Clinical trial NCT06578637: Investigation of β-hydroxybutyrate Supplementation as Chemoprevention in Familial Adenomatous Polyposis
Official title: Investigation of β-hydroxybutyrate Supplementation as Chemoprevention in Familial Adenomatous Polyposis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: FAP
Familial Adenomatous Polyposis
Keywords: FAP
Familial adenomatous polyposis
Chemoprevention
Polyps
BHB
Beta-hydroxybutyrate
Lead sponsor: Abramson Cancer Center at Penn Medicine
Sponsor class: OTHER
Collaborators: name: The V Foundation for Cancer Research
First posted: 2024-08-29
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: We plan to undertake both an initial absorption study (Part A) in up to 9 individuals with FAP followed by a longitudinal, randomized, placebo-controlled study (Part B) in 30 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 who undergo their scheduled colonoscopy/sigmoidoscopy along with an upper endoscopy will be consented and subsequently randomized to receive either placebo (10 individuals) or R-1,3-butanediol at one of two doses (20 individuals). The participants then return every 4 weeks for a blood draw and at that time will also provide a stool sample, which will allow us to monitor the levels of BHB in their systemic circulation and stool. 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.

Eligibility criteria: Part A

Inclusion Criteria:

* 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
* 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)
* Can provide informed consent

Exclusion Criteria:

* Subject is pregnant, a prisoner, or is under 18 years of age
* Prior total proctocolectomy with end ileostomy
* History of inflammatory bowel disease
* History of diabetes mellitus and are currently on medical diabetes therapy
* History of chronic kidney disease with an eGFR \&lt; 60 mL/min/1.73m2
* Cancer diagnosis where the subject is receiving active therapy
* 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:

* 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.
* Scheduled for a colonoscopy or sigmoidoscopy as part of the patient's standard care
* Able to have a concurrent upper endoscopy performed with the standard of care colonoscopy/sigmoidoscopy
* Have at least two colorectal polyps (which can be present anywhere in the colon including the rectal cuff, or in the J-pouch \[if applicable\])
* Can provide informed consent

Exclusion Criteria:

* Subject is pregnant, a prisoner, or is under 18 years of age
* Patient is not able to undergo colonoscopy/sigmoidoscopy or upper endoscopy
* Prior total proctocolectomy with end ileostomy
* History of inflammatory bowel disease
* History of diabetes mellitus and are currently on medical diabetes therapy
* History of chronic kidney disease with an eGFR \&lt; 60 mL/min/1.73m2
* Cancer diagnosis where the subject is receiving active therapy
* 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
* Regular use of any FAP-related chemopreventive agent in the 6 weeks prior to enrollment including aspirin (\&gt; 81mg daily), NSAIDs, BHB supplementation, or any other medication deemed a chemopreventive agent by the study investigators
* Any colonic or small intestinal polyp observed endoscopically that is \&gt; 1 cm in size and is not removed (excluding ampullary adenomas)

Primary outcomes:
measure: Determine whether oral BHB supplementation is safe and tolerable in FAP
timeFrame: Through study completion, which will be approximately 3 years
Secondary outcomes:
measure: Measure whether oral BHB supplementations increases serum BHB levels in FAP
timeFrame: Through study completion, which will be approximately 3 years
measure: Change in transcription and protein expression in the intestinal mucosa and in intestinal polyps in FAP after oral BHB supplementation
timeFrame: Through study completion, which will be approximately 3 years
measure: Determine whether oral BHB supplementation in FAP reduces intestinal polyp burden
timeFrame: Through study completion, which will be approximately 3 years
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Abramson Cancer Center of the University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Bryson W Katona, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dmitrieva-Posocco O, Wong AC, Lundgren P, Golos AM, Descamps HC, Dohnalova L, Cramer Z, Tian Y, Yueh B, Eskiocak O, Egervari G, Lan Y, Liu J, Fan J, Kim J, Madhu B, Schneider KM, Khoziainova S, Andreeva N, Wang Q, Li N, Furth EE, Bailis W, Kelsen JR, Hamilton KE, Kaestner KH, Berger SL, Epstein JA, Jain R, Li M, Beyaz S, Lengner CJ, Katona BW, Grivennikov SI, Thaiss CA, Levy M. beta-Hydroxybutyrate suppresses colorectal cancer. Nature. 2022 May;605(7908):160-165. doi: 10.1038/s41586-022-04649-6. Epub 2022 Apr 27.