H. Tedesco

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.

Everolimus versus Mycophenolate Mofetil in the Prevention of Rejection in De Novo Renal Transplant Recipients: A 3-year Randomized, Multicenter, Phase Iii Study

Background. This 36-month, randomized, parallel-group study compared safety and efficacy of two doses of everolimus with mycophenolate mofetil (MMF) in de novo renal-transplant recipients. Methods. Renal-allograft recipients received 1.5 mg/day or 3 mg/day of everolimus or 2 g/day of MMF, plus full-dose cyclosporine (CsA) and corticosteroids after randomization. For at least their first year, patients received study medication according to a double-blinded, double-dummy design. Concerns over nephrotoxicity led to a protocol amendment to an open-label design with reduced CsA troughs. Results. Incidences of primary efficacy failure at 36 months (biopsy-proven acute rejection, graft loss, death, or loss to follow-up) were everolimus 1.5 mg/day, 33.7% (65/193); everolimus 3 mg/day, 34.0% (66/194); and MMF, 31.1% (61/196) (P=0.810). Antibody-treated acute rejection at 36 months was significantly lower with everolimus 1.5 mg (9.8%) than MMF (18.4%, P=0.014). Discontinuation for adverse events was more frequent with everolimus and hemolytic uremic syndrome, lymphoproliferative disease, and proteinuria, and higher serum creatinine occurred at increased frequency relative to the MMF arm. Creatinine levels in the everolimus arms were stable in follow-up: the mean rise in creatinine over the first 6 months of the open-label phase was 3 &mgr;mol/L or greater with everolimus and 7 &mgr;mol/L with MMF. However, serum creatinine levels were lower in the MMF group throughout. Death and graft loss were higher in the everolimus arms (not significant). Conclusions. As part of triple-drug immunosuppression, everolimus (1.5 or 3 mg/day) was as efficacious as MMF, although the side-effect profile featured increased adverse events. Nephrotoxicity/calcineurin–inhibitor-related adverse events will require judicious lowering of CsA exposure with monitoring of everolimus troughs.

Everolimus therapeutic concentration range defined from a prospective trial with reduced-exposure cyclosporine in de novo kidney transplantation.

Prospective therapeutic drug monitoring of everolimus was performed in a 1-year multicenter trial in 237 de novo kidney transplant patients. Trough blood levels, rejection episodes, and safety parameters were evaluated to define an appropriate therapeutic concentration range for everolimus in this setting. Patients were randomized to everolimus starting doses of 0.75 mg bid (n = 112) or 1.5 mg bid (n = 125). Doses were then individualized based on everolimus trough blood levels (C0) in an attempt to maintain troughs ≥3 ng/mL; no upper limit was specified. The regimen also contained corticosteroids and cyclosporine with an early dose reduction in months 2–3 posttransplant based on concentrations 2 hours postdose (C2). Cyclosporine C0 levels were also collected. Prospective therapeutic drug monitoring of everolimus C0 in patients starting at 0.75 mg bid led to dose adjustments in 52% of patients to an average long-term dose of 0.93 ± 0.36 mg bid. This gave median (10th to 90th percentile) C0 levels of 5.3 (3.4–7.9) ng/mL. In patients starting at 1.5 mg bid, 55% had dose adjustments leading to an average long-term dose of 1.24 ± 0.35 mg bid. This yielded C0 levels of 7.2 (4.4–11.6) ng/mL. Cyclosporine dosing began on average at 274 ± 78 mg bid, was down-titrated in months 2–3 from 181 ± 80 mg to 81 ± 33 mg bid, and stabilized at 70 ± 26 mg bid thereafter. This yielded median C2 levels of 1165 ng/mL in month 1, a down-titration with levels of 853 and 630 ng/mL in months 2 and 3, and a posttitration level of 472 ng/mL. The corresponding median cyclosporine C0 was 242 ng/mL initially and 70 ng/mL in the posttitration phase. In patients starting at 0.75 mg bid everolimus and an early down-titration of cyclosporine, everolimus C0 between 3 and 8 ng/mL was an effective and safe concentration range. Concentrations up to 12 ng/mL were tolerated over the first year posttransplant. This trial demonstrated that therapeutic monitoring of everolimus can be prospectively performed for dose individualization. Maintaining everolimus troughs in the range 3 to 8 ng/mL in the first posttransplant year with reduced-exposure cyclosporine is associated with good efficacy and safety profiles.

Efficacy and safety of oral sirolimus to inhibit in-stent intimal hyperplasia.

Sirolimus systemic administration has shown marked inhibition of neointimal hyperplasia (NIH) after balloon angioplasty in porcine models. In this pilot study, we tested the hypothesis that oral sirolimus is safe and effective to inhibit in‐stent NIH and therefore to prevent and treat in‐stent restenosis (ISR). Twelve patients (18 lesions) with high risk for ISR, including 8 ISR lesions, were admitted. One day before the procedure, patients were given a 15 mg loading dose of oral sirolimus, followed by 5 mg daily for 28 days, with weekly whole blood level measurements. The daily dose was adjusted to keep the concentration at 10–15 ng/ml. Sirolimus was well tolerated by all patients but one, who died at the end of the third week of treatment. The 4‐ and 8‐month follow‐up revealed an angiographic late loss of 0.40 ± 0.24 and 0.67 ± 0.45 mm (P < 0.01), respectively. At the same time points, the intravascular ultrasound in in‐stent relative volumetric obstruction was 14.4% ± 9.1% and 23.2% ± 10.1% (P < 0.01), respectively. At 24‐month clinical follow‐up, adverse events were one (8.3%) death, two (11.1%) target lesion, and four (22.2%) target vessel revascularizations. In conclusion, in this small group of high‐risk ISR patients, oral sirolimus inhibited NIH and therefore may be an effective strategy for the prevention and treatment of ISR. Catheter Cardiovasc Interv 2005;64:413–418.

Effect of systemic immunosuppression on coronary in-stent intimal hyperplasia in renal transplant patients

Cyclosporin, combined with other agents, is an immunosuppressive agent approved for prophylaxis of renal transplant rejection. In experimental studies, cyclosporin has been shown to inhibit smooth muscle cell proliferation in the vascular response to injury. 1,2 Similar experimental results have been observed with systemic use of rapamycin. 3,4 The aim of this clinical investigation was to test the hypothesis that systemic immunosuppression therapy inhibits in-stent restenosis in renal transplant patients with coronary artery disease treated with stenting.

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.

Comparison of MMF efficacy and safety in paediatric vs. adult renal transplantation: Subgroup analysis of the randomised, multicentre FDCC trial

BACKGROUND Mycophenolate mofetil (MMF) is widely used for immunosuppressive therapy in renal transplantation, but comparative data regarding efficacy and safety in paediatric vs. adult kidney allograft recipients in one and the same study are lacking. METHODS We therefore performed this subgroup analysis of the FDCC trial, a 12-month, prospective, randomised study, comparing fixed-dose (FD) with concentration-controlled (CC) MMF dosing in paediatric and adult renal transplant recipients. Sixty-two paediatric and 839 adult de novo patients in 19 countries were randomised 1:1 to receive fixed-dose or concentration-controlled MMF therapy in combination with calcineurin inhibitors and corticosteroids. RESULTS Both patient and allograft survival proved to be excellent in paediatric patients (98.4% and 90.3%) and adults (96.8% and 95.0%). The rates of biopsy-proven acute rejections (BPAR) and treated acute rejection episodes (ARE) were comparable between paediatric (12.9% and 17.7%) and adult patients (15.5% and 20.7%). Transplant function at 12 months post-transplant was similar in paediatric (67.8 ± 45.6 mL/min/1.73 m2;) and adult recipients (64.7 ± 23.3 mL/min/1.73 m2;). Children < 6 years (n = 10) exhibited a numerically higher frequency of leucocytopaenia (20%), diarrhoea (40%) and weight loss (10%) than older children (6-18 years; 5.8%, 28.8% and 1.9%) and adults (16.1%, 24.7% and 1.5%). On the whole, the percentage of patients who experienced adverse events causing interruption of MMF therapy were numerically lower in children (4.8%) than in adults (12.5%). Conclusions. The overall efficacy and tolerability of MMF appear to be comparable between paediatric and adult patients. Further studies are needed to validate these results.

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.

Use of reduced dose of OKT3 (2.5 mg) after renal transplantation.

MONOCLONAL anti-CD3 antibodies have been widely used for the treatment of acute allograft rejection (AR) episodes and for induction therapy (IT). Their impact on long-term survival has been demonstrated mainly in high-risk patients. Recent data have suggested that this antibody may be used at reduced doses without compromising its efficacy. We report here our experience with 58 kidney transplant (Tx) patients in which low daily doses of OKT3 were used as IT or for the treatment of severe or steroid-resistant AR.

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.