Targeting Aging With a Ketone Ester for Function in Frailty (TAKEOFF)

A Randomized, Double-blind, Placebo-controlled, Parallel Group, Pilot Study to Evaluate the Effect of a Ketone Ester on Muscle and Immune Function in Older Men and Women Who Are at Risk for Strength and Mobility Decline

This study aims to find out if a food supplement 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 or placebo supplement at home every day for 20 weeks. Both study products 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.

The study enrolls at three sites across the United States, in California (Buck Institute), Ohio (Ohio State University), and Connecticut (University of Connecticut). The study is coordinated by the San Francisco Coordinating Center (California Pacific Medical Center).

Study Overview

• Status: Recruiting
• Conditions: Aging; Frail Elderly; Muscle Function; Immune Function
• Intervention / Treatment: Other: Ketone ester; Other: Placebo Comparator: Non-ketone placebo

Detailed Description

Screening (Phone and Visit 0):

Subjects are screened for eligibility by telephone for major exclusion criteria. They then attend a screening visit.

At the start of the visit subjects must meet pre-test requirements. During this visit, consent is obtained, followed by a medical history interview, a physical assessment and fasting blood samples are collected for screening analysis. Subjects who meet all the inclusion and none of the exclusion criteria will be scheduled for a Baseline (Visit 1) and at the end of Visit 1 will be randomized into one of the two experimental groups (ketone ester or placebo). Subjects will be shown and instructed on the use of the equipment for the physical function testing and complete a brief familiarization. A 24h diet log will be provided to complete before the next visit. A stool collection kit will also be provided along with use instructions to complete 3 days before Baseline visit.

Baseline Visit (Visit 1- Week 0):

Subjects must meet pre-test requirements. Changes to the subject's health and medication/supplement use will be assessed, and subject's compliance with inclusion/exclusion criteria will be reviewed. Fasted blood samples are collected. A clean catch urine sample is collected for archiving and additional plasma is banked for future aging biomarker analysis. After this a physical assessment will be conducted, including vital signs (after 5 minutes of rest), body weight and waist circumference. Investigators will reassess Katz's Activities of Daily Living (ADL) and Lawton's Instrumental Activities of Daily Living (IADLs) and CSHA Frailty Score (Canadian Study of Health and Aging). Then subjects will complete the following paper questionnaires: Profile of Mood States (Short form), Short Form Health Survey-36, Pittsburgh Sleep Quality Index, Pittsburgh Fatiguability Scale, Geriatric Depression Scale, Lower Urinary Tract Symptom Questionnaire. Subjects will complete cognitive function testing: Montreal Cognitive Assessment, Digit Symbol Substitution Task and Trails A and B. Subjects will complete physical function testing: Short Physical Performance Battery, 1 rep max leg press, sub maximal leg press repetitions to failure, 6-minute walk test and grip strength. Subjects will be given a stool sample collection kit to take home for at-home sample between Week 0 and 1; samples are returned by mail. Subject will be given a month's supply of study product to take home. Subjects will be reminded of study instructions (for study product consumption, daily Study Log completion, and to maintain habitual exercise, meal/diet, and medication/supplementation use). Subjects will be given a wearable actigraphy device and instructed on its use during the study.

At home procedures (Week 0 - 20):

Each day at home, subjects should consume their first meal of the day at a similar time and consume the study product with that first meal. For the first 7 days of the study, subjects will consume a 12.5 gram dose of study product. From day 8 onwards subjects will consume 25 grams of study product. From Week 3 onwards, they will consume a second serving (Week 3 = 12.5 grams, Week 4 - 20 = 25 grams) with their final meal of the day. The goal is to consume a 25 gram dose twice a day, one dose each with the first and last meal of the day. Subjects will complete the Study Log to confirm they consumed their study product. The Study Log will query the presence of specific symptoms in the hours after consumption of the study product with a beverage tolerance questionnaire (BTQ). Between days 6 - 9, subjects will collect a stool sample using the provided kit.

Every 2 weeks (excepting the site visits) the subjects will schedule a phone call with the Study Team in which they will verbally complete the BTQ for symptoms occurring in the preceding 2-week period. Compliance will be assessed, and AEs will also be assessed with an open-ended question. Subjects will be reminded of study instructions (for study product consumption, daily Study Log completion, and to maintain habitual exercise, meal/diet, and medication/supplementation use). After Week 16 check in, subjects will be mailed a stool sample collection kit for sample collection up to 3 days ahead of Visit 4.

From Week 5 onwards, a full BTQ is not completed daily. There is space in the Study Log to note any symptoms, these notes will be used to assess tolerance by interview for the previous 2-week interval; at Visit 2, during phone check-ins (Week 2, 6, 8, 10, 14, 16 and 18) and at Visits 3 and 4. Study product will be provided at one month intervals, it will be distributed directly during Visit 2 (week 4) and Visit 3 (week 12) and it will be shipped to subject's homes to arrive in week 8 and 16.

Intermediate Visit (Visit 2- Week 4): Subjects must meet pre-test requirements on arrival for Visit 2 (fasting ≥ 10 h, no alcohol ≥ 10 h, no exercise ≥ 10 h, no cannabis products ≥ 10 h); a reminder email (or telephone call if preferred by the subject) will be sent out ahead of the visit. On arrival, changes to medication/supplement use will be assessed, and the subject's compliance with inclusion/exclusion criteria will be reviewed. Subjects will be queried to ensure compliance with study instructions. Subjects will be asked to provide any unused product to assess compliance of Study Product consumption, and the Study Log (Part I) will be reviewed and collected. Adherence will be assessed, and adverse events (AEs) will also be assessed with an open-ended question. After this a physical assessment will be conducted, including vital signs (after 5 minutes of rest), body weight, body composition (using bioelectrical impedance), and waist circumference. Fasting blood samples will be collected for the following analysis: clinical chemistry, lipid panel, hematology and liver function. Additional samples will be retained to bank for possible future mechanistic investigations. Then, subjects will be asked to collect a urine sample for archiving. Subjects will verbally complete the BTQ for symptoms occurring in the preceding 2-week period.

Subjects will be reminded of study instructions (for study product consumption, daily Study Log completion, and to maintain habitual exercise, meal/diet, and medication/supplementation use). Subjects will be given a stool sample collection kit (instructions insert shown in Appendix) to take home for at-home sample collection up to 3 days after Visit 2, the stool sample will be returned to investigators using a prepaid mailer. Finally, subjects will be given a 4-week supply of study product to take home and Study Log (Part II). On this day, subjects will be asked to consume study products with their next meal after the test visit is complete.

Visit 3: Interim Endpoints Visit (Visit 4 - Week 12) and Final Visit (Visit 5- Week 20):

Follows identical testing procedures to Baseline Visit (Visit 3- Week 0).

• Study Type: Interventional
• Enrollment (Estimated): 180
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Brianna Stubbs, DPhil; Phone Number: 6709 415-209-2000; Email: bstubbs@buckinstitute.org
• Study Contact Backup: Name: Chatura Senadheera, MSc; Phone Number: 415-209-2072; Email: csenadheera@buckinstitute.org

Study Locations

• United States
  • California
    • Novato, California, United States, 94945
      • Recruiting
      • Buck Institute for Research on Aging
      • Contact: Brianna Stubbs, DPhil; Phone Number: 6709 415-209-2000; Email: bstubbs@buckinstitute.org
      • Contact: Chatura Senadheera, MSc; Phone Number: 415-209-2072; Email: csenadheera@buckinstitute.org
      • Principal Investigator: John Newman, MD, PhD
  • Connecticut
    • Farmington, Connecticut, United States, 06030
      • Recruiting
      • UConn Health
      • Contact: Jenna Bartley, PhD; Phone Number: 860-679-8322; Email: jbartley@uchc.edu
      • Principal Investigator: Jenna Bartley, PhD
      • Contact: Deborah Noujaim, MPH; Phone Number: 860-679-4271; Email: dnoujaim@uchc.edu
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University
      • Contact: Madison L. Kackley, PhD; Email: kackley.19@osu.edu
      • Principal Investigator: Jeff Volek, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Subject is greater than or equal to 65 years of age, inclusive at Screening.
2. Passes the gait speed criteria at Screening.
3. Minimum body weight of 50 kgs at Screening.
4. Subject is willing and able to comply with all study procedures including randomization into any of the experimental groups, maintenance of habitual dietary intake, exercise and medication and supplement use, blood draws and the following prior to test visits: fasting (≥10 h; water only), no alcohol (≥ 10 h), no cannabis products (≥10 h) and no exercise (≥ 10 h).
5. Subject understands the study procedures and can provide informed consent to participate in the study.

Exclusion Criteria:

1. Subject is non ambulatory.
2. Subject has a CSHA clinical frailty score > 5.
3. Subject requires assistance with any activity of daily living, excluding continence.
4. Subject lives in an institutional setting (skilled nursing facility or residential care facility for the elderly).
5. Subject is a female who has not passed menopause.
6. Subject is unable to converse in English (or Spanish, if available at the study site).
7. Subject has been hospitalized within 30 days of Screening.
8. Subject has any physical limitation that would prevent them from performing 1RM leg press based on Medical Officer judgement.
9. Subject has an abnormal laboratory test result(s) of clinical importance at Screening, indicating unstable chronic disease of major organ dysfunction that requires urgent evaluation, at the discretion of the Medical Officer. One re-test will be allowed on a separate day prior to Visit 1, for subjects with abnormal laboratory test results. Additional clinical information may be gathered from the participant if needed to interpret the urgency of laboratory abnormalities (e.g. recent laboratory trends if an electrolyte is abnormal).
10. Subject has uncontrolled hypercholesterolemia on screening labs.
11. Subject has a history or presence of acute or uncontrolled and/or clinically active pulmonary (chronic obstructive pulmonary disease >= Gold 3), cardiac (e.g. >= New York Heart Association class III), hepatic (cirrhosis), renal (chronic kidney disease stage >= IIIb), endocrine (including type 1 diabetes), hematologic, immunologic, neurologic (e.g., Alzheimer's or Parkinson's diseases), psychiatric (including unstable depression and/or anxiety disorders) or biliary disorders. "Uncontrolled" and "clinically active" are per the judgement of the Medical Officer. Stable chronic disease is not an exclusion criterion unless specified. Chronic disease that is managed with the patient's physician per shared decision-making, even if sub optimally by typically recommended care, is not an exclusion criterion unless uncontrolled or clinically active.
12. Subject has a clinically important gastrointestinal condition that would potentially interfere with the evaluation of the study beverage [e.g., inflammatory bowel disease, irritable bowel syndrome, chronic constipation, severe constipation (in the opinion of the Medical Officer), history of frequent diarrhea, history of surgery for weight loss, gastroparesis, systemic disease that might affect gut motility according to the Investigator, history of gastrointestinal ulcers or bleeding, history of pancreatitis, history of hiatal hernia, history of Barrett's esophagus, or history of esophageal cancer].
13. Heavy drinking (For women, 8 or more drinks per week. For men, 15 or more drinks per week).
14. Subject has a history of alcohol or substance abuse.
15. Subject has been instructed not to consume alcohol for medical reasons.
16. Subject has a known, clinically important allergy, intolerance, or sensitivity to any of the ingredients in the study beverages, including soy and milk protein.
17. Subject has uncontrolled hypertension as defined by the blood pressure measured at Screening. For subjects with elevated blood pressure at Screening, they are allowed for the purpose of this criteria to submit home readings from three separate days, or to have a repeat reading taken at the study site on a separate day before Visit 1.
18. Subject is undergoing treatment or active surveillance for cancer or has been diagnosed with cancer in the prior two years, except for non-melanoma skin cancer. Active surveillance is defined as regular imaging or laboratory tests at a frequency greater than annually. Cancer under long-term monitoring such as stable chronic lymphocytic leukemia need not be an exclusion, on the discretion of the Medical Officer.
19. Immunosuppressive disorders, taking immunosuppressive medications (including oral prednisone >10mg/day and biological immunosuppressants), or receiving chemotherapy.
20. Chronic antibiotic use (e.g. expected to be ongoing, regardless of frequency, throughout the study period).
21. Subject has extreme dietary habits (e.g., intermittent fasting or time restricted eating, Atkins diet, vegan, very high protein/low carbohydrate or has used weight-loss medications (including over-the-counter medications and/or supplements) or programs within 30 days of Screening.
22. Subject has followed a ketogenic diet or used ketone supplements (ketone salts or esters, and medium chain triglycerides) within 30 days of Screening.
23. Subject has a condition the Medical Officer believes would interfere with their ability to provide informed consent, comply with the study protocol, which might confound the interpretation of the study results, or put the subject at undue risk.
24. Subject works nights or shifts that means it is not possible to maintain a consistent meal schedule during the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ketone ester; Ketone ester (KE) (Chemical name: Bis-octanoyl-(R)-1,3-butanediol, Common name: C8 ketone di-ester) formulated as a dietary supplement. KE 12.5 g per day for 1 week; followed by KE 25 g per day for 1 week; followed by KE 37.5 g per day split into two doses for 1 week; followed by KE 50 g per day split into two doses for 17 weeks	Other: Ketone ester; Ketone ester (KE) (Chemical name: Bis-octanoyl-(R)-1,3-butanediol, Common name: C8 ketone di-ester) formulated as a dietary supplement. KE 12.5 g per day for 1 week; followed by KE 25 g per day for 1 week; followed by KE 37.5 g per day split into two doses for 1 week; followed by KE 50 g per day split into two doses for 17 weeks
Placebo Comparator: Non-ketone placebo; Placebo oil (non-ketogenic canola oil) formulated as a dietary supplement. Placebo oil 12.5 g per day for 1 week; followed by Placebo oil 25 g per day for 1 week; followed by Placebo oil 37.5 g per day split into two doses for 1 week; followed by Placebo oil 50 g per day split into two doses for 17 weeks	Other: Placebo Comparator: Non-ketone placebo; Placebo oil (non-ketogenic canola oil) formulated as a dietary supplement. Placebo oil 12.5 g per day for 1 week; followed by Placebo oil 25 g per day for 1 week; followed by Placebo oil 37.5 g per day split into two doses for 1 week; followed by Placebo oil 50 g per day split into two doses for 17 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frailty composite score	The primary outcome measure is the difference in the change in a four-item composite score of vigor-frailty (6 minute walk, 1 rep max leg press, digit symbol substitution, Pittsburg Fatigability Scale - Physical sub scale) over 20 weeks between groups. The original composite score was developed by the Study of Muscle Mass and Aging Group, it is continuous, and a higher score corresponds to better function.	Baseline, 12 weeks, 20 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Lab Tests	Changes in clinical laboratory measurements when ketone esters are consumed daily for 20 weeks.	Baseline, Week 4, Week 12, 20 weeks
Leg fatigue - leg press at sub maximal weight	Difference in change in number of repetitions completed on the leg press machine at a sub maximal weight (subject must complete as many repetitions as they can).	20 weeks
Short Physical Performance Battery	Difference in change in Short Physical Performance Battery score	Baseline, Week 12, 20 weeks
Grip Strength	Difference in change in grip strength measured by a hand grip dynamometer	Baseline, Week 12, Week 20
Montreal Cognitive Assessment	Difference in change Montreal Cognitive Assessment score	Baseline, 12 weeks, 20 weeks
Trails A and B	Standard trail making test scores between letters and numbers	Baseline, Week 12, Week 20
Tolerability key symptom index	Proportion of subjects reporting the same moderate to severe symptom (among dizziness, headache or nausea) occurring on more than one day within any given recall period (after week 0 - 2 acclimation period) when ketone esters are consumed daily for 20 weeks.	20 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune phenotyping	Differences in cell subtypes, markers of immune aging and exhaustion, metabolite transporters and systemic inflammation.	20 weeks
Changes in gut microbial diversity	DNA sequencing of bacterial species in stool samples.	Baseline, Week 1, Week 4, Week 12, Week 20
Profile of Mood States	Questionnaire about mood	Baseline, Week 12, Week 20
Lower Urinary Tract Symptoms Questionnaire	Score on questionnaire assessing lower urinary tract symptoms	Baseline, week 12, week 20
Short form 36 questionnaire	Quality of life questionnaire	Baseline, Week 12, 20 weeks
Pittsburg Sleep Quality Index	Questionnaire about sleep quality	Baseline, Week 12, Week 20
Geriatric Depression Scale	Questionnaire about mood	Baseline, Week 12, Week 20
Skeletal muscle size (OSU only)	Differences in muscle size measured by MRI	Baseline, 20 weeks
Skeletal muscle metabolites (OSU only)	Differences in muscle metabolites measured by mass spectrometry	Baseline, 20 weeks
Resting metabolic rate (OSU only)	Differences in resting metabolic rate measured by indirect calorimetry	Baseline, Week 20
Concentration of blood metabolites	Blood samples will be analyzed using targeted and un-targeted mass spectrometry to measure the concentration of metabolites that might be linked to aging. The difference in change over the study will be compared between groups.	Baseline, Week 4, Week 12
Concentration of blood proteins	Blood samples will be analyzed using targeted and un-targeted mass spectrometry to measure the concentration of proteins that might be linked to aging. The difference in change over the study will be compared between groups.	Baseline, Week 12, Week 20
Concentration of urine metabolites	Urine samples will be analyzed using targeted and un-targeted mass spectrometry to measure the concentration of metabolites that might be linked to aging. The difference in change over the study will be compared between groups.	Baseline, Week 12, week 20

Collaborators and Investigators

• Sponsor: Buck Institute for Research on Aging
• Collaborators: Ohio State University; University of Connecticut; California Pacific Medical Center Research Institute
• Investigators: Principal Investigator: Jeff Volek, PhD, Ohio State University; Principal Investigator: John Newman, MD, PhD, Buck Institute; Principal Investigator: Jenna Bartley, PhD, University of Connecticut

Publications and helpful links

General Publications

• Chen O, Blonquist TM, Mah E, Sanoshy K, Beckman D, Nieman KM, Winters BL, Anthony JC, Verdin E, Newman JC, Stubbs BJ. Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults. Nutrients. 2021 Jun 16;13(6):2066. doi: 10.3390/nu13062066.
• Crabtree CD, Blade T, Hyde PN, Buga A, Kackley ML, Sapper TN, Panda O, Roa-Diaz S, Anthony JC, Newman JC, Volek JS, Stubbs BJ. Bis Hexanoyl (R)-1,3-Butanediol, a Novel Ketogenic Ester, Acutely Increases Circulating r- and s-ss-Hydroxybutyrate Concentrations in Healthy Adults. J Am Nutr Assoc. 2023 Feb;42(2):169-177. doi: 10.1080/07315724.2021.2015476. Epub 2022 Mar 25.
• Stubbs BJ, Alvarez Azanedo G, Peralta S, Diaz SR, Gray W, Alexander L, Silverman-Martin W, Garcia TY, Blonquist TM, Upadhyay V, Turnbaugh PJ, Johnson JB, Newman JC. Rationale and protocol for a safety, tolerability and feasibility randomized, parallel arm, double-blind, placebo-controlled, pilot study of a novel ketone ester targeting frailty via immunometabolic geroscience mechanisms. PLoS One. 2024 Sep 18;19(9):e0307951. doi: 10.1371/journal.pone.0307951. eCollection 2024.

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: October 14, 2024
• First Submitted That Met QC Criteria: October 15, 2024
• First Posted (Actual): October 17, 2024

Study Record Updates

• Last Update Posted (Actual): March 13, 2026
• Last Update Submitted That Met QC Criteria: March 12, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: exogenous ketone; ketone ester
• Additional Relevant MeSH Terms: formic acid 4-(3-oxobutyl)phenyl ester
• Other Study ID Numbers: 2024H0061

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No