Abstract# 49 SYMPHONY – COMPARING STANDARD IMMUNOSUPPRESSION TO LOW-DOSE CYCLOSPORINE, TACROLIMUS OR SIROLIMUS IN COMBINATION WITH MMF, DACLIZUMAB AND CORTICOSTEROIDS IN RENAL TRANSPLANTATION. H Ekberg, H Tedesco-Silva, A Demirbas, S Vitko, B Nashan, A Gurkan, R Margreiter, C Hugo, J Grinyo, U Frei, Y Vanrenterghem, P Daloze, P Halloran. Lund Univ, Malmoe, Sweden; Federal Univ, Sao Paulo, Brazil; Akdeniz 49 SYMPHONY – COMPARING STANDARD IMMUNOSUPPRESSION TO LOW-DOSE CYCLOSPORINE, TACROLIMUS OR SIROLIMUS IN COMBINATION WITH MMF, DACLIZUMAB AND CORTICOSTEROIDS IN RENAL TRANSPLANTATION. H Ekberg, H Tedesco-Silva, A Demirbas, S Vitko, B Nashan, A Gurkan, R Margreiter, C Hugo, J Grinyo, U Frei, Y Vanrenterghem, P Daloze, P Halloran. Lund Univ, Malmoe, Sweden; Federal Univ, Sao Paulo, Brazil; Akdeniz Univ, Antalya, Turkey; IKEM, Prague, Czech Republic; Medizinische Hochschule, Hannover, Germany; SSK Tepecik Hospital, Izmir, Turkey; Universitaetsklinik, Innsbruck, Austria; Univ Hospital, Erlangen, Germany; Ciutat Universitaria de Bellvitge, Barcelona, Spain; Virchow-Klinikum, Berlin, Germany; KU Leuven, Leuven, Belgium; Notre-Dame Hospital, CHUM Montreal, Canada; Univ of Alberta, Edmonton, Canada. Introduction: SYMPHONY is a trial comparing standard immunosuppression versus 3 regimens with low-dose or no CNI in de-novo single-organ renal transplant patients over 1 year. Methods: In this prospective, randomized, open study with 4 parallel arms, 1645 patients in 15 countries were randomized to standard immunosuppression with normal-dose cyclosporine (CsA, target trough level 150-300ng/ml for 3 months, 100-200ng/ml thereafter), MMF 1g bid and corticosteroids, or to one of three regimens consisting of daclizumab induction (2mg/kg followed by 4x1mg/kg every 2 weeks), MMF (1g bid) and corticosteroids potentiated by a low-dose of either CsA (50-100 ng/ ml), tacrolimus (TAC, 3-7ng/ml) or sirolimus (SRL, 4-8ng/ml). Primary objective was to determine renal function (GFR calculated with Cockcroft-Gault) at 12 months. Secondary endpoints were biopsy proven acute rejection (BPAR) rate, patient and graft survival rates, treatment failure, GFR time course and safety. Results: Differences in GFR and BPAR were statistically significant among the 4 groups (p<0.0001). The low-dose TAC group was significantly superior to all other groups with respect to GFR and BPAR (p<0.01) and to normaldose CsA and low-dose SRL for graft survival (pair-wise p<0.05). N GFR (12 mo) GFR (12 mo) BPAR Graft Patient (6 / 12 mo) survival survival (12 mo) (12 mo) (ITT) median mean ± SD [%] [%] [%] [ml/min] [ml/min] Normal-dose CsA 385 56.8 56.2 ± 25.9 23.5 / 25.3 90.0 96.5 Low-dose CsA 399 60.9 58.9 ± 25.7 21.4 / 23.5 93.1 98.2 Low-dose TAC 402 65.4 64.5 ± 27.9 11.2 / 12.3 94.2 97.2 Low-dose SRL 399 57.3 55.9 ± 27.5 33.3 / 35.3 89.2 96.8 Conclusion: Immunosuppression consisting of daclizumab induction, MMF, low-dose TAC and corticosteroids provides the most optimal balance between efficacy (control of acute rejection) and toxicity (preserving graft function and graft survival). Abstract# 50 GLUCOSE METABOLISM DISORDERS AFTER RENAL TRANSPLANTATION: RESULTS OF AN INTERNATIONAL, RANDOMIZED TRIAL COMPARING CYCLOSPORINE VERSUS TACROLIMUS. Flavio Vincenti, Styrbjörn Friman, Ernst Scheuermann, Lionel Rostaing. University of California San Francisco, San Francisco, CA; on Behalf of the DIRECT Study Group. 50 GLUCOSE METABOLISM DISORDERS AFTER RENAL TRANSPLANTATION: RESULTS OF AN INTERNATIONAL, RANDOMIZED TRIAL COMPARING CYCLOSPORINE VERSUS TACROLIMUS. Flavio Vincenti, Styrbjörn Friman, Ernst Scheuermann, Lionel Rostaing. University of California San Francisco, San Francisco, CA; on Behalf of the DIRECT Study Group. Choice of calcineurin inhibitor appears to be a modifiable risk factor for glucose metabolism abnormalities post-transplant, but choice of CNI on the basis of diabetogenic risk should not be made at the expense of efficacy. Methods. DIRECT was a 6-month, open-label, randomized, multicenter study which used ADA/WHO criteria to define glucose abnormalities. De novo renal transplant patients were stratified pre-transplant as (1) diabetic (2) non-diabetic/Caucasian or (3) non-diabetic/non-Caucasian, and were randomized to cyclosporine microemulsion (CsA-ME) with C2 monitoring or tacrolimus. All patients received mycophenolic acid therapy, steroids, and basiliximab. The primary safety endpoint was a composite of newonset diabetes mellitus (NODM) or impaired fasting glucose (IFG) at 6 months in patients who were non-diabetic at baseline; the primary efficacy endpoint was a composite of biopsy-proven acute rejection (BPAR), graft loss or death at 6 months in all patients. Results. The population analyzed comprised 682 patients (336 CsA-ME, 346 tacrolimus): 115 were diabetic at baseline, 483 were non-diabetic/Caucasian and 84 were non-diabetic/ non-Caucasian. Patient characteristics, diabetes risk factors and steroid doses were similar between treatment groups. NODM or IFG occurred in 73 CsA-ME patients (26.0%) and 96 tacrolimus patients (33.6%, p=0.046) at 6 months. In the Caucasian and non-Caucasian subpopulations, the 6month incidence was 24.8% and 32.6% with CsA-ME and 32.2% and 39.0% with tacrolimus, respectively. At month 6, 12.5% of CsA-ME patients and 18.0% of tacrolimus patients who were non-diabetic at baseline required hypoglycemic treatment (p<0.05). The incidence of BPAR, graft loss or death was 12.8% with CsA-ME and 9.8% with tacrolimus (p=0.211). Blood pressure and renal function were similar. An increase in both median LDLand HDL-cholesterol occurred in the CsA-ME group (LDL +0.42mmol/L [16mg/dL], p<0.001; HDL +0.23mmol/L [9mg/dL], p<0.001). The ratio of total cholesterol/HDL remained unchanged (4.03 vs 3.98 at month 6, p=0.43). Adverse events were similar between groups. Conclusions: The incidence of NODM or IFG at 6 months post-transplant is significantly lower with CsA-ME than tacrolimus with no difference in terms of efficacy. Abstract# 51 FTY720 VS. MMF IN DE NOVO RENAL TRANSPLANT PATIENTS ON FULL-DOSE NEORAL: 6-MONTH RESULTS OF A DOUBLE-BLIND STUDY. Helio Tedesco, Peter Szakaly, Ahmed Shoker, Claudia Sommerer, Norio Yoshimura, Francesco Schena, Malika Cremer, Abdel Hmissi, Hartmut Mayer, Philippe Lang. Sao Paulo, Brazil; Pecs, Hungary; Saskatoon, Canada; Heidelberg, Germany; Kyoto, Japan; Bari, Italy; Novartis, Basel, Switzerland; Creteil, France. 51 FTY720 VS. MMF IN DE NOVO RENAL TRANSPLANT PATIENTS ON FULL-DOSE NEORAL: 6-MONTH RESULTS OF A DOUBLE-BLIND STUDY. Helio Tedesco, Peter Szakaly, Ahmed Shoker, Claudia Sommerer, Norio Yoshimura, Francesco Schena, Malika Cremer, Abdel Hmissi, Hartmut Mayer, Philippe Lang. Sao Paulo, Brazil; Pecs, Hungary; Saskatoon, Canada; Heidelberg, Germany; Kyoto, Japan; Bari, Italy; Novartis, Basel, Switzerland; Creteil, France. This multicenter, double-blind, phase Iib study evaluated safety and efficacy of two doses of FTY720 (5mg n=87; 2.5mg n=90), plus full-dose Neoral (FDN) versus MMF (n=94) plus FDN in de novo adult renal transplant patients. Results 270 patients, including 57 from Japan, were randomized prior to transplant surgery. Cadaveric donor were 56%, 64% and 51% respectively. Demographic characteristics were comparable among treatment groups. 6 Month after treatment initiation, approximately 69% of patients remained on study medication and 31% had at least 1 dose change.The primary efficacy composite endpoint was the first occurrence of either treated biopsy-proven acute rejection (BPAR), graft loss, death or premature study discontinuation within 6 months post-transplantation. FTY720 5 mg showed statistically superiority over MMF. The MMF results are not in line with historic experience but no obvious reason was identified. FTY720 was generally well tolerated throughout the study. The proportion of adverse events reported was similar across groups. More eye disorders were observed with FTY720 vs. MMF with 1 case of macular edema in the FTY720 2.5mg group at time of analysis. Cytomegalovirus infections were higher in the MMF arm. A lower creatinine clearance was observed in both FTY720 arms compared to MMF. Conclusion In this trial, FTY720 5mg with FDN provided superior protection from acute rejection in de novo renal transplant patients compared to MMF. However renal function was lower and more eye disorders were seen in FTY720 patients.