Peak Study - A Study of Pegasys (Peginterferon Alfa-2a (40KD)) in Combination With Copegus (Ribavirin) in Interferon-Naive Patients With Chronic Hepatitis C (CHC).

Study Overview
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Brief Summary
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This study will examine the viral kinetics and pharmacokinetics of Pegasys plus ribavirin and PEG-Intron plus ribavirin in interferon-naive patients with CHC. The anticipated time on study treatment is 3-12 months, and the target sample size is 100-500 individuals.

Official Title
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A Prospective, Randomized, Open-label Study Evaluating the Viral Kinetics and Pharmacokinetics of Pegasys® Plus Copegus® and PEG-Intron® Plus Rebetol® in Interferon-naïve Patients With Chronic Hepatitis C.

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: Ribavirin
* Drug: Peginterferon alfa-2b (PEG-Intron)
* Drug: Ribavirin
* Drug: Peginterferon alfa-2a [Pegasys]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients at least 18 years of age CHC infection, genotype 1 use of 2 forms of contraception during study in both men and women Exclusion Criteria: previous systemic therapy with anti-viral, anti-neoplastic, or immunomodulatory agents medical condition associated with chronic liver disease (e.g., hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, toxin exposure) decompensated liver disease women who are pregnant or breastfeeding

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: Peginterferon Alfa-2a + Ribavirin<br>Participants received Peginterferon alfa-2a (40 kD) [Pegasys] at a dosage of 180 microgram (μg), subcutaneously (SC), once a week plus Ribavirin [Copegus] 1000 or 1200 milligram (mg)/day), orally, [according to body weight, lesser than or greater than/equal to (< or >/=) 75 kilogram (kg), respectively] twice daily during the randomized treatment period for 12 weeks. Participants who completed the randomized treatment period of 12 weeks and wished to continue therapy were given Peginterferon alfa-2a 180 μg SC once weekly plus Ribavirin 1000 or 1200 mg/day orally (< or >/=75 kg body weight, respectively twice daily for an additional 36 weeks to complete a full 48-week treatment course. After treatment completion, participants were followed-up for safety for 24 weeks. | Drug: Ribavirin<br>* 1000/1200mg/day po<br>* Other names: Copegus;Drug: Peginterferon alfa-2a [Pegasys]<br>* 180 micrograms sc weekly<br>|
| Active Comparator: Peginterferon Alfa-2b + Ribavirin<br>Participants received Peginterferon alfa-2b (12 kD) [PEG-Intron] at a dosage of 1.5 μg/kg SC once weekly plus Ribavirin [Rebetol] 1000 or 1200 mg/day orally (< or >/=75 kg body weight, respectively) twice daily during the randomized treatment period for 12 weeks. Participants who completed the randomized treatment period of 12 weeks and wished to continue therapy were given Peginterferon alfa-2a 180 μg SC once weekly plus Ribavirin 1000 or 1200 mg/day orally (< or >/=75 kg body weight, respectively) twice daily for an additional 36 weeks to complete a full 48-week treatment course. After treatment completion, participants were followed-up for safety for 24 weeks. | Drug: Peginterferon alfa-2b (PEG-Intron)<br>* 1.5 micrograms/kg sc weekly<br>Drug: Ribavirin<br>* 1000/1200mg/day po<br>* Other names: Rebetol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Viral Load (log10 Reduction) at Week 12 | The viral load was determined quantitatively and qualitatively by Hepatitis C virus (HCV)-polymerase chain reaction (PCR). HCV RNA was measured qualitatively using the Roche amplicor PCR assay (lower limit of detection 60 international units per milliliter (U/mL), changed from 50 IU/mL with amendment B) and quantitatively using the Roche amplicor HCV monitor® test v2.0 (lower limit of quantification 600 IU/mL). Log transformations were performed for HCV RNA, and the analyses were done on a log10 scale. The average value of the difference between viral load levels in the serum from baseline to Week 12, expressed in terms of a logarithmic scale with base 10, are presented. | From Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Viral Load (log10 Reduction) at Week 4 and Week 8 | The viral load was determined quantitatively and qualitatively by HCV-PCR. HCV RNA was measured qualitatively using the Roche amplicor PCR assay (lower limit of detection 60 IU/mL, changed from 50 IU/mL with amendment B) and quantitatively using the Roche amplicor HCV monitor® test v2.0 (lower limit of quantification 600 IU/mL). Log transformations were performed for HCV RNA, and the analyses were done on a log10 scale. The average value of the difference between viral load levels in the serum from baseline to week 4 and week 8, expressed in terms of a logarithmic scale with base 10 are presented. | Baseline, Week 4 and Week 8 | 
| Weekly Viral Load Assessed at Drug Trough | The viral load was determined quantitatively and qualitatively by HCV-PCR. HCV RNA was measured qualitatively using the Roche amplicor PCR assay (lower limit of detection 60 IU/mL, changed from 50 IU/mL with amendment B) and quantitatively using the Roche amplicor HCV monitor® test v2.0 (lower limit of quantification 600 IU/mL). Log transformations were performed for HCV RNA, and the analyses were done on a log10 scale. The viral load levels in the serum at baseline and for each week, were expressed in terms of a logarithmic scale with base 10, and averaged for all participants. | Baseline, up to Week 12 | 
| The Area Under the HCV-RNA Curve Estimated From the Two Adjacent Pre-dose Assessments at Each Week | The area under the HCV-RNA curve (HCV AUC) was defined as the area under the polygonal line defined by the HCV RNA values from the beginning of the time window to the end of the time window. Each of these areas was a sum of one or more trapezoids determined from the concentrations over the 7-day interval. The HCV AUC to Week 12 was the sum of the 12 weekly HCV AUCs divided by the time (12 weeks). Summary of weekly HCV AUC values estimated from the two adjacent pre-dose assessments are presented. | From Week -1 to Week 12 | 
| Mean Value of Area Under the HCV-RNA Curve Minus Baseline From Week 1 to Week 12 | The HCV AUC was calculated for each week as the area under the polygonal line defined by the HCV RNA values from the beginning of the time window to the end of the time window. Each of these areas was a sum of one or more trapezoids determined from the concentrations over the 7-day interval. The weekly AUCMB was calculated by subtracting the Week -1 HCV AUC (i.e., baseline) from the weekly HCV AUC and presented. | Baseline, Week 1 to Week 12 | 
| Cumulative Viral Absolute Area Under the HCV RNA Curve Minus Baseline Averaged Over the 12-week Period | The area under the HCV-RNA curve (HCV AUC) was calculated for each week as the area under the polygonal line defined by the HCV RNA values from the beginning of the window to the end of the window. Each of these areas was a sum of one or more trapezoids determined from the concentrations over the 7-day interval. The weekly AUCMB was calculated by subtracting the Week -1 HCV AUC (i.e., baseline) from the weekly HCV AUC. The HCV AUCMB to Week 12 was the sum of the 12 weekly HCV AUCMBs divided by the time (12 weeks). | Up to Week 12 | 
| Weekly Viral Absolute Area Under the HCV RNA Curve Estimated in the Frequent-sampling Cohort for Weeks 1 and 8 | The area under the HCV-RNA curve (HCV AUC) was defined as the area under the polygonal line defined by the HCV RNA values from the beginning of the window to the end of the window. For the frequent-sampling cohort, HCV AUCs over 7 days were calculated for Weeks 1 and 8, with intervals calculated beginning at the dose after which the frequent sampling began (different from the 7-day calendar period used for other AUC calculations). The AUCs for Weeks 1 and 8 in the frequent-sampling cohort (Sparse samples [SS] and frequent samples [FS]) were calculated using the trapezoidal rule. | Week 1 and Week 8 | 
| Percentage of Participants With a ≥ 2-log10 Decrease or Undetectable (< 60 International Units Per Milliliter) HCV RNA at Each Visit | The virological response was determined as the proportion/percentage of participants with a ≥ 2-log10 decrease or undetectable HCV RNA at each week. Detection of >= 2-log10 decrease of <60 IU/mL HCV-RNA was done by amplicor PCR assay at each week. Detection of >=2-log10 decrease or undetectable HCV RNA at Week 12 was considered an early virological response (EVR). | From Week 1 to Week 12 | 
| Percentage of Participants With Undetectable HCV RNA (< 60 International Units/Milliliter) at Each Visit | The viral load was determined quantitatively and qualitatively by HCV-polymerase chain reaction (PCR). Qualitative viral titers will be assessed by Roche amplicor HCV Monitor® test v2.0 (< 600 IU/mL). The virological response was determined as the percentage of participants with undetectable HCV RNA at each week. A <60 IU/mL HCV-RNA was measured by amplicor PCR assay. | From Week 1 to Week 12 | 
| Number of Participants With Marked Hematologic Abnormalities | The values outside the marked reference range for any hematology parameter that represents a defined, clinically relevant change from baseline are considered marked hematology abnormalities. The Roche standard reference ranges for the hematology parameters for which subjects had marked abnormalities were hematocrit [(RR) is 0.42 - 0.52 (fraction)], hemoglobin (RR is 13.0 - 18.0 gram/deciliter), platelets (RR is 150 - 450 10^9 cells/L), white blood cells (WBC) (RR is 4.3 - 10.8 10^9 cells/L), basophils (RR is 0.00 - 0.15 10^9 cells/L), lymphocytes (RR is 1.50 - 4.00 10^9 cells/L), monocytes (RR is 0.20 - 0.95 10^9 cells/L), neutrophils (RR is 1.83 - 7.25 10^9 cells/L), prothrombin time (PT) (RR is 9 - 13 seconds), partial thromboplastin time (Partial Throm.) (Time) (RR is 25.0 - 38.0 seconds) and PT International normalized ratio (INR) [RR is 0.70 - 1.30 (ratio)]. Summary data of number of participants with only marked hematology abnormalities are presented. | Baseline, up to Week 12 | 
| Number of Participants With Marked Biochemical Test Abnormalities | Values outside the marked RR for biochemical test parameters that represent a defined, clinically relevant change from baseline are considered marked biochemical test abnormalities. Roche's standard RR for biochemical parameters were used for this analysis. The biochemical test parameters with marked abnormalities were alanine aminotransferase (ALAT) (RR is 0 - 30 units per liter [U/L]), aspartate aminotransferase (ASAT) (RR is 0 - 25 U/L), gamma-glutamyl transferase (GGT) (RR is 0 - 60 U/L), total bilirubin (RR is 0 - 17 micromole/liter [umol/L]), creatinine (RR is 0 - 133 umol/L), total protein (RR is 60 - 80 g/L), triglycerides (RR is 0.45 - 1.70 millimole/liter [mmol/L]), chloride (RR is 100 - 108 mmol/L), potassium (RR is 3.5 - 5.0 mmol/L), sodium (RR is 133 - 145 mmol/L), calcium (RR is 2.10 - 2.60 mmol/L), random glucose (RR is 3.89 - 7.83 mmol/L), uric acid (140 - 500 umol/L). Summary data of number of participants with only marked biochemical test abnormalities are presented. | Baseline, up to Week 12 | 
| Number of Participants With Marked Abnormalities in Thyroid Function Tests | Values outside the marked reference ranges for thyroid function test parameters that represent a defined, clinically relevant change from baseline are considered marked thyroid function test abnormalities. Roche's standard reference ranges for thyroid function test parameters were used for the analysis. The thyroid function parameters with marked abnormalities were triiodothyronine (T3) (RR is 1.20 - 3.00 nanomole/liter [nmol/L]), thyroxine (T4) (RR is 51 - 154 nmol/L) and thyroid stimulating hormone (TSH) (RR is 0.0 - 5.0 milliunits per liter [mU/L]). Summary data of number of participants with only marked abnormalities in thyroid function tests are presented. | Baseline, up to Week 12 | 
| Mean Trough Interferon Concentrations at Each Week | The weekly Interferon (IFN) concentrations were calculated using the trapezoid rule. The trough IFN concentration was analyzed using an enzyme-linked immunosorbent assay (ELISA), with limits of quantification of 250 picograms per milliliter [pg/mL] for Pegasys and 150 pg/mL for PEG-Intron respectively. | From Week 1 to Week 12 | 
| Area Under the Curve for Interferon in the Frequent-Sampling Cohort | Area Under the Curve (AUC) for Interferon (IFN) for Week 1 and Week 8 in the frequent-sampling cohort were calculated using the trapezoidal rule. | Week 1 and Week 8 | 
| Number of Participants With Adverse Events and Serious Adverse Events | An adverse event (AE) was defined as any untoward medical occurrence in a subject who is administered a study treatment regardless of whether or not the event has a causal relationship with the treatment. An AE, therefore, could be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the study treatment, whether or not related to the treatment. A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect. Number of participants with at least one AE and SAE were reported. | Up to Week 12 | 
| Percentage of Participants With Each of the Identified HCV Quasispecies at Baseline and Weeks 1, 4, 8, and 12 | The determination of evolution of HCV quasispecies in participants was planned through analyzing viral sequences in serum samples drawn at baseline and at Weeks 1, 4, 8, and 12 if HCV RNA tests were positive and if the levels were sufficient to do the analysis. | Baseline, Weeks 1, 4,8, and 12 | 
| Weekly AUC for IFN Concentrations for Pegasys and PEG-Intron Estimated by Population Pharmacokinetic Modeling | The estimation of weekly AUC for IFN concentrations for Pegasys and PEG-Intron was planned through population pharmacokinetic modeling. A population pharmacokinetic method deals with modelling in a cohort which has many participants (usually more than 40). The estimation of weekly AUC for IFN concentrations for Pegasys and PEG-Intron was planned to be studied in the population rather than the individuals in Peginterferon alfa-2a + Ribavirin and Peginterferon alfa-2b + Ribavirin groups. | Up to Week 8 |