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| Name | Class |
|---|---|
| Biofortis Mérieux NutriSciences | OTHER |
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This study is to investigate the tolerability and safety of a ketone promoting ingredient, called a ketone ester (KE), in healthy older adults. This randomized, double-blind, placebo-controlled trial aims to characterize the tolerability and safety of daily consumption of the KE in healthy older adults (over 65 years old) over 12 weeks. Study participants will complete Beverage Tolerability Questionaires (BTQ) to rate any side side effects throughout the study. Safety will also be assessed by collection of blood and urine samples, vital signs, body weight, and monitoring of adverse events (AEs). The study will also collect pilot data to explore possible effects of KE on physical function, cognitive function and quality of life. The findings of this study will be used to facilitate future mechanistic studies of KE in aging.
Screening (Phone and Visit 1): 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 (fasting ≥ 10 h, no alcohol ≥ 10 h, no exercise ≥ 10 h, no cannabis products ≥ 10 h). During this visit, consent is obtained, followed by a medical history interview, a physical assessment (including vital signs, body weight, and waist circumference) and fasting blood samples are collected for screening analysis of: clinical chemistry, hematology, lipid profile, thyroid hormones. A clean catch urine sample is also collected for urinalysis. Subjects eligible and willing to take part in the study are randomized to take one of the two ketone ester serving sizes (12.5 g , 25 g) for the ketone kinetics visit (Visit 2). Subjects will be given a stool sample collection kit to take home for at-home sample collection up to 3 days before Visit 2, the stool sample will be returned to investigators using a prepaid mailer.
Ketone Kinetics Visit (Visit 2): Subjects must meet pre-test requirements (as above). A BTQ (Beverage Tolerability Questionnaire) is used to observe the tolerability of ketone drinks before and after their consumption. Blood glucose and ketone levels are measured from a finger stick sample of a ketone meter at baseline, and at 30, 60, 90,120,180, 240-minute timepoints. Subjects are then randomized to their experimental group ketone ester or placebo for the remainder of the visits (Visit 3-5). Subjects will be given a stool sample collection kit to take home for at-home sample collection up to 3 days before Visit 3; samples are returned by mail.
Baseline Visit (Visit 3- Week 0): Subjects must meet pre-test requirements (as above). Fasted blood samples are collected for screening analysis of: clinical chemistry, hematology, lipid profile, thyroid hormones. A clean catch urine sample is collected for screening analysis and urinalysis and additional plasma is banked for future aging biomarker analysis. Subjects will undergo an interview for 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). Subjects also complete the following paper questionnaires: Profile of Mood States (Short form), The Sexual Quality of Life Questionnaire (Male or Female Version), Short Form Health Survey-36, Pittsburgh Sleep Quality Index, Pittsburgh Fatiguability Scale and Geriatric Depression Scale. Physical and cognitive measures are assessed through the following tests: Montreal Cognitive Assessment, Digit Symbol Substitution Task and Trails A and B. Subjects also complete physical function testing at baseline (Visit 3) and final visit (Visit 5): Short Physical Performance Battery, 1 rep max leg press, sub maximal leg press repetitions to failure, 6-minute walk test and grip strength.
At the end of the testing, a continuous glucose and ketone monitor is applied (lasting 2 weeks). Subjects will be given a stool sample collection kit to take home for at-home sample between Week 1 and 2; 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).
At home procedures (Week 0 - 12): 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. Subjects will complete the Study Log immediately before they consume their second meal of the day or a snack (3 - 6 h after the study beverage). For Days 1 - 14 the Study Log will query the presence of specific symptoms with a beverage tolerance questionnaire (BTQ) and will confirm that subjects consumed their study product. From Day 15 onwards, the Study Log records study product consumption, but a full BTQ is not completed; however, any symptoms can be noted to assess tolerance by interview for the previous 2-week interval; at Visit 4- Week 4, during phone check-ins (Week 5, 8, and 10) and at Visit 5. At Week 8, subjects will be mailed the final mont's supply of study product, a continuous glucose and ketone sensor to apply at home (Week 10), and a stool sample collection kit for at-home sample collection up to 3 days before Visit 5 (Week 12), samples are returned by mail.
Intermediate Visit (Visit 4- Week 4): Subjects must meet pre-test requirements (as above). Fasted blood samples are collected for screening analysis of: clinical chemistry, hematology, lipid profile, thyroid hormones. A clean catch urine sample is collected for screening analysis and urinalysis and additional plasma is banked for future aging biomarker analysis. Tolerance of the study beverage and Adverse Events are assessed by interview. Subjects will be given a month's supply of study product to take home. Subjects will be given a stool sample collection kit to take home for at-home sample collection up to 3 days after Visit 4; samples are returned by mail.
Final Visit (Visit 5- Week 12): Follows identical testing procedures to Baseline Visit (Visit 3, Week 0).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ketone ester | Experimental | Flavored ketone ester beverage 75 mL. Day 0 - 7: half of one bottle consumed daily. Day 8 to end (Week 12): one full bottle consumed daily. |
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| Non-ketone placebo | Placebo Comparator | Flavored beverage with bitter additive 75 mL. Matched for appearance, taste and calories. Day 0 - 7: half of one bottle consumed daily. Day 8 to end (Week 12): one full bottle consumed daily. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ketone ester | Other | 75 mL chocolate flavored beverage containing 25 g of ketone ester. Half a bottle (12.5 g/day) will be consumed for the first 7 days and a complete bottle (25 g/day) will be consumed for the remaining 77 days. |
| Measure | Description | Time Frame |
|---|---|---|
| Tolerance | The primary outcome measure is the 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 12 weeks. | 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Safety Blood Profile | Change from baseline to week 4 and week 12 in the incidence of abnormal laboratory test results | Change from baseline to week 4, and week 12. |
| Ketone changes 4h after ketone ester drinks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Short Physical Performance Battery Score | Standard set of tests to measure physical function in elderly | Measured at baseline (Week 0) and final visit (Week 12) |
| Change in 1 rep max leg press |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| John C Newman, MD, PhD | Buck Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Buck Institute for Research on Aging | Novato | California | 94945 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34208742 | Background | 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. | |
| 35512774 | Background |
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| ID | Term |
|---|---|
| C524675 | formic acid 4-(3-oxobutyl)phenyl ester |
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Parallel group, randomized, double-blind.
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Study products will be allocated a code and labelled by an external team. The coding of the study products will be recorded and sealed in 'unblinding envelopes' that will only be opened in unblinding becomes necessary for subject safety. No one on the study team (including outcome assessor and statisticians) will be aware of the study product identity. The study products are matched for appearance, taste and calories and will not be visibly distinguishable.
| Non-ketone placebo | Other | 75 mL chocolate flavored beverage containing 25 g of non-ketogenic fat. Half a bottle (12.5 g/day) will be consumed for the first 7 days and a complete bottle (25 g/day) will be consumed for the remaining 77 days. |
|
Subjects consume a single serving of either 12.5 g or 25 g of ketone ester. After this, their short-term (regularly over 4h) blood ketone changes are measured using capillary blood sampling.
| 4 hours |
Heaviest weight moved using leg press machine
| Measured at baseline (Week 0) and final visit (Week 12) |
| Change in Sub maximal leg press to fatigue | Number of reps completed at a sub maximal weight | Measured at baseline (Week 0) and final visit (Week 12) |
| Change in 6 minute walk test | Distance covered when walking for 6 minutes | Measured at baseline (Week 0) and final visit (Week 12) |
| Change in Grip strength | Hand grip force measured by dynamometer | Measured at baseline (Week 0) and final visit (Week 12) |
| Change in Montreal Cognitive Assessment score | Standard test for cognitive function in elderly | Measured at baseline (Week 0) and final visit (Week 12) |
| Change in Digit Symbol Substitution Task scores | Task where participant substitutes numbers for symbols in a set time | Measured at baseline (Week 0) and final visit (Week 12) |
| Change in Trails A and B scores | Standard trail making test scores between letters and numbers | Measured at baseline (Week 0) and final visit (Week 12) |
| Change in score on Profile of Mood States (Short form) Questionnaire | Questionnaire | Measured at baseline (Week 0) and final visit (Week 12) |
| Change in score on The Sexual Quality of Life Questionnaire | Questionnaire | Measured at baseline (Week 0) and final visit (Week 12) |
| Change in score on the Short Form Health Survey-36 | Questionnaire | Measured at baseline (Week 0) and final visit (Week 12) |
| Change in score on the Pittsburgh Sleep Quality Index | Questionnaire. | Measured at baseline (Week 0) and final visit (Week 12) |
| Change in score on the Pittsburgh Fatiguability Scale | Questionnaire | Measured at baseline (Week 0) and final visit (Week 12) |
| Change in score on the Geriatric Depression Scale | Questionnaire | Measured at baseline (Week 0) and final visit (Week 12) |
| Changes in gut microbial diversity | DNA sequencing of bacterial species in stool samples. | Change from pre-test to week 1, week 4 and week 12. |
| Ketone changes 4h after powder formulation of ketone drinks | Subjects consume a single serving of either 12.5 g or 25 g of powder formulation ketone ester. After this, their short-term (regularly over 4h) blood ketone changes are measured using capillary blood sampling. | 4h |
| 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. |
| 41313689 | Derived | Stubbs BJ, Stephens EB, Mansfield T, Senadheera C, Diaz SR, Peralta S, Alexander L, Silverman-Martin W, Kurtzig J, Fernando BA, Garcia TY, Yukawa M, Morris J, Yurkovich JT, Newman AB, Johnson JB, Cawthon PM, Newman JC. Exploratory functional and quality of life outcomes with daily consumption of the ketone ester bis-octanoyl (R)-1,3-butanediol in healthy older adults: a randomized, parallel arm, double-blind, placebo-controlled study. J Frailty Aging. 2025 Dec;14(6):100106. doi: 10.1016/j.tjfa.2025.100106. Epub 2025 Nov 27. |
| 39371165 | Derived | Stubbs BJ, Stephens EB, Senadheera C, Diaz SR, Peralta S, Alexander L, Silverman-Martin W, Kurtzig J, Fernando BA, Yurkovich JT, Garcia TY, Yukawa M, Morris J, Johnson JB, Newman JC. Exploratory functional and quality of life outcomes with daily consumption of the ketone ester bis-octanoyl (R)-1,3-butanediol in healthy older adults: a randomized, parallel arm, double-blind, placebo-controlled study. medRxiv [Preprint]. 2024 Sep 18:2024.09.17.24313811. doi: 10.1101/2024.09.17.24313811. |
| 39137624 | Derived | Stubbs BJ, Stephens EB, Senadheera C, Peralta S, Roa-Diaz S, Alexander L, Silverman-Martin W, Garcia TY, Yukawa M, Morris J, Blonquist TM, Johnson JB, Newman JC. Daily consumption of ketone ester, bis-octanoyl (R)-1,3-butanediol, is safe and tolerable in healthy older adults in a randomized, parallel arm, double-blind, placebo-controlled, pilot study. J Nutr Health Aging. 2024 Sep;28(9):100329. doi: 10.1016/j.jnha.2024.100329. Epub 2024 Aug 12. |
| 38746215 | Derived | Stubbs BJ, Stephens EB, Senadheera C, Peralta S, Roa-Diaz S, Alexander L, Silverman-Martin W, Garcia TY, Yukawa M, Morris J, Blonquist TM, Johnson JB, Newman JC. Daily consumption of ketone ester, bis-octanoyl (R)-1,3-butanediol, is safe and tolerable in healthy older adults, a randomized, parallel arm, double-blind, placebo-controlled, pilot study. medRxiv [Preprint]. 2024 May 5:2024.05.03.24306699. doi: 10.1101/2024.05.03.24306699. |