Obeticholic Acid for Prevention in Barrett's Esophagus
Study Details
Study Description
Brief Summary
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, may help increase bile flow from the liver while suppressing bile acid production, therefore reducing the exposure of the liver to toxic levels of bile acids which is potentially linked to cancer development.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVE:
- 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:
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To assess the effect of OCA on FXR expression in Barrett's tissue. II. 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.
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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.
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To assess the effects of treatment with OCA versus placebo on serum levels of C4, a key precursor in bile acid synthesis, and FGF-19, a fibroblast growth factor which downregulates bile acid synthesis.
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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.
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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.
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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.
After completion of the study treatment, patients are followed at 30 weeks.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm I (OCA) Patients receive OCA PO QD for 6 months in the absence of disease progression or unacceptable toxicity. |
Biological: Obeticholic Acid
Given PO
Other Names:
|
| Placebo Comparator: Arm II (placebo) Patients receive placebo PO QD for 6 months in the absence of disease progression or unacceptable toxicity. |
Drug: Placebo Administration
Given PO
|
Outcome Measures
Primary Outcome Measures
- Mean change Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR) 5+ cells [Baseline up to 6 months]
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.
Other Outcome Measures
- FXR Expression [Up to 6 months]
Performed by enzyme-linked immunosorbent assay (ELISA).
- Measurement of OCA and OCA metabolites in blood [Up to 6 months]
These experiments will be performed in the consortium's pharmacokinetics/Pharmacodynamics Core laboratory at the University of Michigan LAO using a specific, sensitive and reliable tandem mass spectrometry (ultraperformance liquid chromatography- tandem mass spectrometry [UPLC-MS/MS]) method.
- Measurement of bile acid levels in plasma, gastric juice and in Barrett's tissue [Up to 6 months]
These experiments will be performed in the consortium's pharmacokinetics/Pharmacodynamics Core laboratory at the University of Michigan LAO using a specific, sensitive and reliable UPLC-MS/MS method to quantify the bile acid and conjugated metabolite concentration in human plasma and tissue samples.
- Measurement of C4 in blood [Up to 6 months]
This experiment will be performed in the consortium's pharmacokinetics/Pharmacodynamics Core laboratory at the University of Michigan LAO using UPLC-MS/MS. The blood based markers will be analyzed using a linear mixed model with study group as the primary between-subjects factor, and time (3-levels) along with the group-by-time interaction as the primary within-subjects factor.
- FGF-19 analysis [Up to 6 months]
FGF19 concentrations will be assayed using the solid-phase enzyme-linked immunoabsorbant assay Quantikine FGF19 Immunoassay (R&D Systems, Minneapolis, Minnesota [MN]) in the Immunology Core facility at the University of Michigan Rogel Cancer Center.
- Changes in markers [Baseline up to 6 months]
Will include markers in proliferation (Ki-67), apoptosis (cleaved caspase 3), oxidative damage (8-hydroxydeoxyguanosine), glandular differentiation - CDX2/SOX2 as well as baseline p53 staining performed by multiplex immunofluorescence.
- Presence of Dysplasia [Up to 6 months]
- CDX2/SOX2 and p 53 staining [Up to 6 months]
- Safety profile of treatment with OCA [During study visits]
Includes incidence and severity of pruritus and changes in serum total cholesterol, low-density lipoprotein, high-density lipoprotein, very low-density lipoprotein and triglycerides.
Eligibility Criteria
Criteria
Inclusion Criteria:
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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
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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
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Participants are on proton pump inhibitors (PPI) therapy for >= 1 month duration
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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
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Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
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Absolute leukocyte count >= 3,000/microliter
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Hemoglobin >= 10g/dL
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Platelets >= 100,000/microliter
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Total bilirubin =< 1.5 X normal institutional limits
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Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 X institutional upper limit of normal
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Creatinine =< 1.5 X institutional upper limit of normal
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Prothrombin time/ international normalized ratio (INR) =< 1.5 X institutional upper limit of normal
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LDL, VLDL =< 2 X institutional upper limit of normal
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HDL >= 1 X institutional lower limit of normal
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The effects of OCA on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
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Ability to understand the study procedures, benefits and risks, and sign a written informed consent document
Exclusion Criteria:
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No history of prior ablative therapy such as radiofrequency ablation, cryotherapy or argon plasma coagulation (APC) in BE segment
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Prior use of OCA
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Prior history or presence of HGD or cancer on pre-intervention endoscopy
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Cutaneous diseases manifesting with severe pruritus
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Individuals with active, known or suspected chronic liver disease including cirrhosis, nonalcoholic steatohepatitis, primary sclerosing cholangitis, biliary atresia
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Individuals with 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)
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Individuals with uncontrolled dyslipidemia
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Individuals with uncontrolled coronary artery disease
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Healthy volunteers may not enroll in the study
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Participants may not be receiving any other investigational agents
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History of allergic reactions attributed to ursodeoxycholic acid
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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
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Pregnant women are excluded from this study because the limited available human data on the use of OCA during pregnancy are not sufficient to inform a drug-associated risk. There is no information on the presence of OCA in human milk, the effects on the breastfed infant or the effects on milk production. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with OCA, breastfeeding should be discontinued if the mother is treated with OCA
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Concurrent use of:
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Bile acid binding resins such as cholestyramine, colestipol, or colesevelam (may reduce the absorption, systemic exposure, and efficacy of OCA)
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Warfarin (INR decreases following coadministration of warfarin and OCA)
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CYP1A2 substrates with narrow therapeutic index (clozapine, theophylline and tizanidine)
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Inhibitors of bile salt efflux pump (cyclosporine may exacerbate accumulation of conjugated bile salts including taurine conjugate of OCA in the liver)
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Dean E Brenner, University of Michigan Rogel Cancer Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NCI-2021-06441
- NCI-2021-06441
- UMI21-05-01
- UMI21-05-01
- P30CA046592
- UG1CA242632