s during the treatment periods.
In a second randomized, open-label, multi-center trial (Study 2), 424 kidney transplant patients received Tacrolimus (N=212) or cyclosporine (N=212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. In this trial, the rate for the combined endpoint of BPAR, graft failure, death, and/or lost to follow-up at 12 months in the Tacrolimus/MMF group was similar to the rate in the cyclosporine/MMF group. There was, however, an imbalance in mortality at 12 months in those patients receiving Tacrolimus/MMF (4%) compared to those receiving cyclosporine/MMF (2%), including cases attributed to overimmunosuppression (Table 20).
Table 20. Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months (Study 2)
Tacrolimus/MMF Cyclosporine/MMF
(N=212) (N=212)
Overall Failure 32 (15.1%) 36 (17.0%)
Components of efficacy failure
BPAR 16 (7.5%) 29 (13.7%)
Graft loss excluding death 6 (2.8%) 4 (1.9%)
Mortality 9 (4.2%) 5 (2.4%)
Lost to follow-up 4 (1.9%) 1 (0.5%)
Treatment Difference of efficacy failure
compared to Tacrolimus/MMF group (95% CIa) 1.9% (-5.2%, 9.0%)
a) 95% confidence interval calculated using Fisher's Exact Test
The protocol-specified target Tacrolimus whole blood trough concentrations (Ctrough,Tac) in Study 2 were 7 to 16 ng/mL for the first three months and 5 to 15 ng/mL thereafter. The observed median Ctroughs,Tac approximated 10 ng/mL during the first three months and 8 ng/mL from month 4 to month 12 (Table 21). Approximately 80% of patients maintained Tacrolimus whole trough blood concentrations between 6 to 16 ng/mL during months 1 through 3 and, then, between 5 to 12 ng/mL from month 4 through 1 year.
Table 21. Tacrolimus Whole Blood Trough Concentrations (Study 2)
Time Median (P10 to P90a) Tacrolimus whole blood trough concentrations
(ng/mL)
Day 30 (N=174) 10.5 (6.3 to 16.8)
Day 60 (N=179) 9.2 (5.9 to 15.3)
Day 120 (N=176) 8.3 (4.6 to 13.3)
Day 180 (N=171) 7.8 (5.5 to 13.2)
Day 365 (N=178) 7.1 (4.2 to 12.4)
a) 10 to 90th Percentile: range of Ctrough,Tac that excludes lowest 10% and highest 10% of Ctrough, Tac
The protocol-specified target cyclosporine whole blood concentrations (Ctrough,CsA) were 125 to 400 ng/mL for the first three months, and 100 to 300 ng/mL thereafter. The observed median Ctroughs, CsA approximated 280 ng/mL during the first three months and 190 ng/mL from month 4 to month 12.
Patients in both groups started MMF at 1gram twice daily. The MMF dose was reduced to less than 2 grams per day by month 12 in 62% of patients in the Tacrolimus/MMF group (Table 22) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse reactions in the Tacrolimus/MMF group and the cyclosporine/MMF group, respectively [see Adverse Reactions (6.1)].
Table 22. MMF Dose Over Time in the Tacrolimus/MMF Group (Study 2)
Time period (Days) Time-averaged MMF dose (g/day)a
Less than 2.0 2.0 Greater than 2.0
0 to 30 (N=212) 25% 69% 6%
0 to 90 (N=212) 41% 53% 6%
0 to 180 (N=212) 52% 41% 7%
0 to 365 (N=212) 62% 34% 4%
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. Two grams per day of time-averaged MMF dose means that MMF dose was not reduced in thos |
