day of canola oil will be consumed for week 2 (for 1 week) also with the first meal of the day. * 112.5 mL tropical flavored beverage containing 37.5g/day of canola oil will be consumed from week 3 (for 1 week). 25g (75mL) with the first meal of the day and 12.5g (37.5mL) with the last meal of the day. * 150 mL tropical flavored beverage containing 50g/day of canola oil will be consumed from week 4 (for 17 week). 25g (75mL) with the first meal of the day and 25g (75mL) with the last meal of the day.

Who Is Running the Clinical Trial?

Buck Institute for Research on Aging

Lead Sponsor

Trials

6

Recruited

1,200+

Ohio State University

Collaborator

Trials

891

Recruited

2,659,000+

University of Connecticut

Collaborator

Trials

194

Recruited

162,000+

Findings from Research

The ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate effectively elevates blood ketone levels in healthy volunteers, reaching maximum plasma concentrations of 3.30 mM for β-hydroxybutyrate within 1-2 hours after ingestion.

This ketone monoester was generally well-tolerated over a 5-day period, although some gastrointestinal side effects were noted at higher doses, indicating it is a safe alternative to traditional ketogenic diets for enhancing physical and cognitive performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Clarke, K., Tchabanenko, K., Pawlosky, R., et al.[2022]

In a study with conscious dogs, the ingestion of R,S-1,3-butanediol diacetoacetate induced ketosis, but the achieved level (0.8 mM) was lower than the levels (1-3 mM) seen in children on a ketogenic diet for epilepsy.

The study suggests that while the ketosis level in dogs was lower, humans might experience higher ketone body concentrations from the same doses of the ester, potentially making it a viable option for managing seizures in children with intractable epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dog model of therapeutic ketosis induced by oral administration of R,S-1,3-butanediol diacetoacetate. Puchowicz, MA., Smith, CL., Bomont, C., et al.[2022]

Oral administration of exogenous ketone supplements over 28 days effectively induced sustained nutritional ketosis in male rats, achieving ketone levels greater than 0.5 mM without the need for carbohydrate restriction.

The study showed that these supplements led to a rapid increase in β-hydroxybutyrate (βHB) levels and a decrease in blood glucose, while having minimal impact on lipid levels, indicating their potential safety and efficacy for therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley rats. Kesl, SL., Poff, AM., Ward, NP., et al.[2020]

In a study involving 80 healthy older adults, the medium-chain triglyceride GSK2981710 increased plasma β-hydroxybutyrate (BHB) levels but did not lead to significant improvements in cognitive function or memory-related neuronal activity over 14 days.

The most common side effect was diarrhea, affecting 100% of participants in the initial part of the study, indicating that while GSK2981710 is generally well-tolerated, it may cause gastrointestinal discomfort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of GSK2981710, a medium-chain triglyceride, on cognitive function in healthy older participants: A randomised, placebo-controlled study. O'Neill, BV., Dodds, CM., Miller, SR., et al.[2020]

Oral administration of the ketone ester (KE) significantly increases ketosis levels in non-fasted mice, reaching a peak of 6.83 mmol/L within 30 minutes, indicating its rapid effectiveness in generating ketone bodies.

The study reveals that KE enhances brain metabolism by increasing acetyl-CoA and citric cycle intermediates, which may inhibit glycolysis and suggest a potential therapeutic role for KE in acute neurological diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ingested Ketone Ester Leads to a Rapid Rise of Acetyl-CoA and Competes with Glucose Metabolism in the Brain of Non-Fasted Mice. Suissa, L., Kotchetkov, P., Guigonis, JM., et al.[2021]

A study involving 24 healthy adults showed that consuming a ketone monoester three times a day for 28 days safely elevated blood ketone levels without affecting body weight, blood glucose, cholesterol, or kidney function.

The only reported side effect was mild nausea in a small number of instances, indicating that the ketone monoester is well-tolerated for sustained use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. Soto-Mota, A., Vansant, H., Evans, RD., et al.[2020]

Two validated LC-MS methods were developed to accurately measure ketone ester and its metabolites in human plasma, ensuring reliable pharmacokinetic profiling for potential therapeutic use.

The study found that ketone ester undergoes non-saturable metabolism in human plasma, indicating its metabolic stability at high concentrations, and that human serum albumin plays a role in its metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative Determination of (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate (Ketone Ester) and Its Metabolites Beta-hydroxybutyrate, 1-3-Butanediol, and Acetoacetate in Human Plasma Using LC-MS. Panse, N., Halquist, M., Gerk, PM.[2023]

In a 28-day study involving 59 healthy adults, the novel exogenous ketone diester bis-hexanoyl-(R)-1,3-butanediol (BH-BD) was found to be well-tolerated and safe, with no significant differences in tolerability scores compared to a placebo.

BH-BD effectively increased blood ketone levels one hour after consumption, indicating its potential for promoting nutritional ketosis without adverse effects on vital signs or laboratory measures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults. Chen, O., Blonquist, TM., Mah, E., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Rationale and protocol for a safety, tolerability and feasibility randomized, parallel group, double-blind, placebo-controlled, pilot study of a novel ketone ester targeting frailty via immunometabolic geroscience mechanisms. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Dog model of therapeutic ketosis induced by oral administration of R,S-1,3-butanediol diacetoacetate. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley rats. [2020]

5. England pubmed.ncbi.nlm.nih.gov

The effects of GSK2981710, a medium-chain triglyceride, on cognitive function in healthy older participants: A randomised, placebo-controlled study. [2020]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Ingested Ketone Ester Leads to a Rapid Rise of Acetyl-CoA and Competes with Glucose Metabolism in the Brain of Non-Fasted Mice. [2021]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Quantitative Determination of (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate (Ketone Ester) and Its Metabolites Beta-hydroxybutyrate, 1-3-Butanediol, and Acetoacetate in Human Plasma Using LC-MS. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Beneficial Effects of Exogenous Ketogenic Supplements on Aging Processes and Age-Related Neurodegenerative Diseases. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults. [2021]