Enal insufficiency or serum creatinine clearance below 50 mL/min.Study DesignPatient

Enal insufficiency or serum creatinine clearance below 50 mL/min.Study DesignPatient disposition is shown in Figure 1 and the study design in Figure 2. Total treatment period is 104 weeks with the primary analysis at 52 weeks. Planned study visits occurred at Weeks 2, 4, 8, 12, 16, 24, 26, 30, 40, 48, and 52. All patients received oral telbivudine (600 mg once daily) for the first 24 weeks. At Week 26, patients with detectable HBV DNA at Week 24 ( 300 copies/mL by COBAS Amplicor) received tenofovir disoproxil fumarate (300 mg once daily) in addition to telbivudine throughout the remaining time on study. Patients with undetectable HBV DNA (,300 copies/mL) at Week 24 continued to receive telbivudine monotherapy.Efficacy and Safety AnalysesThe primary efficacy endpoint was the proportion of patients with undetectable HBV DNA at Week 52. Secondary endpoints included the rate of virological breakthrough; HBV DNA reductions from baseline and proportions with undetectable HBV DNA at each study visit; ALT normalization rates at Weeks 24 and 52, and rates of HBeAg and HBsAg loss and seroconversion at Week 52. Clinical and laboratory adverse events were graded according to pre-specified criteria and reported relationship to study drug was at investigator discretion. ALT flares were defined according to AASLD criteria [18]. Glomerular filtration rates (GFR) at each visit were estimated using both the Cockcroft-Gault [19] and the Modification Of Diet In Renal Disease Study (MDRD) equations [20,21].Materials and MethodsThe protocol for this trial and supporting CONSORT checklist are available as supporting information; see Checklist S1 and Protocol S1.Dimethylenastron Statistical AnalysisThe primary efficacy endpoint was analyzed as a binary variable using last-observation-carried-forward (LOCF) imputaTelbivudine 6 Conditional Tenofovir: 52-Week DataFigure 1. Patient disposition. doi:10.1371/journal.pone.0054279.gtion. The primary endpoint and all binary secondary endpoints were summarized at each visit, with the 95 confidence interval calculated using the normal approximation method for binomial proportion. Differences in baseline demographics and disease characteristics between patients who remained on telbivudine monotherapy through Week 52 and those who added tenofovir after Week 24 were assessed for significance using Fisher’s exact test for categorical variables and two-sided t-tests for continuous variables. Changes from baseline in GFR at Week 52 were assessed for significance using two-sided, paired t-tests. Statistical analyses were carried out using SAS ver 1.3 (SAS Institute, Inc. Carey, NC, USA). The full intention-to-treat (ITT) population comprised all patients who received at least one dose of telbivudine. As this was a study of a specific therapeutic algorithm, a per-protocol population was derived for efficacy assessments ?i.e. the efficacy population ?which excluded one patient with a confirmed baseline rtM204I resistance UKI-1 mutation to telbivudine/lamivudine, 2 patients lost to follow-up before Week 24, and 2 protocol violators who did not receive tenofovir despite detectable Week 24 HBV DNA. The safety population for adverse event monitoring comprised the full ITT population as defined. This was a single-arm study, hence the sample size was not based on power for statistical comparison between treatment groups. The primary objective was to demonstrate antiviral efficacy by estimating the proportion of patients with HBV DNA ,300 copies/mL at Week 5.Enal insufficiency or serum creatinine clearance below 50 mL/min.Study DesignPatient disposition is shown in Figure 1 and the study design in Figure 2. Total treatment period is 104 weeks with the primary analysis at 52 weeks. Planned study visits occurred at Weeks 2, 4, 8, 12, 16, 24, 26, 30, 40, 48, and 52. All patients received oral telbivudine (600 mg once daily) for the first 24 weeks. At Week 26, patients with detectable HBV DNA at Week 24 ( 300 copies/mL by COBAS Amplicor) received tenofovir disoproxil fumarate (300 mg once daily) in addition to telbivudine throughout the remaining time on study. Patients with undetectable HBV DNA (,300 copies/mL) at Week 24 continued to receive telbivudine monotherapy.Efficacy and Safety AnalysesThe primary efficacy endpoint was the proportion of patients with undetectable HBV DNA at Week 52. Secondary endpoints included the rate of virological breakthrough; HBV DNA reductions from baseline and proportions with undetectable HBV DNA at each study visit; ALT normalization rates at Weeks 24 and 52, and rates of HBeAg and HBsAg loss and seroconversion at Week 52. Clinical and laboratory adverse events were graded according to pre-specified criteria and reported relationship to study drug was at investigator discretion. ALT flares were defined according to AASLD criteria [18]. Glomerular filtration rates (GFR) at each visit were estimated using both the Cockcroft-Gault [19] and the Modification Of Diet In Renal Disease Study (MDRD) equations [20,21].Materials and MethodsThe protocol for this trial and supporting CONSORT checklist are available as supporting information; see Checklist S1 and Protocol S1.Statistical AnalysisThe primary efficacy endpoint was analyzed as a binary variable using last-observation-carried-forward (LOCF) imputaTelbivudine 6 Conditional Tenofovir: 52-Week DataFigure 1. Patient disposition. doi:10.1371/journal.pone.0054279.gtion. The primary endpoint and all binary secondary endpoints were summarized at each visit, with the 95 confidence interval calculated using the normal approximation method for binomial proportion. Differences in baseline demographics and disease characteristics between patients who remained on telbivudine monotherapy through Week 52 and those who added tenofovir after Week 24 were assessed for significance using Fisher’s exact test for categorical variables and two-sided t-tests for continuous variables. Changes from baseline in GFR at Week 52 were assessed for significance using two-sided, paired t-tests. Statistical analyses were carried out using SAS ver 1.3 (SAS Institute, Inc. Carey, NC, USA). The full intention-to-treat (ITT) population comprised all patients who received at least one dose of telbivudine. As this was a study of a specific therapeutic algorithm, a per-protocol population was derived for efficacy assessments ?i.e. the efficacy population ?which excluded one patient with a confirmed baseline rtM204I resistance mutation to telbivudine/lamivudine, 2 patients lost to follow-up before Week 24, and 2 protocol violators who did not receive tenofovir despite detectable Week 24 HBV DNA. The safety population for adverse event monitoring comprised the full ITT population as defined. This was a single-arm study, hence the sample size was not based on power for statistical comparison between treatment groups. The primary objective was to demonstrate antiviral efficacy by estimating the proportion of patients with HBV DNA ,300 copies/mL at Week 5.

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