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Pegylated-Interferon and Ribavirin Plus Metformin in the Treatment of Chronic HCV Infection and Insulin Resistance

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ClinicalTrials.gov Identifier: NCT00370617
Recruitment Status : Unknown
Verified November 2006 by University of Turin, Italy.
Recruitment status was:  Recruiting
First Posted : August 31, 2006
Last Update Posted : November 14, 2006
Sponsor:
Information provided by:
University of Turin, Italy

Study Description
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Brief Summary:

Chronic hepatitis C virus (HCV) infection is associated with an increased risk for the development of type 2 diabetes and HCV infection itself may promote insulin resistance, irrespective of the severity of liver disease.

Insulin resistance seems to be genotype specific and may play a role in fibrogenesis in chronic hepatitis C.

In an “in vitro” model, increased levels of insulin may promote increased HCV replication.

RATIONALE Decreased insulin resistance and reduced hyperinsulinemia may facilitate the efficacy of anti-viral drugs on HCV replication.


Condition or disease Intervention/treatment Phase
Chronic Hepatitis C Insulin Resistance Drug: metformin Phase 4

Detailed Description:

Chronic hepatitis C virus (HCV) infection is associated with an increased risk for the development of type 2 diabetes and HCV infection itself may promote insulin resistance, irrespective of the severity of liver disease.

  • In patients with HCV infection, an increase in fasting insulin levels is associated with the presence of serum HCV core, the severity of hepatic fibrosis and a decrease in expression of insulin receptor substrate (IRS) 1 and IRS2, central molecules of the insulin-signaling cascade. Down-regulation of IRS1 and IRS2 has also been observed in HCV core-transgenic mice livers and HCV core-transfected human hepatoma cells.
  • High levels of tumor necrosis factor-alpha, which acts by disturbing tyrosine phosphorylation of insulin receptor substrate-1, may be associated with insulin resistance both in animal models and in HCV patients.

Insulin resistance seems to be genotype specific and may play a role in fibrogenesis in chronic hepatitis C.

  • In patients infected with genotype non-3, insulin resistance is associated with the degree of fibrosis, the rate of fibrosis progression and previous failed antiviral treatment.
  • Insulin resistance, fibrosis, and genotype are independent predictors of the response to antiviral therapy in chronic hepatitis C patients treated with peginterferon plus ribavirin. A sustained virological response is achieved in 33% of patients with genotype 1 and insulin resistance compared with 60% of genotype 1 patients without insulin resistance.
  • Insulin resistance is associated with a 3-fold risk of failure to antiviral treatment in patients with genotype 1 In an “in vitro” model, increased levels of insulin may promote increased HCV replication.

RATIONALE Decreased insulin resistance and reduced hyperinsulinemia may facilitate the efficacy of anti-viral drugs on HCV replication.

INDICATION Genotype 1 Chronic HCV hepatitis (CHC) associated with insulin resistance (IR).

OBJECTIVES To compare the efficacy and safety of Pegylated-Interferon and Ribavirin plus metformin to Pegylated-Interferon and Ribavirin for treatment of naïve patients with Genotype 1 Chronic HCV infection and insulin resistance.


Study Design
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Study Type : Interventional  (Clinical Trial)
Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Efficacy and Safety Study Comparing Pegylated-Interferon and Ribavirin Plus Metformin to Pegylated-Interferon and Ribavirin in the Treatment of naïve Patients With Genotype 1 Chronic HCV Infection and Insulin Resistance
Study Start Date : September 2006
Study Completion Date : January 2009

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Arms and Interventions
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Outcome Measures
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Primary Outcome Measures :
  1. Combined end-point of non-detectable serum HCV-RNA (<100 copies/mL) and
  2. normal serum ALT activity at the end of the 24 week treatment-free follow up period

Secondary Outcome Measures :
  1. End-of-treatment virological and biochemical response
  2. Sustained virological and biochemical response
  3. End-of-treatment improvement of insulin resistance
  4. End-of-treatment improvement of liver histology

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. No previous antiviral treatment
  2. Persistently elevated alanine aminotransferase (ALT) and quantifiable HCV-RNA (>2000 copies/ml)
  3. Liver biopsy (within 12 months) consistent with CHC with or without cirrhosis
  4. Compensated liver disease (Child-Pugh grade A)
  5. Insulin resistance (evaluated by HOMA-R and OGTT)
  6. Negative pregnancy test

Exclusion Criteria:

  1. Type 2 Diabetes (according to ADA criteria)
  2. BMI > 30
  3. Alcohol consumption > 30 g/day
  4. Other forms of liver disease (HBV, autoimmune, genetic), HIV infection.
  5. Anemia
  6. Psychiatric disease
  7. Thyroid disease poorly controlled
  8. Overt cirrhosis, hepatocellular carcinoma
  9. Significant cardiac, renal, pulmonary disease, seizures.
Contacts and Locations
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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): NCT00370617


Contacts
Contact: Mario Rizzetto, MD +39-011-6336397 mrizzetto@molinette.piemonte.it
Contact: Elisabetta Bugianesi, MD +39-011-6336397 ebugianesi@yahoo.it

Locations
Italy
Division of Gastroenterology, University of Torino, Ospedale San Giovanni Battista Recruiting
Torino, Italy, 10126
Contact: Mario Rizzetto, MD    +39-011-6336397    mrizzetto@molinette.piemonte.it   
Contact: Elisabetta Bugianesi, MD    +39-011-6336397    ebugianesi@yahoo.it   
Sub-Investigator: Elisabetta Bugianesi, MD         
Sponsors and Collaborators
University of Turin, Italy
Investigators
Principal Investigator: Mario Rizzetto, MD University of Torino
More Information
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Publications:

ClinicalTrials.gov Identifier: NCT00370617     History of Changes
Other Study ID Numbers: METVIRAL
First Posted: August 31, 2006    Key Record Dates
Last Update Posted: November 14, 2006
Last Verified: November 2006

Keywords provided by University of Turin, Italy:
chronic hepatitis C
insulin resistance
therapy

Additional relevant MeSH terms:
Hepatitis
Hepatitis C
Hepatitis, Chronic
Insulin Resistance
Hepatitis C, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Flaviviridae Infections
RNA Virus Infections
Hyperinsulinism
Glucose Metabolism Disorders
 Metabolic Diseases
Insulin
Metformin
Interferons
Ribavirin
Hypoglycemic Agents
Physiological Effects of Drugs
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action