A Study of PEGASYS (Peginterferon Alfa-2a (40KD)) Plus COPEGUS (Ribavirin) With or Without Pioglitazone in Treatment-Naive Patients With Chronic Hepatitis C and Insulin Resistance.

Study Overview
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Brief Summary
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This 2 arm study will assess the efficacy and safety of PEGASYS plus COPEGUS, with or without concomitant pioglitazone, on hepatitis C virus titers in treatment-naive patients with genotype 1 chronic hepatitis C, and insulin resistance. Patients will be randomized to receive either a)PEGASYS 180 micrograms/week + Copegus 1000-1600 mg/day (according to body weight) for 48 weeks or b)16 weeks of pioglitazone (30 mg daily for 8 weeks, then 45 mg daily for 8 weeks), followed by PEGASYS 180 micrograms/week + Copegus 1000-1600 mg/day + pioglitazone 45 mg daily for 48 weeks. The anticipated time on study treatment is 1-2 years, and the target sample size is 100-500 individuals.

Official Title
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A Randomized, Open-label Study of the Effect of PEGASYS ® Plus COPEGUS® With or Without Concomitant Pioglitazone (Actos®) on Early Viral Kinetics in Treatment-naive Patients With Chronic Hepatitis C, Genotype-1, and Insulin Resistance

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: peginterferon alfa-2a [Pegasys]
* Drug: ribavirin [Copegus]
* Drug: Pioglitazone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, >=18 years of age; chronic hepatitis C, genotype 1; insulin resistance. Exclusion Criteria: other forms of liver disease; cirrhosis; previous treatment for chronic hepatitis C; insulin treatment during prior 2 weeks; type 1 diabetes.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PEG-INF alpha-2a + ribavirin+ pioglitazone<br>Participants received pioglitazone in a 16 week run-in period (30 mg per day orally for 8 weeks followed by 45 mg per day orally for 8 weeks). Participants then received piogliatzone 45 mg daily orally plus 18 μg of Peginterferon Alfa-2a (PEG-INF alpha-2a) subcutaneous (sc) once a week plus ribavirin (1000 - 1600 mg/day orally as a split dose in the morning and the evening based on the participant's body weight) for 48 weeks in the anti-HCV treatment phase. Participants received 45 mg of pioglitazone per day orally in the 24 week follow-up period. | Drug: peginterferon alfa-2a [Pegasys]<br>* 180 micrograms subcutaneous weekly for 48 weeks<br>* Other names: Pegasys;Drug: ribavirin [Copegus]<br>* 1000-1600 mg day orally for 48 weeks.<br>* Other names: Copegus;Drug: Pioglitazone<br>* 30 mg daily for 8 weeks increasing to 45 mg daily for 64 weeks.<br>* Other names: Actos;|
| Active Comparator: PEG-INF alpha-2a + ribavirin<br>Participants received 18 μg of Peginterferon Alfa-2a (PEG-INF alpha-2a) subcutaneous (sc) once a week plus ribavirin (1000 - 1600 mg/day orally as a split dose in the morning and the evening based on the participant's body weight) for 48 weeks in the anti-HCV treatment phase followed by a treatment free 24 week follow-up period. | Drug: peginterferon alfa-2a [Pegasys]<br>* 180 micrograms subcutaneous weekly for 48 weeks<br>* Other names: Pegasys;Drug: ribavirin [Copegus]<br>* 1000-1600 mg day orally for 48 weeks.<br>* Other names: Copegus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Initiation of Pegasys Plus Copegus in log10 Hepatitis C Virus Ribonucleic Acid (HCV RNA) Viral Load to Week 12 of Anti-HCV Therapy | Serum samples were collected for HCV RNA. The change from initiation of Pegasys plus Copegus to Week 12 in HCV RNA titers were calculated. Randomization for the with Pioglitazone arm occurred prior to the 16 week run-in period and randomization for the without Pioglitazone arm occurred prior to the start of anti-HCV treatment. | Initiation of Pegasys plus Copegus, Week 12 of anti-HCV treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Initiation of Pegasys Plus Copegus in log10 HCV RNA Viral Load to Week 24 and Week 48 of Anti-HCV Therapy | Serum samples were collected for HCV RNA. The change from Initiation of Pegasys Plus Copegus to Week 24 and Week 48 in HCV RNA titers were calculated. Randomization for the with Pioglitazone arm occurred prior to the 16 week run-in period and randomization for the without Pioglitazone arm occurred prior to the start of anti-HCV treatment. | Initiation of Pegasys Plus Copegus, Week 24 and Week 48 of anti-HCV therapy | 
| Percentage of Participants Achieving Virologic Response | Virologic response was defined as undetectable HCV RNA < 28 IU/mL. Patients with missing HCV RNA values are considered as non-responders. | Weeks 4, 12, 24, 48, 60, 72 | 
| Percentage of Participants With a ≥ 2 log10 Decrease in HCV RNA From Initiation of Pegasys Plus Copegus to Weeks 4, 12, 24, 48, 60, 72 | Serum samples were collected for HCV RNA. The percentage of participants with a ≥ 2 log10 decrease in HCV RNA from initiation of Pegasys plus Copegus to time point was calculated. | Initiation of Pegasys plus Copegus, Weeks 4, 12, 24, 48, 60, 72 | 
| Percentage of Participants With a Virological Relapse at Week 72 (24 Weeks After the End of Anti-HCV Treatment) | Virologic relapse was defined as the reappearance of HCV-RNA in serum after PEG-INF alpha 2a therapy is discontinued in a patient who was HCV-RNA undetectable at the completion of anti-HCV therapy. | Week 72 | 
| Percentage of Participants With a Confirmed Virological Breakthrough up to 48 Weeks | Virological breakthrough is a detectable HCV RNA at any time during anti-HCV treatment up to Week 48 after the attainment of undetectable HCV RNA. | Up to 48 Weeks | 
| Percentage of Nonresponders During the 48 Week Anti-HCV Treatment Period | Nonresponders are defined as patients who did not achieve undetectable HCV RNA during anti-HCV treatment | Up to 48 Weeks | 
| Change in Log10 HCV RNA Viral Load at Assessments From Randomization to 16 Weeks of Pioglitazone Pretreatment Run-In Period for the Pioglitazone Arm Only | Serum HCV RNA was collected at randomization and during the pioglitazone run-in period at various time points for the with pioglitazone arm only. The change from randomization to each of these time points was calculated. | Randomization (Week-16),Weeks -12, -8, -4 and 0 | 
| Change From Baseline in Fasting Plasma Glucose Levels at Each Time Point Assessed | Blood was collected for plasma fasting glucose levels at various time points throughout the study and was used as a measure of glycemic control (monitoring the ability of the patient to maintain normal blood sugar levels). Baseline for the with pioglitazone arm occurred prior to the start of 16 week run-in period and for the without pioglitazone arm prior to the start of anti-HCV therapy. The change from baseline to Weeks 4 thru 72 after the initiation of anti-HCV therapy is calculated. | Baseline, Weeks 4, 8,12,16,20,24,28,32,36,40,44,48,60,72 | 
| Change From Baseline in Fasting Insulin Levels at Each Time Point Assessed. | Blood was collected for fasting insulin levels at various time points throughout the study and was used as a measure of glycemic control (monitoring the ability of the patient to maintain normal blood sugar levels). Baseline for the with pioglitazone arm occurred prior to the start of 16 week run-in period and for the without pioglitazone arm prior to the start of anti-HCV therapy. The change from baseline to Weeks 4 thru 72 after the initiation of anti-HCV therapy is calculated. | Baseline, Weeks 4, 8,12,16,20,24,28,32,36,40,44,48,60,72 | 
| Change From Baseline in Fasting Hemoglobin A1C (HbA1c) Concentrations at Each Time Point Assessed | Blood was collected for a fasting Hemoglobin A1C level at various time points throughout the study and was used as a measure of glycemic control (monitoring the ability of the patient to maintain normal blood sugar levels). Baseline for the with pioglitazone arm occurred prior to the start of 16 week run-in period and for the without pioglitazone arm prior to the start of anti-HCV therapy. The change from baseline to Weeks 4 thru 72 after the initiation of anti-HCV therapy is calculated. | Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48,60,72 | 
| Change From Baseline in Homeostasis Model Assessment (HOMA) Scores at Each Time Point Assessed | Insulin resistance (IR) is calculated using the following formula: HOMA score = (fasting glucose in mg/dL × fasting insulin in μIU/mL) / 405. Baseline for with pioglitazone arm occurred prior to the start of 16 week run-in period and for without pioglitazone arm prior to the start of anti-HCV therapy. The change from baseline to Weeks 4 thru 72 after the start of anti-HCV therapy is calculated. A normal patient can have a HOMA score up to 3. A patient with a score of >3 is definitely IR. Patients scoring 2-3 can be IR but other factors may be causing this without being IR. | Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48,60,72 | 
| Change From Baseline in Serum Triglyceride Concentrations at Each Time-point Assessed | Blood was collected and assayed for fasting serum triglyceride levels at various time points throughout the study and was used as an indicator of lipid control. Baseline for the with pioglitazone arm occurred prior to the start of 16 week run-in period and for the without pioglitazone arm prior to the start of anti-HCV therapy. The change from baseline to Weeks 4 thru 72 after the initiation of anti-HCV therapy is calculated. | Baseline, Weeks 4, 8,12,16,20,24,28,32,36,40,44,48,60, 72 | 
| Change From Baseline in Total Cholesterol Levels at Each Time-point Assessed | Blood was collected and assayed for fasting serum cholesterol levels at various time points throughout the study and was used as an indicator of lipid control. Baseline for the with pioglitazone arm occurred prior to the start of 16 week run-in period and for the without pioglitazone arm prior to the start of anti-HCV therapy. The change from baseline to Weeks 4 thru 72 after the initiation of anti-HCV therapy is calculated. | Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48,60,72 | 
| Change From Baseline in Low-density Lipoprotein (LDL-cholesterol) Levels at Each Time-point Assessed | Blood was collected and assayed for fasting serum low-density lipoprotein (LDL-cholesterol) levels at various time points throughout the study and was used as an indicator of lipid control. Baseline for the with pioglitazone arm occurred prior to the start of 16 week run-in period and for the without pioglitazone arm prior to the start of anti-HCV therapy. The change from baseline to Weeks 4 thru 72 after the initiation of anti-HCV therapy is calculated. | Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48,60,72 | 
| Change From Baseline in High-density Lipoprotein (HDL-cholesterol) Levels at Each Time-point Assessed | Blood was collected and assayed for fasting high-density lipoprotein (HDL-cholesterol) levels at various time points throughout the study and was used as an indicator of lipid control. Baseline for the with pioglitazone arm occurred prior to the start of 16 week run-in period and for the without pioglitazone arm prior to the start of anti-HCV therapy. The change from baseline to Weeks 4 thru 72 after the initiation of anti-HCV therapy is calculated. | Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48,60,72 | 
| Change From Baseline in Tumor Necrosis Factor Alpha (TNF-α) at Each Time Point Assessed | Blood was collected for tumor necrosis factor alpha at various time points throughout the study and was used as a measure of insulin resistance (the inability of insulin to control blood sugar levels). Baseline for the with pioglitazone arm occurred prior to the start of 16 week run-in period and for the without pioglitazone arm prior to the start of anti-HCV therapy. The change from baseline to Weeks 4 thru 72 after the initiation of anti-HCV therapy is calculated. | Baseline, Weeks 4, 8,12,16,20,24,28,32,36,40,44,48,60,72 | 
| Change From Baseline in Transforming Growth Factor Beta (TGF-β) Levels at Each Time Point Assessed | Blood was collected for Transforming Growth Factor beta at various time points throughout the study and was used as a measure of insulin resistance (the inability of insulin to control blood sugar levels). Baseline for the with pioglitazone arm occurred prior to the start of 16 week run-in period and for the without pioglitazone arm prior to the start of anti-HCV therapy. The change from baseline to Weeks 4 thru 72 after the initiation of anti-HCV therapy is calculated. | Baseline, Weeks 4, 8,12,16,20,24,28,32,36,40,44,48,60,72 | 
| Change From Baseline in Adiponectin Levels at Each Time Point Assessed | Blood was collected for adiponectin at various time points throughout the study and was used as a measure of insulin resistance (the inability of insulin to control blood sugar levels). Baseline for the with pioglitazone arm occurred prior to the start of 16 week run-in period and for the without pioglitazone arm prior to the start of anti-HCV therapy. The change from baseline to Weeks 4 thru 72 after the initiation of anti-HCV therapy is calculated. | Baseline, Weeks 4, 8,12,16,20,24,28,32,36,40,44,48,60,72 | 
| Change From Baseline in Leptin Levels at Each Time Point Assessed | Blood was collected for leptin at various time points throughout the study and was used as a measure of insulin resistance (the inability of insulin to control blood sugar levels). Baseline for the with pioglitazone arm occurred prior to the start of 16 week run-in period and for the without pioglitazone arm prior to the start of anti-HCV therapy. The change from baseline to Weeks 4 thru 72 after the initiation of anti-HCV therapy is calculated. | Baseline, Weeks 4, 8,12,16,20,24,28,32,36,40,44,48,60,72 | 
| Change From Baseline in Free Fatty Acid Levels at Each Time Point Assessed | Blood was collected for free fatty acids at various time points throughout the study and was used as a measure of insulin resistance (the inability of insulin to control blood sugar levels). Baseline for the with pioglitazone arm occurred prior to the start of 16 week run-in period and for the without pioglitazone arm prior to the start of anti-HCV therapy. The change from baseline to Weeks 4 thru 72 after the initiation of anti-HCV therapy is calculated. | Baseline, Weeks 4, 8,12,16,20,24,28,32,36,40,44,48,60,72 | 
| Percentage of Participants With Beck Depression Inventory Fast Screen (BDI-FS) Score ≥ 4 at Each Time Point Assessed | The BDI-FS consisted of seven areas with four statements (labeled 0, 1, 2, and 3) offered to describe the area of interest, with 0 indicating no effect and 3 indicating the worst effect. The individual area scores were summed to provide a total score. The degree of depression was assessed with 0 to 3 indicating minimal depression, 4 to 8 mild depression, 9 to 12 moderate depression and 13 to 21 severe depression. | Weeks 4, 8,12,16,20,24,28,32,36,40,44,48,60,72 |