Alcohol Consumption
Conditions
Brief summary
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.
Interventions
DRUGPlacebo
1 tablet of placebo, taken orally daily with water, approximately 30 minutes prior to breakfast for 4 weeks.
10 mg Obeticholic Acid (OCA) Study medication will be administered orally, once daily, approximately 30 minutes prior to breakfast for 4 weeks.
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Intercept Pharmaceuticals
Suthat Liangpunsakul
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 Fasting Serum Bile Salt Levels | Baseline to 28 days | — |
| Change in Oxidative Stress Level by Measuring Malondialdehyde | Baseline to 28 days | — |
| Change in Activation of Innate Immunity Through Measures of TNF-alpha | Baseline to 28 days | — |
| Change in Gut Permeability Through Lactulose/Mannitol Test | Baseline to 28 days | This is the measurement to quantify two non-metabolized sugar molecules-lactulose and mannitol-to determine the gut permeability |
| 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 | — |
| Change in CYP2E1 Activity by Measuring Chlorzoxazone Clearance | Baseline to 28 days | — |
| Change in Bacterial Translocation Through Measures of Serum sCD14 | Baseline to 28 days | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Heavy Drinkers on placebo
Placebo: 1 tablet of placebo, taken orally daily with water, approximately 30 minutes prior to breakfast for 4 weeks. | 9 |
| 10 mg Obeticholic Acid (OCA) 10 mg Obeticholic Acid (OCA) Study medication will be administered orally, once daily for 4 weeks.
10 mg Obeticholic Acid (OCA): 10 mg Obeticholic Acid (OCA) Study medication will be administered orally, once daily, approximately 30 minutes prior to breakfast for 4 weeks. | 6 |
| Non-drinking Controls Non-drinking healthy controls | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Non-drinking Controls | 10 mg Obeticholic Acid (OCA) |
|---|---|---|---|---|
| Age, Continuous | 31 Years | 39 Years | 47 Years | 49 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 29 Participants | 14 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 13 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 12 Participants | 7 Participants | 2 Participants |
| Region of Enrollment United States | 9 participants | 30 participants | 15 participants | 6 participants |
| Sex: Female, Male Female | 5 Participants | 17 Participants | 10 Participants | 2 Participants |
| Sex: Female, Male Male | 4 Participants | 13 Participants | 5 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 6 | 0 / 15 |
| other Total, other adverse events | 4 / 9 | 3 / 6 | 0 / 15 |
| serious Total, serious adverse events | 0 / 9 | 0 / 6 | 0 / 15 |
Outcome results
Primary
Change in Bile Salt Metabolism (C4 )Levels to Determine Effect of FXR
Time frame: Baseline to 28 days
Population: Zero participants were analyzed due to data not being collected
Primary
Change in FGF19 Levels to Determine Effect of FXR
Time frame: Baseline to 28 days
Population: Zero participants were analyzed due to data not being collected
Secondary
Change in Activation of Innate Immunity Through Measures of IL-1
Time frame: Baseline to 28 days
Population: Due to errors, some results were unable to be processed causing differences in the baseline and day 28.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Activation of Innate Immunity Through Measures of IL-1 | Day 28 | 1.76 Pg/ml | Standard Deviation 0.32 |
| Placebo | Change in Activation of Innate Immunity Through Measures of IL-1 | Baseline | 1.90 Pg/ml | Standard Deviation 0.28 |
| 10 mg Obeticholic Acid (OCA) | Change in Activation of Innate Immunity Through Measures of IL-1 | Day 28 | 1.45 Pg/ml | Standard Deviation 0.78 |
| 10 mg Obeticholic Acid (OCA) | Change in Activation of Innate Immunity Through Measures of IL-1 | Baseline | 1.78 Pg/ml | Standard Deviation 0.24 |
| Non-drinking Controls | Change in Activation of Innate Immunity Through Measures of IL-1 | Baseline | 1.77 Pg/ml | Standard Deviation 0.56 |
| Non-drinking Controls | Change in Activation of Innate Immunity Through Measures of IL-1 | Day 28 | 1.07 Pg/ml | Standard Deviation 0.3 |
Secondary
Change in Activation of Innate Immunity Through Measures of IL-6
Time frame: Baseline to 28 days
Population: Zero participants were analyzed due to data not being collected
Secondary
Change in Activation of Innate Immunity Through Measures of IL-8
Time frame: Baseline to 28 days
Population: Zero participants were analyzed due to data not being collected
Secondary
Change in Activation of Innate Immunity Through Measures of TNF-alpha
Time frame: Baseline to 28 days
Population: Due to errors, some results were unable to be processed causing differences in the baseline and day 28.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Activation of Innate Immunity Through Measures of TNF-alpha | Baseline | 6.53 Pg/ml | Standard Deviation 3.52 |
| Placebo | Change in Activation of Innate Immunity Through Measures of TNF-alpha | Day 28 | 6.36 Pg/ml | Standard Deviation 3 |
| 10 mg Obeticholic Acid (OCA) | Change in Activation of Innate Immunity Through Measures of TNF-alpha | Baseline | 8.99 Pg/ml | Standard Deviation 4.39 |
| 10 mg Obeticholic Acid (OCA) | Change in Activation of Innate Immunity Through Measures of TNF-alpha | Day 28 | 7.97 Pg/ml | Standard Deviation 4.08 |
| Non-drinking Controls | Change in Activation of Innate Immunity Through Measures of TNF-alpha | Baseline | 6.91 Pg/ml | Standard Deviation 3.36 |
| Non-drinking Controls | Change in Activation of Innate Immunity Through Measures of TNF-alpha | Day 28 | 2.89 Pg/ml | Standard Deviation 3.27 |
Secondary
Change in Bacterial Translocation Through Measures of Plasma LPS
Time frame: Baseline to 28 days
Population: Due to errors, some results were unable to be processed causing differences in the baseline and day 28.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Bacterial Translocation Through Measures of Plasma LPS | Baseline | 40.22 Pg/ml | Standard Deviation 9.52 |
| Placebo | Change in Bacterial Translocation Through Measures of Plasma LPS | Day 28 | 47.84 Pg/ml | Standard Deviation 23.1 |
| 10 mg Obeticholic Acid (OCA) | Change in Bacterial Translocation Through Measures of Plasma LPS | Baseline | 58.73 Pg/ml | Standard Deviation 13.3 |
| 10 mg Obeticholic Acid (OCA) | Change in Bacterial Translocation Through Measures of Plasma LPS | Day 28 | 47.0 Pg/ml | Standard Deviation 22.3 |
| Non-drinking Controls | Change in Bacterial Translocation Through Measures of Plasma LPS | Baseline | 58.28 Pg/ml | Standard Deviation 28.8 |
| Non-drinking Controls | Change in Bacterial Translocation Through Measures of Plasma LPS | Day 28 | 19.99 Pg/ml | Standard Deviation 16.93 |
Secondary
Change in Bacterial Translocation Through Measures of Serum sCD14
Time frame: Baseline to 28 days
Population: Due to errors, some results were unable to be processed causing differences in the baseline and day 28.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Bacterial Translocation Through Measures of Serum sCD14 | Baseline | 2.56 µg/ml | Standard Deviation 0.79 |
| Placebo | Change in Bacterial Translocation Through Measures of Serum sCD14 | Day 28 | 2.28 µg/ml | Standard Deviation 0.68 |
| 10 mg Obeticholic Acid (OCA) | Change in Bacterial Translocation Through Measures of Serum sCD14 | Baseline | 3.05 µg/ml | Standard Deviation 0.91 |
| 10 mg Obeticholic Acid (OCA) | Change in Bacterial Translocation Through Measures of Serum sCD14 | Day 28 | 2.28 µg/ml | Standard Deviation 0.57 |
| Non-drinking Controls | Change in Bacterial Translocation Through Measures of Serum sCD14 | Baseline | 2.09 µg/ml | Standard Deviation 0.44 |
| Non-drinking Controls | Change in Bacterial Translocation Through Measures of Serum sCD14 | Day 28 | 1.38 µg/ml | Standard Deviation 0.58 |
Secondary
Change in CYP2E1 Activity by Measuring Chlorzoxazone Clearance
Time frame: Baseline to 28 days
Population: Zero participants were analyzed due to data not being collected
Secondary
Change in Fasting Serum Bile Salt Levels
Time frame: Baseline to 28 days
Population: Zero participants were analyzed due to data not being collected
Secondary
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
Time frame: Baseline to 28 days
Population: Due to errors, some results were unable to be processed causing differences in the baseline and day 28.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Gut Permeability Through Lactulose/Mannitol Test | Baseline | 0.05 lactulose/mannitol ratio | Standard Deviation 0.03 |
| Placebo | Change in Gut Permeability Through Lactulose/Mannitol Test | Day 28 | 0.05 lactulose/mannitol ratio | Standard Deviation 0.03 |
| 10 mg Obeticholic Acid (OCA) | Change in Gut Permeability Through Lactulose/Mannitol Test | Baseline | 0.04 lactulose/mannitol ratio | Standard Deviation 0.01 |
| 10 mg Obeticholic Acid (OCA) | Change in Gut Permeability Through Lactulose/Mannitol Test | Day 28 | 0.07 lactulose/mannitol ratio | Standard Deviation 0.05 |
| Non-drinking Controls | Change in Gut Permeability Through Lactulose/Mannitol Test | Baseline | 0.04 lactulose/mannitol ratio | Standard Deviation 0.02 |
| Non-drinking Controls | Change in Gut Permeability Through Lactulose/Mannitol Test | Day 28 | 0.05 lactulose/mannitol ratio | Standard Deviation 0.05 |
Secondary
Change in Intestinal Inflammation by Measuring Stool Calprotectin
Time frame: Baseline to 28 days
Population: Zero participants were analyzed due to data not being collected
Secondary
Change in Oxidative Stress Level by Measuring Malondialdehyde
Time frame: Baseline to 28 days
Population: Due to errors, some results were unable to be processed causing differences in the baseline and day 28.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Oxidative Stress Level by Measuring Malondialdehyde | Baseline | 2.56 µg/ml | Standard Deviation 0.79 |
| Placebo | Change in Oxidative Stress Level by Measuring Malondialdehyde | Day 28 | 1.54 µg/ml | Standard Deviation 1.77 |
| 10 mg Obeticholic Acid (OCA) | Change in Oxidative Stress Level by Measuring Malondialdehyde | Baseline | 2.79 µg/ml | Standard Deviation 3.44 |
| 10 mg Obeticholic Acid (OCA) | Change in Oxidative Stress Level by Measuring Malondialdehyde | Day 28 | 3.30 µg/ml | Standard Deviation 4.03 |
| Non-drinking Controls | Change in Oxidative Stress Level by Measuring Malondialdehyde | Day 28 | 1.38 µg/ml | Standard Deviation 0.58 |
| Non-drinking Controls | Change in Oxidative Stress Level by Measuring Malondialdehyde | Baseline | 1.03 µg/ml | Standard Deviation 1.46 |