Hepatitis CPhase 4EZE-2NCT02768545
Study of Ezetimibe for Chronic Hepatitis C Virus (HCV) Infection in Liver Transplant Candidates (EZE-2)
A Phase 4 study testing Ezetimibe in people with Hepatitis C, run by Pontificia Universidad Catolica de Chile at 1 site in Chile.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hepatitis C
- What is being tested?
- Ezetimibe
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteChile
- Study dates
- Jun 2013to Jun 2016
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Show all 10Show fewer
- HCV RNA level > 10.000 IU/mL.
- No evidence of sitosterolemia.
- Negative pregnancy test in urine (for females).
- Signed informed consent document.
Who cannot join
- Hepatitis B or HIV co-infection.
Trial locations and contacts
1 site in 1 country.
Chile1 site, 1 recruiting
- Recruiting
Departamento de Gastroenterología, Pontificia Universidad Católica de Chile
Santiago, RM, 833-0024
Alejandro Soza, MD, 56-22-6397780, asoza@med.puc.cl
Hugo Monrroy, MD, 56-22-6397780, hmonrroy@gmail.com
About this study
Official title: Pilot Study of Ezetimibe for Chronic Hepatitis C Virus (HCV) Infection in Liver Transplant Candidates (EZE-2)
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.
Read the 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
- Being tested
- Ezetimibe
- Keywords
- Hepatitis C, Ezetimibe, Cholesterol, Enterohepatic Circulation, Bile, Feces
- Medical subject headings
- Hepatitis C
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EzetimibeDrug
Ezetimibe 10 mg per day before and after transplant
| Study group | Role | What they receive |
|---|---|---|
| Liver transplant candidates | Experimental | Ezetimibe in a dose of 10 mg/d for 12 weeks. Receives: Drug: Ezetimibe |
What is being measured
The primary outcome is the main question the study is designed to answer.
Controlled viral load
Proportion of patients with HCV viral load lower than pre-transplant viral load measured at 4 weeks after liver transplant.
Measured: 4 weeks after liver transplantation
Secondary outcomes (1)
Sustained virologic response
Percentage of participants with HCV viral load < 25 IU/mL after 12 weeks of completing treatment.
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 May 2016 (estimated)
- Study startJun 2013
- Primary completionMay 2016
- Study completionJun 2016 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (9)Papers the sponsor has linked to this study.
- Other trials for Hepatitis CStudies of the same condition, open and under way.
- More trials run by Pontificia Universidad Catolica de ChileThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 12 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Pontificia Universidad Catolica de Chile
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Alejandro Soza, MD, Pontificia Universidad Catolica de Chile
- Investigators
- Alejandro Soza, MD, Principal investigator, Pontificia Universidad Catolica de Chile
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02768545
- Sponsor's protocol ID
- 12-199b
- Acronym
- EZE-2
- Status last verified
- May 2016
- First submitted
- 8 May 2016
- Last updated
- 11 May 2016
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
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. doi: 10.1073/pnas.96.22.12766.
PubMed 10535997Allain CC, Poon LS, Chan CS, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem. 1974 Apr;20(4):470-5. No abstract available.
PubMed 4818200Beld 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. doi: 10.1128/JCM.38.9.3442-3444.2000.
PubMed 10970398Ge 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.
PubMed 18522832Haruna 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. doi: 10.1053/jhep.2001.23435.
PubMed 11283863Jia 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.
PubMed 20809793Nielsen 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. doi: 10.1128/JVI.80.5.2418-2428.2006.
PubMed 16474148Sainz 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.
PubMed 22231557Temel 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. doi: 10.1172/JCI30060.
PubMed 17571164
Study at a glance
From the registry record, last updated by the sponsor on 11 May 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot Study of Ezetimibe for Chronic Hepatitis C Virus (HCV) Infection in Liver Transplant Candidates (EZE-2)
- ClinicalTrials.gov ID
- NCT02768545
- Acronym / sponsor ID
- EZE-2 / 12-199b
- Conditions
- Hepatitis C
- Keywords
- Hepatitis C, Ezetimibe, Cholesterol, Enterohepatic Circulation, Bile, Feces
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 12 participants (estimated)
- Lead sponsor
- Pontificia Universidad Catolica de ChileUniversity, hospital or other
- Study start
- Jun 2013
- Primary completion
- May 2016 (actual)
- Study completion
- Jun 2016 (estimated)
- First posted
- 11 May 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Liver transplant candidates | Experimental | Drug: EzetimibeEzetimibe in a dose of 10 mg/d for 12 weeks. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- 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.
Key exclusion criteria (1 listed)
- Hepatitis B or HIV co-infection.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EzetimibeEzetimibe 10 mg per day before and after transplant | Drug | Liver transplant candidates |
Primary outcome
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.
1 secondary outcome
Sustained virologic response
Time frame: 12 weeks
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 May 2016.
- Background: PubMed 10535997Agnello 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. doi: 10.1073/pnas.96.22.12766.
- Background: PubMed 4818200Allain CC, Poon LS, Chan CS, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem. 1974 Apr;20(4):470-5. No abstract available.
- Background: PubMed 10970398Beld 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. doi: 10.1128/JCM.38.9.3442-3444.2000.
- Background: PubMed 18522832Ge 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.
- Background: PubMed 11283863Haruna 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. doi: 10.1053/jhep.2001.23435.
- Background: PubMed 20809793Jia 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.
- Background: PubMed 16474148Nielsen 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. doi: 10.1128/JVI.80.5.2418-2428.2006.
- Background: PubMed 22231557Sainz 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.
- Background: PubMed 17571164Temel 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. doi: 10.1172/JCI30060.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alejandro Soza, MD principal investigator
Pontificia Universidad Catolica de Chile
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Ezetimibe in people with Hepatitis C, run by Pontificia Universidad Catolica de Chile at 1 site in Chile.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 11 May 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Chile. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Alejandro Soza, MD (56-22-345-3820, asoza@med.puc.cl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Controlled viral load (time frame: 4 weeks after liver transplantation). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02768545, which also lists 9 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 May 2016.