Multicenter trial of everolimus in pediatric renal transplant recipients: results at three year.
ABSTRACT There are few prospective clinical trials of mTOR inhibitors (or proliferation signal inhibitors) combined with CNI inhibitors in de novo pediatric renal transplantation. Results reported here are from a multicenter, open-label study in de novo pediatric renal transplant patients (<or=16 yr), in which patients received everolimus with cyclosporine and corticosteroids for one yr, then entered an extension study for a further two yr. Nineteen patients completed the one-yr study, of whom three discontinued study medication. Fifteen of the remaining 16 patients entered the extension study, eight of whom were aged <10 yr (Group 1) and seven were aged 10-16 yr (Group 2). Mean daily dose of everolimus during the first 36 months was 1.53 mg/m(2) BSA. Biopsy-proven acute rejection occurred in three patients in Group 2 and in one patient in Group 1. Biopsy-proven chronic allograft rejection was reported in four patients (two in each age group). Graft survival at one yr was 100%; one patient in Group 2 lost their graft subsequently during the extension. For patients entering the extension, patient survival at three yr was 100%. There were three cases of viral infection, including one case of cytomegalovirus infection. At three yr, mean total cholesterol was 5.5 +/- 0.8 mm/L (213 +/- 31 mg/dL) and four patients received statin therapy. Mean serum creatinine at 36 months was 96 +/- 36 microm/L (1.1 +/- 0.4 mg/dL). This is the first long-term prospective study to demonstrate that a regimen of everolimus, cyclosporine, and corticosteroids provides good efficacy, tolerability, and safety in de novo pediatric renal transplant patients.
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ABSTRACT: This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with the microemulsion formulation of cyclosporin (CyA) in children undergoing renal transplantation. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 years) were randomly assigned (1:1) to receive either Tac ( n=103) or CyA microemulsion ( n=93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection. Baseline characteristics were comparable between treatment groups. Tac therapy resulted in a significantly lower incidence of acute rejection (36.9%) compared with CyA therapy (59.1%) ( P=0.003). The incidence of corticosteroid-resistant rejection was also significantly lower in the Tac group compared with the CyA group (7.8% vs. 25.8%, P=0.001). The differences were also significant for biopsy-confirmed acute rejection (16.5% vs. 39.8%, P<0.001). At 1 year, patient survival was similar (96.1% vs. 96.6%), while 10 grafts were lost in the Tac group compared with 17 graft losses in the CyA group ( P=0.06). At 1 year, mean glomerular filtration rate (Schwartz estimate) was significantly higher in the Tac group (62+/-20 ml/min per 1.73 m(2), n=84) than in the CyA group (56+/-21 ml/min per 1.73 m(2), n=74, P=0.03). The most frequent adverse events during the first 6 months were hypertension (68.9% vs. 61.3%), hypomagnesemia (34.0% vs. 12.9%, P=0.001), and urinary tract infection (29.1% vs. 33.3%). Statistically significant differences ( P<0.05) were observed for diarrhea (13.6% vs. 3.2%), hypertrichosis (0.0% vs. 7.5%), flu syndrome (0.0% vs. 5.4%), and gum hyperplasia (0.0% vs. 5.4%). In previously non-diabetic children, the incidence of long-term (>30 days) insulin use was 3.0% (Tac) and 2.2% (CyA). Post-transplant lymphoproliferative disease was observed in 1 patient in the Tac group and 2 patients in the CyA group. In conclusion, Tac was significantly more effective than CyA microemulsion in preventing acute rejection after renal transplantation in a pediatric population. The overall safety profiles of the two regimens were comparable.Pediatric Nephrology 04/2002; 17(3):141-9. · 2.94 Impact Factor
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ABSTRACT: Exposure, safety, and efficacy data from the two everolimus randomized, double-blind phase 3 trials were evaluated to identify a therapeutic concentration range applicable in de novo kidney transplantation. A total of 695 evaluable everolimus-treated patients received either 0.75 or 1.5 mg bid in addition to corticosteroids and cyclosporine (troughs 150-400 ng/ml in month 1 and 100-300 ng/ml thereafter). A total of 3355 everolimus trough levels (Cmin) were obtained in weeks 1 and 2 and months 1, 2, 3, and 6 after transplantation. Each patient's average Cmin was calculated and the values were divided into quintiles: 1.0-3.4, 3.5-4.5, 4.6-5.7, 5.8-7.7, 7.8-15.0 ng/ml (139 patients per quintile). Efficacy was freedom from biopsy-confirmed acute rejection. Safety measures were maximum total cholesterol and triglyceride levels and minimum leukocyte and platelet counts. A sigmoid exposure-response model was used to test the significance of these Cmin-efficacy and Cmin-safety relationships. Freedom from acute rejection was significantly related to Cmin with an incidence of 68% at 1.0-3.4 ng/ml, 81-86% at 3.5-7.7 ng/ml, and 91% at 7.8-15.0 ng/ml (P=0.03). The incidence of hypercholesterolemia, defined as >6.5 mmol/liter, ranged from 76 to 87% over the exposure range without a significant relation to Cmin (P=0.37). The incidence of hypertriglyceridemia, defined as >2.9 mmol/liter, rose from 59 to 77% across the exposure groups (P=0.02). Leukocytopenia, defined as <4x10(9)/liter, occurred in 11-19% of patients across the exposure quintiles showing no relationship to Cmin (P=0.76). The incidence of thrombocytopenia, defined as <100x10(9)/liter, occurred in </=10% of patients in the first 3 Cmin quintiles and was 14 and 17% in Cmin quintiles 4 and 5 (P=0.21). A significantly increased risk of acute rejection was observed at everolimus trough levels <3 ng/ml. This is a lower therapeutic concentration limit when everolimus is used with conventionally dosed cyclosporine. Because hyperlipidemias responded to counter-measure therapies and thrombocytopenia had an overall low incidence of 12%, everolimus-related adverse events were manageable up to the highest troughs observed in this population of 15 ng/ml. An upper therapeutic concentration limit is likely more than 15 ng/ml but a precise value could not be derived from these data.Transplantation 03/2002; 73(6):920-5. · 3.78 Impact Factor
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ABSTRACT: Everolimus is a proliferation inhibitor designed to target chronic rejection, including prevention of acute rejection. Everolimus blocks growth factor-mediated transduction signals, preventing organ rejection by a mechanism different than that of calcineurin inhibitors and of mycophenolate mofetil (MMF). METHODS.: Everolimus (1.5 mg or 3 mg daily) was compared with MMF (2 g daily) in a randomized, multicenter, multinational, 12-month double-blind, double-dummy and 2-year open-label, phase 3 trial in de novo renal allograft recipients (n = 588) who also received cyclosporine and corticosteroids as part of a triple immunosuppressive regimen. At 12 months, there were no statistically significant differences between doses of 1.5 and 3 mg/day everolimus and MMF (2 g/day) in incidence of biopsy-proven acute rejection (23.2%, 19.7%, and 24.0%, respectively), graft loss (4.6%, 10.6%, and 9.2%), or death (5.2%, 4.0%, and 2.6%), respectively. Everolimus 1.5 mg/day and MMF were generally equally well tolerated. Both were better tolerated than everolimus 3 mg/day. The incidence of cytomegalovirus infection was significantly lower in patients receiving either 1.5 or 3 mg/day everolimus than in those receiving MMF (5.2% and 7.6% vs. 19.4%, respectively) (P = .001). Everolimus is effective in preventing acute rejection and graft loss in de novo renal allograft recipients receiving a triple immunosuppressive regimen. Prevention of acute rejection, along with reduction in cytomegalovirus infection, addresses two factors known to contribute to chronic rejection in such patients.Transplantation 12/2004; 78(10):1532-40. · 3.78 Impact Factor