Ezetimibe as a Safe and Efficacious Treatment for Chronic Hepatitis C

Study Overview
=================
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.

Official Title
-----------------
Ezetimibe as a Safe and Efficacious Treatment for Chronic Hepatitis C

Conditions
-----------------
Chronic Hepatitis C

Intervention / Treatment
-----------------
* Drug: 20mg ezetimibe
* Drug: Placebo
* Drug: 40mg ezetimibe


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br>placebo | Drug: Placebo<br>* Participants assigned to this intervention will receive placebo every day for 12 weeks<br>|
| Experimental: 20mg/day ezetimibe<br>20mg/day ezetimibe | Drug: 20mg ezetimibe<br>* Participants assigned to this intervention will receive 20mg per day of ezetimibe for 12 weeks.<br>* Other names: 20mg Zetia;|
| Experimental: 40mg/day ezetimibe<br>40mg/day ezetimibe | Drug: 40mg ezetimibe<br>* Participants assigned to this intervention will receive 40mg per day of ezetimibe for 12 weeks.<br>* Other names: 40mg Zetia;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 0 weeks, 8 weeks | 
| 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. | 3 days through 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 8 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hepatitis C virus, antiviral treatment, viral entry inhibitor, mathematical modeling