Chronic Hepatitis C, Hepatitis C Virus, HCV
Conditions
Keywords
HCV GT4, Hepatitis C virus, HCV GT1, HCV, Compensated Cirrhosis, HCV GT6, Hepatitis C Genotype 4 (GT 4), Hepatitis C Genotype 1 (GT1), RBV, Cirrhotic, Hepatitis C, Interferon (IFN) Free, IFN free, HCV GT5, Chronic Hepatitis C, Ribavirin, Child Pugh A, Hepatitis C Genotype 5 (GT 5), Hepatitis C Genotype 6 (GT 6), ABT-493, ABT-530, glecaprevir, pibrentasvir
Brief summary
The purpose of this Phase 2, open-label, 2-part, multicenter study was to evaluate the efficacy, safety, and pharmacokinetics of co-administration of ABT-493 and ABT-530 with and without ribavirin (RBV) at different doses in chronic Hepatitis C virus (HCV) Genotype 1 (GT1), Genotype 4 (GT4), Genotype 5 (GT5), and Genotype 6 (GT6) infection with compensated cirrhosis (GT1 only) or without cirrhosis (GT1, GT4, GT5, or GT6). Although RBV was initially planned in the protocol, it was not administered in any of the study arms.
Detailed description
This study consisted of two independent parts: Part 1 was conducted first followed by Part 2. Part 1 enrolled participants who received ABT-493 and ABT-530 for 12 weeks; Part 2 enrolled participants who received ABT-493 and ABT-530 for 8 or 12 weeks. Participants who completed or prematurely discontinued the treatment period were followed for 24 weeks to monitor HCV RNA to evaluate efficacy and the emergence and persistence of viral variants.
Sponsors
AbbVie
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female between 18 and 70 years of age, inclusive, at time of screening 2. Screening laboratory result indicating hepatitis C virus (HCV) GT1 (Study Parts 1 and 2) or GT4, GT5, or GT6 (Study Part 2) infection 3. Chronic HCV infection defined as one of the following: * Positive for anti-HCV antibody (Ab) or HCV RNA at least 6 months before screening, and positive for HCV RNA and anti-HCV Ab at the time of screening or * Positive for anti-HCV Ab and HCV RNA at the time of screening with a liver biopsy consistent with chronic HCV infection (or a liver biopsy performed prior to enrollment with evidence of chronic HCV infection) 4. Participant had to meet one of the following criteria: * Treatment-naïve: participant had never received treatment for HCV infection * Treatment-experienced: pegylated-interferon alpha-2a or alpha-2b and ribavirin (PR)-null responder (for Study Part 1) or PR-experienced (on-treatment failure or prior relapse) (for Study Part 2) 5. Documented absence of cirrhosis (in Study Part 1 and in corresponding arms of Study Part 2), or compensated cirrhosis (in corresponding arms of Study Part 2, GT1 only), per local standard
Exclusion criteria
1. History of severe, life-threatening or other significant sensitivity to any drug 2. Female who is pregnant, planning to become pregnant during the study or breastfeeding; or male whose partner is pregnant or planning to become pregnant during the study 3. Recent (within 6 months prior to study drug administration) history of drug or alcohol abuse that could preclude adherence to the protocol in the opinion of the investigator 4. Positive test result at Screening for hepatitis B surface antigen (HBsAg) or anti-human immunodeficiency virus antibody (HIV Ab) 5. Hepatitis C virus (HCV) genotype performed during screening indicating co-infection with more than one HCV genotype 6. Any cause of liver disease other than chronic HCV infection 7. Participants with plasma HCV RNA load ≤ 10,000 international units (IU)/mL or unquantifiable or undetectable HCV RNA at screening 8. Previous use of an HCV direct-acting antiviral agent (DAA) 9. Consideration by the investigator, for any reason, that the participant was an unsuitable candidate to receive ABT-493, ABT-530, or RBV (RBV for cirrhotic subjects only) 10. For participants in Study Part 2 who were enrolling with compensated cirrhosis: past clinical evidence of Child-Pugh B or C Classification (score of \> 6) or clinical history of liver decompensation, including ascites (noted on physical exam), bleeding varices, use of beta-blockers for portal hypertension or ascites, or hepatic encephalopathy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response (SVR) 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 quantification \[\<LLOQ\]) 12 weeks after the last dose of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response (SVR) 4 Weeks Post-treatment | 4 weeks after the last actual dose of study drug | The percentage of participants with sustained virologic response (plasma hepatitis C virus ribonucleic acid \[HCV RNA\] less than the lower limit of quantification \[\<LLOQ\]) 4 weeks after the last dose of study drug. |
| Percentage of Participants With On-treatment Virologic Failure | Screening, Day 1, Day 3, treatment weeks 1, 2, 4, 6, 8, 10, and 12 or premature discontinuation from treatment | The percentage of participants with on-treatment virologic failure (defined as confirmed hepatitis C virus ribonucleic acid (HCV RNA) greater than or equal to the lower limit of quantitation \[≥ LLOQ\] after HCV RNA \< LLOQ during treatment), confirmed increase of \> 1 log(subscript)10(subscript) IU/mL above the lowest value post-baseline in HCV RNA 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 hepatitis C virus ribonucleic acid (HCV RNA) greater than or equal to the lower limit of quantitation (≥ 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. |
Participant flow
Pre-assignment details
Safety population: all participants who received at least 1 dose of study drug. Two participants assigned to Arm I received the incorrect dose of study drug throughout their participation in the study (ABT-493 200 mg QD instead of 300 mg) and are therefore included in Arm A instead of Arm I in the safety population.
Participants by arm
| Arm | Count |
|---|---|
| Arm A ABT-493 200 mg once daily (QD) + ABT-530 120 mg QD for 12 weeks in HCV genotype 1-infected participants without cirrhosis | 42 |
| Arm B ABT-493 200 mg once daily (QD) + ABT-530 40 mg QD for 12 weeks in HCV genotype 1- infected participants without cirrhosis | 39 |
| Arm C ABT-493 200 mg once daily (QD) + ABT-530 120 mg QD for 8 weeks in HCV genotype 1-infected participants without cirrhosis (never opened - Sponsor decision) | 0 |
| Arm D ABT-493 200 mg once daily (QD) + ABT-530 40 mg QD for 8 weeks in HCV genotype 1-infected participants without cirrhosis (never opened - Sponsor decision) | 0 |
| Arm E ABT-493 200 mg once daily (QD) + ABT-530 120 mg QD + ribavirin (RBV) 800 mg QD for 12 weeks in HCV genotype 1-infected participants with compensated cirrhosis (never opened - Sponsor decision) | 0 |
| Arm F ABT-493 200 mg once daily (QD) + ABT-530 120 mg QD for 12 weeks in HCV genotype 1- infected participants with compensated cirrhosis | 27 |
| Arm G ABT-493 200 mg once daily (QD) + ABT-530 40 mg QD + ribavirin (RBV) 800 mg QD for 12 weeks in HCV genotype 1-infected participants with compensated cirrhosis (never opened - Sponsor decision) | 0 |
| Arm H ABT-493 200 mg once daily (QD) + ABT-530 40 mg QD for 12 weeks in HCV genotype 1-infected participants with compensated cirrhosis (never opened - Sponsor decision) | 0 |
| Arm I ABT-493 300 mg once daily (QD) + ABT-530 120 mg QD for 12 weeks in HCV genotype 4-, 5-, and 6-infected participants without cirrhosis | 32 |
| Arm J ABT-493 200 mg once daily (QD) + ABT-530 40 mg QD for 12 weeks in HCV genotype 4-, 5-, and 6-infected participants without cirrhosis (never opened - Sponsor decision) | 0 |
| Arm K ABT-493 300 mg once daily (QD) + ABT-530 120 mg QD for 8 weeks in HCV genotype 1- infected participants without cirrhosis | 34 |
| Total | 174 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treated | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Treated | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | Arm A | Arm B | Arm F | Arm I | Arm K | Total | Arm C | Arm D | Arm E | Arm G | Arm H | Arm J |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 52.4 years STANDARD_DEVIATION 10.01 | 52.5 years STANDARD_DEVIATION 10.41 | 58.9 years STANDARD_DEVIATION 5.47 | 55.0 years STANDARD_DEVIATION 11.13 | 53.5 years STANDARD_DEVIATION 10.34 | 54.1 years STANDARD_DEVIATION 9.98 | — | — | — | — | — | — |
| Sex: Female, Male Female | 17 Participants | 21 Participants | 7 Participants | 16 Participants | 15 Participants | 76 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 25 Participants | 18 Participants | 20 Participants | 16 Participants | 19 Participants | 98 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 22 / 42 | 22 / 39 | 9 / 27 | 20 / 32 | 19 / 34 |
| serious Total, serious adverse events | 1 / 42 | 0 / 39 | 1 / 27 | 0 / 32 | 1 / 34 |
Outcome results
Primary
Percentage of Participants With Sustained Virologic Response (SVR) 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 quantification \[\<LLOQ\]) 12 weeks after the last dose of study drug.
Time frame: 12 weeks after the last actual dose of study drug
Population: Intention-to-treat population: all participants who received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks Post-treatment | 100 percentage of participants |
| Arm B | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks Post-treatment | 97.4 percentage of participants |
| Arm F | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks Post-treatment | 96.3 percentage of participants |
| Arm I | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks Post-treatment | 100 percentage of participants |
| Arm K | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks Post-treatment | 97.1 percentage of participants |
Secondary
Percentage of Participants With On-treatment Virologic Failure
The percentage of participants with on-treatment virologic failure (defined as confirmed hepatitis C virus ribonucleic acid (HCV RNA) greater than or equal to the lower limit of quantitation \[≥ LLOQ\] after HCV RNA \< LLOQ during treatment), confirmed increase of \> 1 log(subscript)10(subscript) IU/mL above the lowest value post-baseline in HCV RNA during treatment, or HCV RNA ≥ LLOQ at end of treatment with at least 6 weeks of treatment.
Time frame: Screening, Day 1, Day 3, treatment weeks 1, 2, 4, 6, 8, 10, and 12 or premature discontinuation from treatment
Population: Intention-to-treat population: all participants who received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Percentage of Participants With On-treatment Virologic Failure | 0 percentage of participants |
| Arm B | Percentage of Participants With On-treatment Virologic Failure | 0 percentage of participants |
| Arm F | Percentage of Participants With On-treatment Virologic Failure | 0 percentage of participants |
| Arm I | Percentage of Participants With On-treatment Virologic Failure | 0 percentage of participants |
| Arm K | Percentage of Participants With On-treatment Virologic Failure | 0 percentage of participants |
Secondary
Percentage of Participants With Post-treatment Relapse
Post-treatment relapse was defined as confirmed hepatitis C virus ribonucleic acid (HCV RNA) greater than or equal to the lower limit of quantitation (≥ 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.
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 | 0 percentage of participants |
| Arm B | Percentage of Participants With Post-treatment Relapse | 2.6 percentage of participants |
| Arm F | Percentage of Participants With Post-treatment Relapse | 3.7 percentage of participants |
| Arm I | Percentage of Participants With Post-treatment Relapse | 0 percentage of participants |
| Arm K | Percentage of Participants With Post-treatment Relapse | 0 percentage of participants |
Secondary
Percentage of Participants With Sustained Virologic Response (SVR) 4 Weeks Post-treatment
The percentage of participants with sustained virologic response (plasma hepatitis C virus ribonucleic acid \[HCV RNA\] less than the lower limit of quantification \[\<LLOQ\]) 4 weeks after the last dose of study drug.
Time frame: 4 weeks after the last actual dose of study drug
Population: Intention-to-treat population: all participants who received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Percentage of Participants With Sustained Virologic Response (SVR) 4 Weeks Post-treatment | 100 percentage of participants |
| Arm B | Percentage of Participants With Sustained Virologic Response (SVR) 4 Weeks Post-treatment | 97.4 percentage of participants |
| Arm F | Percentage of Participants With Sustained Virologic Response (SVR) 4 Weeks Post-treatment | 96.3 percentage of participants |
| Arm I | Percentage of Participants With Sustained Virologic Response (SVR) 4 Weeks Post-treatment | 100 percentage of participants |
| Arm K | Percentage of Participants With Sustained Virologic Response (SVR) 4 Weeks Post-treatment | 100 percentage of participants |