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

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 6

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how a supplement called R-1,3-Butanediol (a type of ketone) might benefit people with FAP, a condition that causes adenomas in the intestines. The goal is to determine if this supplement can slow these growths, reducing the need for frequent medical procedures like colonoscopies. Participants will try different doses of the supplement over several weeks. Suitable candidates have FAP, have undergone major colon surgery, and can undergo regular endoscopy procedures. As an unphased trial, this study provides a unique opportunity to contribute to early research that could lead to new treatment options for FAP.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that R-1,3-butanediol, a type of BHB, is generally safe for humans and animals. Most individuals experience only mild side effects, such as an upset stomach or mild diarrhea. Other studies support the safety of similar compounds, like ketone esters, which have been used safely for several weeks. Although researchers continue to study this treatment, current data suggests it is safe for humans, particularly in the short term. These findings may help prospective trial participants feel more confident about the treatment's safety. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Most treatments for adenomatous polyposis typically involve surgical interventions or medications like NSAIDs and COX-2 inhibitors that aim to reduce polyp growth. But the treatment being studied, R-1,3-Butanediol, works differently. Researchers are excited about this approach because R-1,3-Butanediol is a ketone ester that can provide an alternative energy source through ketosis, potentially reducing polyp growth without the need for surgery. Unlike existing options, it's administered orally in liquid form, making it convenient and non-invasive. This treatment offers a novel mechanism of action and a promising new way to address the condition's root problem.

What evidence suggests that this trial's treatments could be effective for adenomatous polyposis?

Research has shown that R-1,3-butanediol supplements, which help produce beta-hydroxybutyrate (BHB), might protect against the growth of intestinal tumors. A recent study found that a ketogenic diet, which naturally increases BHB levels, could slow the growth and spread of colorectal cancer. This suggests that increasing BHB might have similar protective effects. BHB has also reduced inflammation and supported nerve health in other conditions. While direct evidence in humans with adenomatous polyposis is still being gathered, this trial will explore the potential effectiveness of R-1,3-butanediol in managing this condition. Participants in this trial will receive different dosages of R-1,3-butanediol to assess its impact. ^{1 6 7 8 9}

Who Is on the Research Team?

Bryson W Katona, MD, PhD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

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.

Can provide informed consent

I can have an upper endoscopy at the same time as my colon check.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: Part B - 30 grams Experimental Treatment 1 Intervention

Study participants will take one 35mL dose of HVMN Ketone-IQ by mouth three times per day (30 total grams of R-1,3-Butanediol) for 12 weeks, with a possible additional 12 week extension

Group II: 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 III: 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 IV: 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

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06578637?term=BUTYLENE%20GLYCOL&viewType=Table&rank=2

Study Details | NCT06578637 | Investigation of β- ... 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 ...

2. centerwatch.com centerwatch.com/clinical-trials/listings/NCT06578637/investigation-of-b-hydroxybutyrate-supplementation-as-chemoprevention-in-familial-adenomatous-polyposis

Investigation of β-hydroxybutyrate Supplementation as ... After 12 weeks of R-1,3-butanediol consumption, an upper endoscopy and colonoscopy/sigmoidoscopy will be performed, which will be the same as ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10162116/

Ketogenic Diet and Beta-Hydroxybutyrate in Colorectal ... In a recent study in Nature, Dmitrieva-Posocco et al, reveal a potential protective role of the ketogenic diet in colorectal cancer growth and progression.

4. biorxiv.org biorxiv.org/content/10.1101/2025.06.06.658169v2.full-text

Dietary lipids, not ketone body metabolites, influence ... These findings reveal that dietary lipid content, through FAO rather than ketone body metabolism, influences intestinal tumorigenesis and ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1756464623001809

β-hydroxybutyrate attenuates demyelination, modulates ... We found that BHB reduced demyelination, which was confirmed by western blot for myelin-oligodendrocyte glycoprotein (MOG) and myelin proteolipid protein (PLP).

6. withpower.com withpower.com/trial/phase-colorectal-neoplasms-9-2024-ddd6e

BHB Supplements for Adenomatous Polyposis Studies show that BHB, including forms like R-1,3-butanediol, is generally well-tolerated in humans and animals, with mild gastrointestinal symptoms and ...

7. trial.medpath.com trial.medpath.com/clinical-trial/acec42ae11f7945d/nct06578637-investigation-beta-hydroxybutyrate-chemoprevention-familial-adenomatous-polyposis

Investigation of β-hydroxybutyrate Supplementation as ... After 12 weeks of R-1,3-butanediol consumption, an upper endoscopy and colonoscopy/sigmoidoscopy will be performed, which will be the same as the procedure ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34208742/

Tolerability and Safety of a Novel Ketogenic Ester, Bis- ... In this study, we determined the tolerability and safety of a novel exogenous ketone diester, bis-hexanoyl-(R)-1,3-butanediol (BH-BD), in a 28-day, randomized, ...

9. ctv.veeva.com ctv.veeva.com/study/phase-3-trial-of-erapa-in-patients-with-familial-adenomatous-polyposis

Phase 3 Trial of eRapa in Patients With Familial Adenomatous ... The main goal of this clinical trial is to learn if the drug eRapa works to slow down the progression of disease in patients diagnosed with Familial ...