Chronic Hepatitis C, Hepatitis C Virus, Genotype 3 Hepatitis C Virus
Conditions
Keywords
interferon free, Hepatitis C, daclatasvir, Sovaldi, HCV, Hepatitis C Virus, Hepatitis C Genotype 3, Hep C, sofosbuvir, Chronic Hepatitis C, Daklinza
Brief summary
The purpose of this study was to compare the safety and efficacy of ABT-493/ABT-530 to the combination of sofosbuvir (SOF) and daclatasvir (DCV) in adults with genotype 3 (GT3) chronic hepatitis C virus (HCV) infection.
Detailed description
This study was a Phase 3, randomized, open-label, active-controlled multicenter study to compare efficacy and safety of ABT-493/ABT-530 to SOF and DCV in treatment-naïve chronic HCV GT3-infected participants without cirrhosis. The study consisted of 2 periods, a treatment period (participants received 8 or 12 weeks of ABT-493/ABT-530 or 12 weeks of SOF with DCV) and a post-treatment period (participants who completed or prematurely discontinued the treatment period were followed for 24 weeks after their last dose of study drug to evaluate efficacy and to monitor HCV RNA and the emergence and persistence of viral variants).
Interventions
DRUGABT-493/ABT-530
Tablet; ABT-493 coformulated with ABT-530
DRUGSofosbuvir
Tablet
DRUGDaclatasvir
Tablet
Sponsors
AbbVie
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
* Male or female (of nonchildbearing potential, practicing total abstinence, sexually active with female partners only, or using allowed contraceptive methods) at least 18 years of age at time of screening. * Screening laboratory result indicating HCV GT3 infection. * Chronic HCV infection, defined as one of the following: * Positive for anti-HCV antibody (Ab) or HCV RNA at least 6 months before screening; or * A liver biopsy consistent with chronic HCV infection; or * Abnormal alanine aminotransferase (ALT) levels for at least 6 months before screening. * Hepatitis C virus treatment-naïve (i.e., participant had never received any anti-HCV treatment). * Documented as noncirrhotic.
Exclusion criteria
* Female who was pregnant, planning to become pregnant during the study, or breastfeeding; or male whose partner was pregnant or planning to become pregnant during the study. * Recent (within 6 months prior to study drug administration) history of drug or alcohol abuse that could have precluded adherence to the protocol in the opinion of the investigator. * Positive test result at screening for hepatitis B surface antigen (HBsAg) or anti-human immunodeficiency virus Ab (HIV Ab). * Hepatitis C virus genotyping performed during screening indicated co-infection with more than one HCV genotype. * Any cause of liver disease other than chronic HCV infection. * Consideration by the investigator, for any reason, that the participant was an unsuitable candidate to receive ABT-493/ABT-530, SOF, or DCV. * History of severe, life-threatening, or other significant sensitivity to any excipients of the study drug. * Previous use of any anti-HCV treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12): Noninferiority of Arm A to Arm B | 12 weeks after the last actual dose of study drug | SVR12 was defined as plasma hepatitis C virus ribonucleic acid (HCV RNA) level less than the lower limit of quantification \[\<LLOQ\] 12 weeks after the last dose of study drug. The primary efficacy endpoint was noninferiority in the percentage of participants achieving SVR12 of the 12-week regimen (Arm A) to the standard of care (Arm B: 12 weeks of treatment with sofosbuvir \[SOF\] + daclatasvir \[DCV\]), defined as: a) the lower bound of the 95% confidence interval (CI) for the difference was above the non-inferiority margin of -6% and the lower bound of the 95% CI for the SVR12 rate within Arm A was greater than 92%; OR b) the lower bound of the 95% CI for the difference was below the non-inferiority margin of -6% and the lower bound of the 97.5% CI for the SVR12 rate within Arm A was greater than 92%; OR c) the lower bound of the 97.5% CI for the difference was above the non-inferiority margin of -6% and the lower bound of the 95% CI for the SVR12 rate within Arm A was below 92%. |
| Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12): Noninferiority of Arm C to Arm A | 12 weeks after the last actual dose of study drug | SVR12 was defined as plasma HCV RNA level \<LLOQ 12 weeks after the last dose of study drug. If the first primary efficacy objective (noninferiority of Arm A to Arm B) was achieved, then the second primary efficacy objective, noninferiority in the percentage of participants achieving SVR12 of the 8-week regimen (Arm C) to the 12-week regimen (Arm A) was to be tested. Noninferiority was defined as: a) the lower bound of the 95% CI for the difference was above the noninferiority margin of -6% and the lower bound of the 95% CI for the SVR12 rate within Arm C was greater than 92%, OR b) the lower bound of the 95% CI for the difference was below the noninferiority margin of -6% and the lower bound of the 97.5% CI for the SVR12 rate within Arm C was greater than 92%, OR c) the lower bound of the 97.5% CI for the difference was above the noninferiority margin of -6% and the lower bound of the 95% CI for the SVR12 rate within Arm C was below 92%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12): Superiority of Arm A to Arm B | 12 weeks after the last actual dose of study drug | SVR12 was defined as plasma HCV RNA level \<LLOQ 12 weeks after the last dose of study drug. Per statistical analysis plan to adjust for multiplicity among the primary and first secondary hypothesis tests, the test for superiority of Arm A to Arm B was not conducted. |
| Percentage of Participants With On-treatment Virologic Failure | Treatment weeks 1, 2, 4, 8 (end of treatment for Arm C), and 12 (end of treatment for Arms A and B) or premature discontinuation from treatment | On-treatment virologic failure was defined as confirmed increase of \> 1 log(subscript)10(subscript) IU/mL above the lowest value post-baseline in HCV RNA during treatment; confirmed HCV RNA ≥ 100 IU/mL after HCV RNA \< LLOQ during treatment, or HCV RNA ≥ LLOQ at end of treatment with at least 6 weeks of treatment. |
| Percentage of Participants With Post-treatment Relapse | From the end of treatment through 12 weeks after the last dose of study drug | Post-treatment relapse was defined as confirmed HCV RNA ≥ LLOQ between the end of treatment and 12 weeks after the last dose of study drug among participants who completed treatment with HCV RNA levels \< LLOQ at the end of treatment, excluding reinfection. |
Participant flow
Pre-assignment details
A total of 506 participants were randomized and 505 received ≥ 1 dose of study drug. One participant in Arm B was randomized in error and never dispensed study drug. This participant is included in the total number of participants in Arm B who discontinued the study. This study included a 42-day screening period.
Participants by arm
| Arm | Count |
|---|---|
| Arm A ABT-493/ABT-530 (300 mg/120 mg) coformulated once daily (QD) for 12 weeks. | 233 |
| Arm B Sofosbuvir 400 mg once daily (QD) co-administered with daclatasvir 60 mg QD for 12 weeks. | 115 |
| Arm C ABT-493/ABT-530 (300 mg/120 mg) coformulated once daily (QD) for 8 weeks. | 157 |
| Total | 505 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 | 1 |
| Overall Study | Lost to Follow-up | 9 | 2 | 7 |
| Overall Study | Randomized in error; did not receive Tx | 0 | 1 | 0 |
| Overall Study | Withdrew consent | 2 | 0 | 2 |
Baseline characteristics
| Characteristic | Arm A | Arm B | Arm C | Total |
|---|---|---|---|---|
| Age, Continuous | 47.18 years STANDARD_DEVIATION 10.68 | 47.06 years STANDARD_DEVIATION 11.31 | 45.43 years STANDARD_DEVIATION 12.19 | 46.61 years STANDARD_DEVIATION 11.32 |
| Sex: Female, Male Female | 112 Participants | 63 Participants | 64 Participants | 239 Participants |
| Sex: Female, Male Male | 121 Participants | 52 Participants | 93 Participants | 266 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 | 126 / 233 | 53 / 115 | 64 / 157 |
| serious Total, serious adverse events | 5 / 233 | 2 / 115 | 3 / 157 |
Outcome results
Primary
Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12): Noninferiority of Arm A to Arm B
SVR12 was defined as plasma hepatitis C virus ribonucleic acid (HCV RNA) level less than the lower limit of quantification \[\<LLOQ\] 12 weeks after the last dose of study drug. The primary efficacy endpoint was noninferiority in the percentage of participants achieving SVR12 of the 12-week regimen (Arm A) to the standard of care (Arm B: 12 weeks of treatment with sofosbuvir \[SOF\] + daclatasvir \[DCV\]), defined as: a) the lower bound of the 95% confidence interval (CI) for the difference was above the non-inferiority margin of -6% and the lower bound of the 95% CI for the SVR12 rate within Arm A was greater than 92%; OR b) the lower bound of the 95% CI for the difference was below the non-inferiority margin of -6% and the lower bound of the 97.5% CI for the SVR12 rate within Arm A was greater than 92%; OR c) the lower bound of the 97.5% CI for the difference was above the non-inferiority margin of -6% and the lower bound of the 95% CI for the SVR12 rate within Arm A was below 92%.
Time frame: 12 weeks after the last actual dose of study drug
Population: Intent-to-treat population: all participants who received at least 1 dose of study drug; participants with missing data after backwards imputation were counted as nonresponders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12): Noninferiority of Arm A to Arm B | 95.3 percentage of participants |
| Arm B | Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12): Noninferiority of Arm A to Arm B | 96.5 percentage of participants |
Comparison: Difference in SVR12 rates (Arm A - Arm B).95% CI: [-5.6, 3.1]
97.5% CI: [92.2, 98.4]
Comparison: Difference in SVR12 rates (Arm A - Arm B).97.5% CI: [-6.2, 3.7]
Primary
Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12): Noninferiority of Arm C to Arm A
SVR12 was defined as plasma HCV RNA level \<LLOQ 12 weeks after the last dose of study drug. If the first primary efficacy objective (noninferiority of Arm A to Arm B) was achieved, then the second primary efficacy objective, noninferiority in the percentage of participants achieving SVR12 of the 8-week regimen (Arm C) to the 12-week regimen (Arm A) was to be tested. Noninferiority was defined as: a) the lower bound of the 95% CI for the difference was above the noninferiority margin of -6% and the lower bound of the 95% CI for the SVR12 rate within Arm C was greater than 92%, OR b) the lower bound of the 95% CI for the difference was below the noninferiority margin of -6% and the lower bound of the 97.5% CI for the SVR12 rate within Arm C was greater than 92%, OR c) the lower bound of the 97.5% CI for the difference was above the noninferiority margin of -6% and the lower bound of the 95% CI for the SVR12 rate within Arm C was below 92%.
Time frame: 12 weeks after the last actual dose of study drug
Population: All participants who received at least 1 dose of study drug (ITT population); participants with missing data after backwards imputation were imputed as nonresponders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12): Noninferiority of Arm C to Arm A | 95.3 percentage of participants |
| Arm B | Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12): Noninferiority of Arm C to Arm A | 94.9 percentage of participants |
Comparison: Difference in SVR12 rates (Arm C - Arm A)95% CI: [-4.8, 4]
97.5% CI: [91, 98.8]
97.5% CI: [-5.4, 4.6]
Secondary
Percentage of Participants With On-treatment Virologic Failure
On-treatment virologic failure was defined as confirmed increase of \> 1 log(subscript)10(subscript) IU/mL above the lowest value post-baseline in HCV RNA during treatment; confirmed HCV RNA ≥ 100 IU/mL after HCV RNA \< LLOQ during treatment, or HCV RNA ≥ LLOQ at end of treatment with at least 6 weeks of treatment.
Time frame: Treatment weeks 1, 2, 4, 8 (end of treatment for Arm C), and 12 (end of treatment for Arms A and B) or premature discontinuation from treatment
Population: All participants who received at least 1 dose of study drug (ITT population)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Percentage of Participants With On-treatment Virologic Failure | 0.4 percentage of participants |
| Arm B | Percentage of Participants With On-treatment Virologic Failure | 0 percentage of participants |
| Arm C | Percentage of Participants With On-treatment Virologic Failure | 0.6 percentage of participants |
Secondary
Percentage of Participants With Post-treatment Relapse
Post-treatment relapse was defined as confirmed HCV RNA ≥ LLOQ between the end of treatment and 12 weeks after the last dose of study drug among participants who completed treatment with HCV RNA levels \< LLOQ at the end of treatment, excluding reinfection.
Time frame: From the end of treatment through 12 weeks after the last dose of study drug
Population: All participants who received at least 1 dose of study drug, completed treatment, and had HCV RNA \<LLOQ at the final treatment visit
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Percentage of Participants With Post-treatment Relapse | 1.4 percentage of participants |
| Arm B | Percentage of Participants With Post-treatment Relapse | 0.9 percentage of participants |
| Arm C | Percentage of Participants With Post-treatment Relapse | 3.3 percentage of participants |
Secondary
Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12): Superiority of Arm A to Arm B
SVR12 was defined as plasma HCV RNA level \<LLOQ 12 weeks after the last dose of study drug. Per statistical analysis plan to adjust for multiplicity among the primary and first secondary hypothesis tests, the test for superiority of Arm A to Arm B was not conducted.
Time frame: 12 weeks after the last actual dose of study drug
Population: All participants who received at least 1 dose of study drug (ITT population); participants with missing data after backwards imputation were imputed as nonresponders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12): Superiority of Arm A to Arm B | 95.3 percentage of participants |
| Arm B | Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12): Superiority of Arm A to Arm B | 96.5 percentage of participants |