Sirolimus (Page 9 of 12)

14.2 Cyclosporine Withdrawal Study in Renal Transplant Patients

The safety and efficacy of sirolimus as a maintenance regimen were assessed following cyclosporine withdrawal at 3 to 4 months after renal transplantation. Study 3 was a randomized, multicenter, controlled trial conducted at 57 centers in Australia, Canada, and Europe. Five hundred twenty-five (525) patients were enrolled. All patients in this study received the tablet formulation. This study compared patients who were administered sirolimus, cyclosporine, and corticosteroids continuously with patients who received this same standardized therapy for the first 3 months after transplantation (pre-randomization period) followed by the withdrawal of cyclosporine. During cyclosporine withdrawal, the sirolimus dosages were adjusted to achieve targeted sirolimus whole blood trough concentration ranges (16 to 24 ng/mL until month 12, then 12 to 20 ng/mL thereafter, expressed as chromatographic assay values). At 3 months, 430 patients were equally randomized to either continue sirolimus with cyclosporine therapy or to receive sirolimus as a maintenance regimen following cyclosporine withdrawal.

Eligibility for randomization included no Banff Grade 3 acute rejection or vascular rejection episode in the 4 weeks before random assignment, serum creatinine 4.5 mg/dL, and adequate renal function to support

cyclosporine withdrawal (in the opinion of the investigator). The primary efficacy endpoint was graft survival at 12 months after transplantation. Secondary efficacy endpoints were the rate of biopsy-confirmed acute rejection, patient survival, incidence of efficacy failure (defined as the first occurrence of either biopsy-proven acute rejection, graft loss, or death), and treatment failure (defined as the first occurrence of either discontinuation, acute rejection, graft loss, or death).

The following table summarizes the resulting graft and patient survival at 12, 24, and 36 months for this trial. At 12, 24, and 36 months, graft and patient survival were similar for both groups.

TABLE 13: GRAFT AND PATIENT SURVIVAL (%): STUDY 3 a
Parameter	Sirolimus With Cyclosporine Therapy	Sirolimus Following Cyclosporine Withdrawal (n =215)
Graft Survival
Month 12 b	95.3 c	97.2
Month 24	91.6	94.0
Month 36 d	87.0	91.6
Patient Survival
Month 12	97.2	98.1
Month 24	94.4	95.8
Month 36 d	91.6	94.0
a: Includes patients who prematurely discontinued treatment. b: Primary efficacy endpoint c: Survival including loss to follow-up as an event. d: Initial planned duration of the study

The following table summarizes the results of first biopsy-proven acute rejection at 12 and 36 months. There was a significant difference in first biopsy-proven rejection rates between the two groups after randomization and through 12 months. Most of the post-randomization acute rejections occurred in the first 3 months following randomization.

TABLE 14: INCIDENCE OF FIRST BIOPSY-PROVEN ACUTE REJECTION (%) BY TREATMENT GROUP AT 36 MONTHS: STUDY 3 a,b
Treatment	Sirolimus with Cyclosporine Therapy (n = 215)	Sirolimus Following Cyclosporine Withdrawal (n= 215)
Pre-randomization c Post-randomization through 12 months c Post-randomization from 12 to 36 months Post-randomization through 36 months Total at 36 months	9.3 4.2 1.4 5.6 14.9	10.2 9.8 0.5 10.2 20.5
a Includes patients who prematurely discontinued treatment b All patients received corticosteroids c Randomization occurred at 3 months ± 2 weeks.

Patients receiving renal allografts with 4 HLA mismatches experienced significantly higher rates of acute rejection following randomization to the cyclosporine withdrawal group, compared with patients who continued cyclosporine (15.3% versus 3%). Patients receiving renal allografts with 3 HLA mismatches demonstrated similar rates of acute rejection between treatment groups (6.8% versus 7.7%) following randomization.

The following table summarizes the mean calculated GFR in Study 3 (cyclosporine withdrawal study).

TABLE 15: CALCULATED GLOMERULAR FILTRATION RATES (mL/min) BY NANKIVELL EQUATION AT 12, 24, AND 36 MONTHS POST-TRANSPLANT: STUDY 3 a,b,c
Parameter	Sirolimus with Cyclosporine Therapy	Sirolimus Following Cyclosporine Withdrawal
Month 12 Mean ± SEM Month 24 Mean ± SEM Month 36 Mean ± SEM	53.2 ± 1.5 (n = 208) 48.4 ± 1.7 (n = 203) 47.0 ± 1.8 (n = 196)	59.3 ± 1.5 (n = 203) 58.4 ± 1.6 (n = 201) 58.5 ± 1.9 (n = 199)
a Includes patients who prematurely discontinued treatment b Patients who had a graft loss were included in the analysis and had their GFR set to 0.0. c All patients received corticosteroids.

The mean GFR at 12, 24, and 36 months, calculated by the Nankivell equation, was significantly higher for patients receiving sirolimus as a maintenance regimen following cyclosporine withdrawal than for those in the sirolimus with cyclosporine therapy group. Patients who had an acute rejection prior to randomization had a significantly higher GFR following cyclosporine withdrawal compared to those in the sirolimus with cyclosporine group. There was no significant difference in GFR between groups for patients who experienced acute rejection post-randomization.

Although the initial protocol was designed for 36 months, there was a subsequent amendment to extend this study. The results for the cyclosporine withdrawal group at months 48 and 60 were consistent with the results at month 36. Fifty-two percent (112/215) of the patients in the sirolimus with cyclosporine withdrawal group remained on therapy to month 60 and showed sustained GFR.