PRIMARY OBJECTIVE:~I. To evaluate the effect of treatment with OCA versus treatment with placebo on duodenal polyp burden (sum of polyp diameters) in participants with FAP.~SECONDARY OBJECTIVES:~I. To assess the safety profile of treatment with OCA versus placebo in participants with FAP.~II. To evaluate the effect of treatment with OCA versus placebo on rectal and pouch polyp burden (sum of polyp diameters) in participants with FAP.~III. To assess the effect of treatment with OCA versus placebo on polyp burden (absolute number) in the duodenum of participants with FAP.~IV. To assess the effect of treatment with OCA versus placebo on polyp burden (absolute number) in the rectum and rectal pouch of participants with FAP.~V. To evaluate the effect of treatment with OCA versus placebo on serum levels of fibroblast growth factor-19 (FGF19) and 7 alpha-hydroxy-4-cholesten-3-one (7AC4, also known as C4) in participants with FAP.~VI. To determine the effects of treatment with OCA versus placebo on gene expression in duodenal, rectal pouch, and rectal adenomas and uninvolved mucosa in participants with FAP:~VIa. Identify differentially expressed genes between duodenal and colorectal adenomas and uninvolved tissue at baseline and post-intervention for participants who received OCA or placebo; VIb. Quantify the effect of OCA on the expression of downstream targets of FXR in adenomas and uninvolved tissue; VIc. Quantify the effect of OCA on the expression of cancer stem cell markers (e.g. LGR5, ASCL2, LRIG, BMI) and intestinal stem cell markers (e.g. Villin, KRT20, MUC, LYZ) in adenomas and uninvolved tissue.~VII. To evaluate the cell-type specific effects of treatment with OCA versus placebo on gene expression and abundance in duodenal, rectal pouch, and rectal adenomas and uninvolved mucosa in participants with FAP via single-cell transcriptomics.~VIII. To evaluate the effect of treatment with OCA versus placebo on microbiome diversity in duodenal, rectal pouch, and rectal adenomas and uninvolved tissue in participants with FAP.~VIIIa. Compare alpha- and beta-diversity analysis and identify differential abundance in adenomas and uninvolved tissue.~IX. To evaluate the pharmacokinetic (PK) profile of OCA in participants with FAP.~OUTLINE: Patients are randomized to 1 of 2 arms.~ARM I: Patients receive OCA 25 mg orally (PO) once daily (QD) for 6 months in the absence of unacceptable toxicity. Patients also undergo gastrointestinal (GI) endoscopy with biopsy and collection of blood samples at screening and on study.~ARM II: Patients receive matching placebo PO QD for 6 months in the absence of unacceptable toxicity. Patients also undergo GI endoscopy biopsy and collection of blood samples at screening and on study.~After completion of the study treatment, patients are followed within 14-21 days.
This phase IIa trial investigates if giving obeticholic acid (OCA) is safe and has a beneficial effect on the number of polyps in the small bowel and colon in patients with familial adenomatous polyposis (FAP). FAP is a rare gene defect that increases the risk of developing cancer of the intestines and colon. OCA is a drug similar to a bile acid the body makes. It is fluid made and released by the liver. OCA binds to a receptor in the intestine that is believed to have a positive effect on preventing cancer development. OCA has been effective in treating primary biliary cholangitis (PBC), a liver disease, and is approved by the Food and Drug Administration (FDA) for use at a lower dose (10 mg). There have been studies showing that OCA decreases inflammation and fibrosis. However, it is not yet known whether OCA works on reducing the number of polyps in patients with FAP.