Hepatitis C Virus (HCV)
Conditions
Keywords
Chronic Hepatitis C Virus (HCV), Genotype 1 to 6, Asian, non-cirrhotic, Human Immunodeficiency Virus, co-infection, Treatment-naïve, Treatment-experienced, interferon
Brief summary
This study will evaluate the efficacy and safety of glecaprevir/pibrentasvir (ABT-493/ABT-530) in non-cirrhotic chronic hepatitis C virus (HCV) genotype (GT)1 to GT6-infected Asian participants with or without human immunodeficiency virus (HIV) co-infection who are HCV treatment-naïve or treatment-experienced with interferon (IFN) with or without ribavirin (RBV), OR sofosbuvir with RBV with or without IFN.
Detailed description
Randomization was stratified by geographic region (China, South Korea, Singapore), genotype (GT1, GT2, combined GT3 - 6), and HCV/HIV co-infection status (co-infected, not co-infected). In China, eligible participants were randomized to Arm A or Arm B (defined below) in the following ratios: 2:1 for GT1, 2:1 for GT2, and 2:1 for combined GT3-6. In South Korea and Singapore, eligible participants were randomized to Arm A or Arm B in the following ratios: 2:1 for GT1 and 2:1 for GT2. All Primary and Secondary Outcome Measures were pre-specified to be analyzed only in Arm A.
Interventions
DRUGPlacebo
Matching placebo tablet for oral administration
Coformulated tablet for oral administration
Sponsors
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must be of Asian descent * Screening laboratory result indicating hepatitis C virus (HCV) genotype (GT) 1, 2, 3, 4, 5 or 6 infection. * Positive anti-HCV antibody (Ab) and HCV ribonucleic acid (RNA) viral load ≥ 1000 IU/ mL at Screening Visit. * Chronic HCV infection defined as one of the following: * Positive for anti-HCV Ab or HCV RNA at least 6 months before Screening; or * A liver biopsy consistent with chronic HCV infection * HCV treatment-naïve to any approved or investigational HCV treatment or treatment-experienced with interferon (IFN) (alpha, beta or pegylated interferon\[pegIFN\] with or without ribavirin, OR sofosbuvir with RBV with or without IFN. Previous treatment must have been completed ≥ 8 weeks prior to screening. * Participant must be documented as non-cirrhotic. * Participants enrolled with human immunodeficiency virus (HIV)-1 and HCV co-infection must also meet the following criteria: * Positive test result for human immunodeficiency virus antibody (HIV Ab) at Screening * Naïve to treatment with any antiretroviral therapy (ART) with a cluster of differentiation (CD)4+ count greater than or equal to 500 cells/mm³ (or CD4+ percent ≥ 29%) * On a stable, qualifying HIV-1 ART regimen with CD4+ count ≥ 200 cells/mm³ (or CD4+ % ≥ 14%) at Screening and plasma HIV-1 RNA below lower limit of quantification (LLOQ) by an approved plasma HIV-1 RNA quantitative assay at Screening and at least once during the 12 months prior to Screening.
Exclusion criteria
* Positive test result for Hepatitis B surface antigen (HbsAg) or positive test result for hepatitis B virus (HBV) deoxyribonucleic acid (DNA) if HBsAg is negative. * Any cause of liver disease other than chronic HCV-infection. * HCV genotype performed during screening indicating co-infection with more than one HCV genotype * Clinically significant abnormalities, other than HCV infection or HCV/HIV co-infection * Chronic human immunodeficiency virus, type 2 (HIV-2) infection Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of HCV GT1 - GT6-Infected Participants in Arm A Who Achieved Sustained Virologic Response 12 Weeks Post Treatment (SVR12) | 12 weeks after the last actual dose of study drug, Week 20 or Week 28 depending on the treatment regimen. | Sustained virologic response 12 weeks post-treatment (SVR12) was defined as plasma hepatitis C virus ribonucleic acid (HCV RNA) level less than the lower limit of quantification (LLOQ; less than 15 IU/mL) 12 weeks after the last dose of study drug. |
| Percentage of HCV GT1-Infected Participants in Arm A Who Achieved SVR12 | 12 weeks after last actual dose of study drug, Week 20 or Week 28 depending on the treatment regimen | SVR12 was defined as plasma HCV RNA level less than 15 IU/mL 12 weeks after the last dose of study drug. |
| Percentage of HCV GT2-Infected Participants in Arm A Who Achieved SVR12 | 12 weeks after the last dose of study drug, Week 20 or Week 28 depending on the treatment regimen. | SVR12 was defined as plasma HCV RNA level less than 15 IU/mL 12 weeks after the last actual dose of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants in Arm A With On-treatment Virologic Failure | 8 or 16 weeks depending on the treatment regimen | On-treatment virologic failure was defined as meeting one of the following: * confirmed increase from nadir in HCV RNA (two consecutive HCV RNA measurements \> 1 log₁₀ IU/mL above nadir) at any time point during the treatment period; or * confirmed HCV RNA greater than or equal to 100 IU/mL after HCV RNA \< 15 IU/mL during the treatment period, or * HCV RNA ≥ 15 IU/mL at end of treatment with at least 6 weeks of treatment. |
| Percentage of Participants in Arm A With Post-treatment Relapse | From the end of treatment (Weeks 8 or 16) through 12 weeks after the last dose of study drug (Weeks 20 or 28 depending on the treatment regimen). | Post-treatment relapse was defined as confirmed HCV RNA greater than or equal to 15 IU/mL between the end of treatment and 12 weeks after the last dose of study drug among participants who completed treatment with HCV RNA levels \< 15 IU/mL at the end of treatment, excluding re-infection. |
| Percentage of HCV/HIV Co-infected Participants in Arm A Who Achieved SVR12 | 12 weeks after the last actual dose of study drug, Week 20 or 28 depending on the treatment regimen | SVR12 was defined as plasma HCV RNA level less than 15 IU/mL 12 weeks after the last dose of study drug. |
Countries
China, Singapore, South Korea
Participant flow
Recruitment details
This study was conducted at 47 sites in China, South Korea, and Singapore. Eligible participants were non-cirrhotic chronic hepatitis C (HCV) genotype (GT)1-6-infected adults with or without HIV co-infection who were HCV treatment-naïve or treatment-experienced with regimens containing interferon (IFN), pegylated IFN, ribavirin, and/or sofosbuvir.
Pre-assignment details
Randomization was stratified by geographic region, genotype (GT1, GT2, combined GT3 - 6), and HCV/HIV co-infection status (co-infected, not co-infected). Participants were randomized to Arm A or Arm B in the following ratios: China: 2:1 for GT1, 2:1 for GT2, and 2:1 for combined GT3 - 6; South Korea and Singapore: 2:1 for GT1 and 2:1 for GT2.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Glecaprevir/Pibrentasvir Participants received oral glecaprevir/pibrentasvir (300 mg/120 mg) once daily with food for 8 or 16 weeks during the double-blind (DB) treatment period. | 362 |
| Arm B: Placebo / Glecaprevir/Pibrentasvir Participants received placebo to glecaprevir/pibrentasvir for 8 or 16 weeks during the DB treatment period followed by glecaprevir/pibrentasvir (300 mg/120 mg) once daily for 8 or 16 weeks during the open-label (OL) treatment period. | 183 |
| Total | 545 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other | 1 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Arm A: Glecaprevir/Pibrentasvir | Arm B: Placebo / Glecaprevir/Pibrentasvir | Total |
|---|---|---|---|
| Age, Continuous | 48.68 years STANDARD_DEVIATION 12.96 | 49.18 years STANDARD_DEVIATION 13.55 | 48.85 years STANDARD_DEVIATION 13.15 |
| HCV Genotype Genotype 1 | 179 Participants | 89 Participants | 268 Participants |
| HCV Genotype Genotype 2 | 139 Participants | 71 Participants | 210 Participants |
| HCV Genotype Genotype 3 | 26 Participants | 10 Participants | 36 Participants |
| HCV Genotype Genotype 4 | 0 Participants | 1 Participants | 1 Participants |
| HCV Genotype Genotype 5 | 0 Participants | 0 Participants | 0 Participants |
| HCV Genotype Genotype 6 | 18 Participants | 12 Participants | 30 Participants |
| HCV Ribonucleic Acid (RNA) Level | 6.37 log₁₀ IU/mL STANDARD_DEVIATION 0.72 | 6.26 log₁₀ IU/mL STANDARD_DEVIATION 0.79 | 6.33 log₁₀ IU/mL STANDARD_DEVIATION 0.74 |
| Human Immunodeficiency Virus (HIV) Co-infection Status HCV / HIV co-infection | 0 Participants | 0 Participants | 0 Participants |
| Human Immunodeficiency Virus (HIV) Co-infection Status Hepatitis C infection only | 362 Participants | 183 Participants | 545 Participants |
| Prior HCV Treatment History Treatment-experienced | 81 Participants | 28 Participants | 109 Participants |
| Prior HCV Treatment History Treatment-naive | 281 Participants | 155 Participants | 436 Participants |
| Race/Ethnicity, Customized Asian | 362 Participants | 183 Participants | 545 Participants |
| Region of Enrollment China | 259 Participants | 130 Participants | 389 Participants |
| Region of Enrollment Singapore | 21 Participants | 11 Participants | 32 Participants |
| Region of Enrollment South Korea | 82 Participants | 42 Participants | 124 Participants |
| Sex: Female, Male Female | 180 Participants | 97 Participants | 277 Participants |
| Sex: Female, Male Male | 182 Participants | 86 Participants | 268 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 362 | 0 / 183 | 0 / 182 |
| other Total, other adverse events | 36 / 362 | 18 / 183 | 22 / 182 |
| serious Total, serious adverse events | 3 / 362 | 4 / 183 | 5 / 182 |
Outcome results
Primary
Percentage of HCV GT1 - GT6-Infected Participants in Arm A Who Achieved Sustained Virologic Response 12 Weeks Post Treatment (SVR12)
Sustained virologic response 12 weeks post-treatment (SVR12) was defined as plasma hepatitis C virus ribonucleic acid (HCV RNA) level less than the lower limit of quantification (LLOQ; less than 15 IU/mL) 12 weeks after the last dose of study drug.
Time frame: 12 weeks after the last actual dose of study drug, Week 20 or Week 28 depending on the treatment regimen.
Population: This endpoint was pre-specified to be analyzed in participants randomized to Arm A who received at least 1 dose of study drug during the DB Treatment Period. Backward imputation, where applicable, was used to impute missing data. Participants with missing data after backward imputation were counted as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Glecaprevir/Pibrentasvir | Percentage of HCV GT1 - GT6-Infected Participants in Arm A Who Achieved Sustained Virologic Response 12 Weeks Post Treatment (SVR12) | 97.2 percentage of participants |
Comparison: In order to control the Type I error rate, a fixed sequence testing procedure was used for the 3 ranked primary efficacy endpoints. Only if success had been demonstrated for the first primary endpoint was testing to proceed to the second primary endpoint. Similarly, only if success had been demonstrated for the second primary endpoint was testing to proceed to the third primary endpoint.95% CI: [95.5, 98.9]
Primary
Percentage of HCV GT1-Infected Participants in Arm A Who Achieved SVR12
SVR12 was defined as plasma HCV RNA level less than 15 IU/mL 12 weeks after the last dose of study drug.
Time frame: 12 weeks after last actual dose of study drug, Week 20 or Week 28 depending on the treatment regimen
Population: This endpoint was pre-specified to be analyzed in GT1-infected participants randomized to Arm A who received at least one dose of study drug. Backward imputation, where applicable, was used to impute missing data. Participants with missing data after backward imputation were counted as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Glecaprevir/Pibrentasvir | Percentage of HCV GT1-Infected Participants in Arm A Who Achieved SVR12 | 99.4 percentage of participants |
Comparison: In order to control the Type I error rate, a fixed sequence testing procedure was used for the 3 ranked primary efficacy endpoints. Only if success had been demonstrated for the first primary endpoint was testing to proceed to the second primary endpoint. Similarly, only if success had been demonstrated for the second primary endpoint was testing to proceed to the third primary endpoint.95% CI: [98.3, 100]
Primary
Percentage of HCV GT2-Infected Participants in Arm A Who Achieved SVR12
SVR12 was defined as plasma HCV RNA level less than 15 IU/mL 12 weeks after the last actual dose of study drug.
Time frame: 12 weeks after the last dose of study drug, Week 20 or Week 28 depending on the treatment regimen.
Population: This endpoint was pre-specified to be analyzed in genotype 2-infected participants randomized to Arm A who received at least one dose of study drug. Backward imputation, where applicable, was used to impute missing data. Participants with missing data after backward imputation were counted as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Glecaprevir/Pibrentasvir | Percentage of HCV GT2-Infected Participants in Arm A Who Achieved SVR12 | 97.8 percentage of participants |
Comparison: In order to control the Type I error rate, a fixed sequence testing procedure was used for the 3 ranked primary efficacy endpoints. Only if success had been demonstrated for the first primary endpoint was testing to proceed to the second primary endpoint. Similarly, only if success had been demonstrated for the second primary endpoint was testing to proceed to the third primary endpoint.95% CI: [95.4, 100]
Secondary
Percentage of HCV/HIV Co-infected Participants in Arm A Who Achieved SVR12
SVR12 was defined as plasma HCV RNA level less than 15 IU/mL 12 weeks after the last dose of study drug.
Time frame: 12 weeks after the last actual dose of study drug, Week 20 or 28 depending on the treatment regimen
Population: No HCV-HIV co-infected participants were enrolled in the study
Secondary
Percentage of Participants in Arm A With On-treatment Virologic Failure
On-treatment virologic failure was defined as meeting one of the following: * confirmed increase from nadir in HCV RNA (two consecutive HCV RNA measurements \> 1 log₁₀ IU/mL above nadir) at any time point during the treatment period; or * confirmed HCV RNA greater than or equal to 100 IU/mL after HCV RNA \< 15 IU/mL during the treatment period, or * HCV RNA ≥ 15 IU/mL at end of treatment with at least 6 weeks of treatment.
Time frame: 8 or 16 weeks depending on the treatment regimen
Population: This endpoint was pre-specified to be analyzed in all participants randomized to Arm A who received at least 1 dose of study drug during the DB Treatment Period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Glecaprevir/Pibrentasvir | Percentage of Participants in Arm A With On-treatment Virologic Failure | 0.6 percentage of participants |
Secondary
Percentage of Participants in Arm A With Post-treatment Relapse
Post-treatment relapse was defined as confirmed HCV RNA greater than or equal to 15 IU/mL between the end of treatment and 12 weeks after the last dose of study drug among participants who completed treatment with HCV RNA levels \< 15 IU/mL at the end of treatment, excluding re-infection.
Time frame: From the end of treatment (Weeks 8 or 16) through 12 weeks after the last dose of study drug (Weeks 20 or 28 depending on the treatment regimen).
Population: This endpoint was pre-specified to be analyzed in all participants randomized to Arm A who received at least one dose of study drug, with HCV RNA \< 15 IU/mL at the end of treatment, at least one post-treatment HCV RNA value, and who completed the assigned treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Glecaprevir/Pibrentasvir | Percentage of Participants in Arm A With Post-treatment Relapse | 1.7 percentage of participants |