Hepatitis C, Chronic
Conditions
Brief summary
This study examined the influence of ribavirin on the initial virological response in treatment-naïve participants with chronic hepatitis C, genotype 1. Participants were randomized to 1 of 3 treatment groups to receive placebo, ribavirin monotherapy 1000 milligrams (mg) to 1200 mg orally daily depending on body weight or pegylated interferon (PEG-IFN) alfa-2a (Pegasys®) 180 micrograms (mcg) subcutaneously (SC) weekly, for 6 weeks. Following the initial 6 weeks, all participants received combination therapy with PEG-IFN alfa-2a plus ribavirin (Copegus®) for 12 weeks. If there was an initial virological response after 12 weeks of combination therapy, treatment could be continued for a further 36 weeks outside of the study.
Interventions
Pegylated interferon (PEG-IFN) alfa-2a (40 kilodalton \[KD\]) 180 microgram (mcg) subcutaneously (SC) weekly, for 6 weeks during monotherapy and/or 12 weeks during combination therapy.
DRUGPlacebo
Ribavirin matching placebo orally (PO) twice daily for 6 weeks.
DRUGRibavirin
Ribavirin, 1000 mg orally (PO) (400 mg in the morning \[=2 tablets\] and 600 mg in the evening \[=3 tablets\]) in participants with a body weight less than 75 kilogram (kg) or 1200 mg PO (600 mg at each time =3 tablets, in the morning and evening, respectively) in participants with a body weight greater than or equal to 75 kg, PO daily for 6 weeks during monotherapy and/or 12 weeks during combination therapy.
Sponsors
Roche Pharma AG
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Caucasians, male or female aged between 18 and 70 years * Indication: serological proof of a chronic hepatitis C infection with positive result of anti-Hepatitis C virus (HCV) test and detectable HCV- Ribo Nucleic Acid (RNA) in serum * Proven HCV genotype 1 by means of the reverse hybridization assays * Proven histological infection activity within the liver with or without proven compensated cirrhosis within the last 24 months prior to start of the study (Child-Pugh degree A) * Participants without previous anti-HCV therapy
Exclusion criteria
* Known hypersensitivity to interferon or ribavirin or any of the other component parts * Pregnant or nursing women, women with child bearing potential and without using a high effective method of contraception. The urine and serum pregnancy test at visit 0 in fertile participants or cohabitants of participants must show a negative result * Male partners of pregnant women * Infection with HCV genotype 2, 3, 4, 5, or 6 * Pretreatment with interferon and/or ribavirin * Immunocompromised participants * Treatment of systemic anti-neoplastic or immunomodulatoric medication (including supraphysiological doses of steroids or radiation therapy) within the last 6 months prior to the start of treatment and during the complete time interval of study treatment * Chronic hepatitis due to hepatitis C virus (e.g. haemochromatosis, autoimmunohepatitis, metabolic or alcohol-related liver disease) * Decompensated liver cirrhosis or liver disease Child-Pugh degree B or C or condition after decompensation * Signs of a hepatocellular carcinoma within 2 months prior to randomization in case of a cirrhosis or a transition to cirrhosis * Ascites or esophagus varices with bleedings as documented in anamnesis * Any medical condition that questions in the opinion of the investigator the participant's enrollment and participation in the trial * Hemoglobin \<13 grams/deciliter (g/dl) in females and \<14 g/dl in males in screening phase * Patients with an increased anemia risk (e.g. thalassemia, spherocytosis, etc.) or patients which would be at a particular medical risk in case of an anemia * Diagnosed neutropenia \<1.500/microliter (mcl) or thrombocytopenia \<90.000/mcl in screening phase
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Log Likelihood Median Values of Hepatitis C-Virus (HCV) Kinetic Models for Quantitative HCV Ribonucleic Acid (RNA) Measurement With Various Assumptions of Ribavirin Mechanism of Action | Up to Day 126 | To investigate possible action mechanisms, three different models were fitted to viruskinetic data and evaluated using related log-likelihood function values. These models were designed assuming individual effects with respect to infectiousness (model 1), virus production (model 2) or degradation of infected cells rate (model 3). The following viruskinetic parameters were fitted in each model: initial viral load, loss rate of infected cells (delta), effectivity of interferon with respect to a pharmacokinetic-pharmacodynamic model. A lower log likelihood function value indicates a lesser fit for the model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment Response | Up to Day 126 | HCV-RNA level was measured at each visit by a central laboratory. Treatment response was estimated applying the following definitions of response/non-response: 1) Adequate first phase decline: HCV RNA decline ≥ 0.5 log10 International Units/milliliter (IU/mL) from time 0 to 48 hours of PEG-IFN treatment (PEG-IFN arm: day 0 - day 2; placebo and ribavirin arm: day 42-day 44), 2) Rapid virologic response: HCV RNA \< 15 IU/mL (=detection limit) on day 70, 3) Complete early virologic response: HCV RNA \< 15 IU/mL on day 126, 4) Partial early virologic response (log decrease): HCV RNA decrease ≥ 2 log10 IU/mL from day 0 to day 126, 5) Partial early virologic response (cut off): HCV RNA \<30000 IU/mL on day 126, 6) Non-response: HCV RNA decrease \<2 log10 IU/mL from day 0 to day 126, 7) Null-response: HCV RNA decrease \<1 log10 IU/mL from day 0 to day 28 and from day 0 to day 70 for PEG-IFN arm and placebo / ribavirin arm, respectively. |
| Area Under the Concentration-Time Curve (AUC) of Ribavirin | From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126. | Evaluation of ribavirin arm after Day 0. Evaluation of placebo and PEG-IFN arms after Day 42. |
| Maximum Concentration (Cmax) of Ribavirin | From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126. | Cmax was obtained directly from the concentration-time data. Evaluation of ribavirin arm after day 0. Evaluation of placebo and PEG-IFN arms after day 42. |
| Time to Maximum Concentration (Tmax) of Ribavirin | From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126. | Tmax was obtained directly from the concentration-time data. Evaluation of ribavirin arm after day 0. Evaluation of placebo and PEG-IFN arms after day 42. |
| Area Under the Concentration-Time Curve (AUC) of PEG-IFN | From Day 0 at 0 hour (hr), 24 hr, 48 hr and 72 hr, Day 42 at 0 hr and 24 hr and at approximately every other visit up to Day 126 | Evaluation of PEG-IFN arm after Day 0. Evaluation of ribavirin and placebo arms after Day 42. |
| Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | At screening (Days -56 to -1), at end of monotherapy (Week 6) and at end of combination therapy (Week 18) | SF-36 is a psychometric scale to quantify health conditions. This psychometric scale has 8 dimensions of the subjective health status and consists of 36 individual items that have a varying number of related item scores (ranging from yes/no up to a 6-point scale). At first the raw scores were determined by summation over all items and weighted accordingly. Afterwards the raw scores were transformed to ranges of 0-100 with 100 being the highest level of health and compared to published reference scales. The following eight dimensions of subjective health conditions were considered: physical functioning index, role physical index, pain, general health perception, vitality, social functioning index, role emotional index and mental health index. The SF36 questionnaire had to be answered by the patients at screening before monotherapy, after monotherapy and at the end of the study (=end of combination therapy). |
| Time to Maximum Concentration (Tmax) of PEG-IFN | From Day 0 at 0 hour (hr), 24 hr, 48 hr and 72 hr, Day 42 at 0 hr and 24 hr and at approximately every other visit up to Day 126 | Tmax was obtained directly from the concentration-time data. Evaluation of PEG-IFN arm after day 0. Evaluation of ribavirin and placebo arms after day 42. |
| Area Under the Concentration-Time Curve (AUC) of Glutamate-Pyruvate Transaminase (GPT) | From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126. | — |
| Maximum Concentration (Cmax) of GPT | From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126. | Cmax was obtained directly from the concentration-time data. |
| Time to Maximum Concentration (Tmax) of GPT | From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126. | Tmax was obtained directly from the concentration-time data. |
| Maximum Concentration (Cmax) of PEG-IFN | From Day 0 at 0 hour (hr), 24 hr, 48 hr and 72 hr, Day 42 at 0 hr and 24 hr and at approximately every other visit up to Day 126 | Cmax was obtained directly from the concentration-time data. Evaluation of PEG-IFN arm after day 0. Evaluation of ribavirin and placebo arms after day 42. |
Countries
Germany
Participant flow
Pre-assignment details
Enrollment was 68: 1 participant withdrew during the screening phase and 67 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Pegylated Interferon (PEG-IFN) Alfa-2a Participants with chronic hepatitis C, genotype 1, received pegylated interferon (PEG-IFN) alfa-2a monotherapy for 6 weeks. Thereafter, all participants received combination therapy with PEG-IFN alfa-2a plus ribavirin for 12 weeks.
Pegylated Interferon (PEG-IFN) alfa-2a: Pegylated Interferon (PEG-IFN) alfa-2a (40KD) 180 microgram (mcg) subcutaneously (SC) weekly, for 6 weeks during monotherapy and/or 12 weeks during combination therapy.
Ribavirin: Ribavirin, 1000 mg PO (400 mg in the morning \[=2 tablets\] and 600 mg in the evening \[=3 tablets\]) in participants with a body weight less than 75 kilogram (kg) or 1200 mg PO (600 mg at each time =3 tablets, in the morning and evening, respectively) in participants with a body weight greater than or equal to 75 kg, PO daily for 6 weeks during monotherapy and/or 12 weeks during combination therapy. | 14 |
| Placebo Participants with chronic hepatitis C, genotype 1, received ribavirin matching placebo for 6 weeks. Thereafter, all participants received combination therapy with PEG-IFN alfa-2a plus ribavirin for 12 weeks.
Pegylated Interferon (PEG-IFN) alfa-2a: Pegylated Interferon (PEG-IFN) alfa-2a (40KD) 180 microgram (mcg) subcutaneously (SC) weekly, for 6 weeks during monotherapy and/or 12 weeks during combination therapy.
Placebo: Ribavirin matching placebo orally (PO) twice daily for 6 weeks.
Ribavirin: Ribavirin, 1000 mg PO (400 mg in the morning \[=2 tablets\] and 600 mg in the evening \[=3 tablets\]) in participants with a body weight less than 75 kilogram (kg) or 1200 mg PO (600 mg at each time =3 tablets, in the morning and evening, respectively) in participants with a body weight greater than or equal to 75 kg, PO daily for 6 weeks during monotherapy and/or 12 weeks during combination therapy. | 26 |
| Ribavirin Participants with chronic hepatitis C, genotype 1, received ribavirin monotherapy for 6 weeks. Thereafter, all participants received combination therapy with PEG-IFN alfa-2a plus ribavirin for 12 weeks.
Pegylated Interferon (PEG-IFN) alfa-2a: Pegylated Interferon (PEG-IFN) alfa-2a (40KD) 180 microgram (mcg) subcutaneously (SC) weekly, for 6 weeks during monotherapy and/or 12 weeks during combination therapy.
Ribavirin: Ribavirin, 1000 mg PO (400 mg in the morning \[=2 tablets\] and 600 mg in the evening \[=3 tablets\]) in participants with a body weight less than 75 kilogram (kg) or 1200 mg PO (600 mg at each time =3 tablets, in the morning and evening, respectively) in participants with a body weight greater than or equal to 75 kg, PO daily for 6 weeks during monotherapy and/or 12 weeks during combination therapy. | 27 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Combination Therapy | Adverse Event | 0 | 2 | 1 |
| Monotherapy | Adverse Event | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Pegylated Interferon (PEG-IFN) Alfa-2a | Placebo | Ribavirin | Total |
|---|---|---|---|---|
| Age, Continuous | 45.8 years STANDARD_DEVIATION 14.4 | 48.2 years STANDARD_DEVIATION 15.4 | 50.2 years STANDARD_DEVIATION 12.9 | 48.5 years STANDARD_DEVIATION 14.1 |
| Sex: Female, Male Female | 7 Participants | 18 Participants | 17 Participants | 42 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 10 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 14 | 9 / 26 | 12 / 27 | 12 / 14 | 23 / 25 | 24 / 26 |
| serious Total, serious adverse events | 0 / 14 | 1 / 26 | 0 / 27 | 0 / 14 | 2 / 25 | 2 / 26 |
Outcome results
Primary
Log Likelihood Median Values of Hepatitis C-Virus (HCV) Kinetic Models for Quantitative HCV Ribonucleic Acid (RNA) Measurement With Various Assumptions of Ribavirin Mechanism of Action
To investigate possible action mechanisms, three different models were fitted to viruskinetic data and evaluated using related log-likelihood function values. These models were designed assuming individual effects with respect to infectiousness (model 1), virus production (model 2) or degradation of infected cells rate (model 3). The following viruskinetic parameters were fitted in each model: initial viral load, loss rate of infected cells (delta), effectivity of interferon with respect to a pharmacokinetic-pharmacodynamic model. A lower log likelihood function value indicates a lesser fit for the model.
Time frame: Up to Day 126
Population: Per Protocol (PP) population: participants with 6 weeks of monotherapy and at least 4 weeks combination therapy as well as three quantitative HCV-RNA measurements (baseline, period 1, period 2), no major protocol violations, no treatment interruption and no dose reduction below 80% of the planned medication within the first 10 therapy weeks.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pegylated Interferon (PEG-IFN) Alfa-2a | Log Likelihood Median Values of Hepatitis C-Virus (HCV) Kinetic Models for Quantitative HCV Ribonucleic Acid (RNA) Measurement With Various Assumptions of Ribavirin Mechanism of Action | Model 1= infectiousness | -27.0 log likelihood function value |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Log Likelihood Median Values of Hepatitis C-Virus (HCV) Kinetic Models for Quantitative HCV Ribonucleic Acid (RNA) Measurement With Various Assumptions of Ribavirin Mechanism of Action | Model 3= degradation rate | -27.1 log likelihood function value |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Log Likelihood Median Values of Hepatitis C-Virus (HCV) Kinetic Models for Quantitative HCV Ribonucleic Acid (RNA) Measurement With Various Assumptions of Ribavirin Mechanism of Action | Model 2= virus production | -28.2 log likelihood function value |
| Ribavirin | Log Likelihood Median Values of Hepatitis C-Virus (HCV) Kinetic Models for Quantitative HCV Ribonucleic Acid (RNA) Measurement With Various Assumptions of Ribavirin Mechanism of Action | Model 2= virus production | -23.8 log likelihood function value |
| Ribavirin | Log Likelihood Median Values of Hepatitis C-Virus (HCV) Kinetic Models for Quantitative HCV Ribonucleic Acid (RNA) Measurement With Various Assumptions of Ribavirin Mechanism of Action | Model 3= degradation rate | -20.7 log likelihood function value |
| Ribavirin | Log Likelihood Median Values of Hepatitis C-Virus (HCV) Kinetic Models for Quantitative HCV Ribonucleic Acid (RNA) Measurement With Various Assumptions of Ribavirin Mechanism of Action | Model 1= infectiousness | -21.4 log likelihood function value |
| Total Participant Group | Log Likelihood Median Values of Hepatitis C-Virus (HCV) Kinetic Models for Quantitative HCV Ribonucleic Acid (RNA) Measurement With Various Assumptions of Ribavirin Mechanism of Action | Model 2= virus production | -23.9 log likelihood function value |
| Total Participant Group | Log Likelihood Median Values of Hepatitis C-Virus (HCV) Kinetic Models for Quantitative HCV Ribonucleic Acid (RNA) Measurement With Various Assumptions of Ribavirin Mechanism of Action | Model 3= degradation rate | -23.1 log likelihood function value |
| Total Participant Group | Log Likelihood Median Values of Hepatitis C-Virus (HCV) Kinetic Models for Quantitative HCV Ribonucleic Acid (RNA) Measurement With Various Assumptions of Ribavirin Mechanism of Action | Model 1= infectiousness | -22.2 log likelihood function value |
Secondary
Area Under the Concentration-Time Curve (AUC) of Glutamate-Pyruvate Transaminase (GPT)
Time frame: From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126.
Population: All evaluable participants of the ITT population, who were documented for a total of 126 days of the treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pegylated Interferon (PEG-IFN) Alfa-2a | Area Under the Concentration-Time Curve (AUC) of Glutamate-Pyruvate Transaminase (GPT) | 5078.3 (Units/liter)*day ([U/L]*d) |
| Ribavirin | Area Under the Concentration-Time Curve (AUC) of Glutamate-Pyruvate Transaminase (GPT) | 7233.5 (Units/liter)*day ([U/L]*d) |
| Total Participant Group | Area Under the Concentration-Time Curve (AUC) of Glutamate-Pyruvate Transaminase (GPT) | 5231.3 (Units/liter)*day ([U/L]*d) |
Secondary
Area Under the Concentration-Time Curve (AUC) of PEG-IFN
Evaluation of PEG-IFN arm after Day 0. Evaluation of ribavirin and placebo arms after Day 42.
Time frame: From Day 0 at 0 hour (hr), 24 hr, 48 hr and 72 hr, Day 42 at 0 hr and 24 hr and at approximately every other visit up to Day 126
Population: All evaluable participants of the ITT population, who were documented for a total of 126 days of the treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pegylated Interferon (PEG-IFN) Alfa-2a | Area Under the Concentration-Time Curve (AUC) of PEG-IFN | 2097.9 (nanogram/milliliter)*day ([ng/ml]*d) |
| Ribavirin | Area Under the Concentration-Time Curve (AUC) of PEG-IFN | 1270.4 (nanogram/milliliter)*day ([ng/ml]*d) |
| Total Participant Group | Area Under the Concentration-Time Curve (AUC) of PEG-IFN | 1164.9 (nanogram/milliliter)*day ([ng/ml]*d) |
Secondary
Area Under the Concentration-Time Curve (AUC) of Ribavirin
Evaluation of ribavirin arm after Day 0. Evaluation of placebo and PEG-IFN arms after Day 42.
Time frame: From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126.
Population: All evaluable participants of the ITT population, who were documented for a total of 126 days of the treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pegylated Interferon (PEG-IFN) Alfa-2a | Area Under the Concentration-Time Curve (AUC) of Ribavirin | 186.6 (microgram/milliliter)*day ([mcg/ml]*d) |
| Ribavirin | Area Under the Concentration-Time Curve (AUC) of Ribavirin | 179.4 (microgram/milliliter)*day ([mcg/ml]*d) |
| Total Participant Group | Area Under the Concentration-Time Curve (AUC) of Ribavirin | 290.1 (microgram/milliliter)*day ([mcg/ml]*d) |
Secondary
Maximum Concentration (Cmax) of GPT
Cmax was obtained directly from the concentration-time data.
Time frame: From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126.
Population: All evaluable participants of the ITT population, who were documented for a total of 126 days of the treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pegylated Interferon (PEG-IFN) Alfa-2a | Maximum Concentration (Cmax) of GPT | 68.5 U/L |
| Ribavirin | Maximum Concentration (Cmax) of GPT | 88.0 U/L |
| Total Participant Group | Maximum Concentration (Cmax) of GPT | 75.0 U/L |
Secondary
Maximum Concentration (Cmax) of PEG-IFN
Cmax was obtained directly from the concentration-time data. Evaluation of PEG-IFN arm after day 0. Evaluation of ribavirin and placebo arms after day 42.
Time frame: From Day 0 at 0 hour (hr), 24 hr, 48 hr and 72 hr, Day 42 at 0 hr and 24 hr and at approximately every other visit up to Day 126
Population: All evaluable participants of the ITT population, who were documented for a total of 126 days of the treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pegylated Interferon (PEG-IFN) Alfa-2a | Maximum Concentration (Cmax) of PEG-IFN | 28.77 ng/ml |
| Ribavirin | Maximum Concentration (Cmax) of PEG-IFN | 20.36 ng/ml |
| Total Participant Group | Maximum Concentration (Cmax) of PEG-IFN | 19.8 ng/ml |
Secondary
Maximum Concentration (Cmax) of Ribavirin
Cmax was obtained directly from the concentration-time data. Evaluation of ribavirin arm after day 0. Evaluation of placebo and PEG-IFN arms after day 42.
Time frame: From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126.
Population: All evaluable participants of the ITT population, who were documented for a total of 126 days of the treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pegylated Interferon (PEG-IFN) Alfa-2a | Maximum Concentration (Cmax) of Ribavirin | 2.95 mcg/ml |
| Ribavirin | Maximum Concentration (Cmax) of Ribavirin | 2.83 mcg/ml |
| Total Participant Group | Maximum Concentration (Cmax) of Ribavirin | 3.37 mcg/ml |
Secondary
Percentage of Participants With Treatment Response
HCV-RNA level was measured at each visit by a central laboratory. Treatment response was estimated applying the following definitions of response/non-response: 1) Adequate first phase decline: HCV RNA decline ≥ 0.5 log10 International Units/milliliter (IU/mL) from time 0 to 48 hours of PEG-IFN treatment (PEG-IFN arm: day 0 - day 2; placebo and ribavirin arm: day 42-day 44), 2) Rapid virologic response: HCV RNA \< 15 IU/mL (=detection limit) on day 70, 3) Complete early virologic response: HCV RNA \< 15 IU/mL on day 126, 4) Partial early virologic response (log decrease): HCV RNA decrease ≥ 2 log10 IU/mL from day 0 to day 126, 5) Partial early virologic response (cut off): HCV RNA \<30000 IU/mL on day 126, 6) Non-response: HCV RNA decrease \<2 log10 IU/mL from day 0 to day 126, 7) Null-response: HCV RNA decrease \<1 log10 IU/mL from day 0 to day 28 and from day 0 to day 70 for PEG-IFN arm and placebo / ribavirin arm, respectively.
Time frame: Up to Day 126
Population: All evaluable participants of the Intent-to-Treat (ITT) population, who were documented for a total of 126 days of the treatment period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pegylated Interferon (PEG-IFN) Alfa-2a | Percentage of Participants With Treatment Response | Complete early virologic response | 64 percentage of participants |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Percentage of Participants With Treatment Response | Adequate first phase decline | 79 percentage of participants |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Percentage of Participants With Treatment Response | Partial early virologic response (cut off) | 79 percentage of participants |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Percentage of Participants With Treatment Response | Partial early virologic response (log decrease) | 79 percentage of participants |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Percentage of Participants With Treatment Response | Null responder | 36 percentage of participants |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Percentage of Participants With Treatment Response | Non-response | 21 percentage of participants |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Percentage of Participants With Treatment Response | Rapid virologic response | 43 percentage of participants |
| Ribavirin | Percentage of Participants With Treatment Response | Null responder | 26 percentage of participants |
| Ribavirin | Percentage of Participants With Treatment Response | Rapid virologic response | 30 percentage of participants |
| Ribavirin | Percentage of Participants With Treatment Response | Adequate first phase decline | 65 percentage of participants |
| Ribavirin | Percentage of Participants With Treatment Response | Complete early virologic response | 48 percentage of participants |
| Ribavirin | Percentage of Participants With Treatment Response | Partial early virologic response (log decrease) | 78 percentage of participants |
| Ribavirin | Percentage of Participants With Treatment Response | Partial early virologic response (cut off) | 78 percentage of participants |
| Ribavirin | Percentage of Participants With Treatment Response | Non-response | 22 percentage of participants |
| Total Participant Group | Percentage of Participants With Treatment Response | Null responder | 12 percentage of participants |
| Total Participant Group | Percentage of Participants With Treatment Response | Partial early virologic response (cut off) | 84 percentage of participants |
| Total Participant Group | Percentage of Participants With Treatment Response | Adequate first phase decline | 72 percentage of participants |
| Total Participant Group | Percentage of Participants With Treatment Response | Rapid virologic response | 20 percentage of participants |
| Total Participant Group | Percentage of Participants With Treatment Response | Non-response | 16 percentage of participants |
| Total Participant Group | Percentage of Participants With Treatment Response | Partial early virologic response (log decrease) | 84 percentage of participants |
| Total Participant Group | Percentage of Participants With Treatment Response | Complete early virologic response | 72 percentage of participants |
Secondary
Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire
SF-36 is a psychometric scale to quantify health conditions. This psychometric scale has 8 dimensions of the subjective health status and consists of 36 individual items that have a varying number of related item scores (ranging from yes/no up to a 6-point scale). At first the raw scores were determined by summation over all items and weighted accordingly. Afterwards the raw scores were transformed to ranges of 0-100 with 100 being the highest level of health and compared to published reference scales. The following eight dimensions of subjective health conditions were considered: physical functioning index, role physical index, pain, general health perception, vitality, social functioning index, role emotional index and mental health index. The SF36 questionnaire had to be answered by the patients at screening before monotherapy, after monotherapy and at the end of the study (=end of combination therapy).
Time frame: At screening (Days -56 to -1), at end of monotherapy (Week 6) and at end of combination therapy (Week 18)
Population: Intent-to-treat (ITT) population includes all randomized participants who received at least one dose of study drug. Here, 'n' is the number of evaluable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Physical functioning index: End of comb. therapy | 67.1 units on a scale | Standard Deviation 20.7 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | General health perception: Screening | 58.6 units on a scale | Standard Deviation 12.9 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role physical index: Screening | 75.0 units on a scale | Standard Deviation 41.8 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role physical index: End of monotherapy | 66.7 units on a scale | Standard Deviation 34.2 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | General health perception: End of monotherapy | 58.2 units on a scale | Standard Deviation 7.6 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Pain: End of combination therapy | 72.3 units on a scale | Standard Deviation 32.2 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role emotional index: Screening | 55.6 units on a scale | Standard Deviation 50.2 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | General health perception: End of comb. therapy | 60.0 units on a scale | Standard Deviation 14.3 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Mental health index: End of combination therapy | 72.2 units on a scale | Standard Deviation 9 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role emotional index: End of combination therapy | 33.3 units on a scale | Standard Deviation 51.6 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Vitality: Screening | 54.2 units on a scale | Standard Deviation 9.2 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Social functioning index: End of comb. therapy | 68.8 units on a scale | Standard Deviation 23.4 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role physical index: End of combination therapy | 25.0 units on a scale | Standard Deviation 38.7 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Vitality: End of monotherapy | 45.0 units on a scale | Standard Deviation 15.2 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Pain: End of monotherapy | 73.2 units on a scale | Standard Deviation 23.3 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role emotional index: End of monotherapy | 55.6 units on a scale | Standard Deviation 50.2 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Vitality: End of combination therapy | 40.8 units on a scale | Standard Deviation 14.6 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Mental health index: End of monotherapy | 61.3 units on a scale | Standard Deviation 12.3 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Physical functioning index: End of monotherapy | 90.8 units on a scale | Standard Deviation 9.2 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Social functioning index: Screening | 75.0 units on a scale | Standard Deviation 23.7 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Mental health index: Screening | 68.5 units on a scale | Standard Deviation 9.1 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Pain: Screening | 89.3 units on a scale | Standard Deviation 17 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Social functioning index: End of monotherapy | 72.9 units on a scale | Standard Deviation 22.9 |
| Pegylated Interferon (PEG-IFN) Alfa-2a | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Physical functioning index: Screening | 95.6 units on a scale | Standard Deviation 5.2 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Social functioning index: End of monotherapy | 68.2 units on a scale | Standard Deviation 24 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Social functioning index: End of comb. therapy | 61.3 units on a scale | Standard Deviation 19.9 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role emotional index: Screening | 66.7 units on a scale | Standard Deviation 50 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role emotional index: End of monotherapy | 69.7 units on a scale | Standard Deviation 45.8 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Pain: End of monotherapy | 61.5 units on a scale | Standard Deviation 27.4 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role emotional index: End of combination therapy | 50.0 units on a scale | Standard Deviation 42.3 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role physical index: Screening | 55.6 units on a scale | Standard Deviation 41 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Mental health index: Screening | 63.1 units on a scale | Standard Deviation 18.1 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Pain: End of combination therapy | 56.0 units on a scale | Standard Deviation 11.8 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Mental health index: End of combination therapy | 61.6 units on a scale | Standard Deviation 13.2 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Physical functioning index: Screening | 76.5 units on a scale | Standard Deviation 20.2 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Physical functioning index: End of monotherapy | 72.3 units on a scale | Standard Deviation 28.1 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Mental health index: End of monotherapy | 62.8 units on a scale | Standard Deviation 14 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | General health perception: Screening | 53.6 units on a scale | Standard Deviation 14.5 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | General health perception: End of monotherapy | 59.2 units on a scale | Standard Deviation 16.9 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role physical index: End of monotherapy | 56.8 units on a scale | Standard Deviation 43.4 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | General health perception: End of comb. therapy | 55.2 units on a scale | Standard Deviation 15 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Physical functioning index: End of comb. therapy | 73.0 units on a scale | Standard Deviation 14 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Vitality: Screening | 52.8 units on a scale | Standard Deviation 21.5 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Vitality: End of monotherapy | 44.1 units on a scale | Standard Deviation 16.3 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role physical index: End of combination therapy | 40.0 units on a scale | Standard Deviation 35.7 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Vitality: End of combination therapy | 32.5 units on a scale | Standard Deviation 12.1 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Social functioning index: Screening | 79.2 units on a scale | Standard Deviation 24.2 |
| Ribavirin | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Pain: Screening | 70.3 units on a scale | Standard Deviation 26.8 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Mental health index: End of combination therapy | 47.7 units on a scale | Standard Deviation 23 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Physical functioning index: Screening | 79.7 units on a scale | Standard Deviation 28.7 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Physical functioning index: End of monotherapy | 68.4 units on a scale | Standard Deviation 27.7 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Physical functioning index: End of comb. therapy | 53.4 units on a scale | Standard Deviation 31.5 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role physical index: Screening | 62.5 units on a scale | Standard Deviation 40.8 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role physical index: End of monotherapy | 50.5 units on a scale | Standard Deviation 40.5 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role physical index: End of combination therapy | 29.7 units on a scale | Standard Deviation 40 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Pain: Screening | 70.0 units on a scale | Standard Deviation 30.8 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Pain: End of monotherapy | 66.0 units on a scale | Standard Deviation 29.6 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Pain: End of combination therapy | 60.1 units on a scale | Standard Deviation 34.8 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | General health perception: Screening | 62.9 units on a scale | Standard Deviation 14.5 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | General health perception: End of monotherapy | 54.3 units on a scale | Standard Deviation 18 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | General health perception: End of comb. therapy | 47.1 units on a scale | Standard Deviation 20.6 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Vitality: Screening | 50.9 units on a scale | Standard Deviation 18.9 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Vitality: End of monotherapy | 41.8 units on a scale | Standard Deviation 20.1 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Vitality: End of combination therapy | 39.8 units on a scale | Standard Deviation 16.1 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Social functioning index: Screening | 83.8 units on a scale | Standard Deviation 20.6 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Social functioning index: End of monotherapy | 80.1 units on a scale | Standard Deviation 22.6 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Social functioning index: End of comb. therapy | 56.3 units on a scale | Standard Deviation 25.8 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role emotional index: Screening | 62.5 units on a scale | Standard Deviation 43.7 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role emotional index: End of monotherapy | 53.3 units on a scale | Standard Deviation 51.6 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Role emotional index: End of combination therapy | 35.4 units on a scale | Standard Deviation 39.4 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Mental health index: Screening | 64.5 units on a scale | Standard Deviation 15.4 |
| Total Participant Group | Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | Mental health index: End of monotherapy | 61.5 units on a scale | Standard Deviation 19.7 |
Secondary
Time to Maximum Concentration (Tmax) of GPT
Tmax was obtained directly from the concentration-time data.
Time frame: From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126.
Population: All evaluable participants of the ITT population, who were documented for a total of 126 days of the treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pegylated Interferon (PEG-IFN) Alfa-2a | Time to Maximum Concentration (Tmax) of GPT | 2.8 days |
| Ribavirin | Time to Maximum Concentration (Tmax) of GPT | 14.0 days |
| Total Participant Group | Time to Maximum Concentration (Tmax) of GPT | 3.0 days |
Secondary
Time to Maximum Concentration (Tmax) of PEG-IFN
Tmax was obtained directly from the concentration-time data. Evaluation of PEG-IFN arm after day 0. Evaluation of ribavirin and placebo arms after day 42.
Time frame: From Day 0 at 0 hour (hr), 24 hr, 48 hr and 72 hr, Day 42 at 0 hr and 24 hr and at approximately every other visit up to Day 126
Population: All evaluable participants of the ITT population, who were documented for a total of 126 days of the treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pegylated Interferon (PEG-IFN) Alfa-2a | Time to Maximum Concentration (Tmax) of PEG-IFN | 6.3 weeks |
| Ribavirin | Time to Maximum Concentration (Tmax) of PEG-IFN | 12.0 weeks |
| Total Participant Group | Time to Maximum Concentration (Tmax) of PEG-IFN | 6.0 weeks |
Secondary
Time to Maximum Concentration (Tmax) of Ribavirin
Tmax was obtained directly from the concentration-time data. Evaluation of ribavirin arm after day 0. Evaluation of placebo and PEG-IFN arms after day 42.
Time frame: From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126.
Population: All evaluable participants of the ITT population, who were documented for a total of 126 days of the treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pegylated Interferon (PEG-IFN) Alfa-2a | Time to Maximum Concentration (Tmax) of Ribavirin | 6.0 weeks |
| Ribavirin | Time to Maximum Concentration (Tmax) of Ribavirin | 8.0 weeks |
| Total Participant Group | Time to Maximum Concentration (Tmax) of Ribavirin | 6.4 weeks |