BHB Supplements for Adenomatous Polyposis
(BHB-FAP Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Abramson Cancer Center at Penn Medicine
Must not be taking: Diabetes therapy, Chemopreventive agents
Disqualifiers: Pregnancy, Diabetes, Kidney disease, others
Trial Summary
What is the purpose of this trial?
The aim of this study is to evaluate the potential of BHB supplementation as a novel strategy to impede the development and progression of intestinal adenomas in individuals with FAP, thus reducing the need for frequent upper endoscopies and colonoscopies, and potentially preventing the need for risk-reducing surgical intervention.
Will I have to stop taking my current medications?
The trial requires that you stop using any FAP-related chemopreventive agents, such as aspirin (more than 81mg daily), NSAIDs, or BHB supplements, at least 6 weeks before enrolling. If you are on diabetes medication, you cannot participate in the trial.
What evidence supports the effectiveness of the drug R-1,3-Butanediol, β-Hydroxybutyrate, BHB, R-1,3-Butanediol for adenomatous polyposis?
Is BHB generally safe for human use?
How does the drug R-1,3-Butanediol differ from other treatments for adenomatous polyposis?
R-1,3-Butanediol is unique because it is a ketone ester that increases blood levels of beta-hydroxybutyrate (BHB), which may help prevent colonic inflammation and cancer. Unlike traditional treatments, it is taken orally and works by inducing a state of ketosis, potentially offering a novel approach to managing adenomatous polyposis.13578
Eligibility Criteria
This trial is for adults with Familial Adenomatous Polyposis (FAP) who are scheduled for a colonoscopy or sigmoidoscopy. They must have had extensive colonic resection, at least two colorectal polyps, and a confirmed genetic diagnosis of FAP. Pregnant individuals, prisoners, minors, those on diabetes therapy or with inflammatory bowel disease, chronic kidney disease, large untreated polyps (>1cm), active cancer treatment or recent chemopreventive agent use cannot participate.Inclusion Criteria
I am scheduled for a colonoscopy or sigmoidoscopy.
I can have an upper endoscopy at the same time as my colon check.
Can provide informed consent
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Exclusion Criteria
I am not pregnant, imprisoned, or under 18.
I have diabetes and am currently taking medication for it.
I have a history of inflammatory bowel disease.
See 6 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Absorption Study (Part A)
Participants take R-1,3-butanediol at one of three different doses for 2 weeks, with blood samples collected before and after
2 weeks
2 visits (in-person)
Randomized Controlled Study (Part B)
Participants receive either placebo or R-1,3-butanediol for 12 weeks, with regular blood and stool sample collection every 4 weeks
12 weeks
4 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Treatment Details
Interventions
- R-1,3-Butanediol (Dietary Supplement)
Trial OverviewThe study tests if β-hydroxybutyrate (BHB) supplementation can prevent intestinal adenomas in FAP patients. Participants will receive different doses of R-1,3-Butanediol to deliver BHB or a placebo. The goal is to reduce the frequency of endoscopies/colonoscopies and possibly avoid surgery.
Participant Groups
6Treatment groups
Experimental Treatment
Placebo Group
Group I: Part B - 20 gramsExperimental Treatment1 Intervention
Study participants will take one 35mL dose of HVMN Ketone-IQ by mouth twice per day (20 total grams of R-1,3-Butanediol) for 12 weeks
Group II: Part B - 10 gramsExperimental Treatment1 Intervention
Study participants will take one 35mL dose of HVMN Ketone-IQ by mouth per day along with one 35mL dose of placebo ketone drink by mouth per day (10 total grams of R-1,3-Butanediol) for 12 weeks
Group III: Part A - 30 gramsExperimental Treatment1 Intervention
Study participants will take three 35mL dose of HVMN Ketone-IQ by mouth per day (30 total grams of R-1,3-Butanediol) for 2 weeks
Group IV: Part A - 20 gramsExperimental Treatment1 Intervention
Study participants will take two 35mL dose of HVMN Ketone-IQ by mouth per day (20 total grams of R-1,3-Butanediol) for 2 weeks
Group V: Part A - 10 gramsExperimental Treatment1 Intervention
Study participants will take one 35mL dose of HVMN Ketone-IQ by mouth per day (10 total grams of R-1,3-Butanediol) for 2 weeks
Group VI: Part B - PlaceboPlacebo Group1 Intervention
Study participants will take one 35mL dose of placebo ketone drink by mouth twice daily for 12 weeks
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Abramson Cancer Center of the University of PennsylvaniaPhiladelphia, PA
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Who Is Running the Clinical Trial?
Abramson Cancer Center at Penn MedicineLead Sponsor
The V Foundation for Cancer ResearchCollaborator
References
Applications and Mechanism of 3-Hydroxybutyrate (3HB) for Prevention of Colonic Inflammation and Carcinogenesis as a Food Supplement. [2022]Inflammatory bowel disease and colorectal carcinogenesis (CRC) are common diseases without effective prevention approach. 3-Hydroxybutyrate (3HB) reported to have multiple functions as an oral food supplement. This study observes that 3HB prevents mouse colitis and CRC.
New prebiotics by ketone donation. [2023]Integrity of the microbiome is an essential element for human gut health. 3-Hydroxybutyrate (3HB) secreted into the gut lumen has gained attention as a regulator of gut physiology, including stem cell expansion. In this opinion, I propose new prebiotics leading to gut health by use of a ketone (3HB) donor. When exogenous 3HB is supplied through ketone donation, it has the potential to markedly improve gut health by altering the gut microbiome and systemic metabolic status. Poly-hydroxybutyrate (PHB) donates 3HB and primarily influences microbiota, making it an effective prebiotic for improving the gut environment. Thus, exogenous 3HB donation to the lumen of the gut may aid gut health by maintaining the integrity of microbiome.
A randomized, open-label, parallel pilot study investigating metabolic product kinetics of the novel ketone ester, bis-hexanoyl (R)-1,3-butanediol, over one week of ingestion in healthy adults. [2023]Introduction: Bis-hexanoyl (R)-1,3-butanediol (BH-BD) is a novel ketone ester that, when consumed, is hydrolyzed into hexanoic acid (HEX) and (R)-1,3-butanediol (BDO) which are subsequently metabolized into beta-hydroxybutyrate (BHB). Methods: We undertook a randomized, parallel, open-label study in healthy adults (n = 33) to elucidate blood BHB, HEX and BDO concentrations for 8 h following consumption of three different serving sizes (SS) of BH-BD (12.5, 25 and 50 g/day) before (Day 0) and after 7 days of daily BH-BD consumption (Day 7). Results: Maximal concentration and area under the curve of all metabolites increased proportionally to SS and were greatest for BHB followed by BDO then HEX on both Day 0 and 7. Metabolite half-life tended to decrease with increasing SS for BHB and HEX. Time to peak concentration increased with increasing SS for BHB and BDO on both days. In vitro incubation of BH-BD in human plasma demonstrated BH-BD undergoes rapid spontaneous hydrolysis. Conclusion: These results demonstrate that orally ingested BH-BD is hydrolyzed into products that appear in the plasma and undergo conversion to BHB in a SS dependent manner, and that metabolism of BH-BD neither becomes saturated at serving sizes up to 50 g nor displays consistent adaptation after 7 days of daily consumption.
Beta-Hydroxybutyrate Promotes Proliferation, Migration and Stemness in a Subpopulation of 5FU Treated SW480 Cells: Evidence for Metabolic Plasticity in Colon Cancer [2020]Background: Beta-hydroxybutyrate (BHB) as a ketone body is the metabolic fuel in oxidative phosphorylation pathway. So far the effects of BHB on the biology of tumor cells is contradictory. Therefore, we investigated the effect of BHB on viability, metabolism, proliferation and migration of 5FU treated SW480 colon cancer cell line. Methods: we treated the SW480 cells with IC50 dose of 5-fluorouracil (5FU) for 72 h to isolate a subpopulation of 5FU treated cells that were resistant to it. Effects of BHB on cell viability was investigated by MTT assay. Measurement of oxygen consumption rate (OCR) in parallel with extracellular acidification rate (ECAR) upon BHB treatment was used for determination of metabolic profile of these cells. Investigating the relationship between metabolic phenotype and the status of differentiation and stemness was done by analyzing the expression of PGC-1α, c-MYC, NANOG, ALPi and KRT20 genes by qRT-PCR. Clonogenic and scratch assay were performed to determine the proliferation and migration abilities of incubated with BHB compared to untreated cells. Results: BHB increased cell viability in SW480 and 5FU treated SW480 cells. The results showed a significantly decreased ECAR and increased OCR in both cell types following BHB treatment reflecting the superiority of oxidative phosphorylation profile compared to glycolysis in both cell types. Also, treatment with BHB increases the expression of genes normally associated with stemness and mitochondrial biogenesis and decreases the expression of genes related to glycolytic program and differentiation in 5FU treated cells. Self-renewal and migration potential of BHB treated cells increased significantly. Conclusion: These findings suggest that BHB utilization via oxidative mitochondrial metabolism can fuel proliferation, migration and stemness in 5FU treated SW480 colon cancer cells.
In vitro stability and in vivo pharmacokinetics of the novel ketogenic ester, bis hexanoyl (R)-1,3-butanediol. [2021]A novel ketone ester, bis hexanoyl (R)-1,3-butanediol (BH-BD), has been developed as a means to elevate blood ketones, for use as an energy substrate and a signaling metabolite. The metabolism of BH-BD and its effects on blood beta-hydroxybutyrate (BHB) levels was evaluated in various in vitro matrices and through analysis of plasma collected from Sprague Dawley rats and C57/BL6 mice in two oral gavage studies. A well-characterized ketone ester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (HB-BHB), was used as an active control throughout. In vitro assay results demonstrated that BH-BD likely remains intact in the stomach and is hydrolyzed in the small intestine into hexanoate and (R)-1,3-butanediol. If absorbed intact, BH-BD is subject to hydrolysis by non-CYP enzymes in liver and esterases in plasma. If BH-BD reaches the lower intestine it is metabolized by gut flora. Plasma BHB delivery increased in a dose-dependent manner in rats and mice following oral administration of BH-BD. All doses of BH-BD were well tolerated. At doses over 3 g/kg, BHB delivery was similar between BH-BD and HB-BHB. The results of these studies support the hydrolysis of BH-BD into hexanoate and (R)-1,3-butanediol which are metabolized into BHB, delivering a well-tolerated, sustained and dose-dependent increase in plasma BHB in rodents.
An open-label, acute clinical trial in adults to assess ketone levels, gastrointestinal tolerability, and sleepiness following consumption of (R)-1,3-butanediol (Avela™). [2023]Introduction: A study was undertaken to determine the acute effects of a beverage made with Avela™ (R)-1,3-butanediol, on blood beta-hydroxybutyrate (BHB) levels (using the Keto-Mojo monitor), gastrointestinal (GI) tolerability (using the modified visual analogue scale GI Symptoms Tool), and sleepiness (using the Stanford Sleepiness Scale). Methods: Following a 12-h overnight fast, 26 healthy adults consumed one beverage containing 11.5 g of (R)-1,3-butanediol at each of 0, 30, and 60 min, culminating in a total intake of 34.5 g of (R)-1,3-butanediol. Blood BHB levels, GI tolerability, and sleepiness were assessed at baseline (0 min), and at 30, 60, 90, 120, 180, 240, and 300 min. At 240 min, a protein bar was consumed. Results: The mean (±SD) BHB fasting baseline level, maximal concentration, time at maximal concentration, and incremental area under the curve over 300 min were 0.23 ± 0.21 mmol/L, 2.10 ± 0.97 mmol/L, 133.85 ± 57.07 min, and 376.73 ± 156.76 mmol/L*min, respectively. BHB levels at each time point were significantly increased relative to baseline. In females, BHB Tmax was significantly greater (p = 0.046), and BHB iAUC0-300 min nearly significantly greater (p = 0.06) than in males. Discussion: The beverage formulated with Avela™ had no impact on sleepiness and was generally well-tolerated, with no or mild GI symptoms reported in most participants. Mild headaches were reported as an adverse event by five participants and judged possibly related to the study product in two of the participants.
Accumulation of beta-carotene in normal colorectal mucosa and colonic neoplastic lesions in humans. [2013]The quantity of beta-carotene (BC) accumulated in colonic polyps and colonic cancerous tissue in humans in situ was determined relative to the quantity accumulated in normal colon and rectal tissue. Serum concentration of BC, retinol, and alpha-tocopherol and tissue BC concentration were determined by high-performance liquid chromatography in samples obtained before and after oral supplementation with BC (30 mg/day). The serum BC and retinol concentrations significantly increased in response to supplementation in control, polyp, and cancer patients, but there was no change in serum alpha-tocopherol concentration. The BC concentration in tissue (colon, rectum, and tumor) of cancer patients was significantly less than that in tissue samples from control and polyp patients. Relative to baseline values, BC accumulated to a significant extent in tissues from all patients, including polyp and tumor tissue, during supplementation. The results indicate that BC does accumulate in colonic neoplastic tissue in humans and may potentially be utilized to augment cytotoxicity of chemotherapeutics or to prevent malignant transformation of cells.
A Novel Powder Formulation of the Ketone Ester, Bis Hexanoyl (R)-1,3-Butanediol, Rapidly Increases Circulating ß-Hydroxybutyrate Concentrations in Healthy Adults. [2023]Objective: Growing interest in the metabolic state of ketosis has driven development of exogenous ketone products to induce ketosis without dietary changes. Bis hexanoyl (R)-1,3-butanediol (BH-BD) is a novel ketone ester which, when consumed, increases blood beta-hydroxybutyrate (BHB) concentrations. BH-BD is formulated as a powder or ready-to-drink (RTD) beverage; the relative efficacy of these formulations is unknown, but hypothesized to be equivalent.Methods: This randomized, observer-blinded, controlled, crossover decentralized study in healthy adults (n = 15, mean age = 33.7 years, mean BMI = 23.6 kg/m2) aimed to elucidate blood BHB and glucose concentrations before and 15, 30, 45, 60, 90 and 120 minutes following two serving sizes of reconstituted BH-BD powder (POW 25 g, POW 12.5 g), compared to a RTD BH-BD beverage (RTD 12.5 g), and a non-ketogenic control, all taken with a standard meal.Results: All BH-BD products were well tolerated and increased BHB, inducing nutritional ketosis (BHB ≥0.5 mM) after ∼15 minutes, relative to the control. BHB remained elevated 2 h post-consumption. The control did not increase BHB. Ketosis was dose responsive; peak BHB concentration and area under the curve (AUC) were two-fold greater with POW 25 g compared to POW 12.5 g and RTD 12.5 g. There were no differences in peak BHB and AUC between matched powder and RTD formulas. Blood glucose increased in all conditions following the meal but there were neither significant differences in lowest observed concentrations, nor consistent differences at each time point between conditions. These results demonstrate that both powdered and RTD BH-BD formulations similarly induce ketosis with no differences in glucose concentrations in healthy adults.