Tacrolimus (Page 13 of 16)

14 CLINICAL STUDIES

14.1 Kidney Transplantation

Tacrolimus/azathioprine (AZA)

Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a randomized, multicenter, non-blinded, prospective trial. There were 412 kidney transplant patients enrolled at 19 clinical sites in the United States. Study therapy was initiated when renal function was stable as indicated by a serum creatinine ≤ 4 mg/dL (median of 4 days after transplantation, range 1 to 14 days). Patients less than 6 years of age were excluded.

There were 205 patients randomized to tacrolimus-based immunosuppression and 207 patients were randomized to cyclosporine-based immunosuppression. All patients received prophylactic induction therapy consisting of an antilymphocyte antibody preparation, corticosteroids and azathioprine. Overall 1 year patient and graft survival was 96.1% and 89.6%, respectively.

Data from this trial of tacrolimus in conjunction with azathioprine indicate that during the first three months of that trial, 80% of the patients maintained trough concentrations between 7-20 ng/mL, and then between 5-15 ng/mL, through 1 year.

Tacrolimus/mycophenolate mofetil (MMF)

Tacrolimus-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In a randomized, open-label, multi-center trial (Study 1), 1589 kidney transplant patients received Tacrolimus (Group C, n=401), sirolimus (Group D, n=399), or one of two cyclosporine (CsA) regimens (Group A, n=390 and Group B, n=399) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial was conducted outside the United States; the trial population was 93% Caucasian. In this trial, mortality at 12 months in patients receiving Tacrolimus/MMF was similar (3%) compared to patients receiving cyclosporine/MMF (3% and 2%) or sirolimus/MMF (3%). Patients in the Tacrolimus group exhibited higher estimated creatinine clearance rates (eCLcr ) using the Cockcroft-Gault formula (Table 16) and experienced fewer efficacy failures, defined as biopsy proven acute rejection (BPAR), graft loss, death, and/or lost to follow-up (Table 17) in comparison to each of the other three groups. Patients randomized to Tacrolimus/MMF were more likely to develop diarrhea and diabetes after the transplantation and experienced similar rates of infections compared to patients randomized to either cyclosporine/MMF regimen [see Adverse Reactions (6.1)].

Table 16. Estimated Creatinine Clearance at 12 Months (Study 1)

*
a) All death/graft loss (n=41, 27, 23 and 42 in Groups A, B, C and D) and patients whose last recorded creatinine values were prior to month 3 visit (n=10, 9, 7 and 9 in Groups A, B, C and D, respectively) were inputed with Glomerular Filtration Rate (GFR) of 10 mL/min; a subject’s last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n=11, 12, 15 and 19 for Groups A, B, C and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing.
b ) Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.
Group eCLcr [mL/min] at Month 12 *
N MEAN SD MEDIAN Treatment Difference with Group C (99.2%CI )
(A) Cs A/MMF/CS 390 56.5 25.8 56.9 -8.6 (-13.7, -3.7)
(B) CsA/ MMF/CS/Daclizumab 399 58.9 25.6 60.9 -6.2 (-11.2, -1.2)
(C) Tac/ MMF/CS/Daclizumab 401 65.1 27.4 66.2
(D) Siro/ MMF/CS/Daclizumab 399 56.2 27.4 57.3 -8.9 (-14.1, -3.9)
Total 1589 59.2 26.8 60.5
Key: CsA=Cyclosporine, CS=Corticosteroids, Tac=Tacrolimus, Siro=Sirolimus

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

*
a) Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.
Group A N=390 Group B N=399 Group C N=401 Group D N=399
Overall FailureComponents of efficacy failure BPAR Graft loss excluding death Mortality Lost to follow-upTreatment Difference of efficacy failure compared to Group C (99.2% CI *) 141 (36.2%)113 (29.0%)28 (7.2%)13 (3.3%)5 (1.3%)15.8% (7.1%, 24.3%) 126 (31.6%)106 (26.6%)20 (5.0%)7 (1.8%)7 (1.8%)11.2% (2.7%, 19.5%) 82 (20.4%)60 (15.0%)12 (3.0%)11 (2.7%)5 (1.3%)- 185 (46.4%)152 (38.1%)30 (7.5%)12 (3.0%)6 (1.5%)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

The protocol-specified target tacrolimus trough concentrations (Ctrough, Tac ) were 3-7 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 4-11 ng/mL through 1 year post-transplant.

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

*
a) 10 to 90th Percentile: range of Ctrough, Tac that excludes lowest 10% and highest 10% of Ctrough,Tac
Time Median (P10-P90*) tacrolimus whole blood trough concentrations (ng/mL)
Day 30 (N=366) 6.9 (4.4 – 11.3)
Day 90 (N=351) 6.8 (4.1 – 10.7)
Day 180(N=355) 6.5 (4.0 – 9.6)
Day 365 (N=346) 6.5 (3.8 – 10.0)

The protocol-specified target cyclosporine trough concentrations (Ctrough,CsA ) for Group B were 50-100 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 150-300 ng/mL for the first 3 months and 100-200 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)

*
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 patients during the treatment periods.
Time period (Days) Time-averaged MMF dose (g/day)*
Less than 2.0 2.0 Greater than 2.0
0-30 (N=364) 37% 60% 2%
0-90 (N=373) 47% 51% 2%
0-180 (N=377) 56% 42% 2%
0-365 (N=380) 63% 36% 1%
Key: Time-averaged MMF dose = (total MMF dose) / (duration of treatment)

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)

*
a) 95% confidence interval calculated using Fisher’s Exact Test
Tacrolimus/MMF (n=212) Cyclosporin/MMF (n=212)
Overall Failure Components of efficacy failure BPAR Graft loss excluding death Mortality Lost to follow-up Treatment Difference of efficacy failure compared to Tacrolimus/MMF group (95% CI *) 32 (15.1%)16 (7.5%) 6 (2.8%)9 (4.2%) 4 (1.9%) — 36 (17.0%)29 (13.7%) 4 (1.9%)5 (2.4%) 1 (0.5%) 1.9% (-5.2%, 9.0%)

The protocol-specified target tacrolimus whole blood trough concentrations (Ctrough,Tac ) in Study 2 were 7-16 ng/mL for the first three months and 5-15 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)

*
a) 10 to 90th Percentile: range of Ctrough,Tac that excludes lowest 10% and highest 10% of Ctrough, Tac
Time Median (P10-P90*) tacrolimus whole blood trough concentrations (ng/mL)
Day 30 (N=174) 10.5 (6.3 — 16.8)
Day 60 (N=179) 9.2 (5.9 — 15.3)
Day 120 (N=176) 8.3 (4.6 — 13.3)
Day 180 (N=171) 7.8 (5.5 — 13.2)
Day 365 (N=178) 7.1 (4.2 — 12.4)

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)

*
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 those patients during the treatment periods.
Time Period (Days) Time-averaged MMF dose (g/day) *
Less than 2.0 2.0 Greater than 2.0
0-30 (N=212) 25% 69% 6%
0-90 (N=212) 41% 53% 6%
0-180 (N=212) 52% 41% 7%
0-365 (N=212) 62% 34% 4%
Key: Time-averaged MMF dose = (total MMF dose) / (duration of treatment)

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