Peter Bernhardt

Everolimus with Optimized Cyclosporine Dosing in Renal Transplant Recipients: 6-Month Safety and Efficacy Results of Two Randomized Studies

Two prospective, randomized studies evaluated everolimus 1.5 vs. 3 mg/day with steroids and low‐exposure cyclosporine (CsA) (C2 monitoring) in de novo renal transplant patients. Everolimus dosing was adjusted to maintain a minimum trough level of 3 ng/mL. Study 1 (A2306; n = 237) had no induction therapy; in Study 2 (A2307; n = 256) basiliximab was administered (Days 0 and 4). The primary endpoint was renal function at 6 months. CsA C2 target levels, initially 1200 ng/mL in Study 1 and 600 ng/mL in Study 2, were tapered over time post‐transplant. Median creatinine levels in Study 1 were 133 and 132 μmol/L at 6 months in the 1.5 and 3 mg/day groups, respectively, and 130 μmol/L in both groups in Study 2. Biopsy‐proven acute rejection (BPAR) occurred in 25.0% and 15.2% of patients in the 1.5 and 3 mg/day groups in Study 1, and 13.7% and 15.1% in Study 2. Incidence of BPAR was significantly higher in patients with an everolimus trough < 3 ng/mL. There were no significant between‐group differences in the composite endpoint of BPAR, graft loss or death, nor any significant between‐group differences in adverse events in either study. Concentration‐controlled everolimus with low‐exposure CsA provided effective protection against rejection with good renal function.

TrAnsFOrM: a novel study design to evaluate the effect of everolimus on long-term outcomes after kidney transplantation

Two well defined, modifiable risk factors for kidney allograft failure are acute rejection and poor graft function at one year post-transplant. Regulatory bodies and expert panels in the USA and Europe have recognized that both acute rejection and one-year graft function should be assessed when evaluating immunosuppressive regimens. TRANSFORM (Clinicaltrials.gov NCT01950819) is one of the first trials to adopt this approach and the first that applies a novel combined clinically meaningful endpoint to take the first step towards changing the paradigm for immunosuppression in kidney transplant patients. Everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy is a strategy designed to reduce the risk of chronic nephrotoxicity and other dose-dependent complications associated with CNI therapy. In TRANSFORM, de novo kidney transplant patients are randomized to everolimus with reduced-exposure CNI, or mycophenolic acid with standard-exposure CNI, both with induction therapy and maintenance steroids. The primary endpoint is a composite of treated biopsy-proven acute rejection or estimated glomerular filtration rate ,50 mL/min/1.73 m 2 at month 12 post-transplant, which is expected to be sensitive both to the effects of acute and chronic allograft rejection and nephrotoxic side effects of immunosuppressive therapies. The construct of this endpoint allows the integration of a continuous outcome (graft function) with a logistic outcome (rejection). The trial uses a randomized, multicenter, open-label, two-arm design. After completion of a 2-year core study, patients enter a further 3-year prospective observational study. By capturing follow-up to 5 years, TRANSFORM will provide substantial data on the incidence of graft loss, graft dysfunction, cancer, cardiovascular events, and other patient-relevant outcomes. TRANSFORM will determine whether de novo CNI reduction with an everolimus-based regimen achieves short-term outcomes compared with standard CNI. As the largest clinical trial undertaken to date in kidney transplantation, recruiting more than 2,000 patients, and with extended follow-up to 5 years, TRANSFORM will provide critical data required to help maximize long-term outcomes.

Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation

Background Everolimus permits reduced calcineurin inhibitor (CNI) exposure, but the efficacy and safety outcomes of this treatment after kidney transplant require confirmation.Methods In a multicenter noninferiority trial, we 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 using a 10% noninferiority margin.Results In the intent-to-treat population (everolimus n=1022, MPA n=1015), the primary end point incidence was 48.2% (493) with everolimus and 45.1% (457) with MPA (difference 3.2%; 95% confidence interval, -1.3% to 7.6%). Similar between-treatment differences in incidence were observed in the subgroups of patients who received tacrolimus or cyclosporine. Treated biopsy-proven acute rejection, graft loss, or death at post-transplant month 12 occurred in 14.9% and 12.5% of patients treated with everolimus and MPA, respectively (difference 2.3%; 95% confidence interval, -1.7% to 6.4%). De novo donor-specific antibody incidence at 12 months and antibody-mediated rejection rate did not differ between arms. Cytomegalovirus (3.6% versus 13.3%) and BK virus infections (4.3% versus 8.0%) were less frequent in the everolimus arm than in the MPA arm. Overall, 23.0% and 11.9% of patients treated with everolimus and MPA, respectively, discontinued the study drug because of adverse events.Conclusions In kidney transplant recipients at mild-to-moderate immunologic risk, everolimus was noninferior to MPA for a binary composite end point assessing immunosuppressive efficacy and preservation of graft function.

Cardiovascular Parameters to 2 years After Kidney Transplantation Following Early Switch to Everolimus Without Calcineurin Inhibitor Therapy: An Analysis of the Randomized Elevate Study

Background Mammalian target of rapamycin inhibitors may confer cardioprotective advantages, but clinical data are limited. Methods In the open-label ELEVATE trial, kidney transplant patients were randomized at 10 to 14 weeks after transplant to convert from calcineurin inhibitor (CNI) to everolimus or remain on standard CNI therapy. Prespecified end points included left ventricular mass index and, in a subpopulation of patients, arterial stiffness as measured by pulse wave velocity. Results The mean change in left ventricular mass index from randomization was similar with everolimus versus CNI (month 24, −4.37 g/m2.7 versus −5.26 g/m2.7; mean difference, 0.89 [p = 0.392]). At month 24, left ventricular hypertrophy was present in 41.7% versus 37.7% of everolimus and CNI patients, respectively. Mean pulse wave velocity remained stable with both everolimus (mean change from randomization to month 12, −0.24 m/s; month 24, −0.03 m/s) and CNI (month 12, 0.11 m/s; month 24, 0.16 m/s). The change in mean ambulatory nighttime blood pressure from randomization showed a benefit for diastolic pressure at month 12 (P = 0.039) but not at month 24. Major adverse cardiac events occurred in 1.1% and 4.2% of everolimus-treated and CNI-treated patients, respectively, by month 12 (P = 0.018) and 2.3% (8/353) and 4.5% by month 24 (P = 0.145). Conclusions Overall, these data do not suggest a clinically relevant effect on cardiac end points after early conversion from CNI to a CNI-free everolimus-based regimen.

Sustained Virological Response to Antiviral Therapy in a Randomized Trial of Cyclosporine versus Tacrolimus in Liver Transplant Patients with Recurrent Hepatitis C Infection

BACKGROUND Choice of calcineurin inhibitor may influence response to antiviral therapy in liver transplant patients with hepatitis C virus (HCV) infection. MATERIAL AND METHODS In a randomized, multicenter, 80-week trial, liver transplant recipients (>6 months and £10 years post-transplant) with recurrent HCV infection received cyclosporine (n=50) or tacrolimus (n=42) with a 48-week course of pegylated interferon (peg-IFNα2a) and ribavirin. Twenty-three patients in each group completed the trial on study medication. The primary endpoint was sustained virological response (SVR) 24 weeks after the end of antiviral therapy, for which 43 patients were eligible for analysis. RESULTS The rate of SVR was 60.0% (12/20) with cyclosporine and 43.5% (10/23) with tacrolimus (adjusted odds ratio 1.85; 95% CI 0.53-6.43; p=0.331). There were no significant intergroup differences for rapid or early virological response, relapse, HCV RNA viral load, or fibrosis progression. One cyclosporine-treated patient experienced acute rejection. One patient died in each group. Adverse events, treatment-related adverse events, and serious adverse events were similar between groups. CONCLUSIONS Since fewer patients were recruited than planned (92 versus 355), the study was underpowered and robust conclusions cannot be drawn regarding the effect of cyclosporine and tacrolimus on virological responses to antiviral treatment for recurrent HCV after liver transplantation. However, as reported in other trials, SVR was higher in cyclosporine-treated patients.

Efficacy and Safety of Everolimus with Reduced-Dose Calcineurin Inhibitor in De Novo Kidney Transplant Recipients: Results from the TRANSFORM Study

TRANSFORM Study Group. Introduction Strategies that facilitate calcineurin inhibitor (CNI) reduction while retaining immunosuppressive efficacy and improving long-term outcomes are highly desired in kidney transplant recipients (KTxRs). TRANSFORM (NCT01950819) is the largest prospective study in de novo KTxRs till date to compare the efficacy and safety of everolimus (EVR)+reduced-dose CNI (rCNI: tacrolimus [TAC] or cyclosporine [CsA]) regimen to that of mycophenolic acid (MPA)+standard-dose CNI (sCNI) using a composite endpoint of anti-rejection efficacy and renal function. Here, we present the 12-month (M) efficacy and safety data from TRANSFORM. Methods TRANSFORM is a 24M, multicentre, open-label, non-inferiority study in which 2037 KTxRs were randomised to receive either EVR (dose: 1.5 and 3 mg/day with CsA and TAC, respectively; trough level [C0]: 3-8 ng/mL)+rCNI (N=1022; TAC C0: 4-7, 2-5, and 2-4 ng/mL and CsA C0: 100-150, 50-100, and 25-50 ng/mL from Day1-M2, M3-M6, and M7-M24, respectively) or MPA (dose: 1.44 and 2 g/day for enteric-coated mycophenolate sodium and mycophenolate mofetil, respectively)+sCNI (N=1015; TAC C0: 8-12, 6-10, and 5-8 ng/mL and CsA C0: 200-300, 150-200, and 100-200 ng/mL from Day1-M2, M3-M6, and M7-M24, respectively). All patients received basiliximab or anti-thymocyte globulin induction with steroids. The primary objective was incidence of binary composite of treated biopsy-proven acute rejection (tBPAR) or estimated glomerular filtration rate (eGFR) <50 mL/min/1.73m2; key secondary objective was incidence of tBPAR, graft loss, or death at M12. Incidences of donor-specific antibodies (DSA), adverse events (AEs) and infections were also evaluated. Results Overall, 76.9% KTxRs (EVR+rCNI: 72.7%; MPA+sCNI: 81.2%) completed the study medication up to M12. Mean EVR C0 was within target range throughout the study, whereas mean TAC C0 was above the upper limit of the target range in the EVR+rCNI arm and within range in the MPA+sCNI arm. EVR+rCNI was non-inferior (10% margin) to MPA+sCNI (48.2% vs 45.1%, P=0.001) for the primary endpoint (Table). Overall incidence of tBPAR was low, with most episodes of grade IA. Graft loss was comparable between arms, whereas deaths were numerically lower in EVR+rCNI (1.6%) vs MPA+sCNI arm (2.8%; Table). Mean eGFR over M12 was comparable between arms. Incidence of de novo DSA was comparable between arms (EVR+rCNI: 10.2%; MPA+sCNI: 13.6%). Overall AEs were comparable between arms; incidence of AEs leading to study drug discontinuation was higher with EVR+rCNI vs MPA+sCNI, but more dose reduction in MPA+sCNI arm. BK virus and cytomegalovirus (CMV) infections were less frequent in EVR+rCNI vs MPA+sCNI arm. Conclusion M12 results from the TRANSFORM study confirm that an EVR+rCNI-based regimen provides comparable efficacy, safety, and renal function vs an MPA+sCNI-based regimen in KTxRs along with benefit against viral infections. M24 follow-up data on long-term efficacy, safety, and renal function are awaited. Figure. No caption available.

Renal Function Outcomes in De Novo Kidney Transplant Recipients Receiving Everolimus with Reduced-Exposure Calcineurin Inhibitor versus Mycophenolate with Standard-Exposure Calcineurin Inhibitor: Results from the TRANSFORM Study

Introduction Existing evidence suggests that de novo initiation of everolimus (EVR) with reduced-exposure calcineurin inhibitor (rCNI) preserves renal function while maintaining efficacy and safety in kidney transplant recipients (KTxRs). TRANSFORM (NCT01950819) is the largest study conducted in de novo KTxRs to evaluate the benefit of EVR+rCNI compared to mycophenolate (MPA) with sCNI. Here, we present renal function outcomes. Method This is a 24-month (M), phase IV, multicentre, open-label study in de novo adult KTxRs randomised within 24 h of Tx to either EVR+rCNI (N=1022; EVR trough level [C0]: 3-8 ng/mL; tacrolimus [TAC] C0: 4-7, 2-5, and 2-4 ng/mL or cyclosporine [CsA] C0: 100-150, 50-100, and 25-50 ng/mL from Day 1(D1)-M2, M3-M6, and M7-M24, respectively) or MPA+sCNI (N=1015; MPA [1.44 g/day of EC-MPS or 2.0 g/day of MMF]; TAC C0:8-12, 6-10, and 5-8 ng/mL or CsA C0: 200-300, 150-200, and 100-200 ng/mL from D1-M2, M3-M6, and M7-M24, respectively). All patients received basiliximab or rabbit antithymocyte globulin induction and steroids. Renal function assessments included evaluation of eGFR in overall population, Asian sub-population and by CNI type at M12. Results A total of 925 (90.5%) patients in EVR+rCNI arm and 922 (90.8%) in MPA+sCNI arm completed 12M study. Demographics and baseline characteristics were balanced between arms. At M12, mean EVR C0 in EVR+rCNI arm was 5.5 ng/mL with 86.3% of patients within target C0 range. At M12, 40.0% and 47.6% of patients were above the target C0 of TAC and CsA in EVR+rCNI arm, respectively, whereas 62.1% of patients had TAC C0 and 71.6% had CsA C0 within target range in MPA+sCNI arm. At M12, mean eGFR was similar between the EVR+rCNI (53.0 mL/min/1.73 m2) and MPA+sCNI (54.4 mL/min/1.73 m2) arms (Figure 1). Notably, in Asian sub-population, M12 mean eGFR was significantly higher in EVR+rCNI (n = 120) vs MPA+sCNI (n = 142) arm (67.4 vs 60.0 mL/min/1.73 m2; difference: 7.4 mL/min/1.73 m2; P=0.003; Table 1). Frequency of patients with eGFR <50 mL/min/1.73 m2 was similar in EVR+rCNI (45.4%) and MPA+sCNI arms (42.2%; difference: 3.2% [−1.3-7.6]). At M12, mean urinary protein/creatinine ratio was comparable between EVR+rCNI (298.56 mg/g) and MPA+sCNI (233.80 mg/g) arms. Most patients in EVR+rCNI (85.9%) and MPA+sCNI arms (92.0%) had mild proteinuria (30-<500 mg/g). Conclusion Despite CNI C0 being above the target range in most patients in EVR+rCNI arm, renal function was comparable in both treatment arms in the overall population at M12. Long-term effects of the EVR+rCNI regimen on renal function in this population will be further confirmed from the 24M results. Table. No title available.