Hepatitis C, Chronic
Conditions
Keywords
Hepatitis C, Chronic, Telaprevir, Peg-IFN-alfa-2a, Ribavirin
Brief summary
The purpose of this study is to determine the safety, efficacy and tolerability of using two regimens of telaprevir (with and without delayed start) with standard treatment compared to standard treatment alone in participants with chronic, genotype 1, hepatitis C.
Detailed description
This is a randomized, double-blind, placebo-controlled Phase III trial with telaprevir in patients with chronic Hepatitis C Virus (HCV), genotype 1, infection who failed prior treatment with standard treatment. Standard treatment is defined as treatment with Peg-INF and RBV. The trial is designed to compare the efficacy, safety, and tolerability of 2 regimens of telaprevir (with and without delayed start) combined with standard treatment versus standard treatment alone. The trial will consist of a screening period of approximately 4 weeks, a 48-week treatment period, and a 24-week follow-up period. Patients will be eligible to enroll in the trial if they (1) had an undetectable HCV Ribonucleic Acid (RNA) level at the end of a prior course of standard treatment but did not achieve a response (viral relapsers), or (2) never had an undetectable HCV RNA level during or at the end of a prior course of standard treatment (non-responders). Approximately 650 patients (350 prior relapsers and 300 prior non-responders) will be randomized in a 2:2:1 ratio to one of 3 treatment groups: Treatment group A will receive telaprevir with standard treatment for 12 weeks; followed by placebo with standard treatment for 4 weeks; followed by standard treatment for 32 weeks. Treatment group B will receive placebo with standard treatment for 4 weeks; followed by telaprevir with standard treatment for 12 weeks; followed by standard treatment for 32 weeks. Treatment group C will receive placebo with standard treatment for 16 weeks; followed by standard treatment for 32 weeks. In both telaprevir regimens (A and B), patients will receive 12 weeks of 750 mg of telaprevir every 8 hours along with 48 weeks of standard treatment. Telaprevir or placebo will be given by mouth at a dose of 750 mg every 8 hours for 16 weeks. Peg-INF will be given as an injection under the skin at a dose of 180 mcg once every week for 48 weeks. RBV will be given by mouth at a dose of either 1000 or 1200 mg (depending on your body weight) two times per day for 48 weeks.
Interventions
DRUGTelaprevir
Participants will receive telaprevir tablets of 750 mg orally eight hourly for 12 weeks in group A and B.
DRUGPeg-IFN-alfa-2a
Participants will receive 180 µg subcutaneous (under the skin) injection of Peg-IFN-alfa-2a once weekly for 48 weeks in Group A, B and C.
DRUGRibavirin
Participants will receive ribavirin tablets of 1000-1200 mg orally twice daily for 48 weeks in Group A, B, and C.
DRUGPlacebo
Participants will receive telaprevir matching placebo tablets orally for 4 weeks in Group A and B. Participants will receive telaprevir matching placebo tablets orally for 16 weeks in Group C.
Sponsors
Tibotec Pharmaceutical Limited
Tibotec BVBA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Patient must have chronic hepatitis C infection (genotype 1) with HCV RNA level \>= 1000 IU/mL * Patient must have failed at least 1 prior course of Peg-IFN/RBV therapy (standard treatment) * Patient must be willing to use 2 effective methods of birth control for up to 7 months after last dose of study medication
Exclusion criteria
* Patient is a previous non-responder that is classified as a viral breakthrough case * Patient is infected with Hepatitis C virus, genotype 1, exhibiting more than one subtype * Patient has Hepatitis C virus, genotype 1, and exhibits co-infection with any other genotype * Evidence of decompensated liver disease * Patient has condition that requires use of systemic corticosteroids
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Sustained Virologic Response (SVR) 24 Weeks After the Last Planned Dose of Study Medication - SVR24 Planned | Week 72 | SVR24 planned is defined as having undetectable plasma Hepatitis C virus (HCV) ribonucleic acid (RNA) levels 24 weeks after the last planned dose of study medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Acheiving Rapid Virologic Response (RVR) at Week 4 | Week 4 | RVR was defined as having undetectable Hepatitis C virus (HCV) ribonucleic acid (RNA) at Week 4. |
| Number of Participants Acheiving Undetectable Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels at Week 48 (End of Treatment) | Week 48 | — |
| Number of Participants With Sustained Virologic Response (SVR) 12 Weeks After the Last Planned Dose of Study Medication - SVR12 Planned | Week 60 | SVR12 planned was defined as having undetectable plasma Hepatitis C virus (HCV) ribonucleic acid (RNA) levels 12 weeks after the last planned dose of study medication (SVR12 planned). |
| Number of Participants Who Meet the Telaprevir Stopping Rule at Week 4, Week 6, or Week 8 | Week 4, Week 6, or Week 8 | Telaprevir stopping rule is defined as having Hepatitis C virus (HCV) ribonucleic acid (RNA) levels \>100 IU/mL at Week 4, Week 6, or Week 8 after start of telaprevir. |
| Number of Participants Who Have Viral Relapse During Entire Follow-up Period (up to Week 72) | Up to Week 72 | Viral relapse was defined as having confirmed detectable Hepatitis C virus (HCV) ribonucleic acid (RNA) levels during entire follow-up period (up to Week 72). |
| Change From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4 | Baseline (Day 1) to Week 4 | — |
| Number of Participants Acheiving Extended Rapid Virologic Response at Week 4 and Week 12 | Week 4 and Week 12 | Extended rapid virologic response was defined as undetectable Hepatitis C virus (HCV) ribonucleic acid (RNA) levels. |
Countries
Australia, Austria, Belgium, Brazil, Canada, France, Germany, Israel, Netherlands, Poland, Puerto Rico, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 105 sites in 17 countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, Switzerland, Germany, Spain, France, United Kingdom, Israel, Italy, Netherlands, Poland, Sweden, and the United States.
Pre-assignment details
662 participants were treated (266 participants in the T12/PR48 group, 264 participants in the T12(DS)/PR48 group, and 132 participants in the Pbo/PR48 group) in this study.
Participants by arm
| Arm | Count |
|---|---|
| T12/PR48 12 weeks of 750 mg telaprevir eight hourly followed by 4 weeks of Placebo in combination with 48 weeks of Peg-IFN-alfa-2a and ribavirin at standard doses | 266 |
| T12(DS)/PR48 4 weeks of Placebo followed by 12 weeks of 750 mg telaprevir eight hourly in combination with 48 weeks of Peg-IFN-alfa-2a and ribavirin at standard doses | 264 |
| Pbo/PR48 48 weeks of Peg-IFN-alfa-2a and ribavirin at standard doses | 132 |
| Total | 662 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 2 |
| Overall Study | Lost to Follow-up | 6 | 4 | 4 |
| Overall Study | Other | 0 | 0 | 1 |
| Overall Study | Subject Ineligible To Continue The Trial | 6 | 3 | 2 |
| Overall Study | Withdrawal by Subject | 8 | 7 | 13 |
Baseline characteristics
| Characteristic | Total | Pbo/PR48 | T12(DS)/PR48 | T12/PR48 |
|---|---|---|---|---|
| AgeCategoricalOther >= 45 years | 159 participants | 40 participants | 55 participants | 64 participants |
| AgeCategoricalOther >= 65 years | 20 participants | 7 participants | 8 participants | 5 participants |
| AgeCategoricalOther Between 45 and 65 years | 483 participants | 85 participants | 201 participants | 197 participants |
| Age, Continuous | 50.6 years STANDARD_DEVIATION 8.66 | 49.9 years STANDARD_DEVIATION 9.74 | 51 years STANDARD_DEVIATION 8.24 | 50.7 years STANDARD_DEVIATION 8.51 |
| Race/Ethnicity, Customized Asian | 11 Participants | 3 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Black or African American | 30 Participants | 11 Participants | 8 Participants | 11 Participants |
| Race/Ethnicity, Customized Other | 6 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 615 Participants | 117 Participants | 252 Participants | 246 Participants |
| Sex: Female, Male Female | 202 Participants | 44 Participants | 75 Participants | 83 Participants |
| Sex: Female, Male Male | 460 Participants | 88 Participants | 189 Participants | 183 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 | 253 / 266 | 255 / 264 | 126 / 132 | 257 / 266 | 260 / 264 | 126 / 132 |
| serious Total, serious adverse events | 18 / 266 | 17 / 264 | 4 / 132 | 33 / 266 | 32 / 264 | 7 / 132 |
Outcome results
Primary
Number of Participants With Sustained Virologic Response (SVR) 24 Weeks After the Last Planned Dose of Study Medication - SVR24 Planned
SVR24 planned is defined as having undetectable plasma Hepatitis C virus (HCV) ribonucleic acid (RNA) levels 24 weeks after the last planned dose of study medication.
Time frame: Week 72
Population: Full Analysis Set: All randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T12/PR48 | Number of Participants With Sustained Virologic Response (SVR) 24 Weeks After the Last Planned Dose of Study Medication - SVR24 Planned | 171 Participants |
| T12(DS)/PR48 | Number of Participants With Sustained Virologic Response (SVR) 24 Weeks After the Last Planned Dose of Study Medication - SVR24 Planned | 175 Participants |
| Pbo/PR48 | Number of Participants With Sustained Virologic Response (SVR) 24 Weeks After the Last Planned Dose of Study Medication - SVR24 Planned | 22 Participants |
Comparison: Null hypothesis: Assuming a 55% response rate in the groups receiving Treatment T12/PR48, a 29% response rate in the group receiving Treatment Pbo/PR48, a 2-sided continuity corrected Chi-squared test, with an overall significance level of 5% and a 2:2:1 randomization, a sample size of 140 patients receiving Treatment T12/PR48 and 70 patients in receiving Treatment Pbo/PR48 provided a power of approximately 90% to demonstrate a statistically significant difference.p-value: <0.00195% CI: [36.8, 56.7]Regression, Logistic
Comparison: Null hypothesis: Assuming a 55% response rate in the groups receiving Treatment T12/PR48 or T12(DS)/PR48, a 29% response rate in the group receiving Treatment Pbo/PR48, a 2-sided continuity corrected Chi-squared test, with an overall significance level of 5% and a 2:2:1 randomization, a sample size of 140 patients receiving Treatment T12(DS)/PR48 and 70 patients in receiving Treatment Pbo/PR48 provided a power of approximately 90% to demonstrate a statistically significant difference.p-value: <0.00195% CI: [39.9, 59.7]Regression, Logistic
Secondary
Change From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4
Time frame: Baseline (Day 1) to Week 4
Population: All analyses were performed on the full analysis (FA) set, which was defined as all randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T12/PR48 | Change From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4 | -5.5 log10 IU/mL | Standard Deviation 1.06 |
| T12(DS)/PR48 | Change From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4 | -2.0 log10 IU/mL | Standard Deviation 1.42 |
| Pbo/PR48 | Change From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Week 4 | -1.9 log10 IU/mL | Standard Deviation 1.4 |
Secondary
Number of Participants Acheiving Extended Rapid Virologic Response at Week 4 and Week 12
Extended rapid virologic response was defined as undetectable Hepatitis C virus (HCV) ribonucleic acid (RNA) levels.
Time frame: Week 4 and Week 12
Population: All analyses were performed on the full analysis (FA) set, which was defined as all randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T12/PR48 | Number of Participants Acheiving Extended Rapid Virologic Response at Week 4 and Week 12 | 141 Participants |
| T12(DS)/PR48 | Number of Participants Acheiving Extended Rapid Virologic Response at Week 4 and Week 12 | 180 Participants |
| Pbo/PR48 | Number of Participants Acheiving Extended Rapid Virologic Response at Week 4 and Week 12 | 3 Participants |
Secondary
Number of Participants Acheiving Rapid Virologic Response (RVR) at Week 4
RVR was defined as having undetectable Hepatitis C virus (HCV) ribonucleic acid (RNA) at Week 4.
Time frame: Week 4
Population: All analyses were performed on the full analysis (FA) set, which was defined as all randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T12/PR48 | Number of Participants Acheiving Rapid Virologic Response (RVR) at Week 4 | 152 Participants |
| T12(DS)/PR48 | Number of Participants Acheiving Rapid Virologic Response (RVR) at Week 4 | 188 Participants |
| Pbo/PR48 | Number of Participants Acheiving Rapid Virologic Response (RVR) at Week 4 | 3 Participants |
Secondary
Number of Participants Acheiving Undetectable Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels at Week 48 (End of Treatment)
Time frame: Week 48
Population: All analyses were performed on the full analysis (FA) set, which was defined as all randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T12/PR48 | Number of Participants Acheiving Undetectable Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels at Week 48 (End of Treatment) | 184 Participants |
| T12(DS)/PR48 | Number of Participants Acheiving Undetectable Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels at Week 48 (End of Treatment) | 191 Participants |
| Pbo/PR48 | Number of Participants Acheiving Undetectable Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels at Week 48 (End of Treatment) | 49 Participants |
Secondary
Number of Participants Who Have Viral Relapse During Entire Follow-up Period (up to Week 72)
Viral relapse was defined as having confirmed detectable Hepatitis C virus (HCV) ribonucleic acid (RNA) levels during entire follow-up period (up to Week 72).
Time frame: Up to Week 72
Population: All analyses were performed on the full analysis (FA) set, which was defined as all randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T12/PR48 | Number of Participants Who Have Viral Relapse During Entire Follow-up Period (up to Week 72) | 26 Participants |
| T12(DS)/PR48 | Number of Participants Who Have Viral Relapse During Entire Follow-up Period (up to Week 72) | 27 Participants |
| Pbo/PR48 | Number of Participants Who Have Viral Relapse During Entire Follow-up Period (up to Week 72) | 33 Participants |
Secondary
Number of Participants Who Meet the Telaprevir Stopping Rule at Week 4, Week 6, or Week 8
Telaprevir stopping rule is defined as having Hepatitis C virus (HCV) ribonucleic acid (RNA) levels \>100 IU/mL at Week 4, Week 6, or Week 8 after start of telaprevir.
Time frame: Week 4, Week 6, or Week 8
Population: All analyses were performed on the full analysis (FA) set, which was defined as all randomized participants who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| T12/PR48 | Number of Participants Who Meet the Telaprevir Stopping Rule at Week 4, Week 6, or Week 8 | Week 4 | 16 Participants |
| T12/PR48 | Number of Participants Who Meet the Telaprevir Stopping Rule at Week 4, Week 6, or Week 8 | Week 6 | 5 Participants |
| T12/PR48 | Number of Participants Who Meet the Telaprevir Stopping Rule at Week 4, Week 6, or Week 8 | Week 8 | 2 Participants |
| T12(DS)/PR48 | Number of Participants Who Meet the Telaprevir Stopping Rule at Week 4, Week 6, or Week 8 | Week 4 | 14 Participants |
| T12(DS)/PR48 | Number of Participants Who Meet the Telaprevir Stopping Rule at Week 4, Week 6, or Week 8 | Week 6 | 2 Participants |
| T12(DS)/PR48 | Number of Participants Who Meet the Telaprevir Stopping Rule at Week 4, Week 6, or Week 8 | Week 8 | 0 Participants |
Secondary
Number of Participants With Sustained Virologic Response (SVR) 12 Weeks After the Last Planned Dose of Study Medication - SVR12 Planned
SVR12 planned was defined as having undetectable plasma Hepatitis C virus (HCV) ribonucleic acid (RNA) levels 12 weeks after the last planned dose of study medication (SVR12 planned).
Time frame: Week 60
Population: All analyses were performed on the full analysis (FA) set, which was defined as all randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T12/PR48 | Number of Participants With Sustained Virologic Response (SVR) 12 Weeks After the Last Planned Dose of Study Medication - SVR12 Planned | 175 Participants |
| T12(DS)/PR48 | Number of Participants With Sustained Virologic Response (SVR) 12 Weeks After the Last Planned Dose of Study Medication - SVR12 Planned | 178 Participants |
| Pbo/PR48 | Number of Participants With Sustained Virologic Response (SVR) 12 Weeks After the Last Planned Dose of Study Medication - SVR12 Planned | 22 Participants |