LANDMARK TRIALS IN
Maintenance Immunosuppression in Kidney Transplantation
MMF vs CNI
Legend:
RCT with >= 2000 patients
RCT with 1000-1999 patients
RCT with 500-999 patients
RCT with < 500 patients
Pathophysiology
Disease Outcomes and Trajectory
Biomarkers
Date: 1995
Abbreviation: MMF for Prevention of Acute Rejection
A multicenter, randomized, double-blind, study designed to evaluate the efficacy and safety of MMF for the prevention of acute rejection episodes in cadaveric renal transplant adult recipients during the first 6 months. A total of 499 patients were randomized into three arms (MMF 2g treatment group, MMF 3g treatment group, or Azathioprine (1-2mg/kg/day). The primary efficacy endpoint was biopsy-proven rejection or treatment failure (defined as graft loss, death, or premature withdrawal from the study for any reason). Biopsy-proven acute rejection episodes or treatment failure occurred in 47.6% of patients in the azathioprine group compared with 31.1% (P = 0.0015) and 31.3% (P = 0.0021) of patients in the MMF 2 g and 3 g treatment groups, respectively. At 6 months after transplant, graft and patient survival were similar in all 3 treatment groups
Year: 1996
Abbreviation: The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group for prevention of acute rejection in cadaveric renal transplant
A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group
A prospective, double-blind, multi-center trial designed to compare the efficacy and safety of MMF and azathioprine within a standard immunosuppressive regimen for patients receiving a first or second cadaveric renal graft. A total of 503 patients were randomized to groups receiving MMF 3g, MMF 2g, or azathioprine (AZA) 100-150 mg daily. All were treated simultaneously with equivalent doses of cyclosporine and oral corticosteroids and followed for 12 months. The primary endpoint was treatment failure, defined as the occurrence of biopsy-proven graft rejection, graft loss, patient death, or discontinuation of the study drug during the first 6 months after transplantation. Treatment failure occurred in 50% of patients in the AZA group by 6 months after transplantation, compared with 34.8% in the MMF 3g group (P=0.0045) and 38.2 % in the MMF 2g group (P=0.0287). Gastrointestinal toxicity and tissue-invasive cytomegalovirus infection were more common in the MMF 3 g group.
Year: 2007
Abbreviation: Ekberg et al, The ELITE-SYMPHONY trial (CNI minimization)
Reduced Exposure to Calcineurin Inhibitors in Renal Transplantation
A 12-month, prospective, randomized, open-label, multicenter study in four parallel groups of adult renal-transplant recipients (n=1645) to receive standard-dose cyclosporine, mycophenolate mofetil, and corticosteroids, or daclizumab induction, mycophenolate mofetil, and corticosteroids in combination with low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus. The primary endpoint was the estimated glomerular filtration rate (GFR), as calculated by the Cockcroft–Gault formula, 12 months after transplantation. Secondary end points included acute rejection and allograft survival. The mean calculated GFR was higher in patients receiving low-dose tacrolimus (65.4 ml per minute) than in the other three groups (range, 56.7 to 59.4 ml per minute). The rate of biopsy-proven acute rejection was lower in patients receiving low-dose tacrolimus (12.3%) than in those receiving standard-dose cyclosporine (25.8%), low-dose cyclosporine (24.0%), or low-dose sirolimus (37.2%).
Year : 2007
Abbreviation: H Ekberg et al, the CAESAR study (CNI withdrawal regimen)
Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR Study
A Prospective multicenter open-label, RCT of 536 Patients (n = 536) receiving their first renal allograft were randomized to one of three immunosuppressive regimens: daclizumab, mycophenolate mofetil (MMF), corticosteroids (CS) and low-dose CsA (target trough levels of 50-100 ng/mL), weaned from month 4 and withdrawn by month 6; daclizumab, MMF, CS and low-dose CsA; or MMF, CS and standard-dose CsA. Mean GFR 12 months after transplantation (primary end point) was not statistically different in the CsA withdrawal and low-dose CsA groups (both 50.9 mL/min/1.73 m(2)) vs. the standard-dose CsA group (48.6 mL/min/1.73 m(2)). At 12 months, the incidence of biopsy-proven acute rejection was significantly higher in the CsA withdrawal group (38%) vs. the low- or standard-dose CsA groups (25.4% and 27.5%, respectively; p < 0.05).
Year: 2009
Abbreviation: Gaston RS et al, OPTICEPT trial (CNI Minimisation)
Fixed- or controlled-dose mycophenolate mofetil with standard- or reduced-dose calcineurin inhibitors: The OPTICEPT trial
A 2-year, open-label, randomized, multicenter trial designed to compare the efficacy and safety of concentration-controlled MMF (MMF(CC)) dosing with a fixed-dose regimen in 720 kidney recipients. Patients received either (A) MMF(CC) and reduced-level calcineurin inhibitor (MMF(CC)/CNI(RL)); (B) MMF(CC) and standard-level CNI (MMF(CC)/CNI(SL)); or (C) fixed-dose MMF and CNI(SL) (MMF(FD)/CNI(SL)). The primary endpoint was noninferiority (alpha= 0.05) of group A versus group C for treatment failure (including biopsy-proven acute rejection [BPAR], graft loss, and death) at 1 year. MMF(CC) with low-dose CNI resulted in outcomes not inferior to those with standard CNI exposure and MMF(FD), indicating the potential utility of MMF(CC) in CNI-sparing regimens.
Year: 2009
Abbreviation: Schena et al, the CONVERT trial (CNI conversion)
Conversion From Calcineurin Inhibitors to Sirolimus Maintenance Therapy in Renal Allograft Recipients: 24-Month Efficacy and Safety Results From the CONVERT Trial
The efficacy and safety of converting maintenance renal transplant recipients from calcineurin inhibitors (CNIs) to sirolimus (SRL) were evaluated. This is a prospective, open-label, comparative study in which 830 renal allograft recipients, 6 to 120 months post-transplant and receiving cyclosporine or tacrolimus, were randomly assigned to continue CNI (n=275) or convert from CNI to SRL (n=555). Primary endpoints were calculated Nankivell glomerular filtration rate (GFR; stratified at baseline: 20–40 vs. >40 mL/min) and the cumulative rates of biopsy-confirmed acute rejection (BCAR), graft loss, or death at 12 months. At 2 years, SRL conversion among patients with baseline GFR more than 40 mL/min was associated with excellent patient and graft survival, no difference in BCAR, increased urinary protein excretion, and a lower incidence of malignancy compared with CNI continuation.
Year: 2011
Abbreviation: Weir MR et al, SPARE THE NEPHRON TRIAL (CNI Avoidance)
Mycophenolate mofetil-based immunosuppression with sirolimus in renal transplantation: a randomized, controlled Spare-the-Nephron trial
An open-label, multicenter trial. randomized 299 patients, 151 were maintained on MMF and a CNI, 148 on MMF plus SRL (n=120, tacrolimus; n=31, cyclosporine) for evaluating the preservation of renal function in renal allograft recipients. The primary endpoint was measured GFR. After 1 year, the mean percentage change from baseline in the primary end point of measured GFR was significantly higher in the MMF/SRL group compared with the MMF/CNI group. After 2 years, the change was indistinguishable. Thus a 2-year regimen of MMF/SRL resulted in similar measures of renal function but with fewer deaths and a trend to less BPAR and graft loss.
Year: 2011
Abbreviation: ZEUS Study investigators (CNI conversion)
Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomized, controlled trial
A multicentre, open-label study of 503 patients who had received de-novo kidney transplants were enrolled. Patients were randomly assigned at 4·5 months in a 1:1 ratio to undergo calcineurin-inhibitor elimination (everolimus-based regimen that was based on trough concentrations [6-10 ng/mL] and enteric-coated mycophenolate sodium [1440 mg/day] with corticosteroids) or continue standard cyclosporine-based treatment. At 12 months, the everolimus regimen was associated with a significant improvement in GFR versus the ciclosporin regimen. Rates of biopsy-proven acute rejection were higher in the everolimus group than in the cyclosporin group after randomization (15 [10%] of 154 vs five [3%] of 146; p = 0·036), but similar for the full study period (23 [15%] vs 22 [15%]). Early elimination of calcineurin inhibitor by use of everolimus-based immunosuppression improved renal function at 12 months while maintaining efficacy and safety, indicating that this strategy may facilitate improved long-term outcomes in selected patients.
Year: 2011
Abbreviation: S M Flechner et al, the ORION study (CNI avoidance)
The ORION study: Comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients
This was an open-label, randomized, comparative, multinational trial comparing 2 SRL-based regimens with TAC and MMF. 443 renal transplant recipients were randomized into Group 1 (SRL+TAC; week 13 TAC elimination [n = 152]), Group 2 (SRL + MMF [n = 152]) or Group 3 (TAC + MMF [n = 139]) to compare the Safety and efficacy.The primary outcome was GFR at 12 months after transplantation. Group 2 was terminated early due to increased biopsy-proven acute rejection. No significant differences in patient survival, Nankivell GFR, or DGF were found between groups. Although not statistically significant, rates of graft loss (including death with a functioning graft) were numerically higher in both SRL groups.
Year: 2014
Abbreviation: Chadban et al, the SOCRATES trial (CNI withdrawal)
A randomized, controlled trial of everolimus-based dual immunosuppression versus standard of care in de novo kidney transplant recipients
This was a 36-month, prospective, multinational, open-label, non-inferiority randomized controlled trial where 126 kidney transplant recipients were randomized to three arms at 2 weeks post kidney transplantation in a 1:1:1 ratio : cyclosporine withdrawal with everolimus(CNI-WD), steroid withdrawal with everolimus(steroid WD) and continuation of cyclosporine, mycophenolate and steroids. The primary endpoint was Nankivell GFR at 12 months. Secondary end points were incidence of biopsy-proven acute rejection (BPAR), graft survival, death and loss to follow-up and a composite of these.The steroid WD arm was terminated prematurely because of excess discontinuations. Mean eGFR at month 12 for CNI-WD versus control was 65.1 ml/min/1.73 m2 vs. 67.1 ml/min/1.73 m2 by ITT, which met predefined noninferiority criteria (P=0.026). The CNI-WD group experienced a higher rate of BPAR(31% vs. control 13%, P=0.048) and showed a trend towards higher composite treatment failure (BPAR, graft loss, death, loss to follow-up).
Year: 2017
Abbreviation: J W de Fijter et al, the ELEVATE Trial (CNI Conversion)
In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.
Year: 2018
Abbreviation: Julio Pascual et al, the TRANSFORM trial (CNI Minimisation)
Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation
A multicenter noninferiority trial, which randomized 2037 de novo kidney transplant recipients to receive, in combination with induction therapy and corticosteroids, everolimus with reduced-exposure CNI (everolimus arm) or mycophenolic acid (MPA) with standard-exposure CNI (MPA arm). The primary end point was treated biopsy-proven acute rejection or eGFR<50 ml/min per 1.73 m2 at post-transplant month 12. The everolimus group was non-inferior to the MPA group for the primary endpoint and the incidence was 48.2% (493 of 1022) with everolimus versus 45.1% (457 of 1015) with MPA. The de-novo DSA was lower in the Everolimus arm CMV, and BKV infections were lower in the Everolimus arm.
