BHB Supplements for Adenomatous Polyposis

(BHB-FAP Trial)

Overseen By Bryson W Katona, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Abramson Cancer Center at Penn Medicine

Must not be taking: Diabetes therapy, Chemopreventive agents

Disqualifiers: Pregnancy, Diabetes, Kidney disease, others

Compensation: Varies

Number of Visits: 6

30 Participants Needed

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?

Research suggests that 3-Hydroxybutyrate (3HB), a component of the drug, may help prevent colonic inflammation and colorectal cancer in mice, which could be relevant for adenomatous polyposis. Additionally, 3HB has been shown to improve gut health by positively influencing the gut microbiome. ^{1 2 3 4 5}

Is BHB generally safe for human use?

Studies show that BHB, including forms like R-1,3-butanediol, is generally well-tolerated in humans and animals, with mild gastrointestinal symptoms and headaches reported in some cases. These studies suggest that BHB can be safely used as a supplement, although individual reactions may vary. ^{1 2 3 5 6}

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. ^{1 3 5 7 8}

Research Team

Bryson W Katona, MD, PhD

Principal Investigator

University of Pennsylvania

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

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.

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

Trial Overview The 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

Group I: Part B - 20 grams Experimental Treatment 1 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 grams Experimental Treatment 1 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 grams Experimental Treatment 1 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 grams Experimental Treatment 1 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 grams Experimental Treatment 1 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 - Placebo Placebo Group 1 Intervention

Study participants will take one 35mL dose of placebo ketone drink by mouth twice daily for 12 weeks

Who Is Running the Clinical Trial?

Abramson Cancer Center at Penn Medicine

Lead Sponsor

Trials

425

Recruited

464,000+

The V Foundation for Cancer Research

Collaborator

Trials

21

Recruited

1,300+

Findings from Research

3-Hydroxybutyrate (3HB) has been shown to significantly reduce colonic inflammation and the risk of colorectal cancer (CRC) in mouse models, indicating its potential as a preventive food supplement for colon diseases.

The protective effects of 3HB are mediated through its receptor GPR109a, which decreases harmful immune cell populations, such as M1 macrophages and myeloid-derived suppressor cells, thereby reducing inflammation and cancer risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Applications and Mechanism of 3-Hydroxybutyrate (3HB) for Prevention of Colonic Inflammation and Carcinogenesis as a Food Supplement. Li, Z., Zhang, S., Zhang, Y., et al.[2022]

3-Hydroxybutyrate (3HB) has the potential to enhance gut health by regulating the gut microbiome and promoting stem cell expansion, suggesting its role as a key player in gut physiology.

Using poly-hydroxybutyrate (PHB) as a prebiotic can effectively donate 3HB to the gut, potentially improving the gut environment and maintaining microbiome integrity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New prebiotics by ketone donation. Satoh, T.[2023]

In a study involving 33 healthy adults, the novel ketone ester BH-BD was shown to be effectively hydrolyzed into beta-hydroxybutyrate (BHB) and other metabolites, with higher serving sizes leading to greater concentrations of these metabolites in the blood.

The metabolism of BH-BD did not reach saturation even at the highest serving size of 50 g/day, indicating that daily consumption does not lead to a decrease in its effectiveness over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Mah, E., Blonquist, TM., Kaden, VN., et al.[2023]

Beta-hydroxybutyrate (BHB) enhances the viability and proliferation of SW480 colon cancer cells, even in those that have been treated with the chemotherapy drug 5-fluorouracil (5FU), indicating a potential resistance mechanism.

BHB treatment shifts the metabolic profile of these cancer cells towards oxidative phosphorylation, promoting stemness and migration while reducing differentiation, which may contribute to tumor aggressiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beta-Hydroxybutyrate Promotes Proliferation, Migration and Stemness in a Subpopulation of 5FU Treated SW480 Cells: Evidence for Metabolic Plasticity in Colon Cancer Shakery, A., Pourvali, K., Ghorbani, A., et al.[2020]

The novel ketone ester bis hexanoyl (R)-1,3-butanediol (BH-BD) effectively increases blood levels of beta-hydroxybutyrate (BHB) in a dose-dependent manner, as demonstrated in studies with Sprague Dawley rats and C57/BL6 mice.

BH-BD is well tolerated at all tested doses, and its metabolism involves hydrolysis into hexanoate and (R)-1,3-butanediol, which are then converted into BHB, indicating its potential as a safe energy substrate and signaling metabolite.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro stability and in vivo pharmacokinetics of the novel ketogenic ester, bis hexanoyl (R)-1,3-butanediol. Stubbs, BJ., Blade, T., Mills, S., et al.[2021]

The beverage containing Avela™ (R)-1,3-butanediol significantly increased blood beta-hydroxybutyrate (BHB) levels in 26 healthy adults, with a peak concentration of 2.10 ± 0.97 mmol/L observed at around 134 minutes after consumption.

The beverage was well-tolerated with minimal gastrointestinal symptoms, and it did not affect sleepiness; however, mild headaches were reported by some participants, indicating a need for further investigation into potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open-label, acute clinical trial in adults to assess ketone levels, gastrointestinal tolerability, and sleepiness following consumption of (R)-1,3-butanediol (Avela™). Lowder, J., Fallah, S., Venditti, C., et al.[2023]

Oral supplementation with 30 mg/day of beta-carotene significantly increased serum levels of beta-carotene and retinol in patients with colonic polyps and cancer, indicating effective absorption and systemic availability.

Beta-carotene was found to accumulate in colonic neoplastic tissue, suggesting its potential role in enhancing the effectiveness of chemotherapy or preventing cancer cell transformation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accumulation of beta-carotene in normal colorectal mucosa and colonic neoplastic lesions in humans. Maiani, G., Pappalardo, G., Ferro-Luzzi, A., et al.[2013]

Both powdered and ready-to-drink (RTD) formulations of the novel ketone ester BH-BD effectively induce ketosis in healthy adults, increasing blood beta-hydroxybutyrate (BHB) levels within approximately 15 minutes after consumption.

The study found that a higher dose of the powdered formulation (25g) resulted in significantly greater BHB concentrations compared to lower doses and the RTD version, but both formulations were equally effective in raising BHB levels without affecting blood glucose concentrations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Novel Powder Formulation of the Ketone Ester, Bis Hexanoyl (R)-1,3-Butanediol, Rapidly Increases Circulating ß-Hydroxybutyrate Concentrations in Healthy Adults. Nieman, KM., Anthony, JC., Stubbs, BJ.[2023]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Applications and Mechanism of 3-Hydroxybutyrate (3HB) for Prevention of Colonic Inflammation and Carcinogenesis as a Food Supplement. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

New prebiotics by ketone donation. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

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]

4. Thailand pubmed.ncbi.nlm.nih.gov

Beta-Hydroxybutyrate Promotes Proliferation, Migration and Stemness in a Subpopulation of 5FU Treated SW480 Cells: Evidence for Metabolic Plasticity in Colon Cancer [2020]

5. England pubmed.ncbi.nlm.nih.gov

In vitro stability and in vivo pharmacokinetics of the novel ketogenic ester, bis hexanoyl (R)-1,3-butanediol. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

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]

7. United States pubmed.ncbi.nlm.nih.gov

Accumulation of beta-carotene in normal colorectal mucosa and colonic neoplastic lesions in humans. [2013]

8. United States pubmed.ncbi.nlm.nih.gov

A Novel Powder Formulation of the Ketone Ester, Bis Hexanoyl (R)-1,3-Butanediol, Rapidly Increases Circulating ß-Hydroxybutyrate Concentrations in Healthy Adults. [2023]