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

Hepatitis C Clinical Trial

— EZE-2  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02768545
• Other study ID #: 12-199b
• Status: Recruiting
• Phase: Phase 4
• First received: May 8, 2016
• Last updated: May 10, 2016
• Start date: June 2013
• Est. completion date: June 2016

Study information

• Verified date: May 2016
• Source: Pontificia Universidad Catolica de Chile
• Contact: Alejandro Soza, MD
• Phone: 56-22-345-3820
• Email: asoza[@]med.puc.cl
• Is FDA regulated: No
• Health authority: Chile: Comisión Nacional de Investigación Científica y Tecnológica
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 12
• Est. completion date: June 2016
• Est. primary completion date: May 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• Ezetimibe
Ezetimibe 10 mg per day before and after transplant

Locations

Country	Name	City	State
Chile	Departamento de Gastroenterología, Pontificia Universidad Católica de Chile	Santiago	RM

Sponsors (1)

Lead Sponsor	Collaborator
Pontificia Universidad Catolica de Chile

Country where clinical trial is conducted

Chile, 

References & Publications (9)

Agnello V, Abel G, Elfahal M, Knight GB, Zhang QX. Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor. Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12766-71. — View Citation

Allain CC, Poon LS, Chan CS, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem. 1974 Apr;20(4):470-5. — View Citation

Beld M, Sentjens R, Rebers S, Weel J, Wertheim-van Dillen P, Sol C, Boom R. Detection and quantitation of hepatitis C virus RNA in feces of chronically infected individuals. J Clin Microbiol. 2000 Sep;38(9):3442-4. — View Citation

Ge L, Wang J, Qi W, Miao HH, Cao J, Qu YX, Li BL, Song BL. The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1. Cell Metab. 2008 Jun;7(6):508-19. doi: 10.1016/j.cmet.2008.04.001. — View Citation

Haruna Y, Kanda T, Honda M, Takao T, Hayashi N. Detection of hepatitis C virus in the bile and bile duct epithelial cells of hepatitis C virus-infected patients. Hepatology. 2001 Apr;33(4):977-80. — View Citation

Jia L, Betters JL, Yu L. Niemann-pick C1-like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport. Annu Rev Physiol. 2011;73:239-59. doi: 10.1146/annurev-physiol-012110-142233. Review. — View Citation

Nielsen SU, Bassendine MF, Burt AD, Martin C, Pumeechockchai W, Toms GL. Association between hepatitis C virus and very-low-density lipoprotein (VLDL)/LDL analyzed in iodixanol density gradients. J Virol. 2006 Mar;80(5):2418-28. — View Citation

Sainz B Jr, Barretto N, Martin DN, Hiraga N, Imamura M, Hussain S, Marsh KA, Yu X, Chayama K, Alrefai WA, Uprichard SL. Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor. Nat Med. 2012 Jan 8;18(2):281-5. doi: 10.1038/nm.2581. — View Citation

Temel RE, Tang W, Ma Y, Rudel LL, Willingham MC, Ioannou YA, Davies JP, Nilsson LM, Yu L. Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetimibe. J Clin Invest. 2007 Jul;117(7):1968-78. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Controlled viral load	Proportion of patients with HCV viral load lower than pre-transplant viral load measured at 4 weeks after liver transplant.	4 weeks after liver transplantation	No
Secondary	Sustained virologic response	Percentage of participants with HCV viral load < 25 IU/mL after 12 weeks of completing treatment.	12 weeks	No