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 potentially reducing the need for frequent upper endoscopies and colonoscopies and preventing the need for risk-reducing surgical intervention.

We plan to undertake both an initial absorption study (Part A) in up to 9 individuals with FAP followed by a longitudinal open-label study (Part B) in up to 20 individuals with FAP, who will receive R-1,3-butanediol (HVMN Ketone-IQ), an orally administered BHB precursor. Participants with FAP in Part A will have a blood sample collected and then take R-1,3-butanediol at one of three different doses for 2 weeks, which will be followed by another blood sample collection. In Part B, participants with FAP will undergo colonoscopy/sigmoidoscopy along with an upper endoscopy and will then receive R-1,3-butanediol. The participants will return at 4 weeks and 8 weeks for a blood draw and at that time will also provide a stool sample, and participants will check their ketone levels at home weekly. 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 performed on study entry. At this point participants can be finished with the study, or they may have the option of continuing BHB for another 12 weeks in an extension study, followed by a repeat upper endoscopy and colonoscopy/sigmoidoscopy at 24 weeks.

Part A

Inclusion Criteria:

1. Have a diagnosis of FAP with genetic testing demonstrating a pathogenic or likely pathogenic germline variant in APC, must have a clinical FAP phenotype with at least one member of the family who has a pathogenic or likely pathogenic germline variant in APC, or must have a clinical diagnosis of FAP as agreed by two gastrointestinal cancer genetics experts
2. Must have an extensive colonic resection with either a subtotal colectomy with ileorectal anastomosis (STC-IRA) or total proctocolectomy with ileal pouch anal anastomosis (TPC-IPAA)
3. Can provide informed consent

Exclusion Criteria:

1. Subject is pregnant, a prisoner, or is under 18 years of age
2. Prior total proctocolectomy with end ileostomy
3. History of inflammatory bowel disease
4. History of diabetes mellitus and are currently on medical diabetes therapy
5. History of chronic kidney disease with an eGFR < 60 mL/min/1.73m2
6. Cancer diagnosis where the subject is receiving active therapy
7. Use of either a ketogenic diet or intermittent fasting (defined as a fasting period of 16 hours or more per day that is not associated with a medical procedure) during the 4 weeks prior to enrollment

Part B

Inclusion Criteria:

1. Have a diagnosis of FAP with genetic testing demonstrating a pathogenic or likely pathogenic germline variant in APC, must have a clinical FAP phenotype with at least one member of the family who has a pathogenic or likely pathogenic germline variant in APC, or must have a clinical diagnosis of FAP as agreed by two gastrointestinal cancer genetics experts.
2. Willing to undergo a colonoscopy or sigmoidoscopy, which may be part of the patient's routine standard care.
3. Able to have a concurrent upper endoscopy performed with the colonoscopy/sigmoidoscopy. This upper endoscopy may be part of the patient's routine standard care.
4. Have at least two colorectal polyps at enrollment (which can be present anywhere in the colon including the rectal cuff, or in the J-pouch [if applicable]).
5. Can provide informed consent.

Exclusion Criteria:

1. Subject is pregnant, a prisoner, or is under 18 years of age
2. Patient is not able to undergo colonoscopy/sigmoidoscopy or upper endoscopy
3. Prior total proctocolectomy with end ileostomy
4. History of inflammatory bowel disease
5. History of diabetes mellitus and are currently on medical diabetes therapy
6. History of chronic kidney disease with an eGFR < 60 mL/min/1.73m2
7. Cancer diagnosis where the subject is receiving active therapy
8. Use of either a ketogenic diet or intermittent fasting (defined as a fasting period of 16 hours or more per day that is not associated with a medical procedure) during the 4 weeks prior to enrollment
9. Regular use of any FAP-related chemopreventive agent in the 6 weeks prior to enrollment including aspirin (> 81mg daily), NSAIDs, BHB supplementation, or any other medication deemed a chemopreventive agent by the study investigators
10. Any colonic or small intestinal polyp observed endoscopically that is > 1 cm in size and is not removed (excluding ampullary adenomas)