Chronic Hepatitis C Virus, Hepatitis C Virus
Conditions
Keywords
Compensated cirrhosis, Non-cirrhotic, Renal impairment, Hepatitis C virus (HCV), Hepatitis C, Chronic Hepatitis C, Hepatitis C Genotype 1, Hepatitis C Genotype 2, Hepatitis C Genotype 3, Hepatitis C Genotype 4, Hepatitis C Genotype 5, Hepatitis C Genotype 6, DAA-experienced
Brief summary
The purpose of this phase 3, multicenter study is to evaluate the efficacy and safety of ABT-493/ABT-530 in Japanese adults with chronic Hepatitis C Virus (HCV)-infected, HCV direct-acting antiviral agent (DAA) treatment-naïve, and DAA treatment-experienced Japanese adult subjects.
Detailed description
The study consisted of two sub-studies that enrolled in parallel. Substudy 1 was randomized, open-label, and active-controlled, wherein HCV treatment-naïve or interferon (IFN)-experienced (i.e., DAA treatment-naïve), genotype (GT)1-infected participants without cirrhosis were enrolled. Substudy 2 was non-randomized, open label, and enrolled special populations of HCV-infected participants \[GT1- or GT2-infected subjects with compensated cirrhosis, HCV GT3-, 4-, 5- and 6-infected subjects (with compensated cirrhosis or without cirrhosis), HCV GT1- and GT2-infected subjects who had failed prior DAA treatments (with compensated cirrhosis or without cirrhosis), HCV GT1- or GT2-infected subjects with severe renal impairment (with compensated cirrhosis or without cirrhosis)\].
Interventions
DRUGABT-493/ABT-530
Co-formulated tablet
DRUGOBV/PTV/r
Co-formulated 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
* Females were postmenopausal for at least 2 years; surgically sterile or had a vasectomized partner; or, if of childbearing potential and sexually active with a male partner, were currently using at least 1 effective method of birth control at the time of Screening and agreed to practice 1 effective method of birth control from Screening through 30 days after stopping study drug. Sexually active males were surgically sterile or, if sexually active with a female partner of childbearing potential, agreed to practice 1 effective form of birth control from Screening through 30 days after stopping study drug. * Screening central laboratory result indicated HCV single genotype infection for the appropriate treatment arm, without co-infection of any other genotype. * Chronic HCV infection is defined as one of the following: * Positive for anti-HCV antibody (Ab) and/or HCV RNA at least 6 months before Screening. * A liver biopsy consistent with chronic HCV infection. * Agreed to voluntarily sign and date an informed consent form, approved by an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) prior to the initiation of any screening or study specific procedures. * Participants who were able to understand and adhere to the study visit schedule and all other protocol requirements. * Absence of hepatocellular carcinoma (HCC) as indicated by an ultrasound, computed tomography (CT) scan or magnetic resonance imaging (MRI).
Exclusion criteria
* Females who were pregnant or planned to become pregnant, or breastfeeding or males whose partner was pregnant or planning to become pregnant during the study. * Participants co-infected with hepatitis B virus or human immunodeficiency virus. * Use of contraindicated medications or supplements within 2 weeks or 10 half-lives (if known), whichever was longer, prior to the first dose of any study drug. * 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. * Any cause of liver disease other than chronic HCV infection. * Any current or past clinical evidence of Child-Pugh B or C classification or clinical history of decompensated liver disease. * Consideration by the investigator, for any reason, that the participant is an unsuitable candidate to receive ABT-493/ABT-530.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants in Arms A and B With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants in Arm A With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) | 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. 95% CI was calculated using the normal approximation to the binomial distribution. |
| Percentage of Participants for Each Sub-Population in Arms C and D With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) | 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. Subpopulations defined as Genotype 1 and 2 infected cirrhotic participants, prior direct acting antiviral agent (DAA) treatment experienced (T-exp) participants, Genotype 3, 4, 5 or 6-infected participants, and participants with severe renal impairment (RI). 95% CI was calculated using the Wilson score method. |
| Percentage of Participants With On-treatment Virologic Failure | Treatment Weeks 1, 2, 4, 8 (end of treatment for 8-week treatment arm), and 12 (end of treatment for 12-week treatment arm) 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 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. 95% CI was calculated using the Wilson score method. |
| 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 with HCV RNA levels \< LLOQ at the end of treatment, excluding participants who were been shown to be re-infected. The confidence interval was calculated using the Wilson score method. |
Participant flow
Pre-assignment details
Intent-to-treat population: all participants who received at least 1 dose of study drug
Participants by arm
| Arm | Count |
|---|---|
| Arm A ABT-493 (300 mg) once daily (QD) co-administered with ABT-530 (120 mg) once daily (QD) for 8 weeks in HCV genotype 1 (GT1) -infected, DAA treatment-naïve participants without cirrhosis. | 129 |
| Arm B Ombitasvir (25 mg)/paritaprevir (150 mg)/ritonavir (100mg) (OBV/PTV/r) QD for 12 weeks in HCV GT1 infected, DAA treatment-naïve participants without cirrhosis. | 52 |
| Arm C ABT-493 (300 mg) once daily (QD) co-administered with ABT-530 (120 mg) QD for 12 weeks in HCV GT1- or GT2-infected participants with compensated cirrhosis, HCV GT3-, 4-, 5- and 6-infected participants (with compensated cirrhosis or without cirrhosis), HCV GT1- and GT2-infected participants who had failed prior DAA treatments (with compensated cirrhosis or without cirrhosis), and HCV GT1- or GT2-infected participants with severe renal impairment and compensated cirrhosis. | 103 |
| Arm D ABT-493 (300 mg) once daily (QD) co-administered with ABT-530 (120 mg) QD for 8 weeks in GT1- or GT2-infected participants with severe renal impairment and without cirrhosis. | 10 |
| Total | 294 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 2 | 0 |
Baseline characteristics
| Characteristic | Arm A | Arm B | Arm C | Arm D | Total |
|---|---|---|---|---|---|
| Age, Customized < 65 years | 66 participants | 22 participants | 33 participants | 4 participants | 125 participants |
| Age, Customized >= 65 years to < 75 years | 37 participants | 23 participants | 43 participants | 4 participants | 107 participants |
| Age, Customized >= 75 years | 26 participants | 7 participants | 27 participants | 2 participants | 62 participants |
| Sex: Female, Male Female | 82 Participants | 38 Participants | 58 Participants | 6 Participants | 184 Participants |
| Sex: Female, Male Male | 47 Participants | 14 Participants | 45 Participants | 4 Participants | 110 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 51 / 129 | 28 / 52 | 44 / 103 | 8 / 10 |
| serious Total, serious adverse events | 0 / 129 | 3 / 52 | 0 / 103 | 1 / 10 |
Outcome results
Primary
Percentage of Participants in Arms A and B With Sustained Virologic Response 12 Weeks Post-treatment (SVR12)
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.
Time frame: 12 weeks after the last actual dose of study drug
Population: All participants who received at least 1 dose of study drug, excluding participants with the Y93H polymorphism in NS5A at baseline (ITT-PS population); participants with missing data after backwards imputation were imputed as nonresponders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Percentage of Participants in Arms A and B With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) | 99.1 percentage of participants |
| Arm B | Percentage of Participants in Arms A and B With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) | 100 percentage of participants |
95% CI: [-2.8, 0.9]
Secondary
Percentage of Participants for Each Sub-Population in Arms C and D With Sustained Virologic Response 12 Weeks Post-treatment (SVR12)
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. Subpopulations defined as Genotype 1 and 2 infected cirrhotic participants, prior direct acting antiviral agent (DAA) treatment experienced (T-exp) participants, Genotype 3, 4, 5 or 6-infected participants, and participants with severe renal impairment (RI). 95% CI was calculated using the Wilson score method.
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 | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A | Percentage of Participants for Each Sub-Population in Arms C and D With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) | HCV GT1 Participants with Compensated Cirrhosis | 100 percentage of participants |
| Arm A | Percentage of Participants for Each Sub-Population in Arms C and D With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) | HCV GT2 Participants with Compensated Cirrhosis | 100 percentage of participants |
| Arm A | Percentage of Participants for Each Sub-Population in Arms C and D With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) | DAA Experienced Participants | 93.9 percentage of participants |
| Arm A | Percentage of Participants for Each Sub-Population in Arms C and D With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) | HCV GT3,4,5 and 6 Participants | 83.3 percentage of participants |
| Arm A | Percentage of Participants for Each Sub-Population in Arms C and D With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) | Participants With Severe RI and with Cirrhosis | 100.0 percentage of participants |
| Arm B | Percentage of Participants for Each Sub-Population in Arms C and D With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) | Participants With Severe RI and without Cirrhosis | 100 percentage of participants |
Secondary
Percentage of Participants in Arm A With Sustained Virologic Response 12 Weeks Post-treatment (SVR12)
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. 95% CI was calculated using the normal approximation to the binomial distribution.
Time frame: 12 weeks after the last actual dose of study drug
Population: Intent-to-treat (ITT) population: all participants who received at least 1 dose of study drug; participants with missing data after backwards imputation were imputed as nonresponders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Percentage of Participants in Arm A With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) | 99.2 percentage of participants |
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 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. 95% CI was calculated using the Wilson score method.
Time frame: Treatment Weeks 1, 2, 4, 8 (end of treatment for 8-week treatment arm), and 12 (end of treatment for 12-week treatment arm) 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 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 | 1.0 percentage of participants |
| Arm D | 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 HCV RNA ≥ LLOQ between the end of treatment and 12 weeks after the last dose of study drug among participants with HCV RNA levels \< LLOQ at the end of treatment, excluding participants who were been shown to be re-infected. The confidence interval was calculated using the Wilson score method.
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 (ITT population) with at least one post-treatment HCV RNA value, 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 | 0 percentage of participants |
| Arm C | Percentage of Participants With Post-Treatment Relapse | 3.0 percentage of participants |
| Arm D | Percentage of Participants With Post-Treatment Relapse | 0 percentage of participants |