Chronic Hepatitis C Infection, Compensated Cirrhosis
Conditions
Keywords
Cirrhosis, Hepatitis C, Child Pugh A, Compensated Cirrhosis, Hepatitis C Genotype 1, Cirrhotic, Chronic Hepatitis C, Hepatitis C Virus, ombitasvir, paritaprevir, dasabuvir, Interferon-Free, Viekira Pak
Brief summary
The purpose of this study is to evaluate the safety and efficacy of ABT-450/ritonavir/ABT-267 (ABT-450/r/ABT-267; ABT-450 also known as paritaprevir; ABT-267 also known as ombitasvir) and ABT-333 (also known as dasabuvir) coadministered with ribavirin (RBV) in hepatitis C virus (HCV) genotype 1-infected adults with compensated cirrhosis.
Detailed description
During the treatment period of the study, participants received treatment with ABT-450/ritonavir/ABT-267 and ABT-333 coadministered with RBV for either 12 or 24 weeks. Upon completing the treatment period or premature discontinuation of the treatment period, participants entered a 48-week post-treatment period.
Interventions
Tablet; ABT-450 coformulated with ritonavir and ABT-267; ABT-333 tablet
DRUGRibavirin (RBV)
Capsule
Sponsors
AbbVie (prior sponsor, Abbott)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Females must be practicing specific forms of birth control on study treatment, or be post-menopausal for more than 2 years or surgically sterile * Male or female between 18 and 70 years, inclusive, at time of Screening. * Chronic HCV-infection prior to study enrollment. * Screening laboratory result indicating HCV genotype 1-infection. * Compensated cirrhosis defined as a Child-Pugh Score of less than or equal to 6 at Screening * Subject has plasma HCV RNA level greater than 10,000 IU/mL at Screening.
Exclusion criteria
* Significant liver disease with any cause other than HCV as the primary cause * Positive test result for Hepatitis B surface antigen (HBsAg) or anti-Human Immunodeficiency virus antibody (HIV Ab) at screening. * Prior therapy with direct acting antiviral agents for the treatment of HCV, including telaprevir and boceprevir. * Any current or past clinical evidence of Child-Pugh B or C Classification or clinical history of liver decompensation including ascites (noted on physical exam), variceal bleeding or hepatic encephalopathy. * A positive screening ultrasound for hepatocellular carcinoma (HCC) confirmed with a subsequent CT Scan or MRI during the screening period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment | 12 weeks after the last actual dose of study drug | The percentage of participants with sustained virologic response (plasma Hepatitis C virus ribonucleic acid \[HCV RNA\] level less than the lower limit of quantitation \[\< LLOQ\]) 12 weeks after the last dose of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment in the 24-week Arm Compared to the 12-week Arm | 12 weeks after the last actual dose of study drug | A sustained virologic response is defined as plasma Hepatitis C virus ribonucleic acid (HCV RNA) less than the lower limit of quantification (\< LLOQ) 12 weeks after the last dose of study drug. |
| Percentage of Participants in Each Arm With On-treatment Virologic Failure During the Treatment Period | Baseline (Day 1), and Treatment Weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 | Virologic failure during treatment was defined as rebound (confirmed HCV RNA greater than or equal to the lower limit of quantitation \[≥ LLOQ\] after HCV RNA \< LLOQ during treatment, or confirmed increase from the lowest value post baseline in HCV RNA \[2 consecutive HCV RNA measurements \> 1 log(subscript)10(subscript) IU/mL above the lowest value post baseline\] at any time point during treatment), or fail to suppress (HCV RNA ≥ LLOQ persistently during treatment with at least 6 weeks \[≥ 36 days\] of treatment). |
| Percentage of Participants With Virologic Relapse After Treatment | within 12 weeks after the last dose of study drug | Participants were considered to have virologic relapse after treatment if they had confirmed quantifiable plasma Hepatitis C virus ribonucleic acid (HCV RNA) ≥ lower limit of quantification (LLOQ) between the end of treatment and 12 weeks after the last dose of study drug among participants who completed treatment with HCV RNA \< LLOQ at the end of treatment. |
Participant flow
Pre-assignment details
In the 12-week treatment group, one participant withdrew from the study before receiving study drug.
Participants by arm
| Arm | Count |
|---|---|
| ABT-450/r/ABT-267 and ABT-333, Plus RBV for 12 Weeks ABT-450/r/ABT-267 (150/100/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; 1,000 mg/day if \<75 kg or 1,200 mg/day if ≥75 kg, divided twice daily) for 12 weeks | 208 |
| ABT-450/r/ABT-267 and ABT-333, Plus RBV for 24 Weeks ABT-450/r/ABT-267 (150/100/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; 1,000 mg/day if \<75 kg or 1,200 mg/day if ≥75 kg, divided twice daily) for 24 weeks | 172 |
| Total | 380 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
| Overall Study | Lost to Follow-up | 3 | 4 |
| Overall Study | Other (not specified) | 3 | 1 |
| Overall Study | Withdrew consent | 1 | 1 |
| Overall Study | Withdrew consent and personal issues | 1 | 0 |
Baseline characteristics
| Characteristic | ABT-450/r/ABT-267 and ABT-333, Plus RBV for 12 Weeks | ABT-450/r/ABT-267 and ABT-333, Plus RBV for 24 Weeks | Total |
|---|---|---|---|
| Age, Continuous | 57.1 years STANDARD_DEVIATION 7.01 | 56.5 years STANDARD_DEVIATION 7.87 | 56.8 years STANDARD_DEVIATION 7.41 |
| Sex: Female, Male Female | 62 Participants | 51 Participants | 113 Participants |
| Sex: Female, Male Male | 146 Participants | 121 Participants | 267 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 175 / 208 | 146 / 172 |
| serious Total, serious adverse events | 13 / 208 | 7 / 172 |
Outcome results
Primary
Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment
The percentage of participants with sustained virologic response (plasma Hepatitis C virus ribonucleic acid \[HCV RNA\] level less than the lower limit of quantitation \[\< LLOQ\]) 12 weeks after the last dose of study drug.
Time frame: 12 weeks after the last actual dose of study drug
Population: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABT-450/r/ABT-267 and ABT-333, Plus RBV for 12 Weeks | Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment | 91.8 Percentage of participants |
| ABT-450/r/ABT-267 and ABT-333, Plus RBV for 24 Weeks | Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment | 96.5 Percentage of participants |
Comparison: The study planned to enroll 380 subjects to a 12- or 24-week treatment arm. The primary efficacy endpoint (SVR12) was assessed for each arm. With a total sample size of 380 and assuming that 68% of the subjects in each arm would achieve SVR12, the study had greater than 90% power to demonstrate non-inferiority and superiority with a 2-sided 97.5% lower confidence bound greater than 43% and 54%, respectively, based on the normal approximation of a single binomial proportion.97.5% CI: [87.6, 96.1]
Comparison: The primary efficacy endpoints were the SVR12 rates in each arm. The overall 2-sided significance level of 0.05 was split between the arms using a Bonferroni correction of 0.025. A 2-sided 97.5% CI of the SVR12 rate per arm was computed using the normal approximation to the binomial distribution. A gatekeeping testing procedure was used to control the Type I error rate at 0.05, and the primary endpoints for Arm A were tested separately from Arm B in a pre-specified order.97.5% CI: [87.6, 96.1]
97.5% CI: [93.4, 99.7]
97.5% CI: [93.4, 99.7]
Secondary
Percentage of Participants in Each Arm With On-treatment Virologic Failure During the Treatment Period
Virologic failure during treatment was defined as rebound (confirmed HCV RNA greater than or equal to the lower limit of quantitation \[≥ LLOQ\] after HCV RNA \< LLOQ during treatment, or confirmed increase from the lowest value post baseline in HCV RNA \[2 consecutive HCV RNA measurements \> 1 log(subscript)10(subscript) IU/mL above the lowest value post baseline\] at any time point during treatment), or fail to suppress (HCV RNA ≥ LLOQ persistently during treatment with at least 6 weeks \[≥ 36 days\] of treatment).
Time frame: Baseline (Day 1), and Treatment Weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24
Population: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABT-450/r/ABT-267 and ABT-333, Plus RBV for 12 Weeks | Percentage of Participants in Each Arm With On-treatment Virologic Failure During the Treatment Period | 0.5 Percentage of participants |
| ABT-450/r/ABT-267 and ABT-333, Plus RBV for 24 Weeks | Percentage of Participants in Each Arm With On-treatment Virologic Failure During the Treatment Period | 1.7 Percentage of participants |
Secondary
Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment in the 24-week Arm Compared to the 12-week Arm
A sustained virologic response is defined as plasma Hepatitis C virus ribonucleic acid (HCV RNA) less than the lower limit of quantification (\< LLOQ) 12 weeks after the last dose of study drug.
Time frame: 12 weeks after the last actual dose of study drug
Population: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABT-450/r/ABT-267 and ABT-333, Plus RBV for 12 Weeks | Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment in the 24-week Arm Compared to the 12-week Arm | 91.8 Percentage of participants |
| ABT-450/r/ABT-267 and ABT-333, Plus RBV for 24 Weeks | Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment in the 24-week Arm Compared to the 12-week Arm | 96.5 Percentage of participants |
Comparison: To test the hypothesis that the percentages of participants who achieved sustained virologic response 12 weeks after treatment was different between the two treatment groups, the percentages were compared using a logistic regression model with treatment group, baseline log(subscript)10(subscript) HCV RNA level, HCV subgenotype (1a, non-1a), IL28B genotype (CC, non CC), and peginterferon-ribavirin treatment history (treatment-naïve or treatment-experienced) as predictors.p-value: 0.051Regression, Logistic
Secondary
Percentage of Participants With Virologic Relapse After Treatment
Participants were considered to have virologic relapse after treatment if they had confirmed quantifiable plasma Hepatitis C virus ribonucleic acid (HCV RNA) ≥ lower limit of quantification (LLOQ) between the end of treatment and 12 weeks after the last dose of study drug among participants who completed treatment with HCV RNA \< LLOQ at the end of treatment.
Time frame: within 12 weeks after the last dose of study drug
Population: All randomized participants who received at least 1 dose of study drug with HCV RNA \< LLOQ at the final treatment visit who completed treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABT-450/r/ABT-267 and ABT-333, Plus RBV for 12 Weeks | Percentage of Participants With Virologic Relapse After Treatment | 5.9 Percentage of participants |
| ABT-450/r/ABT-267 and ABT-333, Plus RBV for 24 Weeks | Percentage of Participants With Virologic Relapse After Treatment | 0.6 Percentage of participants |