Obeticholic Acid for Prevention in Barrett's Esophagus

Inclusion Criteria:

• Known diagnosis of histologically-confirmed BE with either no dysplasia, indefinitefor dysplasia, or low-grade dysplasia as defined by the presence of specializedcolumnar epithelium on histology and >= 2 cm of involvement on endoscopy

• Adequate Barrett's mucosa, which is defined as at least one sample with >= 50%intestinal metaplasia in biopsies required to satisfy the endpoints of the study

• Participants are on proton pump inhibitors (PPI) therapy for >= 28 days duration

• Age >= of 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 >= 10g/dL or hematocrit >= 30 %

• Leukocyte count >= 3,500/microliter

• Platelet count >= 100,000/microliter

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

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 X 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

• The effects of OCA on the developing human fetus are unknown. For this reason, allmen and women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry,throughout the duration of study participation, and for at least 6 months afterreceiving the last dose of study drug. Should a woman become pregnant or suspect sheis pregnant while participating in this study, she should inform her study physicianimmediately

• Ability to understand the study procedures, benefits and risks, and sign a writteninformed consent document. Non-English speaking participants are allowed to enrolleven if they skip answering quality-of-life (QOL) questionnaires. Special effortswill be made through community advisory boards at participating sites to reachSpanish speaking participants

• Willing to undergo testing for human immunodeficiency virus (HIV) testing if nottested within the past 6 months

• Willing to undergo hepatitis B and C screening if not tested within the past 6months

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

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

• 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)

Exclusion Criteria:

• History of prior ablative therapy such as radiofrequency ablation, cryotherapy orargon plasma coagulation (APC) in BE segment

• Prior use of OCA

• Prior history or presence of high-grade disease (HGD) or cancer on pre-interventionendoscopy

• Cutaneous diseases manifesting with severe pruritus

• Individuals with active, known or suspected chronic liver disease includingcirrhosis, nonalcoholic steatohepatitis (NASH) with fibrosis or cirrhosis, primarysclerosing 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 pancreatic abnormalities

• Individuals with hepatic steatosis and velocity > 1.7 m/sec as determined by liverultrasound elastography. Results of a right upper quadrant ultrasound withelastography performed within 6 months of starting study treatment may be used toassess this criteria

• Individuals with hyperlipidemia that is not well controlled with the use ofpharmacotherapy and/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

• Individuals with known hypersensitivity, allergies, or intolerance to the study drugor compounds of similar 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

• 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 or drug classes is prohibited during OCA/placebotreatment

• 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, certainherbal/dietary supplements, and long-term doxycycline or tetracycline

• 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

• Participants may not be receiving any other investigational agents