- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02971033
Ezetimibe as a Safe and Efficacious Treatment for Chronic Hepatitis C
May 10, 2022 updated by: VA Office of Research and Development
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.
Study Overview
Status
Terminated
Conditions
Intervention / 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.
Study Type
Interventional
Enrollment (Actual)
2
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
Illinois
-
Hines, Illinois, United States, 60141-5000
- Edward Hines Jr. VA Hospital, Hines, IL
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 70 years (ADULT, OLDER_ADULT)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
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
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: DOUBLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
PLACEBO_COMPARATOR: placebo
|
Participants assigned to this intervention will receive placebo every day for 12 weeks
|
EXPERIMENTAL: 20mg/day ezetimibe
|
Participants assigned to this intervention will receive 20mg per day of ezetimibe for 12 weeks.
Other Names:
|
EXPERIMENTAL: 40mg/day ezetimibe
|
Participants assigned to this intervention will receive 40mg per day of ezetimibe for 12 weeks.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Viral Load
Time Frame: 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).
|
0 weeks, 8 weeks
|
Second Phase Slope
Time Frame: 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.
|
3 days through 4 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Alanine Aminotransferase (ALT)
Time Frame: 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).
|
8 weeks
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Investigators
- Principal Investigator: Susan L. Uprichard, PhD, Edward Hines Jr. VA Hospital, Hines, IL
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (ACTUAL)
April 16, 2018
Primary Completion (ACTUAL)
March 31, 2021
Study Completion (ACTUAL)
March 31, 2021
Study Registration Dates
First Submitted
October 21, 2016
First Submitted That Met QC Criteria
November 18, 2016
First Posted (ESTIMATE)
November 22, 2016
Study Record Updates
Last Update Posted (ACTUAL)
June 6, 2022
Last Update Submitted That Met QC Criteria
May 10, 2022
Last Verified
May 1, 2022
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Digestive System Diseases
- RNA Virus Infections
- Virus Diseases
- Infections
- Blood-Borne Infections
- Communicable Diseases
- Liver Diseases
- Flaviviridae Infections
- Hepatitis, Viral, Human
- Enterovirus Infections
- Picornaviridae Infections
- Hepatitis
- Hepatitis A
- Hepatitis C
- Hepatitis, Chronic
- Hepatitis C, Chronic
- Molecular Mechanisms of Pharmacological Action
- Antimetabolites
- Anticholesteremic Agents
- Hypolipidemic Agents
- Lipid Regulating Agents
- Ezetimibe
Other Study ID Numbers
- INFA-015-16S
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
NO
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Yes
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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