Hepatitis C, Chronic
Conditions
Brief summary
The aim of the study is to confirm efficacy and safety of treatment with 600 mg of BID BI 207127 in combination with 120 mg QD FDV and RBV for 16 or 24 weeks in target chronically infected HCV GT1b treatment naïve patients, including patients with compensated cirrhosis.
Interventions
DRUGBI 207127-placebo: 8-week treatment
8 weeks of placebo treatment
DRUGRibavirin: 24-week treatment
24 weeks of active treatment
DRUGBI 207127: 24-week treatment
24 weeks of active treatment
DRUGFaldaprevir: 24-week treatment
24 weeks of active treatment
DRUGRibavirin-placebo: 8-week treatment
8 weeks of placebo treatment
DRUGFaldaprevir-placebo: 8-week treatment
8 weeks of placebo treatment
DRUGFaldaprevir: 16-week treatment
16 weeks of active treatment
DRUGRibavirin: 16-week treatment
16 weeks of active treatment
DRUGRBV: 24-week treatment
24 weeks of active treatment
DRUGBI 207127: 16-week treatment
16 weeks of active treatment
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Chronic hepatitis C infection, diagnosed by positive anti-HCV antibodies and detected HCV RNA at screening 2. HCV infection of sub-GT1b confirmed by genotypic testing at screening. 3. HCV viral load =1,000 IU/mL at randomisation. 4. Patients who have never been previously treated with any other HCV treatment regimen.
Exclusion criteria
1. HCV infection of mixed GT (1/2, 1/3, and 1/4) diagnosed by genotypic testing at screening. 2. HCV infection of sub-GT1a, mixed GT1a/1b, or undefined GT1. 3. Liver disease due to causes other than chronic HCV infection. 4. HIV infection. 5. Hepatitis B virus infection based on presence of HBs-Ag. 6. Confirmed or suspected active malignancy or history of malignancy within the last 5 years prior to screening. 7. History of illicit drug abuse other than cannabis or chronic alcohol abuse within 12 months prior to randomisation. 8. Subject is not willing to comply with the precautionary measures to prevent photosensitivity (avoid excessive sun exposure and use sun block on a daily basis). 9. Decompensated liver disease, or history of decompensated liver disease. 10. Clinical evidence of unstable cardiovascular disease which may further decompensate due to anemia. 11. Red blood cell disorders. 12. Body weight \<40 kg or \>125 kg.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| SVR12 Rates With Historical Control | 12 Week (post-treatment) | Sustained Virologic Response at Week 12 post-treatment (SVR12): Plasma Hepatitis C virus (HCV) RNA level \<25 IU/mL at 12 weeks after end of Treatment (EOT). SVR12, was assessed based on the observed HCV RNA result taken at least 10 weeks after treatment discontinuation. This definition was also applied to patients who discontinued treatment early: if the patient had HCV RNA undetected at least 10 weeks after stopping all treatment, they were considered a responder in the primary analysis. This is the primary analyses of the primary endpoint. The number of participants analyzed are actually adjusted number of participant analyzed. |
| Comparisons of SVR12 Rates Across Treatment Arms | 12 Week (post-treatment) | Sustained Virologic Response rates across treatment arms at Week 12 post-treatment (SVR12). This is the secondary analyses of the primary endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| SVR4: Plasma HCV RNA Level <25 IU/mL at 4 Weeks After EOT. | 4 weeks (after End Of Treatment) | Sustained Virologic Response rates across treatment arms at Week 4 post-treatment (SVR4): Plasma HCV RNA level \<25 IU/mL at 4 weeks after EOT. |
| SVR24: Plasma HCV RNA Level <25 IU/mL at 24 Weeks After EOT. | 4 weeks (after End Of Treatment) | Sustained Virologic Response rates across treatment arms at Week 24 post-treatment (SVR24): Plasma HCV RNA level \<25 IU/mL at 24 weeks after EOT. |
| Prognostic Value of SVR12 Predicting SVR24 | 24 Week (post-treatment) | The positive predictive value of SVR12 predicting SVR24 are the patients with an SVR12 (=YES) and the SVR24 was assessed. |
Countries
Australia, Belgium, Canada, France, Germany, Greece, Italy, New Zealand, Portugal, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 24-wk Non-cirrhotic (NC) Treatment Group 24 weeks of treatment with 600mg twice daily (BID) deleobuvir (DBV) in combination with 120mg once a day (QD) faldaprevir (FDV) plus ribavirin (RBV) in non-cirrhotic patients. | 211 |
| 16-wk Non-cirrhotic (NC) Treatment Group Matching placebo to DBV, Matching placebo to FDV and Matching placebo to RBV for 8 weeks followed by 600mg BID DBV in combination with 120mg FDV plus RBV for 16 weeks in non-cirrhotic patients. | 213 |
| 24-wk Cirrhotic (CR) Treatment Group 24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in cirrhotic patients. | 72 |
| Total | 496 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Termination of DBV | Adverse Event | 14 | 13 | 4 |
| Termination of DBV | Adverse Event (Placebo Period) | 0 | 1 | 0 |
| Termination of DBV | Lack of Efficacy | 14 | 12 | 8 |
| Termination of DBV | Other than stated | 1 | 3 | 0 |
| Termination of DBV | Protocol Violation (Placebo Period) | 0 | 1 | 0 |
| Termination of DBV | Withdrawal by Subject | 9 | 6 | 2 |
| Termination of FDV | Adverse Event | 14 | 13 | 4 |
| Termination of FDV | Adverse Event (Placebo Period) | 0 | 1 | 0 |
| Termination of FDV | Lack of Efficacy | 14 | 12 | 8 |
| Termination of FDV | Other than stated | 1 | 3 | 0 |
| Termination of FDV | Protocol Violation (Placebo Period) | 0 | 1 | 0 |
| Termination of FDV | Withdrawal by Subject | 9 | 6 | 2 |
| Termination of RBV | Adverse Event | 15 | 16 | 5 |
| Termination of RBV | Adverse Event (Placebo Period) | 0 | 1 | 0 |
| Termination of RBV | Lack of Efficacy | 14 | 11 | 7 |
| Termination of RBV | Other than stated | 1 | 3 | 1 |
| Termination of RBV | Protocol Violation (Placebo Period) | 0 | 1 | 0 |
| Termination of RBV | Withdrawal by Subject | 9 | 5 | 2 |
Baseline characteristics
| Characteristic | 24-wk Non-cirrhotic (NC) Treatment Group | 16-wk Non-cirrhotic (NC) Treatment Group | 24-wk Cirrhotic (CR) Treatment Group | Total |
|---|---|---|---|---|
| Age, Continuous | 50.3 Years STANDARD_DEVIATION 12.5 | 50.5 Years STANDARD_DEVIATION 12.3 | 58.0 Years STANDARD_DEVIATION 8.8 | 51.5 Years STANDARD_DEVIATION 12.2 |
| Sex: Female, Male Female | 108 Participants | 120 Participants | 27 Participants | 255 Participants |
| Sex: Female, Male Male | 103 Participants | 93 Participants | 45 Participants | 241 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 198 / 211 | 202 / 213 | 66 / 72 |
| serious Total, serious adverse events | 7 / 211 | 12 / 213 | 8 / 72 |
Outcome results
Primary
Comparisons of SVR12 Rates Across Treatment Arms
Sustained Virologic Response rates across treatment arms at Week 12 post-treatment (SVR12). This is the secondary analyses of the primary endpoint.
Time frame: 12 Week (post-treatment)
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 24-wk Non-cirrhotic (NC)+24-wk Cirrhotic (CR) Treatment Group | Comparisons of SVR12 Rates Across Treatment Arms | 82.0 Percentage of participants |
| 16-wk Non-cirrhotic (NC)+24-wk Cirrhotic (CR) Treatment Group | Comparisons of SVR12 Rates Across Treatment Arms | 75.6 Percentage of participants |
| 24-wk Cirrhotic (CR) Treatment Group | Comparisons of SVR12 Rates Across Treatment Arms | 73.6 Percentage of participants |
Comparison: Koch's stratum-adjusted Mantel Haenszel methods were used to compare durations, adjusting for stratification factors.p-value: 0.053295% CI: [-1.4, 14.2]Koch's method
Primary
SVR12 Rates With Historical Control
Sustained Virologic Response at Week 12 post-treatment (SVR12): Plasma Hepatitis C virus (HCV) RNA level \<25 IU/mL at 12 weeks after end of Treatment (EOT). SVR12, was assessed based on the observed HCV RNA result taken at least 10 weeks after treatment discontinuation. This definition was also applied to patients who discontinued treatment early: if the patient had HCV RNA undetected at least 10 weeks after stopping all treatment, they were considered a responder in the primary analysis. This is the primary analyses of the primary endpoint. The number of participants analyzed are actually adjusted number of participant analyzed.
Time frame: 12 Week (post-treatment)
Population: Modified full analysis set (mFAS): included patients in the full analysis set (FAS) who received at least one dose of active treatment;
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 24-wk Non-cirrhotic (NC)+24-wk Cirrhotic (CR) Treatment Group | SVR12 Rates With Historical Control | PegIFN eligible | 79.95 percentage of participants |
| 24-wk Non-cirrhotic (NC)+24-wk Cirrhotic (CR) Treatment Group | SVR12 Rates With Historical Control | PegIFN ineligible | 88.28 percentage of participants |
| 16-wk Non-cirrhotic (NC)+24-wk Cirrhotic (CR) Treatment Group | SVR12 Rates With Historical Control | PegIFN eligible | 76.68 percentage of participants |
| 16-wk Non-cirrhotic (NC)+24-wk Cirrhotic (CR) Treatment Group | SVR12 Rates With Historical Control | PegIFN ineligible | 70.78 percentage of participants |
Comparison: The proportion of patients achieving SVR12 achieved with 24 weeks of treatment with DBV/FDV/RBV in cirrhotic and non-cirrhotic patients was compared to an acceptable minimum SVR rate achieved with an approved direct acting anti-viral (DAA) in combination with PegIFN from historical data. The acceptable minimum SVR rate was an average of 71% (reference for PegIFN-eligible) and 50% (for PegIFN-ineligible patients), weighted by the sample size in each stratum.p-value: <0.000195% CI: [76.34, 85.87]z-test
Comparison: The proportion of patients achieving SVR12 achieved with 16 weeks of treatment of non-cirrhotic and 24 weeks of treatment of cirrhotic patients was compared to an acceptable minimum SVR rate achieved with an approved direct acting anti-viral (DAA) in combination with PegIFN from historical data. The acceptable minimum SVR rate was an average of 71% (reference for PegIFN-eligible) and 50% (for PegIFN-ineligible patients), weighted by the sample size in each stratum.p-value: 0.00295% CI: [70.63, 81.14]z-test
Secondary
Prognostic Value of SVR12 Predicting SVR24
The positive predictive value of SVR12 predicting SVR24 are the patients with an SVR12 (=YES) and the SVR24 was assessed.
Time frame: 24 Week (post-treatment)
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 24-wk Non-cirrhotic (NC)+24-wk Cirrhotic (CR) Treatment Group | Prognostic Value of SVR12 Predicting SVR24 | 99.0 Percentage of participants |
| 16-wk Non-cirrhotic (NC)+24-wk Cirrhotic (CR) Treatment Group | Prognostic Value of SVR12 Predicting SVR24 | 99.0 Percentage of participants |
| 24-wk Cirrhotic (CR) Treatment Group | Prognostic Value of SVR12 Predicting SVR24 | 98.0 Percentage of participants |
Secondary
SVR24: Plasma HCV RNA Level <25 IU/mL at 24 Weeks After EOT.
Sustained Virologic Response rates across treatment arms at Week 24 post-treatment (SVR24): Plasma HCV RNA level \<25 IU/mL at 24 weeks after EOT.
Time frame: 4 weeks (after End Of Treatment)
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 24-wk Non-cirrhotic (NC)+24-wk Cirrhotic (CR) Treatment Group | SVR24: Plasma HCV RNA Level <25 IU/mL at 24 Weeks After EOT. | 81.0 percentage of participants |
| 16-wk Non-cirrhotic (NC)+24-wk Cirrhotic (CR) Treatment Group | SVR24: Plasma HCV RNA Level <25 IU/mL at 24 Weeks After EOT. | 74.2 percentage of participants |
| 24-wk Cirrhotic (CR) Treatment Group | SVR24: Plasma HCV RNA Level <25 IU/mL at 24 Weeks After EOT. | 72.2 percentage of participants |
Comparison: Koch's stratum-adjusted Mantel Haenszel methods were used to compare durations, adjusting for stratification factors.p-value: 0.044795% CI: [-14.8, 1.1]Koch´s method
Secondary
SVR4: Plasma HCV RNA Level <25 IU/mL at 4 Weeks After EOT.
Sustained Virologic Response rates across treatment arms at Week 4 post-treatment (SVR4): Plasma HCV RNA level \<25 IU/mL at 4 weeks after EOT.
Time frame: 4 weeks (after End Of Treatment)
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 24-wk Non-cirrhotic (NC)+24-wk Cirrhotic (CR) Treatment Group | SVR4: Plasma HCV RNA Level <25 IU/mL at 4 Weeks After EOT. | 83.9 percentage of participants |
| 16-wk Non-cirrhotic (NC)+24-wk Cirrhotic (CR) Treatment Group | SVR4: Plasma HCV RNA Level <25 IU/mL at 4 Weeks After EOT. | 80.3 percentage of participants |
| 24-wk Cirrhotic (CR) Treatment Group | SVR4: Plasma HCV RNA Level <25 IU/mL at 4 Weeks After EOT. | 77.8 percentage of participants |
Comparison: Koch's stratum-adjusted Mantel Haenszel methods were used to compare durations, adjusting for stratification factors.p-value: 0.167195% CI: [-3.7, 10.9]Koch´s method