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Study of Ezetimibe for Chronic Hepatitis C Virus (HCV) Infection in Liver Transplant Candidates (EZE-2) (EZE-2)

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ClinicalTrials.gov Identifier: NCT02768545
Recruitment Status : Unknown
Verified May 2016 by Alejandro Soza, MD, Pontificia Universidad Catolica de Chile.
Recruitment status was:  Recruiting
First Posted : May 11, 2016
Last Update Posted : May 11, 2016
Sponsor:
Information provided by (Responsible Party):
Alejandro Soza, MD, Pontificia Universidad Catolica de Chile

Brief Summary:
NPC1L1 is a key transporter in the enterohepatic cycle of cholesterol. Initial in vitro and in vivo data show that blocking this receptor with ezetimibe results in delaying infection in these models. The investigators hypothesize that HCV has an enterohepatic cycle, being secreted in bile and reabsorbed either in the canalicular membrane or in the intestine by association with NPC1L1, following a path similar to the cycle of cholesterol in humans. To prove this hypothesis the investigators propose to assess the effect of ezetimibe treatment in HCV infected individuals undergoing liver transplantation to avoid or delay HCV infection. For this purpose, the investigators propose to administrate ezetimibe 10 mg/d for 12 weeks to 12 patients with chronic hepatitis C infection listed for a liver transplantation.

Condition or disease Intervention/treatment Phase
Hepatitis C Drug: Ezetimibe Phase 4

Detailed Description:

Infection by hepatitis C virus (HCV) affects more than 170 million people in the World and 80.000 in Chile. It causes more deaths than HIV infection in the US and is a leading cause of liver transplantation in Chile. Even though treatments are evolving with new direct antiviral agents (DAAs) with increasing response rates, there are several issues with these new approaches, including toxicity, need for using interferon and ribavirin, complex algorithms of treatment, high cost, limited effectivity in certain groups (liver transplant patients) and drug interactions. Treatments targeted at host factors required for the viral cycle are becoming increasingly explored as an alternative or complement to DAAs. HCV has a very intimate connection with host lipidic pathways, altering the lipid profile, circulating bound to lipoproteins and using cholesterol receptors and intracellular mechanisms of fat metabolism. It has been recently described that NPC1L1 (Niemann-Pick C1-like 1), the intestinal receptor of cholesterol, serves as an entry factor for HCV. Interestingly, this receptor is not only expressed in the enterocytes (absorbing both endogenous and dietary cholesterol), but also in the canalicular membrane of the hepatocyte, where it functions absorbing cholesterol secreted into the canalicular lumen. NPC1L1 is, therefore, a key transporter in the enterohepatic cycle of cholesterol. Initial in-vitro and in-vivo data show that blocking this receptor with ezetimibe results in delaying infection in these models. Moreover, it has reported the case of a patient that after 3 unsuccessful treatment attempts, cleared HCV RNA with ezetimibe treatment, being the first report of the effect of ezetimibe in humans. In view of these observations, the investigators hypothesize that HCV has an enterohepatic cycle, being secreted in bile and reabsorbed either in the canalicular membrane or in the intestine by association with NPC1L1, following a path similar to the cycle of cholesterol in humans.

This possibility is further supported by the observation that HCV RNA has been detected in bile and feces of infected humans. To prove this hypothesis, the investigators propose to assess the effect of ezetimibe treatment in HCV-infected individuals. Ezetimibe is an approved and generally safe drug used for the management of hypercholesterolemia. HCV RNA and core antigen in plasma and feces will be assessed. An increase in bile or fecal HCV load after antagonizing NPC1L1 with ezetimibe will support the notion that HCV is reabsorbed in the canalicular membrane or at the intestinal level. The second part of the proposed study will be conducted in 12 patients who have chronic hepatitis C and are listed for a liver transplantation. Graft reinfection after liver transplant is universal. Here the investigators anticipate that the use of ezetimibe will directly impact on the reinfection time of the graft, by delaying or even preventing liver reinfection in some patients. Should this study be successful it will for sure have enormous implications for the design of novel management strategies for liver transplant patients.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Study of Ezetimibe for Chronic Hepatitis C Virus (HCV) Infection in Liver Transplant Candidates (EZE-2)
Study Start Date : June 2013
Actual Primary Completion Date : May 2016
Estimated Study Completion Date : June 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Ezetimibe

Arm Intervention/treatment
Experimental: Liver transplant candidates
Ezetimibe in a dose of 10 mg/d for 12 weeks.
Drug: Ezetimibe
Ezetimibe 10 mg per day before and after transplant




Primary Outcome Measures :
  1. Controlled viral load [ Time Frame: 4 weeks after liver transplantation ]
    Proportion of patients with HCV viral load lower than pre-transplant viral load measured at 4 weeks after liver transplant.


Secondary Outcome Measures :
  1. Sustained virologic response [ Time Frame: 12 weeks ]
    Percentage of participants with HCV viral load < 25 IU/mL after 12 weeks of completing treatment.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Chronic hepatitis C defined as detectable HCV RNA for more than 6 months.
  • Age > 18 years old.
  • No current HCV antiviral treatment.
  • No medications for dyslipidemia in the preceding 2 months.
  • Listed in the national waiting list for liver transplant with an estimated time to transplantation of 3 months or less, either for complications of cirrhosis or for hepatocellular carcinoma.
  • No abdominal surgery that could alter biliary or intestinal anatomy.
  • HCV RNA level > 10.000 IU/mL.
  • No evidence of sitosterolemia.
  • Negative pregnancy test in urine (for females).
  • Signed informed consent document.

Exclusion Criteria:

  • Hepatitis B or HIV co-infection.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02768545


Contacts
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Contact: Alejandro Soza, MD 56-22-345-3820 asoza@med.puc.cl
Contact: Hugo Monrroy, MD 56-22-345-3820 hmonrroy@med.puc.cl

Locations
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Chile
Departamento de Gastroenterología, Pontificia Universidad Católica de Chile Recruiting
Santiago, RM, Chile, 833-0024
Contact: Alejandro Soza, MD    56-22-6397780    asoza@med.puc.cl   
Contact: Hugo Monrroy, MD    56-22-6397780    hmonrroy@gmail.com   
Sponsors and Collaborators
Pontificia Universidad Catolica de Chile
Investigators
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Principal Investigator: Alejandro Soza, MD Pontificia Universidad Catolica de Chile

Publications:

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Responsible Party: Alejandro Soza, MD, Associate Professor, Pontificia Universidad Catolica de Chile
ClinicalTrials.gov Identifier: NCT02768545     History of Changes
Other Study ID Numbers: 12-199b
First Posted: May 11, 2016    Key Record Dates
Last Update Posted: May 11, 2016
Last Verified: May 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Alejandro Soza, MD, Pontificia Universidad Catolica de Chile:
Hepatitis C
Ezetimibe
Cholesterol
Enterohepatic Circulation
Bile
Feces
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis C
Hepatitis C, Chronic
Hepatitis
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Hepatitis, Chronic
Ezetimibe
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents