Hepatitis C, Chronic
Conditions
Brief summary
The aim of the study is to confirm efficacy of treatment for 16 and 24 weeks in chronically infected HCV GT1b treatment naïve patients, including patients with compensated cirrhosis.
Interventions
DRUGRibavirin (RBV)
24 weeks of active RBV
DRUGBI 201335 (Faldaprevir)
16 weeks of BI 201335 followed by 8 weeks placebo to BI 201335
DRUGBI 207127
24 weeks of BI 207127
DRUGFaldaprevir (BI 201335)
24 weeks of 201335
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
* Chronic hepatitis C infection, diagnosed by positive HCV Ab or detectable HCV RNA at screening in addition to at least one of the following: 1. positive HCV RNA or HCV antibodies at least 6 months prior to screening, or 2. liver biopsy typical of chronic hepatitis C , or 3. history of elevated ALT at least 6 months prior to screening. * HCV infection of sub-GT1b confirmed by genotypic testing at screening * Treatment naïve defined as: 1. no prior treatment with any interferon, pegylated interferon, and /or ribavirin and 2. no prior treatment with at least one dose of any other licensed or investigational antiviral agent for acute or chronic hepatitis C infection * Plasma HCV RNA \> or = 1,000 IU/mL at screening * Liver biopsy within three years or fibroscan within six months prior to randomization. Patients with compensated liver cirrhosis (score Child-Pugh A) could also be included. * Age 18 to 75 years * Female patients with a negative urine pregnancy test (dipstick) at Visit 2 prior to randomization 1. with documented hysterectomy, or 2. who have had both ovaries removed, or 3. with documented tubal ligation, or 4. who are post-menopausal with last menstrual period at least 12 months prior to screening, or 5. of childbearing potential with a negative serum pregnancy test at screening and a negative urine pregnancy test on Day 1 (Visit 2), that agree to use two non-hormonal methods of birth control from the date of screening until months after the last dose of ribavirin. They must not breast-feed at any time from the date of screening until 7 months after the last dose of ribavirin. Medically accepted methods of contraception for females in this trial are diaphragm with spermicide substance, intrauterine devices, cervical caps and condoms. OR: Male patients 1. who are documented to be sterile, or 2. who consistently and correctly use a condom while their female partners (if of child-bearing potential) agree to use one of the appropriate medically accepted methods of birth control from the date of screening until 7 months after the last dose of ribavirin, and 3. without pregnant female partners. It is in the responsibility of the male patient to ensure that his partner (or partners) is not pregnant prior to enrolment into the study or becomes pregnant during the treatment and follow-up phase. Female partners of childbearing potential must perform monthly pregnancy tests from the date of screening until 7 months after the last dose of ribavirin (tests will be provided by the sponsor).
Exclusion criteria
* HCV infection of mixed genotype (1/2, 1/3, and 1/4) diagnosed by genotypic testing at screening. * HCV subtype 1a, mixed 1a/1b or GT1 undefined * Evidence of liver disease mainly due to causes other than chronic HCV infection such as autoimmune hepatitis, primary biliary cirrhosis, hemochromatosis or Wilson's disease * HIV-1 or HIV-2 infection * Hepatitis B virus (HBV) infection based on presence of HBs-Ag * Evidence of decompensated liver disease, or history of decompensated liver disease, defined as history of ascites, hepatic encephalopathy, or bleeding esophageal varices, * International Normalized Ratio (INR) \> or =1.7 * Serum albumin \< 3.3 g/dL * Serum total bilirubin \>2.0 times the upper limit of normal (ULN) with direct/indirect ratio \>1, unless history of Gilbert's disease * Active or suspected malignancy or history of malignancy within the last 5 years (with the exception of appropriately treated basal cell carcinoma of the skin or in situ carcinoma of the uterine cervix) * Patients with ongoing or historical photosensitivity or recurrent rash
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 ribonucleic acid (HCV RNA) level \<25 international units/millilitre (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 |
| 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 | 4 Week (post-treatment) | Sustained Virologic Response rates across treatment arms at Week 4 post-treatment (SVR4). |
| SVR24 | 24 Week (post-treatment) | Sustained Virologic Response rates across treatment arms at Week 24 post-treatment (SVR24). |
Countries
Austria, Canada, France, Germany, Hungary, Ireland, Italy, Netherlands, Portugal, Romania, Russia, Spain, United Kingdom, United States
Participant flow
Recruitment details
It was planned that approximately 800 patients would be screened in order to randomize and treat approximately 460 patients (195 patients in treatment Groups 1 and 2 each, 40-70 patients in treatment Group 3).
Pre-assignment details
Treatment-naïve patients with chronic hepatitis C infection of genotype (GT)1b were included in the trial. Patients with compensated liver cirrhosis, defined as Ishak Grade ≥5 or METAVIR Grade ≥4 on liver biopsy, or liver stiffness of ≥ 13 kilopascal (kPa) on fibroscan, were assigned to Group 3.
Participants by arm
| Arm | Count |
|---|---|
| 16 wk NC FDV+DBV+RBV 600 mg DBV (BID) + 120mg FDV (QD) + 1000-1200mg RBV (BID) for 16wk followed by DBV placebo, FDV placebo and RBV placebo for 8wk. All were administered per os (orally).
This group included non-cirrhotic patients (NC). | 208 |
| 24 wk NC FDV+DBV+RBV 600 mg DBV (BID) + 120mg FDV (QD) + 1000-1200mg RBV (BID) for 24wk. All were administered per os (orally). This group included non-cirrhotic patients (NC). | 211 |
| 24 wk CR FDV+DBV+RBV 600 mg DBV (BID) + 120mg FDV (QD) + 1000-1200mg RBV (BID) for 24wk. All were administered per os (orally). This group comprised patients with compensated cirrhosis (CR) who received open label treatment. | 51 |
| Total | 470 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 16 | 16 | 4 |
| Overall Study | Lack of Efficacy | 21 | 18 | 5 |
| Overall Study | Lost to Follow-up | 2 | 0 | 0 |
| Overall Study | Other reason not defined above | 1 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 6 | 8 | 2 |
Baseline characteristics
| Characteristic | 16 wk NC FDV+DBV+RBV | 24 wk NC FDV+DBV+RBV | 24 wk CR FDV+DBV+RBV | Total |
|---|---|---|---|---|
| Age, Continuous | 50.1 Years STANDARD_DEVIATION 12.7 | 51.1 Years STANDARD_DEVIATION 12.9 | 57.9 Years STANDARD_DEVIATION 8.8 | 51.4 Years STANDARD_DEVIATION 12.6 |
| Sex: Female, Male Female | 122 Participants | 114 Participants | 18 Participants | 254 Participants |
| Sex: Female, Male Male | 86 Participants | 97 Participants | 33 Participants | 216 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 | 192 / 208 | 198 / 211 | 49 / 51 |
| serious Total, serious adverse events | 7 / 208 | 11 / 211 | 4 / 51 |
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 FDV+DBV+RBV | Comparisons of SVR12 Rates Across Treatment Arms | 71.6 Percentage of participants |
| 16 wk FDV+DBV+RBV | Comparisons of SVR12 Rates Across Treatment Arms | 82.5 Percentage of participants |
| 24 wk CR FDV+DBV+RBV | Comparisons of SVR12 Rates Across Treatment Arms | 72.5 Percentage of participants |
p-value: 0.00495% CI: [2.8, 18.8]z-test
Primary
SVR12 Rates With Historical Control
Sustained Virologic Response at Week 12 post-treatment (SVR12): Plasma Hepatitis C Virus ribonucleic acid (HCV RNA) level \<25 international units/millilitre (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
Time frame: 12 Week (post-treatment)
Population: The primary analyses of efficacy were carried out on an intent-to-treat basis including all randomized patients who were dispensed study medication and were documented to have taken at least one dose of study medication (FAS).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 24 wk FDV+DBV+RBV | SVR12 Rates With Historical Control | non-cirrhotic (N=174, 149) | 82.5 Percentage of participants |
| 24 wk FDV+DBV+RBV | SVR12 Rates With Historical Control | cirrhotic (N=37, 37) | 72.5 Percentage of participants |
| 16 wk FDV+DBV+RBV | SVR12 Rates With Historical Control | non-cirrhotic (N=174, 149) | 71.6 Percentage of participants |
| 16 wk FDV+DBV+RBV | SVR12 Rates With Historical Control | cirrhotic (N=37, 37) | 72.5 Percentage of participants |
Comparison: The proportion of patients achieving SVR12 was compared to an acceptable minimum SVR rate achieved with an approved direct acting anti-viral (DAA) in combination with pegylated interferon-alfa (PegIFN) from historical data. The acceptable minimum SVR rate was 71% (reference for PegIFN-eligible).p-value: <0.000195% CI: [76.6, 86.2]Stratified one sample z-test
Comparison: The proportion of patients achieving SVR12 was compared to an acceptable minimum SVR rate achieved with an approved direct acting anti-viral (DAA) in combination with pegylated interferon-alfa (PegIFN) from historical data. The acceptable minimum SVR rate was 71% (reference for PegIFN-eligible).p-value: 0.398995% CI: [66.1, 77.4]Stratified one sample z-test
Secondary
SVR24
Sustained Virologic Response rates across treatment arms at Week 24 post-treatment (SVR24).
Time frame: 24 Week (post-treatment)
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 24 wk FDV+DBV+RBV | SVR24 | Percentage of patients with response | 70.7 Percantage of participants |
| 24 wk FDV+DBV+RBV | SVR24 | Positive predicted value | 97.0 Percantage of participants |
| 16 wk FDV+DBV+RBV | SVR24 | Percentage of patients with response | 80.6 Percantage of participants |
| 16 wk FDV+DBV+RBV | SVR24 | Positive predicted value | 99.0 Percantage of participants |
| 24 wk CR FDV+DBV+RBV | SVR24 | Percentage of patients with response | 72.5 Percantage of participants |
| 24 wk CR FDV+DBV+RBV | SVR24 | Positive predicted value | 100.0 Percantage of participants |
Comparison: Category: Percentage of patient with responsep-value: 0.008995% CI: [1.7, 18.1]z-test
Secondary
SVR4
Sustained Virologic Response rates across treatment arms at Week 4 post-treatment (SVR4).
Time frame: 4 Week (post-treatment)
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 24 wk FDV+DBV+RBV | SVR4 | Percentage of patients with response | 78.4 Percentage of participants |
| 24 wk FDV+DBV+RBV | SVR4 | Positive predicted value | 94.0 Percentage of participants |
| 16 wk FDV+DBV+RBV | SVR4 | Percentage of patients with response | 84.4 Percentage of participants |
| 16 wk FDV+DBV+RBV | SVR4 | Positive predicted value | 98.0 Percentage of participants |
| 24 wk CR FDV+DBV+RBV | SVR4 | Percentage of patients with response | 76.5 Percentage of participants |
| 24 wk CR FDV+DBV+RBV | SVR4 | Positive predicted value | 95.0 Percentage of participants |
Comparison: Category: Percentage of patient with responsep-value: 0.057595% CI: [-1.5, 13.5]z-test