Patients

Patients were screened from November 2012 through May 2013 at 79 sites in North America, Europe, and Australia. Eligible patients were adults, 18 to 70 years of age, with chronic HCV genotype 1 infection, no cirrhosis, and a plasma HCV RNA level of more than 10,000 IU per milliliter, who had never received antiviral treatment for HCV infection. Patients were excluded if they had a positive test for hepatitis B surface antigen or anti–human immunodeficiency virus antibody during screening. Details of the eligibility criteria are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.

Study Design

Figure 1. Figure 1. SAPPHIRE-I Study Design. During the 12-week double-blind period, patients received either ABT-450 with ritonavir (ABT-450/r)–ombitasvir and dasabuvir with ribavirin (group A) or matching placebos (group B). Patients receiving placebo were treated with the active regimen for 12 weeks in an open-label fashion at the conclusion of the double-blind period. The dashed vertical line indicates the time point at which the primary analysis, which compared the rate of sustained virologic response at 12 weeks after the end of therapy in group A with the rate in a historical control group, was performed. The study is ongoing, and all patients who received the active regimen will be followed through post-treatment week 48.

Patients were randomly assigned, in a 3:1 ratio, to active treatment (group A) or placebo (group B) (Figure 1). Randomization was stratified according to HCV genotype (1a vs. non-1a) and IL28B genotype (CC vs. non-CC). During the double-blind period, patients in group A received 12 weeks of treatment with oral 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 (at a dose of 250 mg twice daily) with ribavirin, administered twice daily in a dose that was determined according to body weight (1000 mg daily if the body weight was <75 kg and 1200 mg daily if the body weight was ≥75 kg). Patients in group B received matching placebos during the double-blind period. After the double-blind period, patients in group B received the active regimen as open-label therapy for 12 weeks.

The investigators, patients, and sponsor were unaware of the treatment assignments during the double-blind period. To prevent implicit unblinding, laboratory results for HCV RNA, hemoglobin, hematocrit, alanine aminotransferase, aspartate aminotransferase, and bilirubin (indirect and total) levels were concealed from these parties. Details are provided in the Supplementary Appendix. The study is ongoing, and all the patients will be followed for 48 weeks after the end of active treatment. Efficacy results in group A through post-treatment week 12 and safety data for both study groups are presented.

Study Oversight

All the patients provided written informed consent. The study was conducted in accordance with the International Conference on Harmonisation guidelines, applicable regulations, and the principles of the Declaration of Helsinki. The study protocol was approved by the independent ethics committee or institutional review board at each study site. The study was designed jointly by the study investigators and the sponsor (AbbVie). The investigators gathered the data, and the sponsor conducted the data analyses. All the authors had full access to the data and signed confidentiality agreements with the sponsor regarding the data. The first draft of the manuscript was written by a medical writer who is an employee of the sponsor, with input from all the authors. All the authors reviewed and provided feedback on all subsequent versions of the manuscript and made the decision to submit the manuscript for publication. All the authors vouch for the completeness and accuracy of the data and analyses presented and affirm that the study was conducted and reported with fidelity to the protocol (available at NEJM.org).

Efficacy Assessments

A central laboratory determined the HCV RNA level with the use of the COBAS TaqMan real-time reverse-transcriptase–polymerase-chain-reaction assay, version 2.0 (Roche). The lower limits of detection and quantification were 15 IU per milliliter and 25 IU per milliliter, respectively. Details regarding the collection of plasma samples, the criteria for virologic failure, and resistance testing are provided in the Supplementary Appendix.

Safety Assessments

Adverse events were assessed at each study visit. The investigator at each site classified events as mild, moderate, or severe. Data on all adverse events were collected from the start of study-drug administration until 30 days after receipt of the last dose. Data on serious adverse events were collected throughout the entire study period. Here we report data on adverse events and serious adverse events occurring during the double-blind period and the 30-day period after the last dose of active study drugs was administered. Clinical laboratory testing was performed at visits during the double-blind treatment period and at weeks 4 and 48 after the end of the treatment period.

Efficacy End Points

The primary efficacy end point was sustained virologic response (HCV RNA level <25 IU per milliliter) at 12 weeks after the end of treatment. Secondary efficacy end points included normalization of the alanine aminotransferase level, sustained virologic response at post-treatment week 12 according to HCV genotype (1a or 1b), virologic failure during treatment, and post-treatment relapse. The primary analysis was performed after all the patients in group A reached post-treatment week 12 and all those in group B reached week 12 of open-label treatment (Figure 1). Primary analysis data are reported.

Normalization of the alanine aminotransferase level was defined as a final level that was no more than the upper limit of the normal range during the double-blind treatment period in patients whose baseline level had been higher than the upper limit of the normal range. Patients were considered to have virologic failure during treatment if they had a confirmed HCV RNA level of 25 IU per milliliter or more after the HCV RNA level had been lower than 25 IU per milliliter during treatment, if they had a confirmed increase in the HCV RNA level of more than 1 log 10 IU per milliliter above the nadir observed during treatment, or if all the HCV RNA values during the treatment with the study drug administered for at least 6 weeks were 25 IU per milliliter or more. Virologic relapse was defined as a confirmed HCV RNA level of 25 IU per milliliter or more between the final treatment visit and 12 weeks after receipt of the last dose of study drug among patients who completed treatment (duration of treatment, ≥77 days), who had an HCV RNA level that was lower than 25 IU per milliliter at the final treatment visit during the double-blind period, and who had HCV RNA data available after treatment.

Statistical Analysis

Analyses were performed in the modified intention-to-treat population, which included all the patients who underwent randomization and received at least one dose of the study drug during the double-blind period. The primary efficacy analyses assessed noninferiority and superiority with respect to the rate of sustained virologic response at post-treatment week 12 associated with the active regimen (ABT-450/r–ombitasvir and dasabuvir with ribavirin) by comparing it with a calculated historical control rate of 78% (95% confidence interval [CI], 75 to 80). This control rate was based on response rates among previously untreated patients without cirrhosis who received telaprevir and peginterferon–ribavirin.12

To establish that the rate of sustained virologic response at post-treatment week 12 associated with the active regimen was noninferior to the historical control rate, the lower boundary of the 95% confidence interval for the rate of sustained virologic response at post-treatment week 12 in group A had to exceed the upper boundary of the 95% confidence interval for the control rate minus 10.5 percentage points (70%). To establish that the rate of sustained virologic response at post-treatment week 12 associated with the active regimen was superior to the historical control rate, the lower boundary of the 95% confidence interval for the rate in group A had to exceed the upper boundary of the confidence interval for the historical rate (80%).

The two-sided 95% confidence intervals were calculated with the use of the normal approximation to the binomial distribution. We calculated that a sample of 600 patients (450 patients in group A) would provide the study with more than 90% power to show noninferiority and superiority of the active regimen, assuming a rate of sustained virologic response at post-treatment week 12 of 92%.

Secondary analyses assessed whether the rates of sustained virologic response at post-treatment week 12 in HCV genotype 1a–infected and HCV genotype 1b–infected subgroups of group A were superior to calculated rates for these subgroups in the historical control group (72% [95% CI, 68 to 75] in patients with HCV genotype 1a infection and 80% [95% CI, 75 to 84] in those with HCV genotype 1b infection).12 If the lower boundary of the 95% confidence interval for the rate of sustained virologic response at post-treatment week 12 exceeded 75% among patients with HCV genotype 1a infection or 84% among those with HCV genotype 1b infection, the rate with the active regimen was considered to be superior to the historical control rate in that subgroup. Details of the noninferiority and superiority analyses and sample-size determination are provided in the Supplementary Appendix. A fixed-sequence testing procedure was used to maintain the type I error rate at a level of 0.05 as the primary and secondary efficacy end points were analyzed in a specific order (see the Supplementary Appendix).

SAS software, version 9.3, for the UNIX operating system (SAS Institute) was used for all analyses. All statistical tests and 95% confidence intervals were two-sided, with a significance level of 0.05. Differences in baseline characteristics between the treatment groups were evaluated with the use of the chi-square test for categorical data and one-way analysis of variance for continuous data. Comparisons of rates of normalization of the alanine aminotransferase level, adverse events, and laboratory abnormalities were performed with the use of Fisher's exact test.

The relationship between prespecified baseline characteristics (e.g., fibrosis score) and the rate of sustained virologic response at post-treatment week 12 was analyzed by means of stepwise logistic regression to determine independent predictors of sustained virologic response at post-treatment week 12. The fibrosis score (on a scale from F0, indicating no fibrosis, to F4, indicating cirrhosis) was determined by means of liver biopsy (Metavir, Batts–Ludwig, Knodell, International Association for the Study of the Liver, Scheuer, Laennec, or Ishak scoring system), FibroTest, or FibroScan (Echosens). Additional details of the stepwise logistic-regression analysis and fibrosis scoring are provided in Table S2 in the Supplementary Appendix.