Hepatitis C Virus
Conditions
Keywords
Compensated Cirrhosis, Hepatitis C, Hepatitis C Genotype 4, Chronic Hepatitis C
Brief summary
The purpose of this study in HCV genotype 4-infected participants with compensated cirrhosis is to assess the safety and to compare the percentage of participants achieving a 12-week sustained virologic response (SVR12), \[HCV ribonucleic acid (RNA) \< lower limit of quantification (LLOQ) 12 weeks following treatment\], to a clinically relevant threshold \[based on SVR rates for HCV genotype 4-infected participants treated with pegylated interferon (pegIFN)/RBV\].
Detailed description
This is a Phase 3, randomized, open-label, multicenter study evaluating the safety and efficacy of ombitasvir/paritaprevir/ritonavir coadministered with RBV for 12, 16, or 24 weeks in HCV genotype 4 (GT4)-infected participants with compensated cirrhosis who are either treatment-naïve or who had previously received only IFN/RBV treatment for HCV. The study also enrolled HCV GT4-infected participants with compensated cirrhosis who had previously experienced virologic failure with either SOF/pegIFN/RBV or sofosbuvir (SOF)/RBV treatment. These participants were treated with ombitasvir/paritaprevir/ritonavir coadministered with RBV for 24 weeks in this study. This study was divided into 2 parts with approximately 184 total participants. Part I included participants who were randomized to receive either 12 or 16 weeks of treatment and Part II included participants who received 24 weeks of treatment. Enrollment into Part II opened once randomization in Part I was completed.
Interventions
tablets
DRUGribavirin
tablets
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
For Arms A, B and C: \- Participants must meet one of the following: * Treatment-naive: Participant has never received antiviral treatment for hepatitis C infection OR * Treatment Experienced (Prior null responders, Partial responders or Relapsers to IFN/RBV); For Arm D: \- Participant must have prior treatment experience with SOF/pegIFN/RBV or SOF/RBV and meet one of the following categories: * Prior SOF breakthrough/non-responder: HCV RNA detectable at the end of treatment with SOF/pegIFN/RBV or SOF/RBV; * Prior SOF relapser: achieved HCV RNA undetectable at end of a prior treatment course SOF/pegIFN/RBV or SOF/RBV, but HCV RNA was detectable within 52 weeks following completion of therapy. For Arms A, B, C and D: * Chronic HCV genotype 4 infection with cirrhosis. * Participant has plasma HCV RNA level \> 1,000 IU/mL at Screening
Exclusion criteria
* Positive test result at Screening for Hepatitis B surface antigen (HBsAg) or anti-human immunodeficiency virus antibody (HIV Ab). * Current enrollment in another interventional clinical study, previous enrollment in this study, or previous use of any protease inhibitor, non-nucleoside polymerase inhibitor, or Nonstructural viral protein (NS) 5A inhibitor, either investigational or commercially available (including previous exposure to paritaprevir or ombitasvir), or receipt of any investigational product within 6 weeks prior to study drug administration. Prior use of any direct-acting antiviral will not be allowed, except for Arm D where prior experience with the nucleoside polymerase inhibitor, sofosbuvir with pegIFN/RBV or SOF with RBV is required. * Any current or past clinical evidence of Child-Pugh B or C classification or clinical history of liver decompensation including ascites, variceal bleeding, or hepatic encephalopathy. * Confirmed presence of hepatocellular carcinoma. * Any cause of liver disease other than chronic HCV infection. * Abnormal laboratory tests.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants in Arms A, B and C 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 With SVR12 in Participants Receiving 12 Weeks (Arm A) of Treatment Compared to Participants Receiving 16 Weeks of Treatment (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. |
| Percentage of Participants With SVR12 in Participants Receiving 16 Weeks (Arm B) of Treatment Compared to Participants Receiving 24 Weeks of Treatment (Arm C) | 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. |
| Percentage of Participants in Arms A, B and C With On-treatment Virologic Failure | Up to Treatment Week 24 (end of treatment) or premature discontinuation from treatment | On-treatment virologic failure was defined as confirmed HCV RNA ≥ 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 all on-treatment values of HCV RNA \>= LLOQ with at least 6 weeks of treatment. |
| Percentage of Participants in Arms A, B and C 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. |
Participant flow
Recruitment details
The study was divided into 2 parts with 184 total participants. Part I (Arms A and B) included participants who received either 12 or 16 weeks of treatment and Part II (Arms C and D) included participants who received 24 weeks of treatment. Enrollment into Part II opened once randomization in Part I was completed.
Pre-assignment details
Safety analysis population: all participants who received at least 1 dose of study drug. One participant randomized to the arm B (16 weeks arm) was erroneously administered study drug for 12 weeks (as in arm A). Therefore this participant is included in arm A for the safety population.
Participants by arm
| Arm | Count |
|---|---|
| Arm A Ombitasvir/paritaprevir/ritonavir (25/150/100 mg) and Ribavirin dosed for 12 weeks for genotype 4 treatment-naïve or treatment-experienced with IFN/RBV. | 60 |
| Arm B Ombitasvir/paritaprevir/ritonavir (25/150/100 mg) and Ribavirin dosed for 16 weeks for genotype 4 treatment-naive or treatment-experienced with IFN/RBV. | 60 |
| Arm C Ombitasvir/paritaprevir/ritonavir (25/150/100 mg) and Ribavirin dosed for 24 weeks for genotype 4 treatment-naive and treatment-experienced with IFN/RBV. | 61 |
| Arm D Ombitasvir/paritaprevir/ritonavir (25/150/100 mg) and Ribavirin dosed for 24 weeks for genotype 4 SOF/pegIFN/RBV or SOF/RBV treatment-experienced. | 3 |
| Total | 184 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| As Treated (Overall Study) | Adverse Event | 1 | 1 | 0 | 0 |
| As Treated (Overall Study) | Lost to Follow-up | 1 | 2 | 6 | 0 |
| As Treated (Overall Study) | Other | 2 | 0 | 3 | 1 |
| As Treated (Overall Study) | Withdrawal by Subject | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Arm A | Arm B | Arm C | Arm D | Total |
|---|---|---|---|---|---|
| Age, Continuous | 57.7 years STANDARD_DEVIATION 8.08 | 57.1 years STANDARD_DEVIATION 9.08 | 54.6 years STANDARD_DEVIATION 9.02 | 62.3 years STANDARD_DEVIATION 8.08 | 56.6 years STANDARD_DEVIATION 8.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 6 Participants | 0 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 58 Participants | 59 Participants | 55 Participants | 3 Participants | 175 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 14 Participants | 22 Participants | 18 Participants | 0 Participants | 54 Participants |
| Sex: Female, Male Male | 46 Participants | 38 Participants | 43 Participants | 3 Participants | 130 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 | 46 / 60 | 55 / 60 | 50 / 61 | 3 / 3 |
| serious Total, serious adverse events | 4 / 60 | 4 / 60 | 3 / 61 | 0 / 3 |
Outcome results
Primary
Percentage of Participants in Arms A, B and C 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: 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 Arms A, B and C With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) | 96.6 percentage of participants |
| Arm B | Percentage of Participants in Arms A, B and C With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) | 100.0 percentage of participants |
| Arm C | Percentage of Participants in Arms A, B and C With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) | 93.4 percentage of participants |
Comparison: The overall 2-sided significance level of 0.05 was split between Part I (arms A and B) and Part II (arm C) using a Bonferroni corrected alpha level of 0.025 for each part. Additionally, a fixed sequence procedure for Part I was used to proceed through the primary efficacy comparisons in the following order: 1) test of superiority of arm B and 2) test of superiority of arm A. The primary outcome within Arm C was tested with a Bonferroni-corrected Type 1 error rate of 0.025 for superiority.97.5% CI: [92.4, 100]
Comparison: The overall 2-sided significance level of 0.05 was split between Part I (arms A and B) and Part II (arm C) using a Bonferroni corrected alpha level of 0.025 for each part. Additionally, a fixed sequence procedure for Part I was used to proceed through the primary efficacy comparisons in the following order: 1) test of superiority of arm B and 2) test of superiority of arm A. The primary outcome within Arm C was tested with a Bonferroni-corrected Type 1 error rate of 0.025 for superiority.97.5% CI: [86.7, 99.2]
Comparison: The overall 2-sided significance level of 0.05 was split between Part I (arms A and B) and Part II (arm C) using a Bonferroni corrected alpha level of 0.025 for each part. Additionally, a fixed sequence procedure for Part I was used to proceed through the primary efficacy comparisons in the following order: 1) test of superiority of arm B and 2) test of superiority of arm A. The primary outcome within Arm C was tested with a Bonferroni-corrected Type 1 error rate of 0.025 for superiority.97.5% CI: [82.6, 97.7]
Secondary
Percentage of Participants in Arms A, B and C With On-treatment Virologic Failure
On-treatment virologic failure was defined as confirmed HCV RNA ≥ 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 all on-treatment values of HCV RNA \>= LLOQ with at least 6 weeks of treatment.
Time frame: Up to Treatment Week 24 (end of treatment) 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 in Arms A, B and C With On-treatment Virologic Failure | 1.7 percentage of participants |
| Arm B | Percentage of Participants in Arms A, B and C With On-treatment Virologic Failure | 0 percentage of participants |
| Arm C | Percentage of Participants in Arms A, B and C With On-treatment Virologic Failure | 0 percentage of participants |
Secondary
Percentage of Participants in Arms A, B and C 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.
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 in Arms A, B and C With Post-treatment Relapse | 0 percentage of participants |
| Arm B | Percentage of Participants in Arms A, B and C With Post-treatment Relapse | 0 percentage of participants |
| Arm C | Percentage of Participants in Arms A, B and C With Post-treatment Relapse | 0 percentage of participants |
Secondary
Percentage of Participants With SVR12 in Participants Receiving 12 Weeks (Arm A) of Treatment Compared to Participants Receiving 16 Weeks of Treatment (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.
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 SVR12 in Participants Receiving 12 Weeks (Arm A) of Treatment Compared to Participants Receiving 16 Weeks of Treatment (Arm B) | 96.6 percentage of participants |
| Arm B | Percentage of Participants With SVR12 in Participants Receiving 12 Weeks (Arm A) of Treatment Compared to Participants Receiving 16 Weeks of Treatment (Arm B) | 100 percentage of participants |
Comparison: Within Part I (arm A and B), since superiority was demonstrated for both arms in the primary outcome measures, testing continued to the first secondary outcome measure.p-value: 0.30495% CI: [-9.85, 3.07]Mantel Haenszel
Secondary
Percentage of Participants With SVR12 in Participants Receiving 16 Weeks (Arm B) of Treatment Compared to Participants Receiving 24 Weeks of Treatment (Arm C)
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 (ITT population); participants with missing data after backwards imputation were imputed as nonresponders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Percentage of Participants With SVR12 in Participants Receiving 16 Weeks (Arm B) of Treatment Compared to Participants Receiving 24 Weeks of Treatment (Arm C) | 100 percentage of participants |
| Arm B | Percentage of Participants With SVR12 in Participants Receiving 16 Weeks (Arm B) of Treatment Compared to Participants Receiving 24 Weeks of Treatment (Arm C) | 93.4 percentage of participants |
Comparison: Within Part II (arm C), since superiority was demonstrated for the primary outcome measure, testing continued to the second secondary outcome measure.p-value: 0.08695% CI: [-0.91, 13.81]Mantel Haenszel