Safety assessments included laboratory values, vital signs, and
monitoring of adverse events (AEs) at each study visit. Patients who discontinued therapy prematurely due to an AE were followed to study completion. Stepwise reductions in peg-IFN, RBV, and TBV dosages were allowed to manage AEs or laboratory abnormalities that had reached predetermined thresholds Decitabine solubility dmso of severity. If a dose modification of TBV or RBV was required for nonhematologic AEs, the dose was decreased in a stepwise manner, starting with a reduction of approximately 20% of the assigned dose. Hematologic AEs, except anemia, initially required a dose reduction of 50%. Anemia AEs were managed according to presence or absence of cardiac disease. Upon AE resolution, increases of peg-IFN, RBV, or TBV dose in a reverse stepwise manner could be attempted at the investigator’s discretion. Use of ESAs was prohibited. Because diarrhea was identified as an AE of special interest in previous clinical trials, a more extensive diarrhea history was obtained at baseline, and a diarrhea-specific AE report form was developed and employed in this trial. Diarrhea was classified on the form by common toxicity criteria grades of 1 to 4 (mild to severe). A diarrhea management plan was developed and employed. An independent data monitoring committee convened at various time points during the study treatment
period to assess safety MCE but also to determine the risk-benefit ratio considering the higher dosages studied. Serial plasma samples for the determination of TBV and RBV concentrations were collected
across Bortezomib the first dosing interval (0-12 hours) of the twice daily dosing regimen at TW4 and TW12 in a representative subset of the patients at select sites for noncompartmental pharmacokinetic analysis and assessment of dose linearity. In addition, predose plasma samples for determination of TBV and RBV concentrations were obtained at each treatment week with an assessment of steady state at TW4. There were 275 patients enrolled in the study, with approximately 70 patients in each of the four treatment groups. The projected study power was 70% to detect a linear trend in proportions as well as to detect noninferiority of TBV versus RBV using a margin of 12%. Analysis of the primary efficacy and safety variables used data from the intent-to-treat (ITT) population, defined as patients who were randomized and received at least one dose of study drug. The per-protocol population, defined as ITT patients with no major protocol deviations, no use of prohibited concomitant medications, and who completed treatment with >80% compliance, was used for the sensitivity analysis at TW12, TW24, and TW48 and FW4, FW12, and FW24. Unless otherwise noted, all tests of hypotheses were two-sided at the overall 5% level of significance.