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

NCT ID: NCT02768545

Last Updated: 2016-05-11

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-06-30
• Study Completion Date: 2016-06-30

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.

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.

Conditions

Hepatitis C

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Liver transplant candidates

Ezetimibe in a dose of 10 mg/d for 12 weeks.

Group Type: EXPERIMENTAL

Ezetimibe

Intervention Type: DRUG

Ezetimibe 10 mg per day before and after transplant

Interventions

Ezetimibe

Ezetimibe 10 mg per day before and after transplant

Intervention Type: DRUG

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pontificia Universidad Catolica de Chile

OTHER

Sponsor Role: lead

Responsible Party

Alejandro Soza, MD

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Alejandro Soza, MD

Role: PRINCIPAL_INVESTIGATOR

Pontificia Universidad Catolica de Chile

Locations

Departamento de Gastroenterología, Pontificia Universidad Católica de Chile

Santiago, RM, Chile

Site Status: RECRUITING

Countries

Chile

Central Contacts

Alejandro Soza, MD

Role: CONTACT

asoza@med.puc.cl

56-22-345-3820

Hugo Monrroy, MD

Role: CONTACT

hmonrroy@med.puc.cl

56-22-345-3820

Facility Contacts

Alejandro Soza, MD

Role: primary

asoza@med.puc.cl

56-22-6397780

Hugo Monrroy, MD

Role: backup

hmonrroy@gmail.com

56-22-6397780

References

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Reference Type: BACKGROUND

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Other Identifiers

12-199b

Identifier Type: -

Identifier Source: org_study_id