Hepatitis C, Chronic
Conditions
Brief summary
This 4 arm study is designed for patients with CHC who have not responded to peginterferon alfa-2b (12KD)/ribavirin combination therapy. In these patients, the effects of lengthening the duration of treatment, as well as including an initial 12-week period of high-dose PEGASYS (360 micrograms sc), are compared with the standard combination therapy of PEGASYS (180 micrograms sc) and ribavirin (1000-1200mg po). The anticipated time on study treatment is 1-2 years and the target sample size is 500+ individuals.
Interventions
DRUGRibavirin
1000/1200mg po daily for 72 weeks
DRUGpeginterferon alfa-2a [Pegasys]
360 micrograms sc weekly for 12 weeks, followed by 180 micrograms sc weekly for 60 weeks
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* adult patients \>=18 years of age; * CHC infection; * liver biopsy (in \<24 calendar months of first dose), with results consistent with CHC infection; * use of 2 forms of contraception during study and 6 months after the study in both men and women; * Lack of response to previous treatment with peginterferon alfa-2b (12KD)/ribavirin combination therapy given for \>=12 weeks.
Exclusion criteria
* women who are pregnant or breastfeeding; * male partners of women who are pregnant; * conditions associated with decompensated liver disease; * other forms of liver disease, including liver cancer; * human immunodeficiency virus infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Sustained Virological Response Rate | Up to 72 weeks (Group A) and 48 weeks (Group D) | Sustained Virological Response (SVR) was defined as the percentage of participants with a undetectable hepatitis C virus- ribonucleic acid (HCV RNA) 24 weeks after the end of the treatment period (defined as a single last HCV RNA \< 50 International Units Per Millilitre (IU/mL) measured \>= 20 weeks after treatment end, ie, \>=140 days after treatment end. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Sustained Virological Response (Groups A + C vs Groups B + D) | At Week 48 and Week 72 | SVR was defined as the percentage of participants with a undetectable hepatitis C virus- ribonucleic acid (HCV RNA) 24 weeks after the end of the treatment period (defined as a single last HCV RNA \< 50 International Units Per Millilitre (IU/mL) measured \>= 20 weeks after treatment end, ie, \>=140 days after treatment end. |
| Percentage of Participants With Undetectable HCV-RNA | At Week 12, 24, 48 and EOT | The percentage of participants with a undetectable HCV RNA 24 weeks after the end of the treatment period (defined as a single last HCV RNA \< 50 IU/mL measured \>= 20 weeks after treatment end, ie, \>=140 days after treatment end) are reported. End-of-treatment (EOT) virological response is defined as last HCV RNA measurement that is not detectable (\<50 IU/mL) at study day of last dose of study medication (+/- 28 days). |
| Percentage of Participants With >=2log Drop in HCV-RNA | At Week 12 and 24 | Reduction in HCV-RNA titers of at least 2 log10 after 12/24 weeks of study treatment (i.e. 99% reduction of viral load) was analyzed. Percentage of participants with at least a 2 log10 drop of HCV-RNA at study week 12 and 24 (lower limit of quantitation 600 IU/mL) as compared to baseline or non-detectable HCV-RNA (lower limit of detection 50 IU/mL) were reported. |
| Number of Participants With Sustained Virological Response (Groups A + B vs Groups C + D) | At Week 48 and Week 72 | SVR was defined as the percentage of participants with a undetectable hepatitis C virus- ribonucleic acid (HCV RNA) 24 weeks after the end of the treatment period (defined as a single last HCV RNA \< 50 International Units Per Millilitre (IU/mL) measured \>= 20 weeks after treatment end, ie, \>=140 days after treatment end. |
| Percentage of Participants With Maintenance of Actual End-of-Treatment Virological Response | Week 96 (Group A and C) and Week 72 (Group B and D) | Maintenance of end-of-treatment virological response was assessed based on all participants treated and according to the actual treatment period (backward imputation method). The percentage of participants who maintained their end-of-treatment virological response was determined. Maintenance of actual end-of-treatment virological response was calculated by dividing the number of participants with a virological response both at the end of the actual untreated follow-up period and at the end of the actual treatment period by the number of participants with a virological response at the actual end of treatment. |
| Percentage of Participants With Relapse After End of Treatment | Week 96 (Group A and C) and Week 72 (Group B and D) | The percentage of participants who relapsed (loss of response) after having achieved a virological response at the end of treatment was determined. |
| Change From Baseline in Reduction of HCV Viremia (Groups A + B vs Groups C + D) | At Week 12 and 24 | The mean change from baseline in HCV RNA level (reduction in viral load) at Week 12 and 24 were determined. HCV RNA result were not detectable (\<50 IU/ML) and not quantifiable (\<600 IU/ML). Baseline value were assessed on Day 1 before the administration of the first dose of study drug. |
Countries
Belgium, Brazil, Canada, France, Germany, Greece, Italy, Portugal, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
The study was conducted from 16 September 2003 to 27 February 2007. Participants were recruited over a total of 106 centers \[(United States (37), Germany (19), Spain (10), France (9), Italy (7), Greece (5), Turkey (4), Belgium (3), Canada (3), Portugal (3), Sweden (3), Brazil (1), Switzerland (1), and UK (1)\] in the study.
Pre-assignment details
A total of 950 participants were randomized (318, 158, 158, and 316 in groups A, B, C, and D, respectively), 942 received the study medication. A total of 8 randomized participants did not receive study drug for various reasons which includes withdrew consent (5), violated the study entry criteria (1), and two had other protocol violations.
Participants by arm
| Arm | Count |
|---|---|
| Group A Participants received 360 microgram (mcg) of peginterferon alfa-2a (PEG-IFN alfa-2a) once weekly plus 1000/1200 mg of ribavirin daily for 12 weeks, and thereafter 180 mcg of PEG-IFN alfa-2a once weekly plus 1000/1200 mg of ribavirin daily for 60 weeks. | 317 |
| Group B Participants received 360 mcg of PEG-IFN alfa-2a once weekly plus 1000/1200 mg of ribavirin daily for 12 weeks, and thereafter 180 mcg of PEG-IFN alfa-2a once weekly plus 1000/1200 mg of ribavirin daily for 36 weeks. | 156 |
| Group C Participants received 180 mcg of PEG-IFN alfa-2a once weekly plus 1000/1200 mg of ribavirin daily for 72 weeks. | 156 |
| Group D Participants received 180 mcg of PEG-IFN alfa-2a once weekly plus 1000/1200 mg of ribavirin daily for 48 weeks. | 313 |
| Total | 942 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Administrative/Other | 6 | 1 | 1 | 2 |
| Overall Study | Adverse Event | 37 | 6 | 18 | 20 |
| Overall Study | Death | 0 | 1 | 0 | 0 |
| Overall Study | Failure to Return | 5 | 2 | 2 | 3 |
| Overall Study | Insufficient therapeutic response | 64 | 24 | 38 | 51 |
| Overall Study | Other Protocol Violation | 3 | 1 | 0 | 0 |
| Overall Study | Refused Treatment/Did Not Cooperate | 13 | 6 | 4 | 5 |
| Overall Study | Violation of Selection Criteria at Entry | 1 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 1 | 2 | 2 |
Baseline characteristics
| Characteristic | Group A | Group B | Group C | Group D | Total |
|---|---|---|---|---|---|
| Age, Continuous | 48.1 years STANDARD_DEVIATION 8.73 | 48.8 years STANDARD_DEVIATION 9.93 | 49.4 years STANDARD_DEVIATION 8.46 | 48.5 years STANDARD_DEVIATION 8.97 | 48.6 years STANDARD_DEVIATION 8.97 |
| Sex: Female, Male Female | 114 Participants | 62 Participants | 49 Participants | 101 Participants | 326 Participants |
| Sex: Female, Male Male | 203 Participants | 94 Participants | 107 Participants | 212 Participants | 616 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 306 / 317 | 151 / 156 | 150 / 156 | 298 / 313 |
| serious Total, serious adverse events | 33 / 317 | 14 / 156 | 28 / 156 | 33 / 313 |
Outcome results
Primary
Number of Participants With Sustained Virological Response Rate
Sustained Virological Response (SVR) was defined as the percentage of participants with a undetectable hepatitis C virus- ribonucleic acid (HCV RNA) 24 weeks after the end of the treatment period (defined as a single last HCV RNA \< 50 International Units Per Millilitre (IU/mL) measured \>= 20 weeks after treatment end, ie, \>=140 days after treatment end.
Time frame: Up to 72 weeks (Group A) and 48 weeks (Group D)
Population: Intent-to-treat analysis population (ITT) included, all participants randomized who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A | Number of Participants With Sustained Virological Response Rate | 52 participants |
| Group D | Number of Participants With Sustained Virological Response Rate | 27 participants |
Comparison: Group A Vs Group Dp-value: 0.00695% CI: [1.21, 3.31]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Reduction of HCV Viremia (Groups A + B vs Groups C + D)
The mean change from baseline in HCV RNA level (reduction in viral load) at Week 12 and 24 were determined. HCV RNA result were not detectable (\<50 IU/ML) and not quantifiable (\<600 IU/ML). Baseline value were assessed on Day 1 before the administration of the first dose of study drug.
Time frame: At Week 12 and 24
Population: ITT population included all participants randomized who received at least one dose of study medication.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Group A | Change From Baseline in Reduction of HCV Viremia (Groups A + B vs Groups C + D) | HCV RNA Change from BL to Week 12 (n= 424, 421) | -2.75 IU/ML |
| Group A | Change From Baseline in Reduction of HCV Viremia (Groups A + B vs Groups C + D) | HCV RNA Change from BL to Week 24 (n= 390, 399) | -2.88 IU/ML |
| Group D | Change From Baseline in Reduction of HCV Viremia (Groups A + B vs Groups C + D) | HCV RNA Change from BL to Week 12 (n= 424, 421) | -2.18 IU/ML |
| Group D | Change From Baseline in Reduction of HCV Viremia (Groups A + B vs Groups C + D) | HCV RNA Change from BL to Week 24 (n= 390, 399) | -2.64 IU/ML |
Secondary
Number of Participants With Sustained Virological Response (Groups A + B vs Groups C + D)
SVR was defined as the percentage of participants with a undetectable hepatitis C virus- ribonucleic acid (HCV RNA) 24 weeks after the end of the treatment period (defined as a single last HCV RNA \< 50 International Units Per Millilitre (IU/mL) measured \>= 20 weeks after treatment end, ie, \>=140 days after treatment end.
Time frame: At Week 48 and Week 72
Population: ITT population included all participants randomized who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A | Number of Participants With Sustained Virological Response (Groups A + B vs Groups C + D) | 63 participants |
| Group D | Number of Participants With Sustained Virological Response (Groups A + B vs Groups C + D) | 49 participants |
p-value: 0.922895% CI: [0.63, 1.51]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Sustained Virological Response (Groups A + C vs Groups B + D)
SVR was defined as the percentage of participants with a undetectable hepatitis C virus- ribonucleic acid (HCV RNA) 24 weeks after the end of the treatment period (defined as a single last HCV RNA \< 50 International Units Per Millilitre (IU/mL) measured \>= 20 weeks after treatment end, ie, \>=140 days after treatment end.
Time frame: At Week 48 and Week 72
Population: ITT population included all participants randomized who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A | Number of Participants With Sustained Virological Response (Groups A + C vs Groups B + D) | 74 participants |
| Group D | Number of Participants With Sustained Virological Response (Groups A + C vs Groups B + D) | 38 participants |
p-value: 0.000695% CI: [1.4, 3.52]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With >=2log Drop in HCV-RNA
Reduction in HCV-RNA titers of at least 2 log10 after 12/24 weeks of study treatment (i.e. 99% reduction of viral load) was analyzed. Percentage of participants with at least a 2 log10 drop of HCV-RNA at study week 12 and 24 (lower limit of quantitation 600 IU/mL) as compared to baseline or non-detectable HCV-RNA (lower limit of detection 50 IU/mL) were reported.
Time frame: At Week 12 and 24
Population: ITT population included all the participants randomized who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A | Percentage of Participants With >=2log Drop in HCV-RNA | Week 12 | 62 percentage of participants |
| Group A | Percentage of Participants With >=2log Drop in HCV-RNA | Week 24 | 51 percentage of participants |
| Group D | Percentage of Participants With >=2log Drop in HCV-RNA | Week 12 | 42 percentage of participants |
| Group D | Percentage of Participants With >=2log Drop in HCV-RNA | Week 24 | 47 percentage of participants |
Comparison: Groups A vs Groups D (Week 12)p-value: <0.000195% CI: [1.67, 3.19]Cochran-Mantel-Haenszel
Comparison: Groups A vs Groups D (Week 24)p-value: 0.338995% CI: [0.85, 1.6]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Maintenance of Actual End-of-Treatment Virological Response
Maintenance of end-of-treatment virological response was assessed based on all participants treated and according to the actual treatment period (backward imputation method). The percentage of participants who maintained their end-of-treatment virological response was determined. Maintenance of actual end-of-treatment virological response was calculated by dividing the number of participants with a virological response both at the end of the actual untreated follow-up period and at the end of the actual treatment period by the number of participants with a virological response at the actual end of treatment.
Time frame: Week 96 (Group A and C) and Week 72 (Group B and D)
Population: ITT population included all participants randomized who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A | Percentage of Participants With Maintenance of Actual End-of-Treatment Virological Response | 51 percentage of participants |
| Group D | Percentage of Participants With Maintenance of Actual End-of-Treatment Virological Response | 22 percentage of participants |
| Group C | Percentage of Participants With Maintenance of Actual End-of-Treatment Virological Response | 41 percentage of participants |
| Group D | Percentage of Participants With Maintenance of Actual End-of-Treatment Virological Response | 33 percentage of participants |
Secondary
Percentage of Participants With Relapse After End of Treatment
The percentage of participants who relapsed (loss of response) after having achieved a virological response at the end of treatment was determined.
Time frame: Week 96 (Group A and C) and Week 72 (Group B and D)
Population: ITT population included all participants randomized who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A | Percentage of Participants With Relapse After End of Treatment | 49 percentage of participants |
| Group D | Percentage of Participants With Relapse After End of Treatment | 78 percentage of participants |
| Group C | Percentage of Participants With Relapse After End of Treatment | 59 percentage of participants |
| Group D | Percentage of Participants With Relapse After End of Treatment | 67 percentage of participants |
Secondary
Percentage of Participants With Undetectable HCV-RNA
The percentage of participants with a undetectable HCV RNA 24 weeks after the end of the treatment period (defined as a single last HCV RNA \< 50 IU/mL measured \>= 20 weeks after treatment end, ie, \>=140 days after treatment end) are reported. End-of-treatment (EOT) virological response is defined as last HCV RNA measurement that is not detectable (\<50 IU/mL) at study day of last dose of study medication (+/- 28 days).
Time frame: At Week 12, 24, 48 and EOT
Population: ITT population included all participants randomized who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A | Percentage of Participants With Undetectable HCV-RNA | At Week 12 | 24 percentage of participants |
| Group A | Percentage of Participants With Undetectable HCV-RNA | At Week 24 | 32 percentage of participants |
| Group A | Percentage of Participants With Undetectable HCV-RNA | At Week 48 | 32 percentage of participants |
| Group A | Percentage of Participants With Undetectable HCV-RNA | At EOT | 31 percentage of participants |
| Group D | Percentage of Participants With Undetectable HCV-RNA | At EOT | 28 percentage of participants |
| Group D | Percentage of Participants With Undetectable HCV-RNA | At Week 12 | 11 percentage of participants |
| Group D | Percentage of Participants With Undetectable HCV-RNA | At Week 48 | 26 percentage of participants |
| Group D | Percentage of Participants With Undetectable HCV-RNA | At Week 24 | 27 percentage of participants |
Comparison: At Week 12p-value: <0.000195% CI: [1.66, 4.18]Cochran-Mantel-Haenszel
Comparison: At Week 24p-value: 0.195595% CI: [0.89, 1.79]Cochran-Mantel-Haenszel
Comparison: At Week 48p-value: 0.088395% CI: [0.95, 1.93]Cochran-Mantel-Haenszel