Obeticholic Acid for Barrett's Esophagus

Recruiting at 10 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Proton pump inhibitors

Must not be taking: Bile acid sequestrants, Clozapine

Disqualifiers: Chronic liver disease, Pancreatitis, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 6 months

30 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial. Specifically, you cannot take investigational agents, certain bile acid medications, clozapine, theophylline derivatives, tizanidine, warfarin, and some hepatotoxic drugs. If you are on these, you must stop them at least 5 days before starting the trial.

What data supports the effectiveness of the drug Obeticholic Acid for Barrett's Esophagus?

Obeticholic Acid has shown effectiveness in treating liver-related conditions like primary biliary cholangitis and non-alcoholic steatohepatitis by reducing liver fat and inflammation. While this is not directly related to Barrett's Esophagus, its ability to influence liver and metabolic conditions suggests potential benefits that might be explored in other diseases. ^{1 2 3 4 5}

Is obeticholic acid safe for humans?

Obeticholic acid has been used safely in humans for conditions like primary biliary cholangitis and nonalcoholic steatohepatitis, with studies evaluating its safety in real-world settings. ^{1 2 3 4 6}

How is the drug Obeticholic Acid unique for treating Barrett's Esophagus?

Obeticholic Acid is unique because it is a farnesoid X receptor (FXR) agonist, which means it works by activating a specific receptor involved in regulating bile acids and metabolism. This mechanism is different from other treatments for Barrett's Esophagus, which may not target these pathways. ^{1 2 3 5 6}

What is the purpose of this trial?

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-1beta and TNFalpha 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.

Research Team

Prashanthi Thota

Principal Investigator

University of Michigan Rogel Cancer Center

Eligibility Criteria

This trial is for adults over 18 with Barrett's Esophagus (BE) who have been on proton pump inhibitors for at least a month. They should not have high-grade dysplasia or cancer, no history of ablative therapy in the BE segment, and must be generally healthy without chronic liver disease or uncontrolled illnesses. Participants need to use contraception and cannot be pregnant or breastfeeding.

Inclusion Criteria

Absolute leukocyte count >= 3,000/microliter

Hemoglobin >= 10g/dL

I am mostly active and can care for myself.

Exclusion Criteria

I am not pregnant or breastfeeding.

I have had recent gallbladder inflammation or a blockage in my bile ducts.

I do not have any severe illnesses or social situations that would stop me from following the study's requirements.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive either obeticholic acid or placebo orally once daily for 6 months

6 months

Regular visits for blood sample collection and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

2-3 weeks

1 visit (in-person)

Treatment Details

Interventions

• Obeticholic Acid

Trial Overview The trial is testing obeticholic acid (OCA), which may reduce damage from bile acids in the esophagus by activating FXR to lower bile acid levels and inflammation. It includes questionnaires, biospecimen collection, biopsies, ultrasonography, endoscopy procedures, OCA administration versus placebo.

Participant Groups

Group I: Arm I (OCA) Experimental Treatment 6 Interventions

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.

Group II: Arm II (placebo) Placebo Group 6 Interventions

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.

Obeticholic Acid is already approved in United States, European Union for the following indications:

Approved in United States as Ocaliva for:

• Primary biliary cholangitis (PBC) without liver problems or with compensated cirrhosis but without portal hypertension

Approved in European Union as Ocaliva for:

• Primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Obeticholic acid (Ocaliva) is an FXR agonist that has received accelerated approval in the USA for treating primary biliary cholangitis, particularly in patients who do not respond adequately to ursodeoxycholic acid or cannot tolerate it.

The drug is currently in preregistration for the same indication in the EU, highlighting its potential as a significant treatment option for liver diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obeticholic Acid: First Global Approval. Markham, A., Keam, SJ.[2018]

In a study of 191 patients with primary biliary cholangitis (PBC), obeticholic acid (OCA) demonstrated effectiveness, with a 42.9% response rate after 12 months, particularly in patients who did not have cirrhosis.

However, patients with cirrhosis experienced lower tolerability and a higher discontinuation rate (30% vs. 12%) due to adverse effects, primarily treatment-induced pruritus, highlighting the need for careful monitoring in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience with obeticholic acid in patients with primary biliary cholangitis. D'Amato, D., De Vincentis, A., Malinverno, F., et al.[2022]

Obeticholic acid (OCA) is an FDA-approved second-line therapy for primary biliary cholangitis (PBC) that significantly reduces serum alkaline phosphatase levels in patients who do not respond to ursodeoxycholic acid, demonstrating its efficacy in treating this condition.

In clinical trials for nonalcoholic steatohepatitis (NASH), OCA has shown promising results by improving liver blood tests and reducing liver fibrosis without worsening the disease, although it may cause dose-dependent pruritus in 1-10% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obeticholic acid-a new therapy in PBC and NASH. Chapman, RW., Lynch, KD.[2021]

In a clinical trial involving 283 patients with non-alcoholic steatohepatitis, obeticholic acid significantly improved liver histology, with 45% of patients showing improvement compared to 21% in the placebo group, indicating its efficacy in treating this condition.

While obeticholic acid was effective, it also caused pruritus (itching) in 23% of patients, compared to 6% in the placebo group, highlighting the need for further investigation into its long-term safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Neuschwander-Tetri, BA., Loomba, R., Sanyal, AJ., et al.[2022]

Obeticholic acid (OCA) is a potent FXR agonist being developed for chronic liver diseases, showing significantly increased plasma levels in patients with hepatic impairment, with increases of 1.4-, 8-, and 13-fold in mild, moderate, and severe cases, respectively.

Despite the increased systemic exposure in patients with liver impairment, the liver exposure of OCA only increased marginally (∼2-fold), suggesting that while OCA is absorbed more in the bloodstream, its effectiveness in the liver may not be as dramatically enhanced.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modeling and Experimental Studies of Obeticholic Acid Exposure and the Impact of Cirrhosis Stage. Edwards, JE., LaCerte, C., Peyret, T., et al.[2018]

In a 6-week double-blind, placebo-controlled study involving 64 patients with type 2 diabetes and nonalcoholic fatty liver disease, obeticholic acid (OCA) significantly improved insulin sensitivity by 28% at a 25 mg dose and 20% at a 50 mg dose, compared to a decrease in the placebo group.

OCA treatment also led to reductions in liver inflammation and fibrosis markers, indicating its potential as a safe and effective therapy for improving liver health in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Mudaliar, S., Henry, RR., Sanyal, AJ., et al.[2022]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Obeticholic Acid: First Global Approval. [2018]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Real-world experience with obeticholic acid in patients with primary biliary cholangitis. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Obeticholic acid-a new therapy in PBC and NASH. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Modeling and Experimental Studies of Obeticholic Acid Exposure and the Impact of Cirrhosis Stage. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. [2022]