Ezetimibe as a Safe and Efficacious Treatment for Chronic Hepatitis C

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Terminated
• CT.gov ID: NCT02971033
• Collaborator: (none)
• Enrollment: 2
• Location: 1
• Arms: 3
• Actual Duration (Months): 35.5
• Patients Per Site Per Month: 0.1

Study Details

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.

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 2 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: Apr 16, 2018
• Actual Primary Completion Date: Mar 31, 2021
• Actual Study Completion Date: Mar 31, 2021

Arms and Interventions

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 Names: 20mg Zetia
Experimental: 40mg/day ezetimibe 40mg/day ezetimibe	Drug: 40mg ezetimibe; Participants assigned to this intervention will receive 40mg per day of ezetimibe for 12 weeks.; Other Names: 40mg Zetia

Outcome Measures

Primary Outcome Measures

1. 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).

2. 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 Outcome Measures

1. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Edward Hines Jr. VA Hospital, Hines, IL	Hines	Illinois	United States	60141-5000

Sponsors and Collaborators

• VA Office of Research and Development

Investigators

• Principal Investigator: Susan L. Uprichard, PhD, Edward Hines Jr. VA Hospital, Hines, IL

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 30, 2022

More Information

Publications

None provided.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT02971033
• Other Study ID Numbers: INFA-015-16S
• First Posted: Nov 22, 2016
• Last Update Posted: Jun 6, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Hepatitis, Chronic; Ezetimibe

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	Placebo	20mg/Day Ezetimibe	40mg/Day Ezetimibe
Arm/Group Description	placebo Placebo: Participants assigned to this intervention will receive placebo every day for 8 weeks	20mg/day ezetimibe 20mg ezetimibe: Participants assigned to this intervention will receive 20mg per day of ezetimibe for 8 weeks.	40mg/day ezetimibe 40mg ezetimibe: Participants assigned to this intervention will receive 40mg per day of ezetimibe for 8 weeks.
Period Title: Overall Study
STARTED	1	1	0
COMPLETED	1	1	0
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Placebo	20mg/Day Ezetimibe	40mg/Day Ezetimibe	Total
Arm/Group Description	placebo Placebo: Participants assigned to this intervention will receive placebo every day for 8 weeks	20mg/day ezetimibe 20mg ezetimibe: Participants assigned to this intervention will receive 20mg per day of ezetimibe for 8 weeks.	40mg/day ezetimibe 40mg ezetimibe: Participants assigned to this intervention will receive 40mg per day of ezetimibe for 8 weeks.	Total of all reporting groups
Overall Participants	1	1	0	2
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 NaN	0 0%
Between 18 and 65 years	1 100%	1 100%	0 NaN	2 100%
>=65 years	0 0%	0 0%	0 NaN	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 NaN	0 0%
Male	1 100%	1 100%	0 NaN	2 100%
Race/Ethnicity, Customized (Count of Participants)
non-hispanic White	0 0%	1 100%	0 NaN	1 50%
non-hispanic Black	1 100%	0 0%	0 NaN	1 50%
Region of Enrollment (Count of Participants)
United States	1 100%	1 100%	0 NaN	2 100%
HCV RNA (International Units per mL) [Mean (Full Range) ]
Mean (Full Range) [International Units per mL]	4030000	5860000	4945000
alanine transaminase (ALT) (Units/Liter) [Mean (Full Range) ]
Mean (Full Range) [Units/Liter]	109	105	107

Outcome Measures

1. Primary Outcome

Title	Change in Viral Load
Description	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

Outcome Measure Data

Analysis Population Description

Participants who were enrolled, were not randomized until they received their study medication. No one was randomized to the 40mg/day arm

Arm/Group Title	Placebo	20mg/Day Ezetimibe	40mg/Day Ezetimibe
Arm/Group Description	placebo Placebo: Participants assigned to this intervention will receive placebo every day for 8 weeks	20mg/day ezetimibe 20mg ezetimibe: Participants assigned to this intervention will receive 20mg per day of ezetimibe for 8 weeks.	40mg/day ezetimibe 40mg ezetimibe: Participants assigned to this intervention will receive 40mg per day of ezetimibe for 8 weeks.
Measure Participants	1	1	0
Mean (Full Range) [international units per milliliter]	-4030000	-5860000

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants who were enrolled, were not randomized until they received their study medication. No one was randomized to the 40mg/day arm

Arm/Group Title	Placebo	20mg/Day Ezetimibe	40mg/Day Ezetimibe
Arm/Group Description	placebo Placebo: Participants assigned to this intervention will receive placebo every day for 8 weeks	20mg/day ezetimibe 20mg ezetimibe: Participants assigned to this intervention will receive 20mg per day of ezetimibe for 8 weeks.	40mg/day ezetimibe 40mg ezetimibe: Participants assigned to this intervention will receive 40mg per day of ezetimibe for 8 weeks.
Measure Participants	1	1	0
Mean (Full Range) [log(copies/mL)/day]	.90	.98

3. Secondary Outcome

Title	Change in Alanine Aminotransferase (ALT)
Description	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

Outcome Measure Data

Analysis Population Description

Participants who were enrolled, were not randomized until they received their study medication. No one was randomized to the 40mg/day arm

Arm/Group Title	Placebo	20mg/Day Ezetimibe	40mg/Day Ezetimibe
Arm/Group Description	placebo Placebo: Participants assigned to this intervention will receive placebo every day for 8 weeks	20mg/day ezetimibe 20mg ezetimibe: Participants assigned to this intervention will receive 20mg per day of ezetimibe for 8 weeks.	40mg/day ezetimibe 40mg ezetimibe: Participants assigned to this intervention will receive 40mg per day of ezetimibe for 8 weeks.
Measure Participants	1	1	0
Mean (Full Range) [units per Liter]	-75	-73

Adverse Events

Time Frame	12 weeks
Adverse Event Reporting Description	there were no patients randomized to the 40mg/day ezetimibe arm
Arm/Group Title	Placebo		20mg/Day Ezetimibe		40mg/Day Ezetimibe
Arm/Group Description	placebo Placebo: Participants assigned to this intervention will receive placebo every day for 8 weeks		20mg/day ezetimibe 20mg ezetimibe: Participants assigned to this intervention will receive 20mg per day of ezetimibe for 8 weeks.		40mg/day ezetimibe 40mg ezetimibe: Participants assigned to this intervention will receive 40mg per day of ezetimibe for 8 weeks.
All Cause Mortality
	Placebo		20mg/Day Ezetimibe		40mg/Day Ezetimibe
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/1 (0%)		0/0 (NaN)
Serious Adverse Events
	Placebo		20mg/Day Ezetimibe		40mg/Day Ezetimibe
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/1 (0%)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Placebo		20mg/Day Ezetimibe		40mg/Day Ezetimibe
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/1 (0%)		0/0 (NaN)

Limitations/Caveats

A major limitation is that the study was that it was interrupted by the CoVID-19 pandemic and then was terminated early leading to small numbers of subjects analyzed. It is not possible to derive conclusions comparing the single patients enrolled in arms 1 and 2. The patient in arm 2 had study medication remaining at the first pill count indicating that EZE dosing was lower than 20mg/day during at least part of the treatment period.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.