The Effects of Oral Hypoglycemic Agents on Chronic Hepatitis C Patients Receiving Peg-Intron Plus Ribavirin

Study Description

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Brief Summary:

Pegylated interferon in combination with ribavirin is the current standard treatment of chronic hepatitis C virus infection, but is expensive and has several adverse effects. To modify this standard treatment by optimizing its therapeutic effect and decreasing its adverse events are important. Recent studies have identified a close link between metabolic profiles, insulin resistance and Hepatitis C Virus (HCV) infection. Several pilot studies in western world have have found beneficial effects of oral hypoglycemic agents on chronic Hepatitis C (CHC) genotype 1 infected patients. Whether this concept still holds true in Taiwanese people remains unknown.

The objective of this clinical trial is to evaluate the effect of oral hypoglycemic agents (daily for 4 weeks of run-in period and 8 weeks of combination treatment) on CHC genotype 1 infected Taiwanese patients receiving 48 weeks of Peg-IFN plus ribavirin (RBA), and the enrolled subjects will be randomized into 4 treatment groups (including Acarbose, Metformin, Pioglitazone and standard care control groups). During the trial and 24 weeks after the end of treatment, serial serum HCV RNA, alanine aminotransferase (ALT) levels, and other clinical data will be evaluated to determine the therapeutic response and adverse events of the CHC patients.

Condition or disease	Intervention/treatment	Phase
Chronic Hepatitis C	Drug: Pioglitazone; Drug: Acarbose; Drug: Metformin	Phase 4

Detailed Description:

Pegylated interferon in combination with ribavirin is the current standard treatment of chronic hepatitis C virus infection, but is expensive and has several adverse effects. To modify this standard treatment by optimizing its therapeutic effect and decreasing its adverse events are important.

Recent studies have identified a close link between metabolic profiles, insulin resistance and HCV infection. Chronic hepatitis C (CHC) patients with higher pretreatment HOMA-IR (insulin resistance) index have poor therapeutic response than the ones with lower HOMA-IR index. Thus, it is reasonable to increase the therapeutic response of CHC patients by lowering insulin resistance. Several pilot studies in western world have been conducted to evaluate this concept by adding oral hypoglycemic agents into pegylated interferon plus ribavirin treatment, and have found beneficial effects of oral hypoglycemic agents on CHC genotype 1 infected patients. Whether this concept still holds true in Taiwanese people remains unknown.

To evaluate the effect of oral hypoglycemic agents on CHC genotype 1 infected Taiwanese patients, we design this study and evaluate the virologic, biochemical and histological responses of CHC patients receiving pegylated interferon plus ribavirin treatment, and hope to identify similar beneficial effects of oral hypoglycemic agents in CHC Taiwanese patients.

We plan to enroll about 80 chronic hepatitis C genotype 1 infected patients from the clinics into this study. All patients should have informed consent, not receive any interferon-based therapy or anti-viral medication, abstinence from alcohol beverage for more than 6 months and conformed to the regulations of Bureau of National Health Insurance, Taiwan. All patients will be randomly assigned into 4 different treatment arms. The patients assigned into the first 3 arms will receive one kind of the following oral hypoglycemic agents, such as Acarbose, Metformin, or Pioglitazone for 12 weeks (including 4 weeks of run-in period and 8 weeks of combination treatment with pegylated interferon alfa plus ribavirin). From week 13, all the patients of the first 3 arms will receive pegylated interferon alfa plus ribavirin for 40 weeks. The last arm is the control group; all the patients in the last arm will receive standard pegylated interferon alfa plus ribavirin treatment for 48 weeks. During the trial and 24 weeks after the end of treatment, the serum HCV RNA levels, clinical and biochemical data will be evaluated to determine the therapeutic response and adverse events of the patients.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	80 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	An Open-label, Multi-center, Randomized Study Comparing the Effects of Oral Hypoglycemic Agents on Viral Kinetics of Chronic Hepatitis C Patients Receiving Pegylated Interferon Alfa 2b Plus Ribavirin
Study Start Date :	November 2009
Estimated Primary Completion Date :	December 2012
Estimated Study Completion Date :	December 2012

Arms and Interventions

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Arm	Intervention/treatment
No Intervention: Standard care of CHC; From week 5, all the patients will receive Peginterferon alfa-2b (1.5/μg per kg) per week plus Ribavirin 1000-1200 mg/day (≥ 75 kg, 1200 mg; < 75 kg, 1000mg) for 48 weeks.
Experimental: Pioglitazone; From week 5, all the patients will receive Peginterferon alfa-2b (1.5/μg per kg) per week plus Ribavirin 1000-1200 mg/day (≥ 75 kg, 1200 mg; < 75 kg, 1000mg) for 48 weeks.	Drug: Pioglitazone; Pioglitazone(30mg qd) for 4 weeks of run-in period and 8 weeks of combination treatment with Peginterferon alfa-2b (1.5/μg per kg) per week plus Ribavirin 1000-1200 mg/day (≥ 75 kg, 1200 mg; < 75 kg, 1000mg).
Experimental: Acarbose; From week 5, all the patients will receive Peginterferon alfa-2b (1.5/μg per kg) per week plus Ribavirin 1000-1200 mg/day (≥ 75 kg, 1200 mg; < 75 kg, 1000mg) for 48 weeks.	Drug: Acarbose; Acarbose (50 mg/per meal) for 4 weeks of run-in period and 8 weeks of combination treatment with Peginterferon alfa-2b (1.5/μg per kg) per week plus Ribavirin 1000-1200 mg/day (≥ 75 kg, 1200 mg; < 75 kg, 1000mg).
Experimental: Metformin; From week 5, all the patients will receive Peginterferon alfa-2b (1.5/μg per kg) per week plus Ribavirin 1000-1200 mg/day (≥ 75 kg, 1200 mg; < 75 kg, 1000mg) for 48 weeks.	Drug: Metformin; Metformin (500 mg tid) 4 weeks of run-in period and 8 weeks of combination treatment with Peginterferon alfa-2b (1.5/μg per kg) per week plus Ribavirin 1000-1200 mg/day (≥ 75 kg, 1200 mg; < 75 kg, 1000mg). From week 13, all the subjects will receive pegylated interferon alfa plus ribavirin for 40 weeks.

Outcome Measures

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Primary Outcome Measures :

1. Sustained Virologic Response [ Time Frame: at the end of 24 weeks post-treatment follow-up ]

Secondary Outcome Measures :

1. serum ALT normalization, and histologic improvement [ Time Frame: at the end of treatment and 24 weeks after the end of treatment ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 80 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Treatment naïve
2. Age old than 18 years old
3. Anti-HCV positive > 6 months
4. Detectable serum quantitative HCV-RNA
5. HCV genotype 1
6. Serum alanine aminotransferase levels above the upper limit of normal with 6 months of enrollment
7. Pre-treatment HOMA-IR ≧ 2.0. (HOMA-IR = fasting insulin (mU/L) x fasting glucose (mg/dL) x 0.05551/22.5)

Exclusion Criteria:

1. Anemia (hemoglobin < 13 gram per deciliter for men and < 12 gram per deciliter for women)
2. Neutropenia (neutrophil count <1,500 per cubic milliliter)
3. Thrombocytopenia (platelet <90,000 per cubic milliliter)
4. Co-infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)
5. Chronic alcohol abuse (daily consumption > 20 gram per day in male and >10gram per day in female).
6. Diabetes Mellitus history or under oral hypoglycemic agents therapy Liver cirrhosis
7. Serum creatinine level more than 1.5 times the upper limit of normal Autoimmune liver disease
8. Neoplastic disease
9. An organ transplant
10. Immunosuppressive therapy
11. Poorly controlled autoimmune diseases, pulmonary diseases, cardiac diseases, psychiatric diseases, neurological diseases, diabetes mellitus
12. Evidence of drug abuse
13. Unwilling to have contraception

Contacts and Locations

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Locations

Taiwan
National Taiwan University Hospital Department of Internal Medicine,
Taipei, Taiwan, 10002

Sponsors and Collaborators

National Taiwan University Hospital

Schering-Plough

Merck Sharp & Dohme Corp.

Investigators

Principal Investigator:	Jia-Horng Kao, M.D., PhD.	National Taiwan University Hospital

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	National Taiwan University Hospital, Jia-Horng Kao, National Taiwan University Hospital
ClinicalTrials.gov Identifier:	NCT01025765 History of Changes
Other Study ID Numbers:	200905056M
First Posted:	December 4, 2009
Last Update Posted:	November 27, 2012
Last Verified:	November 2012

Additional relevant MeSH terms:

Hepatitis; Hepatitis A; Hepatitis C; Hepatitis, Chronic; Hepatitis C, Chronic; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Flaviviridae Infections; Pioglitazone	Metformin; Hypoglycemic Agents; Acarbose; Ribavirin; Interferon-alpha; Peginterferon alfa-2b; Physiological Effects of Drugs; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents; Immunologic Factors; Glycoside Hydrolase Inhibitors; Enzyme Inhibitors