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Study 1: one-year results of the first prospective, randomized, multicenter kidney transplant study comparing tacrolimus and sirolimus versus tacrolimus and mycophenolate mofetil combination therapy
Study 1: One-Year Results of the First Prospective, Randomized, Multicenter Kidney Transplant Study Comparing Tacrolimus and Sirolimus Versus Tacrolimus and Mycophenolate Mofetil Combination Therapy R. Mendez, T. Gonwa, K. Rice, M. Holman, H. Yang, R. Filo, S. Steinberg, S. Weinstein, S. Jensik, B. Philosophe J. Colanna, A. Klein, J. Markowitz, M. Hardy, C. Shield, P.R. Rajagopalan, B. Ketel, G. Barone, W. Concepcion, G. Danovich, S. Tomlanovich, J. Scandling, P. Gores, G. Basadonna, M. Lorber, S. Inokuchi, D. Conti, K. Lake, A. Langnas, M. Kinkhabwala, C. Johnson, M. Johnson, M. Hart, J. Dunn, W. Fitzsimmons, D. Tolzman, G. Harrison, and P. Vanveldhuisen
T
he purpose of this study was to compare the safety and efficacy of the combination therapy tacrolimus (TAC) plus sirolimus (SRL) versus TAC plus mycophenolate mofetil (MMF). Before transplant, adult recipients of a primary kidney from either a living non–human leukocyte antigen identical or cadaveric donor were randomized 1:1 to receive TAC plus steroids with either SRL (n ⫽ 185) or MMF (n ⫽ 176). The primary end point was biopsy-proven acute rejection (BPAR). Patient and graft survival, renal function, infections, drug
From the National Institute of Transplantation, Los Angeles, CA; Mayo Clinic Transplant Center, Jacksonville, FL; Baylor College of Medicine, Dallas, TX; Harrisburg Hospital, Harrisburg, PA; Indiana University, Indianapolis, IN; Sharp Memorial Hospital, San Diego, CA; Tampa General Hospital/LifeLink, Tampa, FL; Rush Presbyterian-St Luke’s Medical Center, Chicago, IL; University of Maryland, Baltimore, MD; Johns Hopkins University, Baltimore, MD; Columbia Presbyterian, New York, NY; Via Christi, Wichita, KS; Medical University of South Carolina, Charleston, SC; University of Arkansas, Little Rock, AK; Loma Linda University, Loma Linda, CA; University of California, Los Angeles, Los Angeles, CA; University of California, San Francisco, San Francisco, CA; Stanford University, Stanford, CA; Carolinas Medical Center, Charlotte, NC; Yale University, New Haven, CT; California Pacific Medical Center, San Francisco, CA; Albany Medical Center, Albany, NY; University of Michigan, Ann Arbor, MI; University of Nebraska, Omaha, NE; New York Hospital, Cornell, New York, NY; Medical College of Wisconsin, Milwaukee, WI; University of North Carolina, Chapel Hill, NC; University of California, San Diego, San Diego, CA; Fujisawa Healthcare, Inc., Deerfield, IL; and the EMMES Corporation, Rockville, MD. Supported by Fujisawa Healthcare, Inc. © 2003 Elsevier Inc. All rights reserved. 0955-470X/03/1704-0000$30.00/0 doi:10.1016/j.trre.2003.10.031
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levels, and adverse events were also evaluated. Target trough levels were 5 to 15 ng/mL for TAC and 4 to 12 ng/mL for SRL. Included here are the 1-year results of this study conducted at 27 US centers (Table 1).There were no significant differences between the groups regarding percent panel reactive antibody, cold ischemia time, gender, race, or donor demographics. Patients in the MMF treatment arm were older (mean age, 47.8 vs 45.3 years; P ⫽ .05). There was a trend toward more zero antigen mismatches in the SRL treatment group (10.3% vs 5.1%, P ⫽ .07). MMF-treated patients had more delayed graft function (31.3% vs 22.7%, P ⫽ .07), and of these, 22 SRL (12%) and 37 MMF (21%) patients had dialysis in the first week (P ⫽ .02). More patients discontinued SRL primarily because of hyperlipidemia (26.5% vs 14.8%, P ⫽ .006). More MMF patients required dose changes (53.4% vs 25.9%, P ⫽ .001) compared with those in the SRL treatment group, primarily because of diarrhea and leukopenia. The most common reasons for dose changes for the SRL treatment group were hyperlipidemia and wound healing. More SRLtreated patients had total cholesterol values ⬎200 mg/dL (56.5% vs 37.4%, P ⫽ .0001), and the SRL treatment group also had more patients who required treatment with lipid-lowering agents (60.8% vs 37.0%, P ⫽ .0001) at 6 months. Patients in the SRL group also had more first rehospitalizations for cardiovascular events (4.9% vs 0.6%, P ⫽ .02) compared with patients in the MMF treatment group. The incidence of new-onset insulin-dependent diabetes mellitus at 6 months was similar in both groups
Transplantation Reviews, Vol 17, No 4 (October), 2003: pp S66-S67
Comparison of TAC Plus SRL Versus TAC Plus MMF
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Table 1. 1-Year Results
% Biopsy-proven acute rejection* % Graft survival Without delayed graft function Living donors % Patient survival Median TAC level (ng/mL)* Median SRL-MMF dose (mg) Median serum creatinine (mg/dL) % Serum creatinine ⬎1.5 mg/dL % Serum creatinine ⬎2.0 mg/dL % New-onset insulin-dependent diabetes mellitus* Mean total cholesterol (mg/dL)* Mean LDL cholesterol (mg/dL)* % Patients treated with lipid-lowering therapy* % SRL-MMF discontinuations
TAC-SRL (n ⫽ 185)
TAC-MMF (n ⫽ 176)
13 90.8 93.0 91.0 95.7 8.5 3.0 1.5 45.4 20.4 7.6 218 111 60 26.5
11.4 94.3 99.0 98.0 97.2 8.7 1500 1.3 35.7 11.0 7.7 192 98 37 14.8
P Value 0.21 0.014 0.067
0.03 0.08 0.02 0.05 0.05 0.05 0.006
*6 months.
(7.6% SRL vs 7.7% MMF). TAC levels for patients with biopsy-proven acute rejection were lower during the first 2 weeks after transplantation in both groups. The probability of 1-year graft survival was similar between the groups (91% SRL vs 94% MMF, P ⫽ 0.22); however, in those patients without delayed graft function, the probability of graft survival was statistically significantly better for those receiving the combination of TAC plus MMF (99% vs 93%, P ⫽ .01). One-year graft survival for patients who received an organ from a living donor had a trend toward a better outcome for those in the TAC plus MMF group (98% vs 91%, P ⫽ .07). Patients who received the combination of TAC plus MMF had better renal function at 6 months (median, 1.5 for
SRL vs 1.4 for MMF; P ⫽ .019) and at 1 year (1.5 for SRL vs 1.3 for MMF, P ⫽ .03). Conclusion: These data show that patient and graft survival were excellent and equivalent, that biopsy-proven acute rejection was similar between the 2 treatment groups, and that TAC is safe and effective when combined with either SRL or MMF. The TAC-MMF combination may optimize renal function, minimize cardiovascular risk factors, and benefit patients without delayed graft function and with living donor kidney transplants.
Acknowledgment Disclosure: This multicenter study was sponsored by Fujisawa Healthcare, Inc.
T
he purpose of this study was to compare the safety and efficacy of the combination therapy tacrolimus (TAC) plus sirolimus (SRL) versus TAC plus mycophenolate mofetil (MMF). Before transplant, adult recipients of a primary kidney from either a living non–human leukocyte antigen identical or cadaveric donor were randomized 1:1 to receive TAC plus steroids with either SRL (n ⫽ 185) or MMF (n ⫽ 176). The primary end point was biopsy-proven acute rejection (BPAR). Patient and graft survival, renal function, infections, drug
From the National Institute of Transplantation, Los Angeles, CA; Mayo Clinic Transplant Center, Jacksonville, FL; Baylor College of Medicine, Dallas, TX; Harrisburg Hospital, Harrisburg, PA; Indiana University, Indianapolis, IN; Sharp Memorial Hospital, San Diego, CA; Tampa General Hospital/LifeLink, Tampa, FL; Rush Presbyterian-St Luke’s Medical Center, Chicago, IL; University of Maryland, Baltimore, MD; Johns Hopkins University, Baltimore, MD; Columbia Presbyterian, New York, NY; Via Christi, Wichita, KS; Medical University of South Carolina, Charleston, SC; University of Arkansas, Little Rock, AK; Loma Linda University, Loma Linda, CA; University of California, Los Angeles, Los Angeles, CA; University of California, San Francisco, San Francisco, CA; Stanford University, Stanford, CA; Carolinas Medical Center, Charlotte, NC; Yale University, New Haven, CT; California Pacific Medical Center, San Francisco, CA; Albany Medical Center, Albany, NY; University of Michigan, Ann Arbor, MI; University of Nebraska, Omaha, NE; New York Hospital, Cornell, New York, NY; Medical College of Wisconsin, Milwaukee, WI; University of North Carolina, Chapel Hill, NC; University of California, San Diego, San Diego, CA; Fujisawa Healthcare, Inc., Deerfield, IL; and the EMMES Corporation, Rockville, MD. Supported by Fujisawa Healthcare, Inc. © 2003 Elsevier Inc. All rights reserved. 0955-470X/03/1704-0000$30.00/0 doi:10.1016/j.trre.2003.10.031
S66
levels, and adverse events were also evaluated. Target trough levels were 5 to 15 ng/mL for TAC and 4 to 12 ng/mL for SRL. Included here are the 1-year results of this study conducted at 27 US centers (Table 1).There were no significant differences between the groups regarding percent panel reactive antibody, cold ischemia time, gender, race, or donor demographics. Patients in the MMF treatment arm were older (mean age, 47.8 vs 45.3 years; P ⫽ .05). There was a trend toward more zero antigen mismatches in the SRL treatment group (10.3% vs 5.1%, P ⫽ .07). MMF-treated patients had more delayed graft function (31.3% vs 22.7%, P ⫽ .07), and of these, 22 SRL (12%) and 37 MMF (21%) patients had dialysis in the first week (P ⫽ .02). More patients discontinued SRL primarily because of hyperlipidemia (26.5% vs 14.8%, P ⫽ .006). More MMF patients required dose changes (53.4% vs 25.9%, P ⫽ .001) compared with those in the SRL treatment group, primarily because of diarrhea and leukopenia. The most common reasons for dose changes for the SRL treatment group were hyperlipidemia and wound healing. More SRLtreated patients had total cholesterol values ⬎200 mg/dL (56.5% vs 37.4%, P ⫽ .0001), and the SRL treatment group also had more patients who required treatment with lipid-lowering agents (60.8% vs 37.0%, P ⫽ .0001) at 6 months. Patients in the SRL group also had more first rehospitalizations for cardiovascular events (4.9% vs 0.6%, P ⫽ .02) compared with patients in the MMF treatment group. The incidence of new-onset insulin-dependent diabetes mellitus at 6 months was similar in both groups
Transplantation Reviews, Vol 17, No 4 (October), 2003: pp S66-S67
Comparison of TAC Plus SRL Versus TAC Plus MMF
S67
Table 1. 1-Year Results
% Biopsy-proven acute rejection* % Graft survival Without delayed graft function Living donors % Patient survival Median TAC level (ng/mL)* Median SRL-MMF dose (mg) Median serum creatinine (mg/dL) % Serum creatinine ⬎1.5 mg/dL % Serum creatinine ⬎2.0 mg/dL % New-onset insulin-dependent diabetes mellitus* Mean total cholesterol (mg/dL)* Mean LDL cholesterol (mg/dL)* % Patients treated with lipid-lowering therapy* % SRL-MMF discontinuations
TAC-SRL (n ⫽ 185)
TAC-MMF (n ⫽ 176)
13 90.8 93.0 91.0 95.7 8.5 3.0 1.5 45.4 20.4 7.6 218 111 60 26.5
11.4 94.3 99.0 98.0 97.2 8.7 1500 1.3 35.7 11.0 7.7 192 98 37 14.8
P Value 0.21 0.014 0.067
0.03 0.08 0.02 0.05 0.05 0.05 0.006
*6 months.
(7.6% SRL vs 7.7% MMF). TAC levels for patients with biopsy-proven acute rejection were lower during the first 2 weeks after transplantation in both groups. The probability of 1-year graft survival was similar between the groups (91% SRL vs 94% MMF, P ⫽ 0.22); however, in those patients without delayed graft function, the probability of graft survival was statistically significantly better for those receiving the combination of TAC plus MMF (99% vs 93%, P ⫽ .01). One-year graft survival for patients who received an organ from a living donor had a trend toward a better outcome for those in the TAC plus MMF group (98% vs 91%, P ⫽ .07). Patients who received the combination of TAC plus MMF had better renal function at 6 months (median, 1.5 for
SRL vs 1.4 for MMF; P ⫽ .019) and at 1 year (1.5 for SRL vs 1.3 for MMF, P ⫽ .03). Conclusion: These data show that patient and graft survival were excellent and equivalent, that biopsy-proven acute rejection was similar between the 2 treatment groups, and that TAC is safe and effective when combined with either SRL or MMF. The TAC-MMF combination may optimize renal function, minimize cardiovascular risk factors, and benefit patients without delayed graft function and with living donor kidney transplants.
Acknowledgment Disclosure: This multicenter study was sponsored by Fujisawa Healthcare, Inc.