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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
385
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.
Time frame: From Baseline to Week 12
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.
Time frame: 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.
Time frame: Baseline, up to Week 12
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180 micrograms sc weekly
Unnamed facility
Birmingham, Alabama, United States
Unnamed facility
Little Rock, Arkansas, United States
Unnamed facility
Sacramento, California, United States
Unnamed facility
San Diego, California, United States
Unnamed facility
San Diego, California, United States
Unnamed facility
San Francisco, California, United States
Unnamed facility
San Mateo, California, United States
Unnamed facility
San Rafael, California, United States
Unnamed facility
Farmington, Connecticut, United States
Unnamed facility
Hartford, Connecticut, United States
...and 31 more locations
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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Up to Week 8