Ezetimibe as a Safe and Efficacious Treatment for Chronic Hepatitis C

NCT02971033 | Terminated Phase 2 Results FDA Drug

• 1 other identifier: INFA-015-16S
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

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.

Conditions

Chronic Hepatitis C

Keywords

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

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (1)

• Change in Alanine Aminotransferase (ALT)

  8 weeks

Study Arms (3)

placebo

PLACEBO COMPARATOR

placebo

Drug: Placebo

20mg/day ezetimibe

EXPERIMENTAL

20mg/day ezetimibe

Drug: 20mg ezetimibe

40mg/day ezetimibe

EXPERIMENTAL

40mg/day ezetimibe

Drug: 40mg ezetimibe

Interventions

20mg ezetimibe DRUG

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

Also known as: 20mg Zetia

20mg/day ezetimibe

Placebo DRUG

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

placebo

40mg ezetimibe DRUG

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

Also known as: 40mg Zetia

40mg/day ezetimibe

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (1)

Edward Hines Jr. VA Hospital, Hines, IL

Hines, Illinois, 60141-5000, United States

Location

MeSH Terms

Conditions

Hepatitis C, Chronic; Hepatitis C

Interventions

Ezetimibe

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Azetidines; Azetines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

1. 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. 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.

Results Point of Contact

• Title: Susan L. Uprichard
• Organization: Edward Hines Jr. Veterans Administration Hospital

susan.uprichard@va.gov

(336) 402-1086

Study Officials

• Susan L. Uprichard, PhD

  Edward Hines Jr. VA Hospital, Hines, IL

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 21, 2016
• First Posted: November 22, 2016
• Study Start: April 16, 2018
• Primary Completion: March 31, 2021
• Study Completion: March 31, 2021
• Last Updated: June 6, 2022
• Results First Posted: June 6, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)