Obeticholic Acid for Prevention in Barrett's Esophagus

Study Overview
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Brief Summary
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This phase II trial studies the effect of obeticholic acid in treating patients with Barrett's esophagus. Bile acids present in duodenogastroesophageal reflux contribute to neoplastic progression in Barrett's esophagus. Obeticholic acid has shown anti-cholestatic, anti-inflammatory and anti-fibrotic effects mediated by FXR activation. It down regulates bile acid availability and decreases proinflammatory cytokine production including IL-1β and TNFα in human enterocytes and immune cells. This chain of events reduces the bile acid exposure in esophagus tissue thereby limiting bile acid induced damage and dysplastic progression.

Detailed Description
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PRIMARY OBJECTIVE: I. To assess the mean change from baseline in the leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) + cells in the crypts of esophageal tissue among patients with Barrett's esophagus (BE) receiving 25 mg of obeticholic acid (OCA), once daily from 0 to 180 days as compared to placebo. EXPLORATORY OBJECTIVES: I. To determine OCA concentrations and concentrations of the two major active metabolites, taurine, and glycine conjugates, in plasma after dosing with OCA 25 mg to determine the concentrations reached. II. To assess the effects of treatment with OCA versus placebo on total and individual bile acid composition in Barrett's tissue, gastric aspirate, and serum. III. To assess the effects of treatment with OCA versus placebo on serum levels of 7alpha-hydroxy-4- cholesten-3-one (C4), a key precursor in bile acid synthesis, and fibroblast growth factor-19 (FGF-19), a fibroblast growth factor which downregulates bile acid synthesis. IV. To assess the effect of OCA on FXR expression in Barrett's tissue. V. To assess the effects of treatment with OCA versus placebo on biomarkers of the carcinogenic process - proliferation (Ki-67), apoptosis (cleaved caspase 3), and oxidative damage (8-hydroxydeoxyguanosine) as determined from Barrett's mucosal biopsies. VI. To assess the effects of treatment with OCA versus placebo on histologic changes in Barrett's samples pre and post-intervention for development/ resolution of dysplasia. VII. To assess the effects of treatment with OCA versus placebo on markers of differentiation- CDX2/SOX2/p53 expression in Barrett's tissue. VIII. To assess the safety profile of treatment with OCA versus placebo which includes incidence and severity of pruritus and changes in serum total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL) and triglycerides. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive OCA orally (PO) once daily (QD) for 6 months in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive placebo PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Patients undergo liver ultrasound with elastography during screening, esophagogastroduodenoscopy (EGD) with biopsies, brushings and gastric aspirate at end of treatment visit and blood sample collection throughout the study. After completion of the study treatment, patients are followed at 14-21 days.

Official Title
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Obeticholic Acid for Prevention in Barrett's Esophagus

Conditions
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Barrett Esophagus

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Procedure: Esophageal Biopsy
* Procedure: Esophagogastroduodenoscopy
* Procedure: Liver Ultrasonographic Elastography
* Biological: Obeticholic Acid
* Drug: Placebo Administration
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Known diagnosis of histologically-confirmed diagnosis of BE with either no dysplasia, indefinite for dysplasia or low-grade dysplasia as defined by the presence of specialized columnar epithelium on histology and >= 2 cm of involvement on endoscopy Adequate Barrett's mucosa, which is defined as >= 1 out of 4 research samples (i.e. >= 25 %) with >= 50% intestinal metaplasia in biopsies required to satisfy the endpoints of the study Participants are on proton pump inhibitors (PPI) therapy for >= 1 month duration Age >= of 18 years. Because no dosing or adverse event (AE) data are currently available on the use of OCA in participants < 18 years of age, children are excluded from 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 Leukocyte count >= 3,500/microliter Platelet count >= 100,000/microliter Absolute neutrophil count >= 1,500/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, all men 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 after receiving the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately Ability to understand the study procedures, benefits and risks, and sign a written informed consent document. Non-English speaking participants are allowed to enroll even if they skip answering quality-of-life (QOL) questionnaires. Special efforts will be made through community advisory boards at participating sites to reach Spanish speaking participants Willing to undergo testing for human immunodeficiency virus (HIV) testing if not tested within the past 6 months Willing to undergo hepatitis B and C screening Willing and able to adhere to the prohibitions and restrictions specified in the approved protocol Willingness to moderate alcohol intake (consuming no more than 1 or 2 alcoholic drinks per day for women and men, respectively) Participants must have no evidence of active or recurrent invasive cancer for 6 months prior to screening and must be at least 6 months from any prior cancer-directed treatment (such as surgical resection, chemotherapy, immunotherapy, hormonal therapy or radiation) Exclusion Criteria: History of prior ablative therapy such as radiofrequency ablation, cryotherapy or argon plasma coagulation (APC) in BE segment Prior use of OCA Prior history or presence of high-grade disease (HGD) or cancer on pre-intervention endoscopy Cutaneous diseases manifesting with severe pruritus Individuals with active, known or suspected chronic liver disease including cirrhosis, nonalcoholic steatohepatitis (NASH) with fibrosis or cirrhosis, primary sclerosing cholangitis, biliary atresia Individuals with cholelithiasis or choledocholithiasis; acute cholecystitis (defined by a syndrome of right upper quadrant pain, fever, and leukocytosis associated with gallbladder inflammation diagnosed within the prior 6 weeks) or biliary obstruction (defined by extrahepatic cholestasis) Individuals with a history of pancreatitis or pancreatic abnormalities Individuals with hepatic steatosis and velocity > 1.7 as determined by liver ultrasound elastography Individuals with hyperlipidemia not well controlled with the use of pharmacotherapy 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 Known hypersensitivity, allergies, or intolerance to the study drug or compounds of similar chemical or biologic composition Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with participant's safety, obtaining informed consent, or compliance to the study procedures Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Individuals with active and untreated hepatitis C virus (HCV) and/or or hepatitis B virus (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 or suspected drug interactions with OCA Consultation with the participant's infectious disease specialist may be obtained Pregnant, breast-feeding, or women of childbearing potential unwilling to use a reliable contraceptive method. Pregnant women are excluded from this study because OCA is an agent with unknown effects on the developing human fetus. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with OCA, breastfeeding should be discontinued if the mother is treated with OCA Individuals taking the drugs listed below may not be randomized unless they are willing to stop the medications (and possibly change to alternative non-excluded medications to treat the same conditions) no less than 5 half-lives days prior to starting OCA or placebo on this study. Consultation with the participant's primary care provider may be obtained but is not required. The use of the following drugs or drug 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/dietary supplements, and long-term doxycycline or tetracycline Participants may not be receiving any other investigational agents

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (OCA)<br>Patients receive OCA PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Patients undergo liver ultrasound during screening, EGD with biopsies, brushings and gastric aspirate at end of treatment visit and blood sample collection throughout the study. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Esophageal Biopsy<br>* Undergo esophageal biopsy, brushings and gastric aspirate<br>* Other names: Biopsy of Esophagus;Procedure: Esophagogastroduodenoscopy<br>* Undergo EGD<br>* Other names: EGD;Procedure: Liver Ultrasonographic Elastography<br>* Undergo liver ultrasound with elastography<br>* Other names: Vibration-Controlled Transient Elastrography;Biological: Obeticholic Acid<br>* Given PO<br>* Other names: Ocaliva;Other: Questionnaire Administration<br>* Ancillary study<br>|
| Placebo Comparator: Arm II (placebo)<br>Patients receive placebo PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Patients undergo liver ultrasound during screening, EGD with biopsies, brushings and gastric aspirate at end of treatment visit and blood sample collection throughout the study. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Esophageal Biopsy<br>* Undergo esophageal biopsy, brushings and gastric aspirate<br>* Other names: Biopsy of Esophagus;Procedure: Esophagogastroduodenoscopy<br>* Undergo EGD<br>* Other names: EGD;Procedure: Liver Ultrasonographic Elastography<br>* Undergo liver ultrasound with elastography<br>* Other names: Vibration-Controlled Transient Elastrography;Drug: Placebo Administration<br>* Given PO<br>Other: Questionnaire Administration<br>* Ancillary study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR) 5+ cells | The mean difference in this percentage is compared across the two study arms by means of a two-sample t-test. As a further sensitivity analysis, the outcome of change will be analyzed under a linear regression model framework, controlling for factors such as age, gender, body mass index, and grade of dysplasia. | Baseline up to 6 months |