Chronic Hepatitis C Infection
Conditions
Keywords
Partial responder, Interferon free, Treatment-experienced, Relapser, Hepatitis C Virus, Null responder, Hepatitis C Genotype 1, paritaprevir, ombitasvir, dasabuvir, ribavirin, Viekira PAK, Chronic hepatitis C
Brief summary
The purpose of this study is to evaluate the safety and antiviral activity of 3 direct-acting antiviral agents (DAAs; ABT-450/ritonavir/ABT-267 \[ABT-450/r/ABT-267; ABT-267 also known as ombitasvir\] and ABT-333 \[also known as dasabuvir\]) plus ribavirin (RBV) compared with telaprevir (TPV) with pegylated interferon/ribavirin (pegIFN/RBV) in patients with chronic hepatitis C virus genotype 1 (HCV GT1) infection without cirrhosis who were previously treated with pegylated interferon/ribavirin (pegIFN/RBV).
Detailed description
A randomized, open-label, parallel-arm, multicenter study to evaluate the safety and antiviral activity of the 3-DAA regimen (ABT-450/ritonavir/ABT-267 \[ABT-450/r/ABT-267\] and ABT-333) plus ribavirin (3-DAA/RBV) compared with the combination of telaprevir (TPV) with RBV and pegIFN (TPV/RBV) in noncirrhotic participants with chronic hepatitis C virus genotype 1 (HCV GT1) infection who were previously treated with pegylated interferon/ribavirin (pegIFN/RBV). Participants were randomized in a 2:1 ratio to receive 3-DAA/RBV (ABT-450/r/ABT-267 and ABT-333 plus RBV for 12 weeks) or TPV/RBV (TPV co-administered with pegIFN and RBV for 12 weeks, followed by followed by pegIFN and RBV for either 12 or 36 weeks, per local prescribing information).
Interventions
Tablet; ABT-450 coformulated with ritonavir and ABT-267, ABT-333 tablet
DRUGRibavirin
Tablet
DRUGPegylated Interferon a-2a (PegINF)
Pre-filled syringe
DRUGTelaprevir
Film-coated tablet
Sponsors
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 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 * Chronic hepatitis C infection (positive for anti-HCV antibody or HCV RNA at least 6 months before screening and at the time of screening; or positive for anti-HCV antibody or HCV RNA at the time of screening with a liver biopsy consistent with chronic HCV infection) * Screening laboratory result indicating HCV genotype 1 infection (HCV GT1) * Participant must have documentation of adherence to a prior pegIFN/RBV combination therapy and meet one of the protocol definitions for treatment failure: null responder, partial responder, relapser * No evidence of liver cirrhosis
Exclusion criteria
* Positive hepatitis B surface antigen or anti-human immunodeficiency virus antibody * Positive screen for drugs or alcohol * Significant sensitivity to any drug * Use of contraindicated medications within 2 weeks of dosing * Abnormal laboratory tests
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response 12 Weeks After Treatment | 12 weeks after the last 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. The LLOQ for the assay was 25 IU/mL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline to Final Treatment Visit in the Mental Component Summary (MCS) Score of the Short-Form 36 Health Survey - Version 2 (SF-36v2) | Baseline and Final Treatment Visit (up to Week 12 for 3-DAA/RBV and up to Week 24 or 48 for TPV/RBV) | The SF-36v2 is a general health-related quality of life (HRQoL) instrument with extensive use in multiple disease states. The SF-36v2 instrument comprises a total of 36 items (questions) targeting a participant's functional health and well-being in 8 domains (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health). Domain scores were aggregated into an MCS score (from 0 to 100; a higher score indicates better mental function and well-being). |
| Mean Change From Baseline to Final Treatment Visit in the Physical Component Summary (PCS) Score of the Short-Form 36 Health Survey - Version 2 (SF-36v2) | Baseline and Final Treatment Visit (up to Week 12 for 3-DAA/RBV and up to Week 24 or 48 for TPV/RBV) | The SF-36v2 is a general health-related quality of life (HRQoL) instrument with extensive use in multiple disease states. The SF-36v2 instrument comprises a total of 36 items (questions) targeting a participant's functional health and well-being in 8 domains (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health). Domain scores were aggregated into a PCS score (range = 0 to 100; a higher score indicates better mental function and well-being). |
| Percentage of Participants With Sustained Virologic Response 24 Weeks After Treatment | 24 weeks after the last 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 \[\< LLOQ\]) 24 weeks after the last dose of study drug. The LLOQ for the assay was 25 IU/mL. |
| Percentage of Participants With Virologic Failure During Treatment | Baseline to end of treatment (12 weeks for 3-DAA/RBV and 24 or 48 weeks for TPV/RBV) | Virologic failure during treatment was defined as HCV ribonucleic acid (RNA) confirmed greater than or equal to the lower limit of quantification (≥ LLOQ) after HCV RNA \< LLOQ during treatment or confirmed HCV RNA ≥ LLOQ at the end of treatment. |
| Percentage of Participants With Virologic Relapse After Treatment | Between end of treatment (Week 12 for 3-DAA/RBV and Week 24 or 48 for TPV/RBV) and Post-treatment (up to Week 12 Post-treatment) | Participants who completed treatment with plasma HCV RNA less than the lower limit of quantification (\<LLOQ) at the end of treatment were considered to have virologic relapse if they had confirmed HCV RNA ≥ LLOQ during the post-treatment period. |
Participant flow
Pre-assignment details
A total of 154 participants were randomized: 6 participants did not receive at least 1 dose of study drug and were excluded from the analyses; 148 participants received at least 1 dose and were included in the intent-to-treat (ITT) population.
Participants by arm
| Arm | Count |
|---|---|
| 3-DAA/RBV 3-DAA (ABT-450/r/ABT-267 \[150 mg/ 100 mg/ 25 mg once daily\] and ABT-333 \[250 mg twice daily\]) plus weight-based RBV (dosed 1,000 or 1,200 mg daily divided twice a day) for 12 weeks. | 101 |
| TPV/RBV TPV (750 mg every 8 hours) coadministered with pegIFN (180 micrograms subcutaneously \[SC\] weekly) and weight-based RBV (dosed 1,000 or 1,200 mg daily divided twice a day) for 12 weeks, followed by pegIFN (180 micrograms SC weekly) and weight-based RBV (dosed 1,000 or 1,200 mg daily divided twice a day) for either 12 or 36 weeks, per local prescribing information. | 47 |
| Total | 148 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 4 |
| Overall Study | Virologic Failure | 0 | 9 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | 3-DAA/RBV | TPV/RBV | Total |
|---|---|---|---|
| Age, Continuous | 46.9 years STANDARD_DEVIATION 12.15 | 45.0 years STANDARD_DEVIATION 10.35 | 46.3 years STANDARD_DEVIATION 11.61 |
| Sex: Female, Male Female | 46 Participants | 19 Participants | 65 Participants |
| Sex: Female, Male Male | 55 Participants | 28 Participants | 83 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 54 / 101 | 43 / 47 |
| serious Total, serious adverse events | 1 / 101 | 5 / 47 |
Outcome results
Primary
Percentage of Participants With Sustained Virologic Response 12 Weeks After 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. The LLOQ for the assay was 25 IU/mL.
Time frame: 12 weeks after the last dose of study drug
Population: ITT population: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 3-DAA/RBV | Percentage of Participants With Sustained Virologic Response 12 Weeks After Treatment | 100.0 percentage of participants |
| TPV/RBV | Percentage of Participants With Sustained Virologic Response 12 Weeks After Treatment | 66.0 percentage of participants |
Comparison: P-value for the difference in sustained virologic response rates 12 weeks after the last dose between treatment groups with HCV subgenotype (1a, non-1a) from stratum adjusted Mantel-Haenszel with previous type of response to pegIFN/RBV treatment (relapser, partial or null responder) as strata.p-value: <0.00195% CI: [21.09, 47.42]Stratum adjusted Mantel-Haenszel
Secondary
Mean Change From Baseline to Final Treatment Visit in the Mental Component Summary (MCS) Score of the Short-Form 36 Health Survey - Version 2 (SF-36v2)
The SF-36v2 is a general health-related quality of life (HRQoL) instrument with extensive use in multiple disease states. The SF-36v2 instrument comprises a total of 36 items (questions) targeting a participant's functional health and well-being in 8 domains (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health). Domain scores were aggregated into an MCS score (from 0 to 100; a higher score indicates better mental function and well-being).
Time frame: Baseline and Final Treatment Visit (up to Week 12 for 3-DAA/RBV and up to Week 24 or 48 for TPV/RBV)
Population: All participants in the ITT population with evaluable data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 3-DAA/RBV | Mean Change From Baseline to Final Treatment Visit in the Mental Component Summary (MCS) Score of the Short-Form 36 Health Survey - Version 2 (SF-36v2) | -1.3 units on a scale | Standard Deviation 8.32 |
| TPV/RBV | Mean Change From Baseline to Final Treatment Visit in the Mental Component Summary (MCS) Score of the Short-Form 36 Health Survey - Version 2 (SF-36v2) | -9.8 units on a scale | Standard Deviation 11.05 |
Comparison: P-value from ANCOVA model including baseline score and region as covariates and treatment arm as a factor.p-value: <0.00195% CI: [5.43, 11.85]ANCOVA
Secondary
Mean Change From Baseline to Final Treatment Visit in the Physical Component Summary (PCS) Score of the Short-Form 36 Health Survey - Version 2 (SF-36v2)
The SF-36v2 is a general health-related quality of life (HRQoL) instrument with extensive use in multiple disease states. The SF-36v2 instrument comprises a total of 36 items (questions) targeting a participant's functional health and well-being in 8 domains (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health). Domain scores were aggregated into a PCS score (range = 0 to 100; a higher score indicates better mental function and well-being).
Time frame: Baseline and Final Treatment Visit (up to Week 12 for 3-DAA/RBV and up to Week 24 or 48 for TPV/RBV)
Population: All participants in the ITT population with evaluable data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 3-DAA/RBV | Mean Change From Baseline to Final Treatment Visit in the Physical Component Summary (PCS) Score of the Short-Form 36 Health Survey - Version 2 (SF-36v2) | 0.4 units on a scale | Standard Deviation 7.16 |
| TPV/RBV | Mean Change From Baseline to Final Treatment Visit in the Physical Component Summary (PCS) Score of the Short-Form 36 Health Survey - Version 2 (SF-36v2) | -7.7 units on a scale | Standard Deviation 7.72 |
Comparison: P-value from ANCOVA model including baseline score and region as covariates and treatment arm as a factor.p-value: <0.00195% CI: [5.11, 9.98]ANCOVA
Secondary
Percentage of Participants With Sustained Virologic Response 24 Weeks After 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 \[\< LLOQ\]) 24 weeks after the last dose of study drug. The LLOQ for the assay was 25 IU/mL.
Time frame: 24 weeks after the last dose of study drug
Population: All participants in the ITT population with evaluable data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 3-DAA/RBV | Percentage of Participants With Sustained Virologic Response 24 Weeks After Treatment | 99.0 percentage of participants |
| TPV/RBV | Percentage of Participants With Sustained Virologic Response 24 Weeks After Treatment | 66.0 percentage of participants |
Comparison: P-value from logistic regression model including treatment arm, baseline log10 HCV RNA level, HCV subgenotype, and previous response to pegIFN/RBV treatment as predictors.p-value: <0.00195% CI: [6.9, 435.1]Regression, Logistic
Secondary
Percentage of Participants With Virologic Failure During Treatment
Virologic failure during treatment was defined as HCV ribonucleic acid (RNA) confirmed greater than or equal to the lower limit of quantification (≥ LLOQ) after HCV RNA \< LLOQ during treatment or confirmed HCV RNA ≥ LLOQ at the end of treatment.
Time frame: Baseline to end of treatment (12 weeks for 3-DAA/RBV and 24 or 48 weeks for TPV/RBV)
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 3-DAA/RBV | Percentage of Participants With Virologic Failure During Treatment | 0 percentage of participants |
| TPV/RBV | Percentage of Participants With Virologic Failure During Treatment | 19.1 percentage of participants |
Secondary
Percentage of Participants With Virologic Relapse After Treatment
Participants who completed treatment with plasma HCV RNA less than the lower limit of quantification (\<LLOQ) at the end of treatment were considered to have virologic relapse if they had confirmed HCV RNA ≥ LLOQ during the post-treatment period.
Time frame: Between end of treatment (Week 12 for 3-DAA/RBV and Week 24 or 48 for TPV/RBV) and Post-treatment (up to Week 12 Post-treatment)
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 3-DAA/RBV | Percentage of Participants With Virologic Relapse After Treatment | 0 percentage of participants |
| TPV/RBV | Percentage of Participants With Virologic Relapse After Treatment | 6.3 percentage of participants |