- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04939051
Obeticholic Acid for Prevention in Barrett's Esophagus
Study Overview
Status
Conditions
Detailed Description
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.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
Kansas
-
Kansas City, Kansas, United States, 66160
- Recruiting
- University of Kansas Cancer Center
-
Principal Investigator:
- Ajay Bansal
-
Contact:
- Ajay Bansal
- Phone Number: 816-861-4700
- Email: abansal@kumc.edu
-
-
Michigan
-
Ann Arbor, Michigan, United States, 48109
- Recruiting
- University of Michigan Comprehensive Cancer Center
-
Contact:
- Dean E. Brenner
- Phone Number: 734-647-8903
- Email: dbrenner@umich.edu
-
Principal Investigator:
- Dean E. Brenner
-
-
Missouri
-
Saint Louis, Missouri, United States, 63110
- Recruiting
- Washington University School of Medicine
-
Principal Investigator:
- Dayna S. Early
-
Contact:
- Dayna S. Early
- Phone Number: 314-454-5960
- Email: dearly@wustl.edu
-
-
North Carolina
-
Chapel Hill, North Carolina, United States, 27599
- Recruiting
- UNC Lineberger Comprehensive Cancer Center
-
Contact:
- Nicholas J. Shaheen
- Phone Number: 919-966-7047
- Email: nshaheen@med.unc.edu
-
Principal Investigator:
- Nicholas J. Shaheen
-
-
Ohio
-
Cleveland, Ohio, United States, 44195
- Recruiting
- Cleveland Clinic
-
Contact:
- Prashanthi Thota
- Phone Number: 216-444-0780
- Email: thotap@ccf.org
-
Principal Investigator:
- Prashanthi Thota
-
Cleveland, Ohio, United States, 44106
- Not yet recruiting
- University Hospitals Cleveland Medical Center
-
Contact:
- Amitabh Chak
- Phone Number: 216-286-0151
- Email: Amitabh.chak@uhhospitals.org
-
Principal Investigator:
- Amitabh Chak
-
Cleveland, Ohio, United States, 44106
- Not yet recruiting
- Seidman Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center
-
Contact:
- Joseph E. Willis
- Phone Number: 216-286-0151
- Email: josephe.willis@uhhospitals.org
-
Principal Investigator:
- Joseph E. Willis
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Arm I (OCA)
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.
|
Undergo blood sample collection
Other Names:
Ancillary study
Given PO
Other Names:
Undergo EGD
Other Names:
Undergo esophageal biopsy, brushings and gastric aspirate
Other Names:
Undergo liver ultrasound with elastography
Other Names:
|
Placebo Comparator: Arm II (placebo)
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.
|
Undergo blood sample collection
Other Names:
Given PO
Ancillary study
Undergo EGD
Other Names:
Undergo esophageal biopsy, brushings and gastric aspirate
Other Names:
Undergo liver ultrasound with elastography
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Mean change Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR) 5+ cells
Time Frame: 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.
|
Baseline up to 6 months
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Measurement of obeticholic acid (OCA ) and OCA metabolites in blood
Time Frame: 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.
The exploratory outcomes are continuous, measured at either two or three time points.
The most common framework for analyzing such longitudinal data is linear mixed models (LMM) with time, group, and time-by-group interaction as primary covariates.
|
Up to 6 months
|
Measurement of bile acid levels in plasma, gastric juice and in Barrett's tissue
Time Frame: 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.
The exploratory outcomes are continuous, measured at either two or three time points.
The most common framework for analyzing such longitudinal data is LMM with time, group, and time-by-group interaction as primary covariates.
|
Up to 6 months
|
Measurement of C4 in blood
Time Frame: 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.
The exploratory outcomes are continuous, measured at either two or three time points.
The most common framework for analyzing such longitudinal data is LMM with time, group, and time-by-group interaction as primary covariates.
|
Up to 6 months
|
FGF-19 analysis
Time Frame: 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) in the Immunology Core facility at the University of Michigan Rogel Cancer Center.
The exploratory outcomes are continuous, measured at either two or three time points.
The most common framework for analyzing such longitudinal data is LMM with time, group, and time-by-group interaction as primary covariates.
|
Up to 6 months
|
FXR Expression
Time Frame: Up to 6 months
|
Performed by enzyme-linked immunosorbent assay.
The exploratory outcomes are continuous, measured at either two or three time points.
The most common framework for analyzing such longitudinal data is LMM with time, group, and time-by-group interaction as primary covariates.
|
Up to 6 months
|
Changes in markers
Time Frame: 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.
The exploratory outcomes are continuous, measured at either two or three time points.
The most common framework for analyzing such longitudinal data is LMM with time, group, and time-by-group interaction as primary covariates.
|
Baseline up to 6 months
|
Presence of dysplasia
Time Frame: Up to 6 months
|
The exploratory outcomes are continuous, measured at either two or three time points.
The most common framework for analyzing such longitudinal data is LMM with time, group, and time-by-group interaction as primary covariates.
|
Up to 6 months
|
CDX2/SOX2 and p53 staining
Time Frame: Up to 6 months
|
Performed in the Molecular Pathology Core Resource at University of Michigan Rogel Cancer Center.
The exploratory outcomes are continuous, measured at either two or three time points.
The most common framework for analyzing such longitudinal data is LMM with time, group, and time-by-group interaction as primary covariates.
|
Up to 6 months
|
Safety profile of treatment with OCA
Time Frame: 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.
The exploratory outcomes are continuous, measured at either two or three time points.
The most common framework for analyzing such longitudinal data is LMM with time, group, and time-by-group interaction as primary covariates.
|
During study visits
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Dean E Brenner, University of Michigan Rogel Cancer Center
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- NCI-2021-06441 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- P30CA046592 (U.S. NIH Grant/Contract)
- UG1CA242632 (U.S. NIH Grant/Contract)
- UMI21-05-01 (Other Identifier: DCP)
- UMCC 2022.048 (Other Identifier: University of Michigan Comprehensive Cancer Center)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Barrett Esophagus
-
Erbe Elektromedizin GmbHNAMSA; Kansas City Veteran Affairs Medical Center; Erbe USA IncorporatedTerminatedBarrett's Esophagus | High-grade Dysplasia in Barrett Esophagus | Low Grade Dysplasia in Barrett EsophagusUnited States
-
University Medical Center GroningenCompletedEsophageal Cancer | Barrett Esophagus | Dysplasia in Barrett EsophagusNetherlands
-
Academisch Medisch Centrum - Universiteit van Amsterdam...CompletedBarrett Esophagus | Barrett AdenocarcinomaNetherlands
-
Mayo ClinicTerminatedBarretts Esophagus With High Grade Dysplasia | Barrett AdenocarcinomaUnited States
-
Academisch Medisch Centrum - Universiteit van Amsterdam...University Medical Center Groningen; UMC Utrecht; Erasmus Medical Center; Catharina... and other collaboratorsNot yet recruitingEsophageal Cancer | Barrett Adenocarcinoma | Barretts Esophagus With Dysplasia
-
Portsmouth Hospitals NHS TrustUniversity of PortsmouthUnknownBarrett Esophagus | Barrett Adenocarcinoma | Barrett Metaplasia | Barrett Oesophagitis With DysplasiaUnited Kingdom
-
Professor Michael BourkeWithdrawn
-
Medical University of South CarolinaCompletedBarretts Esophagus With DysplasiaUnited States
-
Allegheny Singer Research Institute (also known...Integra LifeSciences CorporationTerminatedBarrett Esophagus | High Grade Dysplasia | EsophagusUnited States
-
Lucid Diagnostics, Inc.RecruitingBarrett Esophagus | Barretts Esophagus With Dysplasia | Esophagus AdenocarcinomaUnited States
Clinical Trials on Biospecimen Collection
-
Mayo ClinicNational Cancer Institute (NCI)RecruitingBreast Adenocarcinoma | HER2-Positive Breast CarcinomaUnited States
-
National Cancer Institute (NCI)Active, not recruitingAnatomic Stage III Breast Cancer AJCC v8 | Anatomic Stage IIIA Breast Cancer AJCC v8 | Anatomic Stage IIIB Breast Cancer AJCC v8 | Anatomic Stage IIIC Breast Cancer AJCC v8 | Prognostic Stage III Breast Cancer AJCC v8 | Prognostic Stage IIIA Breast Cancer AJCC v8 | Prognostic Stage IIIB Breast... and other conditionsUnited States, Puerto Rico
-
LLS PedAL Initiative, LLCNational Cancer Institute (NCI); Children's Oncology GroupRecruitingAcute Myeloid Leukemia | Juvenile Myelomonocytic Leukemia | Acute Lymphoblastic Leukemia | Myelodysplastic Syndrome | Myeloid Leukemia Associated With Down Syndrome | Mixed Phenotype Acute Leukemia | Acute Myeloid Leukemia Post Cytotoxic Therapy | Myelodysplastic Syndrome Post Cytotoxic TherapyUnited States, Canada, Australia, Puerto Rico, New Zealand
-
Thomas Jefferson UniversityNational Cancer Institute (NCI)Active, not recruiting
-
Mayo ClinicRecruitingEarly Stage Breast Carcinoma | Chemotherapy-Related Nausea and/or VomitingUnited States
-
Mayo ClinicNational Cancer Institute (NCI)Active, not recruiting
-
Mayo ClinicNational Cancer Institute (NCI)RecruitingMetastatic Renal Cell Carcinoma | Stage IV Renal Cell Cancer AJCC v8United States
-
Ohio State University Comprehensive Cancer CenterGuardant Health, Inc.RecruitingColorectal CarcinomaUnited States
-
M.D. Anderson Cancer CenterRecruitingCholangiocarcinoma | Malignant Digestive System NeoplasmUnited States
-
Mayo ClinicNational Cancer Institute (NCI)Recruiting