Strategies to Augment Ketosis: Optimization of Ketone Delivery Strategies
STAK: OK'd
2 other identifiers
interventional
14
1 country
1
Brief Summary
One important difference between KE compounds is the ketone-promoting components, which determines the circulating ratio of blood ketone bodies, BHB and AcAc, and may in turn lead to important metabolic and signaling differences. Whereas some actions of the ketone bodies BHB and AcAc are shared, R-BHB has a broad range of signaling functions that are distinct from AcAc, some of which are shared by the non-circulating, non-oxidizable enantiomer, S-BHB. AcAc also has metabolic and signaling actions that are independent of BHB and is selectively oxidized in some cells that cannot oxidize BHB. Furthermore, responses to different ketone bodies vary between tissue types. A second difference between KE arises from the balance between direct delivery of ketones compared to indirectly elevating ketone concentration via metabolism of non-classical or classical ketogenic precursors. Classical ketogenesis itself may drive adaptation and some of the functional benefits associated with ketosis. BDO is included in all of the KE compounds, but it is currently unknown how consumption of BDO alone, and its metabolism via non-classical ketogenesis acutely affects metabolism. Additionally, ketogenesis is now understood to occur in certain cells outside the liver with important local biological effects, for example ketogenesis driven by medium chain fatty acids has been reported in astrocytes in vitro. Provision of systemic BHB by a KE may elicit different biological effects in some tissues such as the brain versus promoting in situ ketogenesis in that tissue. Overall, not only are functional effects of KE incompletely defined, but also it is unknown which effects are common to all KE versus which are specific to an individual KE compound (i.e., BHB Monoester vs AcAc Diester) or which may be attributable to the BDO precursor common to all of the KE. This study will be the first comparative full crossover study of all available KE and the precursor BDO at two serving sizes. Outcomes will focus on established effects of the BHB Monoester (including the effects on ketones, glucose and acid-base balance) and compare these with the effects of the AcAc Diester, C8 Ketonef Diester and BDO.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for not_applicable
Started Jun 2023
Longer than P75 for not_applicable
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
August 1, 2022
CompletedFirst Posted
Study publicly available on registry
August 15, 2022
CompletedStudy Start
First participant enrolled
June 5, 2023
CompletedPrimary Completion
Last participant's last visit for primary outcome
September 1, 2026
ExpectedStudy Completion
Last participant's last visit for all outcomes
September 1, 2027
May 29, 2025
May 1, 2025
3.2 years
August 1, 2022
May 28, 2025
Conditions
Outcome Measures
Primary Outcomes (1)
Total Plasma Ketone AUC
Difference in total plasma ketone appearance (AUC) between the two serving sizes of study products and control
Up to ~ 4 weeks
Secondary Outcomes (16)
Capillary d-BHB concentrations
Up to ~ 4 weeks
AcAc, R-BHB and S-BHB changes across trials
Up to ~ 4 weeks
Continuous Ketone and Glucose Monitoring
Up to ~ 4 weeks
Ketone Excretion
Up to ~ 4 weeks
Ketone in breathe expiration
Up to ~ 4 weeks
- +11 more secondary outcomes
Study Arms (9)
BHB Mono-ester 180mg/kg
EXPERIMENTALBHB mono-ester 360mg/kg
EXPERIMENTALC8 Ketone Di-ester 180mg/kg
EXPERIMENTALC8 Ketone Di-ester 360mg/kg
EXPERIMENTALAcAc Di-ester 180mg/kg
EXPERIMENTALAcAc Di-ester 360mg/kg
EXPERIMENTAL(R)-1,3 butanediol 180mg/kg
EXPERIMENTAL(R)-1,3 butanediol 360mg/kg
EXPERIMENTALControl
PLACEBO COMPARATORInterventions
Four different exogenous ketone products at two serving sizes or a non-ketogenic placebo (one study product per test day). 1) Monoester of BHB (R)-1,3 butanediol (BHB Mono-ester), 2) diester of hexanoic acid (a ketogenic medium chain fatty acid) and (R)-1,3 butanediol (C6 Di-ester) 3) diester of AcAc and (R,S)-1,3 butanediol (AcAc Di-ester) \& 4) (R) -1,3 butanediol only (BDO). All products will be delivered in 2 different dosages 180mg/kg and 360mg/kg on separate testing days.
Beverage Tolerability Questionnaire (BTQ) and satiety visual analogue scale will be administered at beginning and end of testing day to tests palatability of supplement
IV cannula will be inserted at the start of each Test Day, and removed at the end of each Test Day, Blood samples will be collected according to the schedule in Figure 1. Cannula will be flushed with a small volume of saline after each sample to maintain patency. We will draw 504 mL of blood, which is about 2.1 cups throughout the 4-week intervention
Participants will breathe into a commercially available handheld breath acetone analyzer according to the schedule. Participants will wear a fitted face mask attached to a metabolic cart for a 10-minute period every 60 minutes
Participants will wear a Bluetooth heart rate monitor chest strap throughout the test day.
Continuous Ketone Monitor will be applied at the start of Test Day 1. The sensor will be checked by the study team at each test day and will be removed and replaced by a fresh sensor at \~2- week intervals during the study. The sensor will be removed at the end of the final test day
Prior to consumption of the Study Product, participants will be asked to completely void bladder. And hydration status will be determined via urine specific gravity (USG) reporting \<1.025. Urine passed after the ingestion of the study product will be collected in a plastic container; participants will be asked to void their bladder and collect urine at the end of the test day. The volume produced will be recorded at the end of the study and aliquots will be frozen and stored for future analysis
Eligibility Criteria
You may qualify if:
- Male
- BMI between 18 and 29 kg/m2
- Aged 20 - 30 years
- Participant is willing and able to comply with all study procedures including the following prior to Test Days: fasting (\>10 h; water only), no alcohol (\>24 h), no exercise (\>24 h), no acute illness and controlled feeding before each Test Day, maintain diet, exercise, medication, and supplement habits throughout the study.
- Participant has no health conditions that would prevent completion of the study requirements as judged by the Investigator based on health history.
- Participant understands the study procedures and signs forms providing informed consent to participate in the study and authorizes the release of relevant protected health information to the Investigator.
You may not qualify if:
- Participant follows a low-carbohydrate diet (\<30% energy from carbohydrate) or have used exogenous ketone supplements within 4-months of study participation.
- Participant has a Primary Care Physician diagnosed history or presence of uncontrolled and/or clinically important hypertension (blood pressure \>150/95 mmHg), pulmonary, cardiac, hepatic, renal, endocrine (including type 1 and 2 diabetes), hematologic, immunologic, neurologic (e.g., Alzheimer's or Parkinson's diseases), psychiatric (including unstable depression and/or anxiety disorders) or biliary disorders.
- Participant has a known allergy, intolerance, or sensitivity to any of the ingredients in the study beverages, including soy and milk protein, wheat, shellfish, fin fish, eggs, tree nuts or peanuts (production facility handles nuts).
- Participant has unstable use of a medication or supplement that the Investigator considers may affect the outcomes of the trial.
- Consumption of alcohol more than 3 drinks per day or more than 18 drinks per week.
- Consumption of tobacco.
- Consumption of cannabis.
- Participant is currently in another research study or has been in the 14 days before screening.
- Participant has had a blood draw or donation in the last 8 weeks.
- Participant has a clinically important gastrointestinal (GI) condition that would potentially interfere with the evaluation of the study beverage \[e.g., inflammatory bowel disease, irritable bowel syndrome, chronic constipation, severe constipation (in the opinion of the Investigator), history of frequent diarrhea, history of surgery for weight loss, gastroparesis, systemic disease that might affect gut motility according to the Investigator, medication managed reflux and/or clinically important lactose intolerance\].
- Participant has a condition the Investigator believes would interfere with his ability to provide informed consent, comply with the study protocol, which might confound the interpretation of the study results, or put the participant at undue risk.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
The Ohio State University
Columbus, Ohio, 43210, United States
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Jeff S Volek, PhD
Ohio State University
Study Design
- Study Type
- interventional
- Phase
- not applicable
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- BASIC SCIENCE
- Intervention Model
- CROSSOVER
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Professor
Study Record Dates
First Submitted
August 1, 2022
First Posted
August 15, 2022
Study Start
June 5, 2023
Primary Completion (Estimated)
September 1, 2026
Study Completion (Estimated)
September 1, 2027
Last Updated
May 29, 2025
Record last verified: 2025-05