Testing Obeticholic Acid for Familial Adenomatous Polyposis

Inclusion Criteria:

• Participants must have a diagnosis of phenotypic FAP with disease involvement of theduodenum and rectum as defined by:

• Genetic diagnosis: APC germline mutation (with or without family history) orobligate carrier

• Clinical diagnosis: FAP phenotype with > 100 adenomas in large intestine andparticipant has a family history of FAP

• Clinical diagnosis: FAP phenotype who are status post colectomy for polyposis,participant has a family history of FAP, and 2 FAP experts agree to thediagnosis

• Attenuated FAP diagnosis: APC germline mutation required

• Participants must have no evidence of active or recurrent invasive cancer for 6months prior to screening and must be at least 6 months from any priorcancer-directed treatment (such as surgical resection, chemotherapy, immunotherapy,hormonal therapy or radiation)

• Age >= 18 years. Because no dosing or adverse event (AE) data are currentlyavailable on the use of OCA in participants < 18 years of age, children are excludedfrom this study but will be eligible for future pediatric trials, if applicable

• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

• Hemoglobin >= 10 g/dL or hematocrit >= 30%

• Leukocyte count >= 3,500/microliter

• Platelet count >= 100,000/microliter

• Absolute neutrophil count >= 1,500/microliter

• Creatinine clearance (calculated if measured is not available) >= 30 mL/min/1.73m^2

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x the institutional upper limit of normal (ULN)

• Total bilirubin =< 1.0 x ULN

• Alkaline phosphatase =< 1.5 x ULN

• Gamma-glutamyl transferase (GGT) =< 1.5 x ULN

• Presence of Spigelman stage II or III duodenal polyposis at screening

• Presence of intact rectum or ileo-rectal anastomosis (IRA) or ileal pouch-analanastomosis (IPAA) or end ileostomy

• Participants must have a negative test result for human immunodeficiency virus (HIV); if tested within the past 6 months, result will be accepted without repeatingthe test

• Participants must have negative test for hepatitis C virus (HCV) and B virus (HBV)

• Willing and able to adhere to the prohibitions and restrictions specified in thefinal approved protocol

• The effects of OCA on the developing human fetus at the recommended therapeutic doseare unknown. For this reason, women of child-bearing potential and men must agree touse adequate contraception (hormonal or barrier method of birth control; abstinence)prior to study entry, throughout the duration of study participation, and for atleast 6 months after receiving the last dose of study drug. Should a woman becomepregnant or suspect she is pregnant while participating in this study, she shouldinform her study physician immediately

• Willingness to moderate alcohol intake (consuming no more than 1 or 2 alcoholicdrinks per day for women and men, respectively)

• Ability to understand and the willingness to sign a written informed consentdocument

Exclusion Criteria:

• Prior use of study drug

• Duodenal or rectal/pouch polyp burden that is not quantifiable

• Histologically-confirmed high-grade dysplasia or cancer on biopsy at screening

• Individuals with active, known or suspected chronic liver disease includingcirrhosis, nonalcoholic steatohepatitis (NASH) with liver fibrosis, NASH withcirrhosis, primary sclerosing cholangitis, biliary atresia

• Individuals with acute cholecystitis (defined by a syndrome of right upper quadrantpain, fever, and leukocytosis associated with gallbladder inflammation)

• Individuals with a history of pancreatitis or presence of pancreatic abnormalitiessuggestive of increased risk of pancreatitis

• Individuals with hepatic steatosis and velocity > 1.7 meters/second (m/s) asdetermined by liver ultrasound elastography

• Individuals with hyperlipidemia not well controlled with the use of pharmacotherapyand/or dietary modifications

• History of severe, progressive, or uncontrolled renal, genitourinary, hepatic,hematologic, endocrine, cardiac, vascular, pulmonary, rheumatologic, neurologic,psychiatric, or metabolic disturbances, or signs and symptoms thereof

• Pregnant, breast-feeding, or women of childbearing potential unwilling to use areliable contraceptive method. Pregnant women are excluded from this study becauseOCA is an agent with unknown effects on the developing human fetus. Because there isan unknown but potential risk for adverse events in nursing infants secondary totreatment of the mother with OCA, breastfeeding should be discontinued if the motheris treated with OCA

• Known hypersensitivity, allergies, or intolerance to the study drug or compounds ofsimilar chemical or biologic composition

• Any serious and/or unstable pre-existing medical disorder (aside from malignancyexception above), psychiatric disorder, or other conditions that could interferewith participant's safety, obtaining informed consent, or compliance to the studyprocedures

• Participants may not be receiving any other investigational agents

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements

• Individuals with active and untreated hepatitis C virus (HCV) and/or or hepatitis Bvirus (HBV) infection

• Individuals with HIV infection are eligible for participation if:

• CD4+ count >= 300/uL

• Viral load is undetectable

• Receiving highly active antiretroviral therapy (HAART) without known orsuspected drug interactions with OCA

• Consultation with the participant's infectious disease specialist may beobtained

• Individuals taking the drugs listed below may not be randomized unless they arewilling to stop the medications (and possibly change to alternative non-excludedmedications to treat the same conditions) no less than 5 half-lives days prior tostarting OCA or placebo on this study. Consultation with the participant's primarycare provider may be obtained but is not required. The use of the following drugs ordrug classes is prohibited during OCA/placebo treatment:

• Investigational agents

• Bile acid sequestrants (bile acid binding resins): cholestyramine, colestipol,or colesevelam

• Bile salt efflux pump (BSEP) inhibitors

• Clozapine

• Theophylline derivatives

• Tizanidine

• Warfarin

• Hepatotoxic drugs such as amiodarone, sodium valproate, certain herbal/dietarysupplements, and long-term doxycycline or tetracycline