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Role of Heme Oxygenase in the Pathogenesis of Hepatocellular Injury in Chronic Hepatitis C Virus (HCV) Infection

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ClinicalTrials.gov Identifier: NCT00842205
Recruitment Status : Unknown
Verified February 2009 by Charles University, Czech Republic.
Recruitment status was:  Recruiting
First Posted : February 12, 2009
Last Update Posted : February 12, 2009
Sponsor:
Collaborator:
IGA MZ, Czech Republic
Information provided by:
Charles University, Czech Republic

Study Description
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Brief Summary:
In the presented project, the role of heme oxygenase 1 and 2 in the procesess associated with fibroproduction in the chronic HCV infection will be studied. Heme oxygenase expression will be evaluated by the techniques of molecular genetics and immunohistochemistry, both in the liver tissue and in peripheral blood mononuclear cells. These parameters will be correlated with basic virological and clinical characteristics of the chronic HCV infection. The investigators' expected results may help in understanding the mechanisms of fibroproduction in chronic HVC infection and, therefore, contribute to explain individual differences in the development of chronic HCV infection.

Condition or disease Intervention/treatment Phase
Chronic HCV Infection Nonalcoholic Steatohepatitis Drug: pegylated interferon Drug: Ribavarin Not Applicable

Detailed Description:
Hepatitis C virus (HCV) is a single stranded positive RNA virus belonging to the Flaviviridae family. HCV is a major cause of chronic hepatitis and progressive liver fibrosis leading to cirrhosis. Currently, the mechanisms responsible for hepatocellular injury are not fully understood. Oxidative damage has been hypothesized to play a role in HCV-induced liver disease, with reactive oxygen species (ROS), generated from HCV-infected hepatocytes and infiltrating immune cells. Persistence of recurrent hepatocellular injury leads to wound-healing process in which oxidative stress, inflammatory response mediated by immune cells and/or cytokines, and activation of hepatic stellate cells (HSCs) contribute to cascade of fibrogenesis. HCV can infect peripheral blood mononuclear cells (PBMC) of patients with chronic HCV infection . PBMC play key roles both in innate and adaptive antigen-specific immunity and they constitute critical components of the immune response.Heme oxygenase (HO) is the rate-limiting enzyme in the heme catabolic pathway. It cleaves pro-oxidant heme into equimolar amounts of carbon monoxide (CO), free iron, and biliverdin, which is rapidly metabolized to bilirubin by biliverdin reductase.The human HO-1 gene is located at chromosome 22q12 and a variable number of tandem repeat polymorphism (VNTR) was identified in the proximal promoter region. It is suggested that these highly polymorphic (GT)n repeats could alter the transcriptional activity. In recent years, enhanced HO enzymatic activity has been reported - probably through its formation of bioactive products - to possess antioxidant, cytoprotective, and neurotransmitter activity and to play a role in anti-inflammatory functions . AIMS: AIM 1.To characterize HO expression in liver biopsies in patients with chronic hepatitis C comparing to expression in patients with other types of hepatitis (esp. autoimmune) and to normal liver tissue. To investigate the relationship between HO expression and hepatitis C virus concentration, duration of infection, level of fibrosis and inflammation, ALT, AST activities, bilirubin levels, response to the standard treatment and a level of apoptosis. AIM 2. To characterize HO expression in PBMC in patients with chronic hepatitis C before, in the week 12 and after the standard treatment (PEG-IFN+RBV). To correlate HO expression in PBMC with viral concentration in sera and a response to the standard treatment.AIM 3. To investigate HO polymorphisms in patients with chronic hepatitis C. AIM 4. To investigate UGT1A1 28 polymorphism which is responsible for benign hyperbilirubinemia. Expected results: 1. This study could elucidate a relationship between development of liver fibrosis and inflammation and HO expression. 2. This project may, for the first time, show the relationship between chronic HCV infection and regulation of HO expression in PBMC. 3.This project will answer the question whether genetic predisposition, length polymorphism in HO promoter responsible for its lower transcriptional activity, could be a risk factor for fibrosis/cirrhosis development in patients infected with hepatitis C virus. UGT1A1 28 polymorphism is connected with low prevalence of diseases in which the oxidative stress is increased. We suggest that HCV infected persons might have low prevalence of this polymorphism or this polymorphism might be connected to low efficacy of antiviral treatment in these persons.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Role of Heme Oxygenase in the Pathogenesis od Hepatocellular Injury in Chronic HCV Infection
Study Start Date : January 2007
Estimated Primary Completion Date : June 2009
Estimated Study Completion Date : December 2009

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Arms and Interventions
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Arm Intervention/treatment
Active Comparator: 1 HCV positive pts

Patients with chronic HCV infection undergoing liver biopsy followed by antiviral treatment.

peg-IFN alfa 2a 180ug s.c. QW + ribavirin 1000-1200mg p.o. daily 48weeks or peg-IFN alfa 2b 1.5 ug/kg s.c. QW + ribavirin 100-1200mg p.o. daily 48 weeks

 Drug: pegylated interferon
peg-IFN alfa 2a 180ug s.c. QW or peg-IFN alfa 2b 1.5 ug/kg s.c. QW
Other Names:
  • Pegasys
  • Pegintron

Drug: Ribavarin
ribavirin 1000-1200mg p.o. daily 48weeks or ribavirin 100-1200mg p.o. daily 48 weeks
Other Names:
  • Copegus
  • Rebetol
No Intervention: 2 Other liver disease
pts. with NASH (or other liver disease) undergoing liver biopsy.


Outcome Measures
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Primary Outcome Measures :
  1. 1. the relation between HO activity and basic virologic and histologic parameters in chronic HCV patients. 2. changes of HO activity within antiviral treatment 3. relation of HO gene polymorphisms to the course of disease [ Time Frame: from HCV transmission in each individual patient to the time of liver biopsy and begining of antiviral treatment ]

Secondary Outcome Measures :
  1. Relation of HO gene polymorphisms and UGT1A1*28 polymorphism. [ Time Frame: 3 years ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • chronic HCV infection
  • must undergo liver biopsy
  • must undergo antiviral treatment

Exclusion Criteria:

  • liver sample not obtained
  • blood samples for HCV testing not obtained in specified time points during antiviral therapy
Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00842205


Locations
Czech Republic
Cetral Military Hospital Recruiting
Prague, Czech Republic, 16202
Contact: Petr Urbanek, Doc., MD, CSc    +420973203049    petr.urbanek@uvn.cz   
Principal Investigator: Petr Urbanek, Doc., MD, CSc         
Sponsors and Collaborators
Charles University, Czech Republic
IGA MZ, Czech Republic
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Petr Urbanek, Doc. MUDr., CSc, Dept of Internal Medicine, 1st Medical Faculty Charles University and Central Military Hospital Prague, Czech Republic
ClinicalTrials.gov Identifier: NCT00842205     History of Changes
Other Study ID Numbers: IGA MZ CR NR9412-3
First Posted: February 12, 2009    Key Record Dates
Last Update Posted: February 12, 2009
Last Verified: February 2009

Keywords provided by Charles University, Czech Republic:
hepatitis C
NASH
Hem Oxygenase
Gene polymorphism

Additional relevant MeSH terms:
Infection
Communicable Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases
Interferons
 Interferon-alpha
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs