Chronic Hepatitis C Virus (HCV) Infection Genotype 1
Conditions
Keywords
Hepatitis C Genotype 1, Compensated Cirrhosis, Cirrhosis, Naive, Hepatitis C, Hepatitis C Virus, Treatment-Experienced, Relapser, Null responder, Non responder
Brief summary
The purpose of this study was to evaluate the effect of treatment with ABT-450 co-formulated with ritonavir and ABT-267 (ABT-450/r/ABT-267) and ABT-333; 3-DAA regimen, with or without ribavirin (RBV) in adults with chronic hepatitis C virus genotype 1 (HCV GT1) infection.
Detailed description
This study (TOPAZ-I; M14-423), was a Phase 3b, open-label, multicenter study conducted outside of the United States which, together with its companion study TOPAZ-II (M14-222; NCT 02167945) conducted in the United States, was designed with the primary objective of assessing the effect of treatment response on long-term clinical outcomes in adults with chronic HCV GT1 infection with or without compensated cirrhosis, who were either treatment-naïve or interferon/ribavirin (IFN/RBV) treatment- experienced. In both studies, participants were treated with the 3-DAA regimen with or without RBV. This study consisted of a screening period of up to 42 days, a treatment period of either 12 weeks for HCV GT1a-infected subjects without cirrhosis and for HCV GT1b-infected subjects without cirrhosis or with compensated cirrhosis or 24 weeks for GT1a-infected participants with compensated cirrhosis, and a 260-week post-treatment period.
Interventions
DRUGABT-333
Tablet for oral use
Tablet for oral use
DRUGRibavirin (RBV)
Ribavirin was provided as 200 mg tablets, and dosed based on weight,1000 to 1200 mg divided twice daily per local label. For example, for participants weighing \< 75 kg, RBV may have been taken orally as 2 tablets in the morning and 3 tablets in the evening which corresponds to a 1000 mg total daily dose. For participants weighing ≥ 75 kg, RBV may have been taken orally as 3 tablets in the morning and 3 tablets in the evening which corresponds to a 1200 mg total daily dose.
Sponsors
AbbVie
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Males and females at least 18 years old at screening 2. Females must be post-menopausal for more than 2 years or surgically sterile or practicing acceptable forms of birth control 3. Chronic hepatitis C, genotype 1 infection 4. Males must be surgically sterile or agree to practice acceptable forms of birth control 5. Screening laboratory result indicating HCV genotype 1 infection
Exclusion criteria
1. Use of contraindicated medications within 2 weeks of dosing 2. Abnormal laboratory tests 3. Current or past clinical evidence of Child-Pugh B or C classification or history of liver decompensation 4. Confirmed presence of hepatocellular carcinoma 5. History of solid organ transplant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-Cause Death, Liver-Related Death, Liver Decompensation, Liver Transplantation, Hepatocellular Carcinoma: Time to Event | At Post-Treatment Weeks 52, 104, 156, 208, and 260 | Time to the composite of clinical outcomes is the time to the first occurrence of all-cause death, liver-related death, liver decompensation, liver transplantation, or hepatocellular carcinoma. All first occurrences were to be included, regardless of whether it occurred while the participant was still taking study drug or had previously discontinued study drug. If the participant did not experience any of these events, their data was to be censored at the date of their last available assessment of clinical outcomes. For participants with no post-baseline assessment, the participant's data was to be censored on the first day of study drug dosing. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. Pre-specified analysis included pooled data from this study and from TOPAZ-II; NCT02167945. |
| Liver Transplantation: Time to Event | At Post-Treatment Weeks 52, 104, 156, 208, and 260 | Time to liver transplantation was defined as days from 1st day of study drug dosing for subject to date of liver transplantation. All liver transplantation was to be included, whether it occurred while the subject was still taking study drug or had previously discontinued study drug. If the subject didn't experience event of interest nor had died (all-cause death), their data was to be censored at the date of their last available assessment. For those with no post-baseline assessment, data was to be censored on 1st day of study drug dosing. All-cause death was a censoring event for liver transplantation. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. The pre-specified analysis of liver transplantation included pooled data from TOPAZ-I (this study) and the companion study TOPAZ-II (M14-222; NCT02167945). |
| Hepatocellular Carcinoma: Time to Event | At Post-Treatment Weeks 52, 104, 156, 208, and 260 | Time to hepatocellular carcinoma (HCC) was defined as number of days from 1st day of study drug dosing for subject to date of hepatocellular carcinoma. All HCC was to be included, whether it occurred while subject was still taking study drug or had previously discontinued study drug. If the subject didn't experience the event of interest nor had died (all-cause death), their data was to be censored at the date of their last available assessment. For those with no post-baseline assessment, their data was to be censored on the 1st day of study drug dosing. All-cause death was a censoring event for HCC. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. The pre-specified analysis of hepatocellular carcinoma included pooled data from TOPAZ-I (this study) and the companion study TOPAZ-II (M14-222; NCT02167945). |
| All-Cause Death: Time to Event | At Post-Treatment Weeks 52, 104, 156, 208, and 260 | Time to all-cause death was defined as the number of days from the first day of study drug dosing for the participant to the date of death. All deaths were to be included, regardless of whether the death occurred while the participant was still taking study drug or had previously discontinued study drug. If the participant did not die, their data was to be censored at the date of their last available assessment of clinical outcomes. For participants with no post-baseline assessment, the participant's data was to be censored on the first day of study drug dosing. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. The pre-specified analysis of all-cause death included pooled data from TOPAZ-I (this study) and the companion study TOPAZ-II (M14-222; NCT02167945). |
| Liver-Related Death: Time to Event | At Post-Treatment Weeks 52, 104, 156, 208, and 260 | Time to liver-related death was defined as days from the 1st day of study drug dosing for the subject to date of liver-related death. All liver-related deaths were to be included, regardless of whether the death occurred while subject was still taking study drug or had previously discontinued study drug. If the subject didn't experience event of interest nor had died (all-cause death), their data was to be censored at date of last available assessment. For those with no post-baseline assessment, data was to be censored on 1st day of study drug dosing. All-cause death was a censoring event for liver-related death. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. The pre-specified analysis of liver-related death included pooled data from TOPAZ-I (this study) and the companion study TOPAZ-II (M14-222; NCT02167945). |
| Liver Decompensation: Time to Event | At Post-Treatment Weeks 52, 104, 156, 208, and 260 | Time to liver decompensation was defined as number of days from the 1st day of study drug dosing for the participant to the date of liver decompensation. All liver decompensation was to be included, regardless of whether it occurred while the participant was still taking study drug or had previously discontinued study drug. If the participant didn't experience the event of interest nor had died (all-cause death), their data was to be censored at the date of their last available assessment of clinical outcomes. For participants with no post-baseline assessment, their data was to be censored on the 1st day of study drug dosing. All-cause death was a censoring event for liver decompensation. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. The pre-specified analysis of liver decompensation included pooled data from TOPAZ-I (this study) and the companion study TOPAZ-II (M14-222; NCT02167945). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) | 12 weeks after the last actual dose of study drug | SVR12 is defined as hepatitis C virus ribonucleic acid (HCV RNA) less than the lower limit of quantification (LLOQ) 12 weeks after the last actual dose of study drug. Flanking imputation, where applicable, was used to impute missing data. After applying flanking imputation, if there was no value in the window but there was an HCV RNA value from a local laboratory present, then it was to be imputed into the SVR window. Otherwise, participants with missing data were counted as failures. |
| Change From Baseline in FibroScan Score by SVR12 Status | At the final treatment visit and Post-Treatment Weeks 12, 24, 52, 104, 156, 208, and 260 | The FibroScan test is a validated non-invasive test used to assess liver fibrosis in participants with chronic liver disease, and it was performed at study sites where it was available. For participants with Hepatitis C infection, a FibroScan score of 2-7 kPa indicates no liver scarring or mild scarring; a score of 8 or 9 is associated with moderate liver scarring; 9-14 indicates severe liver scarring; and 14 or higher is indicative of advanced liver scarring, cirrhosis. Negative changes from baseline indicate improvement in liver fibrosis. |
Countries
Algeria, Australia, Austria, Belgium, Bulgaria, Canada, Denmark, Finland, France, Germany, Greece, Ireland, Israel, Italy, Mexico, Netherlands, Norway, Poland, Portugal, Romania, Russia, Saudi Arabia, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom
Participant flow
Pre-assignment details
Safety population: All participants enrolled in this study (M14-423; TOPAZ-I) who received at least one dose of study drug
Participants by arm
| Arm | Count |
|---|---|
| ABT-450/r/ABT-267 Plus ABT-333 With or Without Ribavirin (RBV) Participants with HCV GT1b without cirrhosis received the 3-DAA (ABT-450/ritonavir/ABT-267 and ABT-333) regimen: two 75 mg ABT-450/50 mg ritonavir/12.5 mg ABT-267 tablets taken orally every morning (QD) and one ABT-333 250 mg tablet taken orally twice a day (BID) for 12 weeks. Participants with HCV GT1a without cirrhosis and those with HCV GT1b with cirrhosis received the 3-DAA regimen and weight-based ribavirin (RBV; 1000 to 1200 mg divided twice daily per local label) for 12 weeks. Participants with HCV GT1a with cirrhosis received the 3-DAA regimen and weight-based RBV per local label for 24 weeks. | 1,596 |
| Total | 1,596 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 24 |
| Overall Study | COVID-19 infection | 2 |
| Overall Study | COVID-19 logistical restrictions | 33 |
| Overall Study | Lost to Follow-up | 126 |
| Overall Study | Other, not specified | 57 |
| Overall Study | Withdrew consent | 96 |
Baseline characteristics
| Characteristic | ABT-450/r/ABT-267 Plus ABT-333 With or Without Ribavirin (RBV) |
|---|---|
| Age, Continuous | 51.2 years STANDARD_DEVIATION 11.62 |
| HCV Genotype 1 Subtype GT1b with compensated cirrhosis | 142 Participants |
| HCV Genotype 1 Subtype GT1b without cirrhosis | 757 Participants |
| HCV Genotype 1 Subtype GT1 Non-b with compensated cirrhosis | 97 Participants |
| HCV Genotype 1 Subtype GT1 Non-b without cirrhosis | 597 Participants |
| HCV Genotype 1 Subtype Missing | 3 Participants |
| Prior HCV Treatment History Treatment Experienced | 814 Participants |
| Prior HCV Treatment History Treatment Naïve | 782 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Asian | 39 Participants |
| Race/Ethnicity, Customized Black or African American | 10 Participants |
| Race/Ethnicity, Customized Multiple | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized White | 1544 Participants |
| Sex: Female, Male Female | 800 Participants |
| Sex: Female, Male Male | 796 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 28 / 1,596 |
| other Total, other adverse events | 805 / 1,596 |
| serious Total, serious adverse events | 40 / 1,596 |
Outcome results
Primary
All-Cause Death, Liver-Related Death, Liver Decompensation, Liver Transplantation, Hepatocellular Carcinoma: Time to Event
Time to the composite of clinical outcomes is the time to the first occurrence of all-cause death, liver-related death, liver decompensation, liver transplantation, or hepatocellular carcinoma. All first occurrences were to be included, regardless of whether it occurred while the participant was still taking study drug or had previously discontinued study drug. If the participant did not experience any of these events, their data was to be censored at the date of their last available assessment of clinical outcomes. For participants with no post-baseline assessment, the participant's data was to be censored on the first day of study drug dosing. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. Pre-specified analysis included pooled data from this study and from TOPAZ-II; NCT02167945.
Time frame: At Post-Treatment Weeks 52, 104, 156, 208, and 260
Population: Intent-to-treat (ITT) population: all enrolled participants in this study (TOPAZ-I; M14-423; ITT-I) and in companion study M14-422 (TOPAZ-II; NCT02167945; ITT-II) who received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | All-Cause Death, Liver-Related Death, Liver Decompensation, Liver Transplantation, Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 104 | 11.4 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | All-Cause Death, Liver-Related Death, Liver Decompensation, Liver Transplantation, Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 208 | 11.4 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | All-Cause Death, Liver-Related Death, Liver Decompensation, Liver Transplantation, Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 156 | 11.4 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | All-Cause Death, Liver-Related Death, Liver Decompensation, Liver Transplantation, Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 260 | 11.4 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | All-Cause Death, Liver-Related Death, Liver Decompensation, Liver Transplantation, Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 52 | 11.4 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | All-Cause Death, Liver-Related Death, Liver Decompensation, Liver Transplantation, Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 260 | 3.2 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | All-Cause Death, Liver-Related Death, Liver Decompensation, Liver Transplantation, Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 52 | 0.5 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | All-Cause Death, Liver-Related Death, Liver Decompensation, Liver Transplantation, Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 104 | 1.2 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | All-Cause Death, Liver-Related Death, Liver Decompensation, Liver Transplantation, Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 156 | 1.9 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | All-Cause Death, Liver-Related Death, Liver Decompensation, Liver Transplantation, Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 208 | 2.3 percentage of participants |
Comparison: Comparisons between participants in studies M14-222 and M14-423 who achieved SVR12 and those who did not were performed using a log-rank test.p-value: <0.001Log-rank test
Comparison: A Cox proportional hazards (PH) model was constructed. The covariates for the model included baseline age, BMI, HCV genotype 1 subtype (1b, non-1b), IL28B genotype (CC, non-CC), prior treatment history (naive, experienced), baseline HCV RNA levels, baseline fibrosis stage (F0-1, F2, F3, F4), baseline albumin, baseline creatinine clearance, baseline platelet count, history of diabetes (yes, no), APRI, race (white, other), and alcohol use status (current, former, non-drinker).p-value: <0.00195% CI: [0.057, 0.313]Cox proportional hazards model
Primary
All-Cause Death: Time to Event
Time to all-cause death was defined as the number of days from the first day of study drug dosing for the participant to the date of death. All deaths were to be included, regardless of whether the death occurred while the participant was still taking study drug or had previously discontinued study drug. If the participant did not die, their data was to be censored at the date of their last available assessment of clinical outcomes. For participants with no post-baseline assessment, the participant's data was to be censored on the first day of study drug dosing. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. The pre-specified analysis of all-cause death included pooled data from TOPAZ-I (this study) and the companion study TOPAZ-II (M14-222; NCT02167945).
Time frame: At Post-Treatment Weeks 52, 104, 156, 208, and 260
Population: Intent-to-treat (ITT) population: all enrolled participants in this study (TOPAZ-I; M14-423; ITT-I) and in companion study M14-422 (TOPAZ-II; NCT02167945; ITT-II) who received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | All-Cause Death: Time to Event | Kaplan-Meier estimate at PT Week 104 | 8.3 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | All-Cause Death: Time to Event | Kaplan-Meier estimate at PT Week 208 | 8.3 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | All-Cause Death: Time to Event | Kaplan-Meier estimate at PT Week 156 | 8.3 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | All-Cause Death: Time to Event | Kaplan-Meier estimate at PT Week 260 | 8.3 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | All-Cause Death: Time to Event | Kaplan-Meier estimate at PT Week 52 | 8.3 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | All-Cause Death: Time to Event | Kaplan-Meier estimate at PT Week 260 | 2.0 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | All-Cause Death: Time to Event | Kaplan-Meier estimate at PT Week 52 | 0.1 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | All-Cause Death: Time to Event | Kaplan-Meier estimate at PT Week 104 | 0.7 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | All-Cause Death: Time to Event | Kaplan-Meier estimate at PT Week 156 | 1.2 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | All-Cause Death: Time to Event | Kaplan-Meier estimate at PT Week 208 | 1.5 percentage of participants |
Comparison: Comparisons between participants in studies M14-222 and M14-423 who achieved SVR12 and those who did not were performed using a log-rank test.p-value: <0.001Log-rank test
Comparison: A Cox proportional hazards (PH) model was constructed. The covariates for the model included baseline age, BMI, HCV genotype 1 subtype (1b, non-1b), IL28B genotype (CC, non-CC), prior treatment history (naive, experienced), baseline HCV RNA levels, baseline fibrosis stage (F0-1, F2, F3, F4), baseline albumin, baseline creatinine clearance, baseline platelet count, history of diabetes (yes, no), APRI, race (white, other), and alcohol use status (current, former, non-drinker).p-value: <0.00195% CI: [0.044, 0.358]Cox proportional hazards model
Primary
Hepatocellular Carcinoma: Time to Event
Time to hepatocellular carcinoma (HCC) was defined as number of days from 1st day of study drug dosing for subject to date of hepatocellular carcinoma. All HCC was to be included, whether it occurred while subject was still taking study drug or had previously discontinued study drug. If the subject didn't experience the event of interest nor had died (all-cause death), their data was to be censored at the date of their last available assessment. For those with no post-baseline assessment, their data was to be censored on the 1st day of study drug dosing. All-cause death was a censoring event for HCC. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. The pre-specified analysis of hepatocellular carcinoma included pooled data from TOPAZ-I (this study) and the companion study TOPAZ-II (M14-222; NCT02167945).
Time frame: At Post-Treatment Weeks 52, 104, 156, 208, and 260
Population: Intent-to-treat (ITT) population: all enrolled participants in this study (TOPAZ-I; M14-423; ITT-I) and in companion study M14-422 (TOPAZ-II; NCT02167945; ITT-II) who received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 104 | 0 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 208 | 0 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 156 | 0 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 260 | 0 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 52 | 0 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 260 | 0.9 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 52 | 0.2 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 104 | 0.4 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 156 | 0.5 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Hepatocellular Carcinoma: Time to Event | Kaplan-Meier estimate at PT Week 208 | 0.6 percentage of participants |
Comparison: Comparisons between participants in studies M14-222 and M14-423 who achieved SVR12 and those who did not were performed using a log-rank test.p-value: 0.608Log-rank test
Comparison: A Cox proportional hazards (PH) model was constructed. The covariates for the model included baseline age, BMI, HCV genotype 1 subtype (1b, non-1b), IL28B genotype (CC, non-CC), prior treatment history (naive, experienced), baseline HCV RNA levels, baseline fibrosis stage (F0-1, F2, F3, F4), baseline albumin, baseline creatinine clearance, baseline platelet count, history of diabetes (yes, no), APRI, race (white, other), and alcohol use status (current, former, non-drinker).p-value: 0.992Cox proportional hazards model
Primary
Liver Decompensation: Time to Event
Time to liver decompensation was defined as number of days from the 1st day of study drug dosing for the participant to the date of liver decompensation. All liver decompensation was to be included, regardless of whether it occurred while the participant was still taking study drug or had previously discontinued study drug. If the participant didn't experience the event of interest nor had died (all-cause death), their data was to be censored at the date of their last available assessment of clinical outcomes. For participants with no post-baseline assessment, their data was to be censored on the 1st day of study drug dosing. All-cause death was a censoring event for liver decompensation. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. The pre-specified analysis of liver decompensation included pooled data from TOPAZ-I (this study) and the companion study TOPAZ-II (M14-222; NCT02167945).
Time frame: At Post-Treatment Weeks 52, 104, 156, 208, and 260
Population: Intent-to-treat (ITT) population: all enrolled participants in this study (TOPAZ-I; M14-423; ITT-I) and in companion study M14-422 (TOPAZ-II; NCT02167945; ITT-II) who received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Liver Decompensation: Time to Event | Kaplan-Meier estimate at PT Week 104 | 4.5 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Liver Decompensation: Time to Event | Kaplan-Meier estimate at PT Week 208 | 4.5 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Liver Decompensation: Time to Event | Kaplan-Meier estimate at PT Week 156 | 4.5 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Liver Decompensation: Time to Event | Kaplan-Meier estimate at PT Week 260 | 4.5 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Liver Decompensation: Time to Event | Kaplan-Meier estimate at PT Week 52 | 4.5 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Liver Decompensation: Time to Event | Kaplan-Meier estimate at PT Week 260 | 0.5 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Liver Decompensation: Time to Event | Kaplan-Meier estimate at PT Week 52 | 0.2 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Liver Decompensation: Time to Event | Kaplan-Meier estimate at PT Week 104 | 0.2 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Liver Decompensation: Time to Event | Kaplan-Meier estimate at PT Week 156 | 0.3 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Liver Decompensation: Time to Event | Kaplan-Meier estimate at PT Week 208 | 0.3 percentage of participants |
Comparison: Comparisons between participants in studies M14-222 and M14-423 who achieved SVR12 and those who did not were performed using a log-rank test.p-value: <0.001Log-rank test
Comparison: A Cox proportional hazards (PH) model was constructed. The covariates for the model included baseline age, BMI, HCV genotype 1 subtype (1b, non-1b), IL28B genotype (CC, non-CC), prior treatment history (naive, experienced), baseline HCV RNA levels, baseline fibrosis stage (F0-1, F2, F3, F4), baseline albumin, baseline creatinine clearance, baseline platelet count, history of diabetes (yes, no), APRI, race (white, other), and alcohol use status (current, former, non-drinker).p-value: <0.00195% CI: [0.009, 0.156]Cox proportional hazards model
Primary
Liver-Related Death: Time to Event
Time to liver-related death was defined as days from the 1st day of study drug dosing for the subject to date of liver-related death. All liver-related deaths were to be included, regardless of whether the death occurred while subject was still taking study drug or had previously discontinued study drug. If the subject didn't experience event of interest nor had died (all-cause death), their data was to be censored at date of last available assessment. For those with no post-baseline assessment, data was to be censored on 1st day of study drug dosing. All-cause death was a censoring event for liver-related death. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. The pre-specified analysis of liver-related death included pooled data from TOPAZ-I (this study) and the companion study TOPAZ-II (M14-222; NCT02167945).
Time frame: At Post-Treatment Weeks 52, 104, 156, 208, and 260
Population: Intent-to-treat (ITT) population: all enrolled participants in this study (TOPAZ-I; M14-423; ITT-I) and in companion study M14-422 (TOPAZ-II; NCT02167945; ITT-II) who received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Liver-Related Death: Time to Event | Kaplan-Meier estimate at PT Week 104 | 1.4 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Liver-Related Death: Time to Event | Kaplan-Meier estimate at PT Week 208 | 1.4 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Liver-Related Death: Time to Event | Kaplan-Meier estimate at PT Week 156 | 1.4 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Liver-Related Death: Time to Event | Kaplan-Meier estimate at PT Week 260 | 1.4 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Liver-Related Death: Time to Event | Kaplan-Meier estimate at PT Week 52 | 1.4 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Liver-Related Death: Time to Event | Kaplan-Meier estimate at PT Week 260 | 0.1 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Liver-Related Death: Time to Event | Kaplan-Meier estimate at PT Week 52 | 0 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Liver-Related Death: Time to Event | Kaplan-Meier estimate at PT Week 104 | 0 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Liver-Related Death: Time to Event | Kaplan-Meier estimate at PT Week 156 | 0.1 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Liver-Related Death: Time to Event | Kaplan-Meier estimate at PT Week 208 | 0.1 percentage of participants |
Comparison: Comparisons between participants in studies M14-222 and M14-423 who achieved SVR12 and those who did not were performed using a log-rank test.p-value: <0.001Log-rank test
Comparison: A Cox proportional hazards (PH) model was constructed. The covariates for the model included baseline age, BMI, HCV genotype 1 subtype (1b, non-1b), IL28B genotype (CC, non-CC), prior treatment history (naive, experienced), baseline HCV RNA levels, baseline fibrosis stage (F0-1, F2, F3, F4), baseline albumin, baseline creatinine clearance, baseline platelet count, history of diabetes (yes, no), APRI, race (white, other), and alcohol use status (current, former, non-drinker).p-value: 0.00795% CI: [0.003, 0.38]Cox proportional hazards model
Primary
Liver Transplantation: Time to Event
Time to liver transplantation was defined as days from 1st day of study drug dosing for subject to date of liver transplantation. All liver transplantation was to be included, whether it occurred while the subject was still taking study drug or had previously discontinued study drug. If the subject didn't experience event of interest nor had died (all-cause death), their data was to be censored at the date of their last available assessment. For those with no post-baseline assessment, data was to be censored on 1st day of study drug dosing. All-cause death was a censoring event for liver transplantation. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. The pre-specified analysis of liver transplantation included pooled data from TOPAZ-I (this study) and the companion study TOPAZ-II (M14-222; NCT02167945).
Time frame: At Post-Treatment Weeks 52, 104, 156, 208, and 260
Population: Intent-to-treat (ITT) population: all enrolled participants in this study (TOPAZ-I; M14-423; ITT-I) and in companion study M14-422 (TOPAZ-II; NCT02167945; ITT-II) who received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Liver Transplantation: Time to Event | Kaplan-Meier estimate at PT Week 104 | 0 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Liver Transplantation: Time to Event | Kaplan-Meier estimate at PT Week 208 | 0 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Liver Transplantation: Time to Event | Kaplan-Meier estimate at PT Week 156 | 0 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Liver Transplantation: Time to Event | Kaplan-Meier estimate at PT Week 260 | 0 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Liver Transplantation: Time to Event | Kaplan-Meier estimate at PT Week 52 | 0 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Liver Transplantation: Time to Event | Kaplan-Meier estimate at PT Week 260 | 0.2 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Liver Transplantation: Time to Event | Kaplan-Meier estimate at PT Week 52 | 0 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Liver Transplantation: Time to Event | Kaplan-Meier estimate at PT Week 104 | 0 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Liver Transplantation: Time to Event | Kaplan-Meier estimate at PT Week 156 | 0.1 percentage of participants |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Liver Transplantation: Time to Event | Kaplan-Meier estimate at PT Week 208 | 0.1 percentage of participants |
Comparison: Comparisons between participants in studies M14-222 and M14-423 who achieved SVR12 and those who did not were performed using a log-rank test.p-value: 0.86Log-rank test
Comparison: A Cox proportional hazards (PH) model was constructed. The covariates for the model included baseline age, BMI, HCV genotype 1 subtype (1b, non-1b), IL28B genotype (CC, non-CC), prior treatment history (naive, experienced), baseline HCV RNA levels, baseline fibrosis stage (F0-1, F2, F3, F4), baseline albumin, baseline creatinine clearance, baseline platelet count, history of diabetes (yes, no), APRI, race (white, other), and alcohol use status (current, former, non-drinker).p-value: 0.997Cox proportional hazards model
Secondary
Change From Baseline in FibroScan Score by SVR12 Status
The FibroScan test is a validated non-invasive test used to assess liver fibrosis in participants with chronic liver disease, and it was performed at study sites where it was available. For participants with Hepatitis C infection, a FibroScan score of 2-7 kPa indicates no liver scarring or mild scarring; a score of 8 or 9 is associated with moderate liver scarring; 9-14 indicates severe liver scarring; and 14 or higher is indicative of advanced liver scarring, cirrhosis. Negative changes from baseline indicate improvement in liver fibrosis.
Time frame: At the final treatment visit and Post-Treatment Weeks 12, 24, 52, 104, 156, 208, and 260
Population: ITT-I population: all participants enrolled in this study (M14-423; TOPAZ-I) who received at least one dose of study drug with available data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Change From Baseline in FibroScan Score by SVR12 Status | At the final treatment visit | -2.55 kPa | Standard Deviation 3.282 |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Change From Baseline in FibroScan Score by SVR12 Status | Post-Treatment Week 12 | -1.81 kPa | Standard Deviation 2.624 |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Change From Baseline in FibroScan Score by SVR12 Status | Post-Treatment Week 24 | -1.26 kPa | Standard Deviation 3.211 |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Change From Baseline in FibroScan Score by SVR12 Status | Post-Treatment Week 52 | -0.30 kPa | Standard Deviation 1.986 |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Change From Baseline in FibroScan Score by SVR12 Status | Post-Treatment Week 104 | -0.35 kPa | Standard Deviation 3.306 |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Change From Baseline in FibroScan Score by SVR12 Status | Post-Treatment Week 156 | -0.37 kPa | Standard Deviation 3.999 |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Change From Baseline in FibroScan Score by SVR12 Status | Post-Treatment Week 208 | -0.88 kPa | Standard Deviation 2.445 |
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Change From Baseline in FibroScan Score by SVR12 Status | Post-Treatment Week 260 | -1.31 kPa | Standard Deviation 3.706 |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Change From Baseline in FibroScan Score by SVR12 Status | Post-Treatment Week 260 | -3.08 kPa | Standard Deviation 5.662 |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Change From Baseline in FibroScan Score by SVR12 Status | At the final treatment visit | -1.41 kPa | Standard Deviation 4.283 |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Change From Baseline in FibroScan Score by SVR12 Status | Post-Treatment Week 104 | -2.80 kPa | Standard Deviation 5.195 |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Change From Baseline in FibroScan Score by SVR12 Status | Post-Treatment Week 12 | -1.76 kPa | Standard Deviation 4.213 |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Change From Baseline in FibroScan Score by SVR12 Status | Post-Treatment Week 208 | -3.08 kPa | Standard Deviation 5.56 |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Change From Baseline in FibroScan Score by SVR12 Status | Post-Treatment Week 24 | -1.98 kPa | Standard Deviation 4.363 |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Change From Baseline in FibroScan Score by SVR12 Status | Post-Treatment Week 156 | -2.92 kPa | Standard Deviation 5.249 |
| Participants in Studies M14-222 and M14-423 Who Achieved SVR12 | Change From Baseline in FibroScan Score by SVR12 Status | Post-Treatment Week 52 | -2.46 kPa | Standard Deviation 4.858 |
Comparison: Final Treatment Visit~The effect of sustained virologic response on change from baseline in FibroScan score was evaluated by comparing mean change from baseline between subjects who achieved SVR12 and those who did not using ANCOVA analyses. SVR12 status was included as a factor and baseline FibroScan score was included as a covariate in the ANCOVA model.p-value: 0.15195% CI: [-0.37, 2.37]ANCOVA
Comparison: Post-Treatment Week 12~The effect of sustained virologic response on change from baseline in FibroScan score was evaluated by comparing mean change from baseline between subjects who achieved SVR12 and those who did not using ANCOVA analyses. SVR12 status was included as a factor and baseline FibroScan score was included as a covariate in the ANCOVA model.p-value: 0.87895% CI: [-1.64, 1.4]ANCOVA
Comparison: Post-Treatment Week 24~The effect of sustained virologic response on change from baseline in FibroScan score was evaluated by comparing mean change from baseline between subjects who achieved SVR12 and those who did not using ANCOVA analyses. SVR12 status was included as a factor and baseline FibroScan score was included as a covariate in the ANCOVA model.p-value: =0.19995% CI: [-2.33, 0.48]ANCOVA
Comparison: Post-Treatment Week 52~The effect of sustained virologic response on change from baseline in FibroScan score was evaluated by comparing mean change from baseline between subjects who achieved SVR12 and those who did not using ANCOVA analyses. SVR12 status was included as a factor and baseline FibroScan score was included as a covariate in the ANCOVA model.p-value: 0.02195% CI: [-4, -0.33]ANCOVA
Comparison: Post-Treatment Week 104~The effect of sustained virologic response on change from baseline in FibroScan score was evaluated by comparing mean change from baseline between subjects who achieved SVR12 and those who did not using ANCOVA analyses. SVR12 status was included as a factor and baseline FibroScan score was included as a covariate in the ANCOVA model.p-value: 0.00695% CI: [-4.22, -0.71]ANCOVA
Comparison: Post-Treatment Week 156~The effect of sustained virologic response on change from baseline in FibroScan score was evaluated by comparing mean change from baseline between subjects who achieved SVR12 and those who did not using ANCOVA analyses. SVR12 status was included as a factor and baseline FibroScan score was included as a covariate in the ANCOVA model.p-value: 0.00595% CI: [-4.38, -0.79]ANCOVA
Comparison: Post-Treatment Week 208~The effect of sustained virologic response on change from baseline in FibroScan score was evaluated by comparing mean change from baseline between subjects who achieved SVR12 and those who did not using ANCOVA analyses. SVR12 status was included as a factor and baseline FibroScan score was included as a covariate in the ANCOVA model.p-value: 0.17295% CI: [-3.32, 0.59]ANCOVA
Comparison: Post-Treatment Week 260~The effect of sustained virologic response on change from baseline in FibroScan score was evaluated by comparing mean change from baseline between subjects who achieved SVR12 and those who did not using ANCOVA analyses. SVR12 status was included as a factor and baseline FibroScan score was included as a covariate in the ANCOVA model.p-value: 0.32295% CI: [-3.35, 1.1]ANCOVA
Secondary
Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12)
SVR12 is defined as hepatitis C virus ribonucleic acid (HCV RNA) less than the lower limit of quantification (LLOQ) 12 weeks after the last actual dose of study drug. Flanking imputation, where applicable, was used to impute missing data. After applying flanking imputation, if there was no value in the window but there was an HCV RNA value from a local laboratory present, then it was to be imputed into the SVR window. Otherwise, participants with missing data were counted as failures.
Time frame: 12 weeks after the last actual dose of study drug
Population: ITT-I population: all participants enrolled in this study (M14-423; TOPAZ-I) who received at least one dose of study drug with available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Participants in Studies M14-222 and M14-423 Who Did Not Achieve SVR12 | Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) | 97.0 percentage of participants |