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Ezetimibe as a Safe and Efficacious Treatment for Chronic Hepatitis C

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ClinicalTrials.gov Identifier: NCT02971033
Recruitment Status : Recruiting
First Posted : November 22, 2016
Last Update Posted : October 22, 2020
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

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.

Condition or disease Intervention/treatment Phase
Chronic Hepatitis C Drug: 20mg ezetimibe Drug: Placebo Drug: 40mg ezetimibe Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 95 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Ezetimibe as a Safe and Efficacious Treatment for Chronic Hepatitis C
Actual Study Start Date : April 16, 2018
Estimated Primary Completion Date : March 31, 2021
Estimated Study Completion Date : March 31, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Ezetimibe

Arm Intervention/treatment
Placebo Comparator: placebo
placebo
Drug: Placebo
Participants assigned to this intervention will receive placebo every day for 12 weeks

Experimental: 20mg/day ezetimibe
20mg/day ezetimibe
Drug: 20mg ezetimibe
Participants assigned to this intervention will receive 20mg per day of ezetimibe for 12 weeks.
Other Name: 20mg Zetia

Experimental: 40mg/day exetimibe
40mg/day ezetimibe
Drug: 40mg ezetimibe
Participants assigned to this intervention will receive 40mg per day of ezetimibe for 12 weeks.
Other Name: 40mg Zetia




Primary Outcome Measures :
  1. Change in viral decline [ Time Frame: 12 weeks ]
    Participants will have their HCV-RNA measured in copies per milliliter at baseline and 12 weeks. HCV-RNA in copies per milliliter ranges from 0 to infinity, with higher levels indicating HCV positivity. The change in copies 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).


Secondary Outcome Measures :
  1. Change in alanine aminotransferase (ALT) [ Time Frame: 12 weeks ]
    Participants will have their ALT levels measured in units per liter (U/L) at baseline and 12 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).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02971033


Contacts
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Contact: Susan L Uprichard, PhD (708) 202-8387 ext 25848 Susan.Uprichard@va.gov

Locations
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United States, Illinois
Edward Hines Jr. VA Hospital, Hines, IL Recruiting
Hines, Illinois, United States, 60141-5000
Contact: Susan L Uprichard, PhD    708-202-8387 ext 25848    Susan.Uprichard@va.gov   
Principal Investigator: Susan L. Uprichard, PhD         
Sponsors and Collaborators
VA Office of Research and Development
Investigators
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Principal Investigator: Susan L. Uprichard, PhD Edward Hines Jr. VA Hospital, Hines, IL
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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT02971033    
Other Study ID Numbers: INFA-015-16S
First Posted: November 22, 2016    Key Record Dates
Last Update Posted: October 22, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by VA Office of Research and Development:
hepatitis C virus
antiviral treatment
viral entry inhibitor
mathematical modeling
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis C
Hepatitis C, Chronic
Hepatitis
Hepatitis, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Ezetimibe
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents