Study Patients

Patients were screened from October 24, 2012, through April 30, 2013, at 78 sites in North America and Europe. Patients 18 to 70 years of age were eligible for enrollment if they had previously untreated or previously treated chronic HCV genotype 1 infection and a plasma HCV RNA level of more than 10,000 IU per milliliter. Eligible patients had documentation of cirrhosis by means of liver biopsy (Metavir score >3 or Ishak score >4) or FibroScan result (≥14.6 kPa within 6 months before screening or during screening), a Child–Pugh class A score of less than 7 at screening, and no current or past clinical evidence of Child–Pugh class B or C disease. Key eligibility criteria were a platelet count of 60,000 per cubic millimeter or more, a serum albumin level of 2.8 g per deciliter or more, a total bilirubin level of less than 3 mg per deciliter, an international normalized ratio of 2.3 or less, and a serum alpha-fetoprotein level of 100 ng per milliliter or less. Exclusion criteria were prior therapy with direct-acting antiviral agents (e.g., telaprevir and boceprevir) for the treatment of HCV infection and a diagnosis of hepatocellular carcinoma. For detailed eligibility criteria, see the Supplementary Appendix, available with the full text of this article at NEJM.org.

Study Design and Oversight

Patients were randomly assigned in a ratio of approximately 1:1 (see the Supplementary Appendix) to the 12-week or 24-week treatment group (Fig. S1 in the Supplementary Appendix), with stratification according to previous peginterferon–ribavirin treatment for HCV infection (no vs. yes). Previously untreated patients were stratified according to HCV subgenotype (1a vs. 1b) and interleukin 28B (IL28B) genotype (CC vs. non-CC), a genetic marker associated with treatment outcomes.26 Previously treated patients were stratified according to HCV subgenotype and type of previous treatment failure: null response, partial response, or relapse (see the Supplementary Appendix). Patients received coformulated ABT-450/r–ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir) and dasabuvir (250 mg twice daily) with ribavirin (1000 mg or 1200 mg daily, according to body weight, in two doses) for 12 weeks or 24 weeks.

The study was designed by the study investigators and the sponsor (AbbVie) according to Good Clinical Practice guidelines, the principles of the Declaration of Helsinki, and applicable regulations, with approval by an institutional review board at each study site. All the patients provided written informed consent. The site investigators gathered the data, and the sponsor conducted the data analysis. The first draft of the manuscript was written by a medical writer employed by the sponsor. All the authors had full access to the data and participated in the development of the manuscript. All the authors confirm that the results presented are complete and accurate and that the study was conducted and reported according to the protocol (available at NEJM.org).

Efficacy and Safety Assessments

The collection of plasma samples and measurement of HCV RNA levels are described in the Supplementary Appendix. Vital signs were monitored, adverse events were assessed, and clinical laboratory testing was performed at each visit during the treatment and post-treatment periods. Adverse events were classified by the site investigator as mild, moderate, or severe, and data on adverse events were collected from the time of the first dose of study medication until 30 days after the last dose. Data on serious adverse events were collected throughout the study.

Efficacy End Points

The primary efficacy end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter [the lower limit of quantitation]) 12 weeks after the end of study-drug administration. HCV RNA levels were measured with the use of the COBAS TaqMan real-time reverse-transcriptase–polymerase-chain-reaction assay, version 2.0 (Roche). The primary study objectives were to assess the rate of sustained virologic response in the 12-week and 24-week groups for noninferiority and superiority to a historical rate with telaprevir plus peginterferon–ribavirin among patients with HCV genotype 1 infection and cirrhosis. The key secondary efficacy end point was the percentage of patients with a sustained virologic response in the 24-week group as compared with the 12-week group. Other secondary efficacy end points were the percentage of patients in each group with virologic failure during treatment or relapse after treatment. A gatekeeping multiple-testing procedure (described in the Supplementary Appendix) was used for the primary efficacy end point and the key secondary efficacy end point. Rates of virologic failure during treatment and relapse after treatment were not part of the multiple-testing procedure, because no hypothesis was being tested for those two end points. The rate of sustained virologic response at post-treatment week 12 was also determined for patient subgroups defined according to prespecified baseline demographic or clinical characteristics.

Virologic failure during treatment was defined as two consecutive HCV RNA measurements of more than 1 log 10 IU per milliliter above the nadir at any time during treatment, an HCV RNA level of 25 IU per milliliter or more at all assessments during treatment among patients who received at least 6 weeks of treatment, or a confirmed HCV RNA level of 25 IU per milliliter or more after a level of less than 25 IU per milliliter during treatment. Virologic relapse was defined as a confirmed HCV RNA level of 25 IU per milliliter or more between the end of treatment and 12 weeks after the last dose of study drug among patients who completed treatment and had an HCV RNA level of less than 25 IU per milliliter at the final visit during the treatment period.

Statistical Analysis

Analyses were performed on the modified intent-to-treat population (all randomly assigned patients who received at least one dose of study drugs). For efficacy evaluations, the percentage of patients with a sustained virologic response at post-treatment week 12 and a two-sided 97.5% confidence interval (based on the normal approximation to the binomial distribution) were calculated for each treatment group.

Rates of sustained virologic response at post-treatment week 24 that were previously reported for telaprevir11,12 were used to calculate a weighted average of rates of sustained virologic response among previously untreated and previously treated patients, reflective of the population that we expected to enroll in the TURQUOISE-II study (see the Supplementary Appendix). The estimated rate used for comparison was 47% (95% confidence interval [CI], 41 to 54). The noninferiority margin was 10.5 percentage points; for the rate of sustained virologic response with ABT-450/r–ombitasvir, dasabuvir, and ribavirin to be considered noninferior, the lower confidence bound had to exceed 43% (equal to the upper confidence bound of the historical rate with telaprevir plus peginterferon–ribavirin, 54%, minus 10.5 percentage points and rounded). For the rate of sustained virologic response with ABT-450/r–ombitasvir, dasabuvir, and ribavirin to be considered superior, the lower confidence bound had to exceed the upper confidence bound of the historical rate (54%).

The 12-week and 24-week groups were compared with the use of a logistic-regression model, as prespecified in the protocol for the key secondary efficacy end point, with treatment group, baseline log 10 HCV RNA level, HCV subgenotype (1a vs. 1b), IL28B genotype (CC vs. non-CC), and previous peginterferon–ribavirin treatment (no vs. yes) as predictors of the rate of sustained virologic response at post-treatment week 12. Rates of sustained virologic response were summarized for each treatment group and randomization stratum to assess responses across stratification variables. For exploratory purposes, a stepwise logistic-regression model was used to assess the association between the rate of sustained virologic response at post-treatment week 12 and continuous and categorical subgroup variables.

Statistical analyses were performed with the use of SAS software, version 9.3 (SAS Institute). A gatekeeping multiple-testing procedure was used to maintain a type I error rate of 0.05 for the analyses of the primary and key secondary efficacy end points (see the Supplementary Appendix, including Fig. S2). All statistical tests and confidence intervals were two-sided, with a significance level of 0.05. The number and percentage of patients with adverse events, abnormalities in laboratory values of grade 3 or 4, or abnormalities in hemoglobin levels were compared between treatment groups with the use of Fisher's exact test. For additional details, see the Supplementary Appendix.