Ezetimibe as a Safe and Efficacious Treatment for Chronic Hepatitis C
| Status: | Recruiting |
|---|---|
| Conditions: | Hepatitis, Hepatitis, Hepatitis |
| Therapuetic Areas: | Immunology / Infectious Diseases |
| Healthy: | No |
| Age Range: | 18 - 70 |
| Updated: | 11/18/2018 |
| Start Date: | April 16, 2018 |
| End Date: | June 30, 2020 |
| Contact: | Susan L Uprichard, PhD |
| Email: | Susan.Uprichard@va.gov |
| Phone: | (708) 202-8387 |
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.
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.
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.
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.
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
We found this trial at
1
site
Hines, Illinois 60141
Principal Investigator: Susan L. Uprichard, PhD
Phone: 708-202-8387
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