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Ezetimibe as a Safe and Efficacious Treatment for Chronic Hepatitis C

Primary Purpose

Chronic Hepatitis C

Status

Terminated

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

20mg ezetimibe

Placebo

40mg ezetimibe

About this trial

This is an interventional treatment trial for Chronic Hepatitis C focused on measuring hepatitis C virus, antiviral treatment, viral entry inhibitor, mathematical modeling

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Edward Hines Jr. VA Hospital, Hines, IL

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Placebo Comparator

Experimental

Arm Label

placebo

20mg/day ezetimibe

40mg/day ezetimibe

Arm Description

placebo

20mg/day ezetimibe

40mg/day ezetimibe

Outcomes

Primary Outcome Measures

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).

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.

Secondary Outcome Measures

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).

Full Information

NCT ID

NCT02971033

First Posted

October 21, 2016

Last Updated

May 10, 2022

Sponsor

VA Office of Research and Development

1. Study Identification

Unique Protocol Identification Number

NCT02971033

Brief Title

Ezetimibe as a Safe and Efficacious Treatment for Chronic Hepatitis C

Official Title

Ezetimibe as a Safe and Efficacious Treatment for Chronic Hepatitis C

Study Type

Interventional

2. Study Status

Record Verification Date

May 2022

Overall Recruitment Status

Terminated

Why Stopped

Study Funding ended

Study Start Date

April 16, 2018 (Actual)

Primary Completion Date

March 31, 2021 (Actual)

Study Completion Date

March 31, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

VA Office of Research and Development

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Hepatitis C

Keywords

hepatitis C virus, antiviral treatment, viral entry inhibitor, mathematical modeling

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

2 (Actual)

8. Arms, Groups, and Interventions

Arm Title

placebo

Arm Type

Placebo Comparator

Arm Description

placebo

Arm Title

20mg/day ezetimibe

Arm Type

Experimental

Arm Description

20mg/day ezetimibe

Arm Title

40mg/day ezetimibe

Arm Type

Experimental

Arm Description

40mg/day ezetimibe

Intervention Type

Drug

Intervention Name(s)

20mg ezetimibe

Other Intervention Name(s)

20mg Zetia

Intervention Description

Participants assigned to this intervention will receive 20mg per day of ezetimibe for 12 weeks.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Participants assigned to this intervention will receive placebo every day for 12 weeks

Intervention Type

Drug

Intervention Name(s)

40mg ezetimibe

Other Intervention Name(s)

40mg Zetia

Intervention Description

Participants assigned to this intervention will receive 40mg per day of ezetimibe for 12 weeks.

Primary Outcome Measure Information:

Title

Change in Viral Load

Description

Time Frame

0 weeks, 8 weeks

Title

Second Phase Slope

Description

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

Secondary Outcome Measure Information:

Title

Change in Alanine Aminotransferase (ALT)

Description

Time Frame

8 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Susan L. Uprichard, PhD

Organizational Affiliation

Edward Hines Jr. VA Hospital, Hines, IL

Official's Role

Principal Investigator

Facility Information:

Facility Name

Edward Hines Jr. VA Hospital, Hines, IL

City

Hines

State/Province

Illinois

ZIP/Postal Code

60141-5000

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

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Ezetimibe as a Safe and Efficacious Treatment for Chronic Hepatitis C

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