Clinical trial NCT06645847: Targeting Aging with a Ketone Ester for Function in Frailty
Official title: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Frail Elderly
Aging
Immune Function
Muscle Function
Keywords: ketone ester
exogenous ketone
Lead sponsor: Buck Institute for Research on Aging
Sponsor class: OTHER
Collaborators: name: Ohio State University
name: University of Connecticut
First posted: 2024-10-17
Enrollment: 600
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel group, randomized, double-blind, placebo controlled
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

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 beverage 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 within 5 minutes of finishing their first meal. For the first 7 days of the study, subjects will consume 37.5 mL of study product, measured in a provided measuring cup. From day 8 onwards subjects will consume 75 mL of study product measured in a provided measuring cup. From Week 3 onwards, they will consume a second serving (Week 3 = 37.5 mL, Week 4 - 20 = 75 mL) within 5 minutes of finishing their final 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 beverage 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 beverage 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 beverages 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).

Eligibility criteria: 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.

Primary outcomes:
measure: Frailty composite score
timeFrame: Baseline, 12 weeks, 20 weeks
Secondary outcomes:
measure: Tolerability
timeFrame: 20 weeks
measure: Safety Lab Tests
timeFrame: Baseline, Week 4, Week 12, 20 weeks
measure: Leg fatigue - leg press at sub maximal weight
timeFrame: 20 weeks
measure: Short Physical Performance Battery
timeFrame: Baseline, Week 12, 20 weeks
measure: Grip Strength
timeFrame: Baseline, Week 12, Week 20
measure: Montreal Cognitive Assessment
timeFrame: Baseline, 12 weeks, 20 weeks
measure: Trails A and B
timeFrame: Baseline, Week 12, Week 20
Other outcomes:
measure: Immune phenotyping
timeFrame: 20 weeks
measure: Changes in gut microbial diversity
timeFrame: Baseline, Week 1, Week 4, Week 12, Week 20
measure: Profile of Mood States
timeFrame: Baseline, Week 12, Week 20
measure: Lower Urinary Tract Symptoms Questionnaire
timeFrame: Baseline, week 12, week 20
measure: Short form 36 questionnaire
timeFrame: Baseline, Week 12, 20 weeks
measure: Pittsburg Sleep Quality Index
timeFrame: Baseline, Week 12, Week 20
measure: Geriatric Depression Scale
timeFrame: Baseline, Week 12, Week 20
measure: Skeletal muscle size (OSU only)
timeFrame: Baseline, 20 weeks
measure: Skeletal muscle metabolites (OSU only)
timeFrame: Baseline, 20 weeks
measure: Resting metabolic rate (OSU only)
timeFrame: Baseline, Week 20
measure: Concentration of blood metabolites
timeFrame: Baseline, Week 4, Week 12
measure: Concentration of blood proteins
timeFrame: Baseline, Week 12, Week 20
measure: Concentration of urine metabolites
timeFrame: Baseline, Week 12, week 20
Locations:
city: Novato
country: United States
facility: Buck Institute for Research on Aging
state: California
city: Farmington
country: United States
facility: UConn Health
state: Connecticut
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
Study officials:
affiliation: Buck Institute
name: John Newman, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ohio State University
name: Jeff Volek, Phd
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Connecticut
name: Jenna Bartley, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.