b) Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.

Table 17. Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months (Study 1)

  Group A Group B Group C Group D
  N=390 N=399 N=401 N=399
Overall Failure 141 (36.2%) 126 (31.6%) 82 (20.4%) 185 (46.4%)
Components of efficacy failure        
BPAR 113 (29.0%) 106 (26.6%) 60 (15.0%) 152 (38.1%)
Graft loss excluding death 28 (7.2%) 20 (5.0%) 12 (3.0%) 30 (7.5%)
Mortality 13 (3.3%) 7 (1.8%) 11 (2.7%) 12 (3.0%)
Lost to follow-up 5 (1.3%) 7 (1.8%) 5 (1.3%) 6 (1.5%)
Treatment Difference of efficacy failure
compared to Group C (99.2% CIa) 15.8%
(7.1%, 24.3%) 11.2%
(2.7%, 19.5%)   - 26.0%
(17.2%, 34.7%)
Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, and D = Siro/MMF/CS/Daclizumab

a) Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.

The protocol-specified target Tacrolimus trough concentrations (Ctrough,Tac) were 3 to 7 ng/mL; however, the observed median Ctroughs,Tac approximated 7 ng/mL throughout the 12 month trial (Table 18). Approximately 80% of patients maintained Tacrolimus whole blood concentrations between 4 to 11 ng/mL through 1 year post-transplant.

Table 18. Tacrolimus Whole Blood Trough Concentrations (Study 1)

Time Median (P10 to P90a) Tacrolimus whole blood trough concentrations
(ng/mL)
Day 30 (N=366) 6.9 (4.4 to 11.3)
Day 90 (N=351) 6.8 (4.1 to 10.7)
Day 180 (N=355) 6.5 (4.0 to 9.6)
Day 365 (N=346) 6.5 (3.8 to 10.0)
a) 10 to 90th Percentile: range of Ctrough, Tac that excludes lowest 10% and highest 10% of Ctrough,Tac
The protocol-specified target cyclosporine trough concentrations (Ctrough,CsA) for Group B were 50 to 100 ng/mL; however, the observed median Ctroughs,CsA approximated 100 ng/mL throughout the 12 month trial. The protocol-specified target Ctroughs,CsA for Group A were 150 to 300 ng/mL for the first 3 months and 100 to 200 ng/mL from month 4 to month 12; the observed median Ctroughs, CsA approximated 225 ng/mL for the first 3 months and 140 ng/mL from month 4 to month 12.
While patients in all groups started MMF at 1gram twice daily, the MMF dose was reduced to less than 2 g per day in 63% of patients in the Tacrolimus treatment arm by month 12 (Table 19); approximately 50% of these MMF dose reductions were due to adverse reactions. By comparison, the MMF dose was reduced to less than 2 g per day in 49% and 45% of patients in the two cyclosporine arms (Group A and Group B, respectively), by month 12 and approximately 40% of MMF dose reductions were due to adverse reactions.
Table 19. MMF Dose Over Time in Tacrolimus/MMF (Group C) (Study 1)
Time period (Days) Time-averaged MMF dose (grams per day)a
Less than 2.0 2.0 Greater than 2.0  
0 to 30 (N=364) 37% 60% 2%  
0 to 90 (N=373) 47% 51% 2%  
0 to 180 (N=377) 56% 42% 2%  
0 to 365 (N=380) 63% 36% 1%  
Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)
a) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per day of time-averaged MMF dose means that MMF dose was not reduced in those patient