Effect of Heavy Alcohol Consumption on Farnesoid X Receptor (FXR) Signaling

Study Overview
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Brief Summary
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The main purpose of this study is to see whether heavy drinking will interfere with a specific pathway, called FXR signaling in the liver. The abnormality of this pathway may lead to liver injury in some patients who drink heavily.

Official Title
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Effect of Heavy Alcohol Consumption on Farnesoid X Receptor (FXR) Signaling

Conditions
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Alcohol Consumption

Intervention / Treatment
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* Drug: Placebo
* Drug: 10 mg Obeticholic Acid (OCA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals ≥ 21 to 65 years old Able to provide informed consent & negative urine pregnancy test where appropriate Healthy controls must have not consumed any alcohol within 3 months prior to the screening visit Heavy alcohol drinking is defined as > 40 grams per day on average in women and > 60 grams per day on average in men for a minimum of 6 months Women of child bearing potential should be willing to practice contraception throughout the treatment period Exclusion Criteria: Active infection as evidenced by positive urine culture, blood culture, or pneumonia Serum creatinine > 1.5 mg/dL Known co-existing infection with hepatitis C, hepatitis B, or HIV Significant systemic or major illness including COPD, CHF and renal failure that in the opinion of the Investigator would preclude the patient from participating in and completing the study. Participation in another investigational drug, biologic, or medical device trial within 30 days prior to Screening Previous history of jaundice or signs of liver diseases such as spider angiomata, ascites, or history of esophageal varices or hepatic encephalopathy Total bilirubin > 2 mg/dl and INR > 1.5 Page 20 of 37 Women who are pregnant or nursing Presence of any other disease or condition that is interfering with the absorption, distribution, metabolism, or excretion of drugs including bile salt metabolism in the intestine. Patients who have undergone gastric bypass procedures will be excluded (gastric lap band is acceptable). Subjects who are taking warfarin

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Heavy Drinkers on placebo | Drug: Placebo<br>* 1 tablet of placebo, taken orally daily with water, approximately 30 minutes prior to breakfast for 4 weeks.<br>|
| Experimental: 10 mg Obeticholic Acid (OCA)<br>10 mg Obeticholic Acid (OCA) Study medication will be administered orally, once daily for 4 weeks. | Drug: 10 mg Obeticholic Acid (OCA)<br>* 10 mg Obeticholic Acid (OCA) Study medication will be administered orally, once daily, approximately 30 minutes prior to breakfast for 4 weeks.<br>|
| No Intervention: Non-drinking Controls<br>Non-drinking healthy controls | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Bile Salt Metabolism (C4 )Levels to Determine Effect of FXR |  | Baseline to 28 days | 
| Change in FGF19 Levels to Determine Effect of FXR |  | Baseline to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fasting Serum Bile Salt Levels |  | Baseline to 28 days | 
| Change in Oxidative Stress Level by Measuring Malondialdehyde |  | Baseline to 28 days | 
| Change in CYP2E1 Activity by Measuring Chlorzoxazone Clearance |  | Baseline to 28 days | 
| Change in Gut Permeability Through Lactulose/Mannitol Test | This is the measurement to quantify two non-metabolized sugar molecules-lactulose and mannitol-to determine the gut permeability | Baseline to 28 days | 
| Change in Bacterial Translocation Through Measures of Plasma LPS |  | Baseline to 28 days | 
| Change in Intestinal Inflammation by Measuring Stool Calprotectin |  | Baseline to 28 days | 
| Change in Activation of Innate Immunity Through Measures of TNF-alpha |  | Baseline to 28 days | 
| Change in Bacterial Translocation Through Measures of Serum sCD14 |  | Baseline to 28 days | 
| Change in Activation of Innate Immunity Through Measures of IL-6 |  | Baseline to 28 days | 
| Change in Activation of Innate Immunity Through Measures of IL-8 |  | Baseline to 28 days | 
| Change in Activation of Innate Immunity Through Measures of IL-1 |  | Baseline to 28 days |