Chronic Hepatitis C
Conditions
Keywords
hepatitis C virus, antiviral treatment, viral entry inhibitor, mathematical modeling
Brief summary
To address the need for more affordable hepatitis C virus (HCV) antivirals with high barriers to viral resistance and strategies to shorten the current treatment duration, the goal is to develop affordable therapeutic regimens to prevent HCV entry/spread and test the efficacy of those inhibitors for treating HCV infection. The investigators recently discovered that a major cholesterol uptake receptor is required for HCV entry into hepatocytes and that there is already an FDA-approved drug that inhibits cholesterol uptake by this receptor. Importantly the same drug also potently blocks HCV entry in human liver cells both in cell culture and in a small animal model. Further, looking back at people who were previously treated for HCV infection, the investigators found treatment response to be better (i.e. larger viral log reduction) in patients who happened to be taking ezetimibe (EZE). Hence, the objective of this study is to assess whether the FDA-approved drug (ezetimibe) is useful for the treatment of chronic HCV. The investigators predict that when administered as monotherapy ezetimibe will reduce HCV viremia perhaps allowing for viral clearance and that when included in combination treatment regimens that EZE will increase HCV decline resulting in faster viral clearance (i.e. shorter/cheaper direct-acting antiviral \[DAA\] therapy). To test these hypotheses, the investigators will execute the following aims: (1) Assess the efficacy of EZE monotherapy in chronically HCV infected and predict time to cure; (2) Assess the efficacy of EZE as an adjunct therapy in chronically HCV infected patients undergoing currently approved HCV DAA treatment.
Detailed description
To address the need for more affordable HCV antivirals with high barriers to viral resistance and/or strategies to shorten the current treatment duration, the goal is to develop affordable therapeutic regimens to prevent HCV entry/spread and test the efficacy of those inhibitors for treating HCV infection. The investigators recently discovered that the Niemann-Pick C1 Like-1 (NPC1L1) cellular cholesterol uptake receptor is required for HCV entry into hepatocytes and that ezetimibe, an FDA-approved drug that inhibits NPC1L1-mediated cholesterol uptake potently blocks HCV entry in human hepatoma cells and human hepatocytes transplanted into urokinase-type plasminogen activator-severe combined immunodeficiency (uPA-SCID) mice. Further, retrospective analysis of the National VA database using multivariable logistic regression models to control for age, sex, race, alcohol use, drug use, and other co-morbidities, the investigators found HCV prevalence to be lower (p \<.001) and interferon/ribavirin (IFN/RBV) treatment response to be better (i.e. larger viral log reduction) in patients taking ezetimibe. Hence, the specific objective of this application is to assess the efficacy of EZE for the treatment of chronic HCV. Based on preliminary in vitro, in vivo, clinical retrospective data and HCV/DAA modeling, the investigators hypothesize that when administered as monotherapy EZE will reduce HCV viremia perhaps allowing for viral clearance and that when included in combination treatment regimens that EZE will augment 2nd phase HCV decline resulting in faster viral clearance (i.e. shorter/cheaper DAA therapy). To test these hypotheses, the investigators will execute the following aims: (1) Assess the efficacy of EZE monotherapy in chronically HCV infected and predict time to cure; (2) Assess the efficacy of EZE as an adjunct therapy in chronically HCV infected patients undergoing currently approved HCV DAA treatment.
Interventions
DRUG20mg ezetimibe
Participants assigned to this intervention will receive 20mg per day of ezetimibe for 12 weeks.
DRUGPlacebo
Participants assigned to this intervention will receive placebo every day for 12 weeks
DRUG40mg ezetimibe
Participants assigned to this intervention will receive 40mg per day of ezetimibe for 12 weeks.
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Males/females 18 - 70 yrs of age * Serum HCV RNA \>2,000 IU/ml * Hepatitis C genotype 1 * Other causes of chronic liver disease excluded by appropriate clinical, laboratory, or histologic evaluation * The following hematological criteria must be met: * Hemoglobin \> 12 g/dl * Absolute neutrophil count (ANC) \> 1.0x109 /L * Platelets 150 x 108 /L (i.e normal) * Serum creatinine \<1.5 times the upper limit of normal (ULN) at screening. * Fasting blood sugar normal for non-diabetics or hemoglobin A1C \< 8.5% with diabetes * Women of childbearing potential must have a negative pregnancy test prior to receiving treatment. Sexually active women must take adequate precautions to prevent pregnancy during the study. Pregnancy tests will be done at the final clinic visits and every 4 weeks * Patient provides written informed consent
Exclusion criteria
* Evidence of liver disease other than HCV: * Antinuclear antibodies (ANA) \>1:160 * Active alcoholic liver disease. * Hepatitis B surface antigen positive * Hemochromatosis * Wilson disease * Alpha-1-antitrypsin deficiency * Recent hepatotoxic drug exposure * Cirrhosis with complications of portal hypertension including esophageal varices (\> grade 1 by endoscopy), ascites, or hepatic encephalopathy, or bilirubin \>2.0 mg/dl * Patients with advanced fibrosis (defined herein as decompensated cirrhosis, FIB4 \> 2.5, platelet count \<150 x 103/uL, clinical or radiographic evidence of cirrhosis) * Extrahepatic manifestations of liver disease or HIV co-infection * Use of fibric acid, Fenofibrate or cholestyramine * Active substance abuse including, but not limited to alcohol or i.v./inhaled drugs * Use of chemotherapy or systemic steroid therapy within 30 days prior to enrollment * Pregnancy, females who are breast feeding, or females of child bearing potential who are not using adequate birth control measures * History of a medical condition that could interfere with participation or completion of the protocol * Organ transplant recipient * History of hypersensitivity to ezetimibe
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Viral Load | 0 weeks, 8 weeks | Participants will have their HCV-RNA measured in international unit per milliliter at baseline and 8 weeks. HCV RNA international unit per milliliter ranges from 0 to infinity, with higher levels indicating HCV positivity. The change in international unit per milliliter will be compared among the three intervention groups (i.e., placebo or control cohort, those assigned to 20mg ezetimibe per day, and 40mg ezetimibe per day). Change is calculated based on 8 weeks minus baseline (0 weeks). |
| Second Phase Slope | 3 days through 4 weeks | HCV declines in a biphasic manner under HCV treatment. Here we are measuring the slope (i.e., rate) at which HCV is declining during the second slower phase of viral decline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Alanine Aminotransferase (ALT) | 8 weeks | Participants will have their ALT levels measured in units per liter (U/L) at baseline and 8 weeks. ALT ranges from 0 to infinity with higher levels of ALT indicating hepatocyte death. The change in ALT levels will be compared among the three intervention groups (i.e., placebo or control cohort, those assigned to 20mg ezetimibe per day, and 40mg ezetimibe per day). |
Countries
United States
Participant flow
Pre-assignment details
Patients are enrolled, but then are not randomized until they pick up clinical and study medication with the investigational pharmacist at a subsequent visit. As such, one can be enrolled but never randomized if they patient does not return for the medication.
Participants by arm
| Arm | Count |
|---|---|
| Placebo placebo
Placebo: Participants assigned to this intervention will receive placebo every day for 8 weeks | 1 |
| 20mg/Day Ezetimibe 20mg/day ezetimibe
20mg ezetimibe: Participants assigned to this intervention will receive 20mg per day of ezetimibe for 8 weeks. | 1 |
| 40mg/Day Ezetimibe 40mg/day ezetimibe
40mg ezetimibe: Participants assigned to this intervention will receive 40mg per day of ezetimibe for 8 weeks. | 0 |
| Total | 2 |
Baseline characteristics
| Characteristic | Placebo | 20mg/Day Ezetimibe | 40mg/Day Ezetimibe | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| alanine transaminase (ALT) | 109 Units/Liter | 105 Units/Liter | — | 107 Units/Liter |
| HCV RNA | 4030000 International Units per mL | 5860000 International Units per mL | — | 4945000 International Units per mL |
| Race/Ethnicity, Customized non-hispanic Black | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized non-hispanic White | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 | 0 / 0 |
| other Total, other adverse events | 0 / 1 | 0 / 1 | 0 / 0 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 | 0 / 0 |
Outcome results
Primary
Change in Viral Load
Participants will have their HCV-RNA measured in international unit per milliliter at baseline and 8 weeks. HCV RNA international unit per milliliter ranges from 0 to infinity, with higher levels indicating HCV positivity. The change in international unit per milliliter will be compared among the three intervention groups (i.e., placebo or control cohort, those assigned to 20mg ezetimibe per day, and 40mg ezetimibe per day). Change is calculated based on 8 weeks minus baseline (0 weeks).
Time frame: 0 weeks, 8 weeks
Population: Participants who were enrolled, were not randomized until they received their study medication. No one was randomized to the 40mg/day arm
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change in Viral Load | -4030000 international units per milliliter |
| 20mg/Day Ezetimibe | Change in Viral Load | -5860000 international units per milliliter |
Primary
Second Phase Slope
HCV declines in a biphasic manner under HCV treatment. Here we are measuring the slope (i.e., rate) at which HCV is declining during the second slower phase of viral decline.
Time frame: 3 days through 4 weeks
Population: Participants who were enrolled, were not randomized until they received their study medication. No one was randomized to the 40mg/day arm
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Second Phase Slope | .90 log(copies/mL)/day |
| 20mg/Day Ezetimibe | Second Phase Slope | .98 log(copies/mL)/day |
Secondary
Change in Alanine Aminotransferase (ALT)
Participants will have their ALT levels measured in units per liter (U/L) at baseline and 8 weeks. ALT ranges from 0 to infinity with higher levels of ALT indicating hepatocyte death. The change in ALT levels will be compared among the three intervention groups (i.e., placebo or control cohort, those assigned to 20mg ezetimibe per day, and 40mg ezetimibe per day).
Time frame: 8 weeks
Population: Participants who were enrolled, were not randomized until they received their study medication. No one was randomized to the 40mg/day arm
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change in Alanine Aminotransferase (ALT) | -75 units per Liter |
| 20mg/Day Ezetimibe | Change in Alanine Aminotransferase (ALT) | -73 units per Liter |