ABT-450/r/Ombitasvir and Dasabuvir for HCV
ABT-450/r/Ombitasvir and Dasabuvir for HCV
Adults were age 18–70 years at the time of screening from 43 sites in Austria, Belgium, Italy, The Netherlands, Portugal, Puerto Rico, Sweden, Switzerland, Turkey, and the United States. Patients were required to have documentation that they previously failed treatment with pegIFN/RBV. Eligible patients were required to be noncirrhotic with chronic HCV genotype 1b infection for at least 6 months with an HCV-RNA level greater than 10, 000 IU/mL at screening. Patients were excluded if they had evidence of co-infection with any HCV genotype other than 1b or tested positive for hepatitis B surface antigen or anti–human immunodeficiency virus antibody at screening. Detailed eligibility criteria are provided in the Supplementary Appendix http://www.gastrojournal.org/article/S0016-5085%2814%2900603-9/addons.
Patients were stratified by type of previous nonresponse to pegIFN/RBV treatment (null responders, partial responders, and relapsers) and randomized 1:1 to receive the 12-week regimen of coformulated ABT-450/ritonavir/ombitasvir (150/100/25 mg once daily) and dasabuvir (250 mg twice daily) with either weight-based RBV dosed twice daily (1000 mg daily if body weight < 75 kg, 1200 mg daily if body weight was ≥ 75 kg) for group 1 or without RBV for group 2 (Supplementary Figure 1 http://www.gastrojournal.org/article/S0016-5085%2814%2900603-9/addons). After 12 weeks of treatment, patients were followed up for an 48 additional weeks. Additional details on study design are in the Supplementary Appendix http://www.gastrojournal.org/article/S0016-5085%2814%2900603-9/addons.
The study was conducted in accordance with the International Conference of Harmonisation guidelines, applicable regulations, and guidelines governing clinical study conduct and ethical principles that have their origin in the Declaration of Helsinki. All patients provided written informed consent. All authors had access to relevant data, and critically reviewed, revised, and approved the manuscript.
Adverse event assessments were reported from the time of study drug administration until 30 days after the last dose and were judged as mild, moderate, or severe; clinical laboratory testing was performed at each study visit. Serious AEs were recorded throughout the study.
Plasma samples were collected at screening and at each study visit and HCV-RNA levels were determined using the Roche COBAS TaqMan real-time reverse-transcription polymerase chain reaction assay v2.0 (Roche Molecular Diagnostics, Pleasanton, CA) at a central laboratory. A fixed-sequence testing procedure was used to control type I error at 0.05. The primary efficacy end point was noninferiority of the SVR12 rates (assessed by HCV-RNA level < 25 IU/mL) in group 2 and group 1 to the historical SVR12 rate for telaprevir plus pegIFN/RBV in HCV genotype 1b–infected patients who were relapsers, partial responders, or null responders to previous pegIFN/RBV treatment, adjusted for noncirrhotic patients in this study. Group 1 and group 2 noninferiority could be claimed if the SVR12 lower limit of the 95% confidence interval (CI) was greater than the upper limit of the CI for the historical rate minus a 10.5% noninferiority margin (64%). Further details of historical noninferiority calculations are provided in the Supplementary Appendix http://www.gastrojournal.org/article/S0016-5085%2814%2900603-9/addons. Secondary efficacy end points in the fixed sequence included the following: (1) comparison of the percentage of patients with a decrease in hemoglobin level to less than the lower limit of normal at the end of treatment; (2) superiority of group 1 and group 2 to the historical rate for telaprevir plus pegIFN/RBV (75%); and (3) noninferiority of group 2 to group 1 using a 10.5% noninferiority margin for the SVR12 difference. The percentage of patients with on-treatment virologic failure and post-treatment relapse also was assessed.
Virologic failure leading to discontinuation of study drug was determined if the following criteria occurred: confirmed increase from nadir in HCV-RNA level (defined as 2 consecutive HCV-RNA measurements greater than 1 log10 IU/mL greater than nadir) at any point during treatment; failure to achieve HCV-RNA level less than 25 IU/mL by week 6; and confirmed HCV-RNA level of 25 IU/mL or greater in 2 consecutive measurements at any point during treatment after HCV-RNA level was less than 25 IU/mL. Post-treatment relapse was confirmed in patients with HCV-RNA level less than 25 IU/mL at the end of treatment and subsequent HCV-RNA level of 25 IU/mL or greater in 2 consecutive measurements.
Efficacy analyses were performed using the intent-to-treat population, defined as all randomized HCV genotype 1b–infected patients who received at least one dose of coformulated ABT-450/ritonavir/ombitasvir. The safety population included all patients who received at least one dose of study drug. A population of 90 patients per treatment arm was calculated to provide greater than 90% power to achieve noninferiority of the active regimen to the historical threshold (64%).
SAS software (SAS Institute, Inc, Cary, NC) for the UNIX operating system was used for all analyses. All statistical tests and all confidence intervals were 2-sided with a significance level of .05.
Materials and Methods
Patients
Adults were age 18–70 years at the time of screening from 43 sites in Austria, Belgium, Italy, The Netherlands, Portugal, Puerto Rico, Sweden, Switzerland, Turkey, and the United States. Patients were required to have documentation that they previously failed treatment with pegIFN/RBV. Eligible patients were required to be noncirrhotic with chronic HCV genotype 1b infection for at least 6 months with an HCV-RNA level greater than 10, 000 IU/mL at screening. Patients were excluded if they had evidence of co-infection with any HCV genotype other than 1b or tested positive for hepatitis B surface antigen or anti–human immunodeficiency virus antibody at screening. Detailed eligibility criteria are provided in the Supplementary Appendix http://www.gastrojournal.org/article/S0016-5085%2814%2900603-9/addons.
Study Design
Patients were stratified by type of previous nonresponse to pegIFN/RBV treatment (null responders, partial responders, and relapsers) and randomized 1:1 to receive the 12-week regimen of coformulated ABT-450/ritonavir/ombitasvir (150/100/25 mg once daily) and dasabuvir (250 mg twice daily) with either weight-based RBV dosed twice daily (1000 mg daily if body weight < 75 kg, 1200 mg daily if body weight was ≥ 75 kg) for group 1 or without RBV for group 2 (Supplementary Figure 1 http://www.gastrojournal.org/article/S0016-5085%2814%2900603-9/addons). After 12 weeks of treatment, patients were followed up for an 48 additional weeks. Additional details on study design are in the Supplementary Appendix http://www.gastrojournal.org/article/S0016-5085%2814%2900603-9/addons.
The study was conducted in accordance with the International Conference of Harmonisation guidelines, applicable regulations, and guidelines governing clinical study conduct and ethical principles that have their origin in the Declaration of Helsinki. All patients provided written informed consent. All authors had access to relevant data, and critically reviewed, revised, and approved the manuscript.
Safety Assessments
Adverse event assessments were reported from the time of study drug administration until 30 days after the last dose and were judged as mild, moderate, or severe; clinical laboratory testing was performed at each study visit. Serious AEs were recorded throughout the study.
Efficacy End Points
Plasma samples were collected at screening and at each study visit and HCV-RNA levels were determined using the Roche COBAS TaqMan real-time reverse-transcription polymerase chain reaction assay v2.0 (Roche Molecular Diagnostics, Pleasanton, CA) at a central laboratory. A fixed-sequence testing procedure was used to control type I error at 0.05. The primary efficacy end point was noninferiority of the SVR12 rates (assessed by HCV-RNA level < 25 IU/mL) in group 2 and group 1 to the historical SVR12 rate for telaprevir plus pegIFN/RBV in HCV genotype 1b–infected patients who were relapsers, partial responders, or null responders to previous pegIFN/RBV treatment, adjusted for noncirrhotic patients in this study. Group 1 and group 2 noninferiority could be claimed if the SVR12 lower limit of the 95% confidence interval (CI) was greater than the upper limit of the CI for the historical rate minus a 10.5% noninferiority margin (64%). Further details of historical noninferiority calculations are provided in the Supplementary Appendix http://www.gastrojournal.org/article/S0016-5085%2814%2900603-9/addons. Secondary efficacy end points in the fixed sequence included the following: (1) comparison of the percentage of patients with a decrease in hemoglobin level to less than the lower limit of normal at the end of treatment; (2) superiority of group 1 and group 2 to the historical rate for telaprevir plus pegIFN/RBV (75%); and (3) noninferiority of group 2 to group 1 using a 10.5% noninferiority margin for the SVR12 difference. The percentage of patients with on-treatment virologic failure and post-treatment relapse also was assessed.
Virologic Failure Criteria
Virologic failure leading to discontinuation of study drug was determined if the following criteria occurred: confirmed increase from nadir in HCV-RNA level (defined as 2 consecutive HCV-RNA measurements greater than 1 log10 IU/mL greater than nadir) at any point during treatment; failure to achieve HCV-RNA level less than 25 IU/mL by week 6; and confirmed HCV-RNA level of 25 IU/mL or greater in 2 consecutive measurements at any point during treatment after HCV-RNA level was less than 25 IU/mL. Post-treatment relapse was confirmed in patients with HCV-RNA level less than 25 IU/mL at the end of treatment and subsequent HCV-RNA level of 25 IU/mL or greater in 2 consecutive measurements.
Statistical Analyses
Efficacy analyses were performed using the intent-to-treat population, defined as all randomized HCV genotype 1b–infected patients who received at least one dose of coformulated ABT-450/ritonavir/ombitasvir. The safety population included all patients who received at least one dose of study drug. A population of 90 patients per treatment arm was calculated to provide greater than 90% power to achieve noninferiority of the active regimen to the historical threshold (64%).
SAS software (SAS Institute, Inc, Cary, NC) for the UNIX operating system was used for all analyses. All statistical tests and all confidence intervals were 2-sided with a significance level of .05.
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