The Causal Role of Ketone Bodies in Obesity-associated Disease Prevention - Combining Genetic Epidemiology With a Randomised Trial to Infer Causality
NCT ID: NCT06668168
Last Updated: 2025-07-31
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
NA
69 participants
INTERVENTIONAL
2025-05-06
2030-01-31
Brief Summary
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Low-carbohydrate (ketogenic) diets are popular for weight control. Ketogenic diets increase circulating ketones, which can have favourable effects on cardiometabolic health markers. However, the ketogenic diet has a nutrient composition associated with harms (high-saturated fat/red meat, and low-fibre). The net effects of ketogenic diets on long-term health are unclear. Ketone supplements can increase circulating ketones and could provide benefits of ketosis without needing to adhere to a potentially harmful diet.
Establishing causality between complex exposures (e.g., diet) and long-term outcomes (e.g., disease), is challenging. The MRC \& NIHR Review of Nutrition and Human Health Research (2017) highlighted an "overreliance (as opposed to reasonable reliance) on observational studies" as a key barrier to progression in the field of nutrition and health. Randomised controlled trials (RCTs) facilitate causal inference, but for long-term outcomes are expensive, time-consuming, and often suffer from waning adherence. Mendelian randomization (MR) can estimate causal effects subject to key assumptions. A challenge to these assumptions includes complex behavioural exposures (e.g., diet), which could be intercorrelated with causal factors.
Our proposal will address these limitations with a novel combination of study designs to establish causal effects of ketosis (via diet and supplementation) on obesity-associated disease risk in humans.
The investigators will combine a tightly controlled, short-term RCT, with MR to link short-term responses to long-term endpoints. The investigators will examine the circulating (blood) and tissue-specific (adipose) transcriptomic and proteomic responses in the fasted and postprandial state in response to our dietary interventions and translate these to MR by identifying single-nucleotide polymorphisms from genome wide association studies. This approach overcomes limitations of RCTs and MR, as adherence to diets will be confirmed with controlled feeding, and intermediate molecular traits as exposure for MR are less likely to be intercorrelated with causal traits.
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
BASIC_SCIENCE
NONE
Study Groups
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CONTROL
No interventions assigned to this group
KETONE ESTER
Ketone Monoester (KE)
25g ketone ester 3x/day. The ketone ester will be a beta-hydroxybutyrate monoester \[(R)-3-hydroxybutyl (R)-3-hydroxybutyrate\].
KETOGENIC DIET
Ketogenic diet
Ketogenic diet (\<50 g carbohydrate per day)
Interventions
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Ketone Monoester (KE)
25g ketone ester 3x/day. The ketone ester will be a beta-hydroxybutyrate monoester \[(R)-3-hydroxybutyl (R)-3-hydroxybutyrate\].
Ketogenic diet
Ketogenic diet (\<50 g carbohydrate per day)
Eligibility Criteria
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Inclusion Criteria
* Waist circumference \>93.9 (males) or \>79.9 (females)
Exclusion Criteria
* Diagnosis of cardiovascular disease, renal failure, liver disease or type 2 diabetes
* Contraindications to a ketogenic diet (e.g., pancreatitis, liver failure, disorders of fat metabolism, primary carnitine deficiency, carnitine palmitoyltransferase deficiency, carnitine translocase deficiency, porphyrias, or pyruvate kinase deficiency)
* Unable to understand English language
18 Years
65 Years
ALL
Yes
Sponsors
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University of Bristol
OTHER
Imperial College London
OTHER
University of Bath
OTHER
Responsible Party
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Javier Gonzalez
Professor of Nutrition and Metabolism
Locations
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University of Bath
Bath, Bath, United Kingdom
Countries
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Central Contacts
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Facility Contacts
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Other Identifiers
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23-09665
Identifier Type: -
Identifier Source: org_study_id
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