Ignite Creation Date:
2024-05-05 @ 11:56 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00189163
Status:
COMPLETED
Last Update Posted:
2016-12-16
First Post:
2005-09-13
Brief Title:
Pioglitazone in Hepatitis C
Sponsor:
University of Michigan
Organization:
University of Michigan
Study Overview
Official Title:
Pioglitazone in Hepatitis C A Randomized Double Blind Placebo-controlled Study
Status:
COMPLETED
Status Verified Date:
2016-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The presence of insulin resistance IR appears to be a key factor in the development of steatosis and disease progression in patience with Hepatitis C virus HCV genotype-1 infections similar to levels in Non-alcoholic fatty liver disease NAFLD The objective of this study is to determine whether Pioglatizone when given along with Interferon and Ribavirin reduces insulin resistance and lowers HCV viral levels and improved response in patients who have HCV genotype-1 infection when compared to a placebo
Detailed Description:
RESEARCH PLAN
Chronic hepatitis C is a leading cause of cirrhosis and hepatocellular carcinoma in the US and is the most common cause for liver transplantation Treatment of chronic hepatitis C remains problematic and unsatisfactory Several factors influence the response to treatment most importantly hepatitis C virus HCV genotype sustained virological responseSVR seen in 40-45 vs 75-80 using pegylated IFN ribavirin combination therapy genotype 1 vs 23 Recently the presence of hepatic steatosis has been shown to be an important predictor of disease progression and also response to antiviral therapy especially in patients with genotype 1 infection The mechanisms of hepatic steatosis in HCV are multi-factorial the presence of insulin resistance IR appears to be a key factor especially in genotype 1 metabolic steatosis similar to that seen in patients with non-alcoholic fatty liver disease NAFLD Whereas metabolic steatosis appears to be a factor in resistance to antiviral therapy viral steatosis direct viral induced as in genotype 3 is reduced in those who achieve an SVR We recently also observed that IR is common in type 1 HCV infection even at low BMIs and is present even in the non-steatotic hepatitis C patients suggesting a direct effect of viral infection on insulin sensitivity and that IR may precede hepatic steatosis We hypothesize that in patients with HCV genotype 1 infection therapy aimed at improving insulin sensitivity in conjunction with standard antiviral therapy may not only reduce the insulin resistance in hepatitis C but also improve hepatic steatosis decrease expression of pro-inflammatory cytokines and reduce oxidative stress thereby preventing disease progression In addition we also hypothesize that improvement in IR and hepatic steatosis may also result in improved virological response to antiviral therapy
This study introduces a novel concept of using the insulin sensitizing thiazolidinedione agent pioglitazone to improve insulin sensitivity improve hepatic steatosis and possibly result in a higher rate of virological response when given in conjunction with standard antiviral therapy in treatment naïve patients with genotype 1 infection Our main goals are to study the effect of pioglitazone on insulin sensitivity and hepatic steatosis in addition to its effect on SVR along with confirming the safety of pioglitazone in patients with hepatitis C To our knowledge this is the first randomized placebo-controlled study of an insulin sensitizing agent in the treatment of patients with chronic hepatitis C We hope that the findings in this study will shed new light into the mechanisms associated with the pathogenesis of hepatitis C and lead to new and effective treatments in the management of this very important disease
Insulin resistance IR a key factor in the development of steatosis is a common finding in patients with hepatitis C virus HCV infection In patients with genotype 1 infection IR has been noted in up to 80 of patients in some studies In patients with non-alcoholic fatty liver disease NAFLD who have evidence of nonalcoholic steatohepatitis NASH the role of IR leading to decreased fatty acid oxidation increased production of pro-inflammatory cytokines and increased oxidative stress had been proposed as an important mechanism leading to steatosis and subsequent liver cell injury Recently an association between steatosis and hepatic fibrosis has been emphasized in HCV infection similar to that described in patients with NAFLD While IR and hepatic steatosis are common findings in patients with HCV infection the latter with prevalence rates of 40 to 70 and different HCV genotypes confers distinct risks for steatosis a greater degree of steatosis is seen in patients with genotype 3 infection compared to others Similar to that seen in patients with NAFLD patients infected with genotype 1 HCV show a relationship between body mass index BMI and risk for steatosis However in up to 30 of patients with HCV infection and hepatic steatosis no other risk factors for steatosis can be identified The investigators preliminary data will show that even in HCV infected individuals with low BMI and no steatosis there is IR and the risk for steatosis is increased when directly compared to NAFLD patients Recent data also suggest that the presence of hepatic steatosis is an independent predictor of decreased response to antiviral therapy even when controlling for genotype This is especially important in patients with type 1 infection
The investigators hypothesize that in patients with HCV genotype 1 infection treatment with antiviral therapy will have a partial effect on reducing insulin resistance IR and steatosis and this is augmented by the addition of an insulin sensitizing thiazolidinedione TZD agent such as pioglitazone to the treatment regimen The investigators also hypothesize that the rate of sustained virological response SVR will be higher in the antiviral regimen pioglitazone treated group compared to patients receiving antiviral therapy alone
The investigators specific aims are the following
1 To assess the improvement in insulin sensitivity in patients with treatment naïve genotype 1 chronic hepatitis C treated with standard antiviral therapy pioglitazone or placebo
2 To assess the improvement in hepatic steatosis in patients with treatment naïve genotype 1 chronic hepatitis C after treatment with standard antiviral therapy pioglitazone or placebo
3 To assess the rates of sustained virological response SVR among patients with treatment naïve genotype 1 chronic hepatitis C treated with standard antiviral therapy pioglitazone compared to standard antiviral therapy placebo
CLINICAL STUDY DESIGN AND METHODS
Overview
This is a randomized double-blind placebo-controlled study of pioglitazone given in combination with standard antiviral therapy for the treatment of genotype 1 infected hepatitis C patients who are treatment naïve We will determine the rates of improvement in homeostasis model assessment of insulin resistance HOMA-IR and hepatic steatosis after 48 weeks of therapy compared to baseline along with determining the rate of SVR in the two treatment groups In addition we will also assess the safety of pioglitazone in patients with chronic hepatitis C infection
All eligible patients will have undergone a percutaneous liver biopsy within 6 months of enrollment to assess the severity of hepatitis C steatosis and features of steatohepatitis by the study pathologist A period of 6 months prior to enrollment was selected in order to have a more recent representation of the degree of steatosis and histologic severity of hepatitis C as the effect of therapy on these histologic features is one of the important aims in this study A HOMA index value of 20 was selected to define IR in this study see below Inclusion criteria as this value is considered abnormal and indicative of decreased insulin sensitivity Histological severity of chronic hepatitis C will be done using the modified histological activity index HAI scoring system by Ishak for grading and staging chronic viral hepatitis and that for steatosis and steatohepatitis will be done using the scoring system that is currently being used in the NIH-funded Virahep-C study which the PI is currently a member
We currently have an IRB approved protocol at the University of Michigan to collect a sample of liver tissue at the time of liver biopsy in all patients with hepatitis C and NAFLD to study fat gene expression We will collect samples on patients being considered for this study who are undergoing a liver biopsy at initial evaluation We will also collect similar samples at the time of repeat liver biopsies in this study This will give us a unique opportunity to study the effect of pioglitazone on fat-related gene expression and its relationship to responses being studied in this study changes in IR and steatosis and virological response to therapy
Given that this is a pilot study of pioglitazone in patients with hepatitis C and the potential hepatotoxicity of this drug in hepatitis C is not well known due to limited available data we plan to enroll treatment-naïve patients with evidence of at least some fibrosis on liver biopsy a minimum Ishak fibrosis score of 1 although we do not have any reason to expect any significant drug induced liver injury with this drug Patients with evidence of cirrhosis on liver biopsy Ishak fibrosis score 5 and 6 will be excluded since cirrhosis itself can be associated with IR and thereby bias the findings Although we do not expect to see any increased hepatotoxicity due to pioglitazone in patients with hepatitis C in general whether cirrhosis increases potential risk is unknown at this time
Similarly we also plan to exclude patients with known diabetes mellitus DM to minimize any bias especially since interferon therapy itself can affect glucose tolerance and may lead to difficult control in patients with pre-existing diabetes In our hepatitis C patient population although prevalence of DM is less than 15 the addition of diabetic patients may also confound the analysis unless we stratify randomization based on presence or absence of DM and since this is a pilot study with a limited sample size we decided to exclude diabetics Another factor would be correcting the influence of glucose controlling agents on insulin sensitivity during the study
All eligible patients who are interested in the study will be invited to come to the GCRC at regular intervals for study assessment During these visits a brief physical examination will be performed and blood will be collected and stored for future research purposes The current standard treatment for chronic hepatitis C patients with genotype 1 infection is a combination of pegylated interferon and ribavirin for 48 weeks Treatment response is defined as follows
Sustained Virological Responder SVR - undetectable HCV RNA in serum during therapy and at 24 weeks follow-up
Relapser - undetectable HCV RNA in serum during and end of treatment and reappearance of RNA once therapy is stopped we expect less than 15 of initial responders to relapse after stopping treatment
Non-Responder - presence of HCV RNA in serum at the end of therapy and during follow-up
Although patients with genotype 1 who have detectable HCV RNA at 24 weeks of therapy are usually labeled as non-responders and treatment is stopped in clinical practice all patients in this study will complete 48 weeks of treatment unless the regimen has to be stopped due to side effects or patient preference This is because of potential beneficial effects of therapy addition of pioglitazone to antiviral therapy on IR and hepatic steatosis and possibly even fibrosis even among viral non-responders when treated for 48 weeks
Once treatment is completed all patients will be invited to come to GCRC 12 weeks following the end of treatment to undergo a repeat liver biopsy Total follow-up once treatment is stopped will be 24 weeks in all patients
Patient Population
All eligible adult patients with compensated liver disease due to chronic infection with HCV and genotype 1 infection who are treatment naïve will be enrolled into the study All racial and ethnic groups will be recruited into this study Patients with cirrhosis and decompensated liver disease and any patient in whom a liver biopsy is contraindicated will be excluded Race African AmericanBlack or non-Hispanic white or other will be assigned based on the information given by the patient It reflects the individuals recognition in the community This assignment of raceethnicity will be similar to that practiced by governmental agencies including the US Census Bureau and the Center for Disease Control All patients will sign an IRB approved HIPAA compliant consent form before enrolling into the study
Chronic hepatitis C is a leading cause of cirrhosis and hepatocellular carcinoma in the US and is the most common cause for liver transplantation Treatment of chronic hepatitis C remains problematic and unsatisfactory Several factors influence the response to treatment most importantly hepatitis C virus HCV genotype sustained virological responseSVR seen in 40-45 vs 75-80 using pegylated IFN ribavirin combination therapy genotype 1 vs 23 Recently the presence of hepatic steatosis has been shown to be an important predictor of disease progression and also response to antiviral therapy especially in patients with genotype 1 infection The mechanisms of hepatic steatosis in HCV are multi-factorial the presence of insulin resistance IR appears to be a key factor especially in genotype 1 metabolic steatosis similar to that seen in patients with non-alcoholic fatty liver disease NAFLD Whereas metabolic steatosis appears to be a factor in resistance to antiviral therapy viral steatosis direct viral induced as in genotype 3 is reduced in those who achieve an SVR We recently also observed that IR is common in type 1 HCV infection even at low BMIs and is present even in the non-steatotic hepatitis C patients suggesting a direct effect of viral infection on insulin sensitivity and that IR may precede hepatic steatosis We hypothesize that in patients with HCV genotype 1 infection therapy aimed at improving insulin sensitivity in conjunction with standard antiviral therapy may not only reduce the insulin resistance in hepatitis C but also improve hepatic steatosis decrease expression of pro-inflammatory cytokines and reduce oxidative stress thereby preventing disease progression In addition we also hypothesize that improvement in IR and hepatic steatosis may also result in improved virological response to antiviral therapy
This study introduces a novel concept of using the insulin sensitizing thiazolidinedione agent pioglitazone to improve insulin sensitivity improve hepatic steatosis and possibly result in a higher rate of virological response when given in conjunction with standard antiviral therapy in treatment naïve patients with genotype 1 infection Our main goals are to study the effect of pioglitazone on insulin sensitivity and hepatic steatosis in addition to its effect on SVR along with confirming the safety of pioglitazone in patients with hepatitis C To our knowledge this is the first randomized placebo-controlled study of an insulin sensitizing agent in the treatment of patients with chronic hepatitis C We hope that the findings in this study will shed new light into the mechanisms associated with the pathogenesis of hepatitis C and lead to new and effective treatments in the management of this very important disease
Insulin resistance IR a key factor in the development of steatosis is a common finding in patients with hepatitis C virus HCV infection In patients with genotype 1 infection IR has been noted in up to 80 of patients in some studies In patients with non-alcoholic fatty liver disease NAFLD who have evidence of nonalcoholic steatohepatitis NASH the role of IR leading to decreased fatty acid oxidation increased production of pro-inflammatory cytokines and increased oxidative stress had been proposed as an important mechanism leading to steatosis and subsequent liver cell injury Recently an association between steatosis and hepatic fibrosis has been emphasized in HCV infection similar to that described in patients with NAFLD While IR and hepatic steatosis are common findings in patients with HCV infection the latter with prevalence rates of 40 to 70 and different HCV genotypes confers distinct risks for steatosis a greater degree of steatosis is seen in patients with genotype 3 infection compared to others Similar to that seen in patients with NAFLD patients infected with genotype 1 HCV show a relationship between body mass index BMI and risk for steatosis However in up to 30 of patients with HCV infection and hepatic steatosis no other risk factors for steatosis can be identified The investigators preliminary data will show that even in HCV infected individuals with low BMI and no steatosis there is IR and the risk for steatosis is increased when directly compared to NAFLD patients Recent data also suggest that the presence of hepatic steatosis is an independent predictor of decreased response to antiviral therapy even when controlling for genotype This is especially important in patients with type 1 infection
The investigators hypothesize that in patients with HCV genotype 1 infection treatment with antiviral therapy will have a partial effect on reducing insulin resistance IR and steatosis and this is augmented by the addition of an insulin sensitizing thiazolidinedione TZD agent such as pioglitazone to the treatment regimen The investigators also hypothesize that the rate of sustained virological response SVR will be higher in the antiviral regimen pioglitazone treated group compared to patients receiving antiviral therapy alone
The investigators specific aims are the following
1 To assess the improvement in insulin sensitivity in patients with treatment naïve genotype 1 chronic hepatitis C treated with standard antiviral therapy pioglitazone or placebo
2 To assess the improvement in hepatic steatosis in patients with treatment naïve genotype 1 chronic hepatitis C after treatment with standard antiviral therapy pioglitazone or placebo
3 To assess the rates of sustained virological response SVR among patients with treatment naïve genotype 1 chronic hepatitis C treated with standard antiviral therapy pioglitazone compared to standard antiviral therapy placebo
CLINICAL STUDY DESIGN AND METHODS
Overview
This is a randomized double-blind placebo-controlled study of pioglitazone given in combination with standard antiviral therapy for the treatment of genotype 1 infected hepatitis C patients who are treatment naïve We will determine the rates of improvement in homeostasis model assessment of insulin resistance HOMA-IR and hepatic steatosis after 48 weeks of therapy compared to baseline along with determining the rate of SVR in the two treatment groups In addition we will also assess the safety of pioglitazone in patients with chronic hepatitis C infection
All eligible patients will have undergone a percutaneous liver biopsy within 6 months of enrollment to assess the severity of hepatitis C steatosis and features of steatohepatitis by the study pathologist A period of 6 months prior to enrollment was selected in order to have a more recent representation of the degree of steatosis and histologic severity of hepatitis C as the effect of therapy on these histologic features is one of the important aims in this study A HOMA index value of 20 was selected to define IR in this study see below Inclusion criteria as this value is considered abnormal and indicative of decreased insulin sensitivity Histological severity of chronic hepatitis C will be done using the modified histological activity index HAI scoring system by Ishak for grading and staging chronic viral hepatitis and that for steatosis and steatohepatitis will be done using the scoring system that is currently being used in the NIH-funded Virahep-C study which the PI is currently a member
We currently have an IRB approved protocol at the University of Michigan to collect a sample of liver tissue at the time of liver biopsy in all patients with hepatitis C and NAFLD to study fat gene expression We will collect samples on patients being considered for this study who are undergoing a liver biopsy at initial evaluation We will also collect similar samples at the time of repeat liver biopsies in this study This will give us a unique opportunity to study the effect of pioglitazone on fat-related gene expression and its relationship to responses being studied in this study changes in IR and steatosis and virological response to therapy
Given that this is a pilot study of pioglitazone in patients with hepatitis C and the potential hepatotoxicity of this drug in hepatitis C is not well known due to limited available data we plan to enroll treatment-naïve patients with evidence of at least some fibrosis on liver biopsy a minimum Ishak fibrosis score of 1 although we do not have any reason to expect any significant drug induced liver injury with this drug Patients with evidence of cirrhosis on liver biopsy Ishak fibrosis score 5 and 6 will be excluded since cirrhosis itself can be associated with IR and thereby bias the findings Although we do not expect to see any increased hepatotoxicity due to pioglitazone in patients with hepatitis C in general whether cirrhosis increases potential risk is unknown at this time
Similarly we also plan to exclude patients with known diabetes mellitus DM to minimize any bias especially since interferon therapy itself can affect glucose tolerance and may lead to difficult control in patients with pre-existing diabetes In our hepatitis C patient population although prevalence of DM is less than 15 the addition of diabetic patients may also confound the analysis unless we stratify randomization based on presence or absence of DM and since this is a pilot study with a limited sample size we decided to exclude diabetics Another factor would be correcting the influence of glucose controlling agents on insulin sensitivity during the study
All eligible patients who are interested in the study will be invited to come to the GCRC at regular intervals for study assessment During these visits a brief physical examination will be performed and blood will be collected and stored for future research purposes The current standard treatment for chronic hepatitis C patients with genotype 1 infection is a combination of pegylated interferon and ribavirin for 48 weeks Treatment response is defined as follows
Sustained Virological Responder SVR - undetectable HCV RNA in serum during therapy and at 24 weeks follow-up
Relapser - undetectable HCV RNA in serum during and end of treatment and reappearance of RNA once therapy is stopped we expect less than 15 of initial responders to relapse after stopping treatment
Non-Responder - presence of HCV RNA in serum at the end of therapy and during follow-up
Although patients with genotype 1 who have detectable HCV RNA at 24 weeks of therapy are usually labeled as non-responders and treatment is stopped in clinical practice all patients in this study will complete 48 weeks of treatment unless the regimen has to be stopped due to side effects or patient preference This is because of potential beneficial effects of therapy addition of pioglitazone to antiviral therapy on IR and hepatic steatosis and possibly even fibrosis even among viral non-responders when treated for 48 weeks
Once treatment is completed all patients will be invited to come to GCRC 12 weeks following the end of treatment to undergo a repeat liver biopsy Total follow-up once treatment is stopped will be 24 weeks in all patients
Patient Population
All eligible adult patients with compensated liver disease due to chronic infection with HCV and genotype 1 infection who are treatment naïve will be enrolled into the study All racial and ethnic groups will be recruited into this study Patients with cirrhosis and decompensated liver disease and any patient in whom a liver biopsy is contraindicated will be excluded Race African AmericanBlack or non-Hispanic white or other will be assigned based on the information given by the patient It reflects the individuals recognition in the community This assignment of raceethnicity will be similar to that practiced by governmental agencies including the US Census Bureau and the Center for Disease Control All patients will sign an IRB approved HIPAA compliant consent form before enrolling into the study
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| GCRC Protocol Number 2085 | None | None | None |
| IRB Protocol Number 2004-0883 | None | None | None |