This study compared the incidence of CMV infection/disease in de novo kidney transplant recipients receiving everolimus or mycophenolate and no CMV pharmacological prophylaxis. We randomized 288 ...patients to receive a single 3 mg/kg dose of antithymocyte globulin, tacrolimus, everolimus, and prednisone (r‐ATG/EVR, n = 85); basiliximab, tacrolimus, everolimus, and prednisone (BAS/EVR, n = 102); or basiliximab, tacrolimus, mycophenolate, and prednisone (BAS/MPS, n = 101). The primary end‐point was the incidence of first CMV infection/disease in the intention‐to‐treat population at 12 months. Patients treated with r‐ATG/EVR showed a 90% proportional reduction (4.7% vs. 37.6%, HR 0.10, 95% CI 0.037–0.29; p < 0.001), while those treated with BAS/EVR showed a 75% proportional reduction (10.8% vs. 37.6%, HR 0.25, 95% CI 0.13–0.48; p < 0.001) in the incidence of CMV infection/disease compared to BAS/MPS. There were no differences in the incidence of acute rejection (9.4 vs. 18.6 vs. 15.8%, p = 0.403), wound‐healing complications, delayed graft function, and proteinuria. Mean estimated glomerular filtration rate was lower in BAS/EVR (65.7 ± 21.8 vs. 60.6 ± 20.9 vs. 69.5 ± 21.5 ml/min, p = 0.021). In de novo kidney transplant recipients receiving no pharmacological CMV prophylaxis, reduced‐dose tacrolimus and everolimus was associated with a significant reduction in the incidence of CMV infection/disease compared to standard tacrolimus dose and mycophenolate (ClinicalTrials.gov NCT01354301).
This study shows that in de novo kidney transplant recipients receiving no CMV pharmacological prophylaxis, the use of everolimus and low‐dose tacrolimus is associated with lower incidence of CMV infection/disease compared to a standard tacrolimus and mycophenolate combination.
This multicenter, 1:1‐randomized, parallel‐group, noninferiority study compared the efficacy and safety of twice‐daily tacrolimus (Tacrolimus BID; Prograf) and once‐daily tacrolimus prolonged release ...(Tacrolimus QD; Advagraf), combined with steroids and low‐dose mycophenolate mofetil without antibody induction, in 667 de novo kidney transplant recipients. A double‐blind, double‐dummy 24‐week period was followed by an open extension of up to 12 months posttransplant. Biopsy‐proven acute rejection rate at 24 weeks (primary endpoint, per‐protocol analysis) was 15.8% for Tacrolimus BID versus 20.4% for Tacrolimus QD (p = 0.182; treatment difference 4.5%, 95% confidence interval—1.8%, 10.9%, just outside the prespecified 10% noninferiority margin). Kaplan–Meier 12‐month patient and graft survival rates were 97.5% and 92.8% for Tacrolimus BID and 96.9% and 91.5% for QD. Both treatment groups showed equally well‐maintained renal function at 12 months (mean creatinine clearance approximately 67 mL/min) and similar adverse event profiles. Overall results obtained with either Tacrolimus QD or BID, without antibody induction, were good, supporting use of the once‐daily formulation as an effective alternative to the established twice‐daily formulation.
This international, multicenter, randomized, double‐blind, double‐dummy, phase III study finds that once‐daily, prolonged‐release tacrolimus has therapeutic equivalence and a comparable safety profile to twice‐daily tacrolimus in renal transplant recipients. See editorial by Srinivas et al on page 2571.
Everolimus allows calcineurin‐inhibitor reduction without loss of efficacy and may improve renal‐transplant outcomes. In a 24‐month, open‐label study, 833 de novo renal‐transplant recipients were ...randomized to everolimus 1.5 or 3.0 mg/day (target troughs 3–8 and 6–12 ng/mL, respectively) with reduced‐exposure CsA, or mycophenolic acid (MPA) 1.44 g/day plus standard‐exposure CsA. Patients received basiliximab ± corticosteroids. The primary endpoint was composite efficacy failure (treated biopsy‐proven acute rejection, graft loss, death or loss to follow‐up) and the main safety endpoint was renal function (estimated glomerular filtration rate eGFR, by Modification of Diet in Renal Disease MDRD) at Month 12 (last‐observation‐carried‐forward analyses). Month 12 efficacy failure rates were noninferior in the everolimus 1.5 mg (25.3%) and 3.0 mg (21.9%) versus MPA (24.2%) groups. Mean eGFR at Month 12 was noninferior in the everolimus groups versus the MPA group (54.6 and 51.3 vs 52.2 mL/min/1.73 m2 in the everolimus 1.5 mg, 3.0 mg and MPA groups, respectively; 95% confidence intervals for everolimus 1.5 mg and 3.0 mg vs MPA: −1.7, 6.4 and −5.0, 3.2, respectively). The overall incidence of adverse events was comparable between groups. The use of everolimus with progressive reduction in CsA exposure, up to 60% at 1 year, resulted in similar efficacy and renal function compared with standard‐exposure CsA plus MPA.
Everolimus plus progressively reduced CsA exposure yields similar efficacy and renal function compared with standard‐exposure CsA plus MPA in de‐novo renal‐transplant recipients at 1 year.
The Symphony study showed that at 1 year posttransplant, a regimen based on daclizumab induction, 2 g mycophenolate mofetil (MMF), low‐dose tacrolimus and steroids resulted in better renal function ...and lower acute rejection and graft loss rates compared with three other regimens: two with low‐doses of cyclosporine or sirolimus instead of tacrolimus and one with no induction and standard cyclosporine dosage. This is an observational follow‐up for 2 additional years with the same endpoints as the core study. Overall, 958 patients participated in the follow‐up. During the study, many patients changed their immunosuppressive regimen (e.g. switched from sirolimus to tacrolimus), but the vast majority (95%) remained on MMF. During the follow‐up, renal function remained stable (mean change: −0.6 ml/min), and rates of death, graft loss and acute rejection were low (all about 1% per year). The MMF and low‐dose tacrolimus arm continued to have the highest GFR (68.6 ± 23.8 ml/min vs. 65.9 ± 26.2 ml/min in the standard‐dose cyclosporine, 64.0 ± 23.1 ml/min in the low‐dose cyclosporine and 65.3 ± 26.2 ml/min in the low‐dose sirolimus arm), but the difference with the other arms was not significant (p = 0.17 in an overall test and 0.077, 0.039 and 0.11, respectively, in pair‐wise tests). The MMF and low‐dose tacrolimus arm also had the highest graft survival rate, but with reduced differences between groups over time, and the least acute rejection rate. In the Symphony study, the largest ever prospective study in de novo kidney transplantation, over 3 years, daclizumab induction, MMF, steroids and low‐dose tacrolimus proved highly efficacious, without the negative effects on renal function commonly reported for standard CNI regimens.
Three‐year extended follow up of the Symphony study populations shows that renal function remains stable with few acute rejection or graft loss events, and similar treatment group differences as those at one year but with reduced statistical power.
In this Phase 2b study, 331 low‐to‐moderate risk de novo kidney transplant patients (approximately 60% deceased donors) were randomized to a more intensive (MI) or less intensive (LI) regimen of ...tofacitinib (CP‐690, 550), an oral Janus kinase inhibitor or cyclosporine (CsA). All patients received basiliximab induction, mycophenolic acid and corticosteroids. Primary endpoints were: incidence of biopsy‐proven acute rejection (BPAR) with a serum creatinine increase of ≥0.3 mg/dL and ≥20% (clinical BPAR) at Month 6 and measured GFR at Month 12. Similar 6‐month incidences of clinical BPAR (11%, 7% and 9%) were observed for MI, LI and CsA. Measured GFRs were higher (p < 0.01) at Month 12 for MI and LI versus CsA (65 mL/min, 65 mL/min vs. 54 mL/min). Fewer (p < 0.05) patients in MI or LI developed chronic allograft nephropathy at Month 12 compared with CsA (25%, 24% vs. 48%). Serious infections developed in 45%, 37% and 25% of patients in MI, LI and CsA, respectively. Anemia, neutropenia and posttransplant lymphoproliferative disorder occurred more frequently in MI and LI compared with CsA. Tofacitinib was equivalent to CsA in preventing acute rejection, was associated with improved renal function and less chronic allograft histological injury, but had side‐effects at the doses evaluated.
The authors present the results of a phase 2b trial of tofacitinib in renal transplantation.
Objective To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus. Design Systematic review and meta-analysis of individual patient ...data. Data sources Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to March 2013. Eligibility Randomized controlled trials comparing immunosuppressive regimens with and without sirolimus in recipients of kidney or combined pancreatic and renal transplant for which the author was willing to provide individual patient level data. Two reviewers independently screened titles/abstracts and full text reports of potentially eligible trials to identify studies for inclusion. All eligible trials reported data on malignancy or survival. Results The search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls. Conclusions Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.
Two large, prospective studies (12-03; OSAKA) compared the efficacy and tolerability of prolonged-release versus immediate-release tacrolimus in kidney transplant patients also receiving ...mycophenolate mofetil and low-dose corticosteroids (without induction therapy).
Data were combined into one database to compare results over 24 weeks using 3 alternative endpoints: biopsy-confirmed acute rejection (BCAR); the Food and Drug Administration composite endpoint (graft loss, BCAR, and loss to follow-up), and the European Medicines Agency composite endpoint (graft loss, BCAR, and graft dysfunction). The 95% confidence intervals were calculated (10% noninferiority margin).
Overall, 633 patients received prolonged-release tacrolimus (12-03, n = 331; OSAKA, n = 302) and 645 received immediate-release tacrolimus (n = 336; n = 309). Baseline characteristics were comparable. Proportionately more patients receiving prolonged-release tacrolimus had trough levels of 5–15 ng/mL on day 1 (60.8%) and 2 (56.6%) versus immediate-release tacrolimus (42.5% and 43.9%, respectively, both P < .001). Efficacy of prolonged-release and immediate-release tacrolimus were similar as assessed by BCAR (13.9% vs 14.1%, respectively), European Medicines Agency composite endpoint (40.3% vs 38.3%) and US Food and Drug Administration composite endpoint (21.5% vs 19.8%).
Novel efficacy endpoints as required by the European Medicines Agency and US Food and Drug Administration demonstrate noninferiority of prolonged-release versus immediate-release tacrolimus. Significantly more patients treated with prolonged-release tacrolimus versus immediate-release tacrolimus achieved trough levels of 5 to 15 ng/mL early after transplantation. ClinicalTrials.govNCT00189839; NCT00717470.
•Analysis from a combined database of two large, randomized, controlled trials.•Prolonged- versus immediate-release tacrolimus in de novo kidney transplantation.•Prolonged-release tacrolimus efficacy noninferior to immediate-release tacrolimus.•Variability of exposure was lower with prolonged- versus immediate-release tacrolimus.
The clinical benefit of machine perfusion (MP) was recently assessed in a 1-year Brazilian multicenter prospective randomized trial, that showed that the use of MP was associated with a reduced ...incidence of delayed graft function (DGF) compared to static cold storage (SCS) in kidney transplant recipients (45% vs 61%). The objective of the present analysis is to consider the cost-effectiveness of MP relative to SCS based on clinical data from this Brazilian cohort. A decision tree model was constructed to simulate a population of 1000 kidney transplant recipients based on data derived from this Brazilian multicenter clinical trial. The model accounts for different health state utilities to estimate the cost-effectiveness of deceased donor kidney transplantation in Brazil comparing 2 kidney preservation methods: MP and SCS. The model accounts for 3 possible graft outcomes at 1 year post-transplantation: success (an immediate functioning kidney), failure (primary nonfunction requiring a return to dialysis), or DGF 1 year post-transplant. MP provided 612 total quality-adjusted life years (QALYs) (0.61 QALYs per patient) as compared to SCS (553 total QALYs, 0.55 QALYs per patient). MP was cost effective relative to SCS (US$22,117/QALY, R$70,606/QALY). The use of MP also resulted in more functioning grafts than SCS (821 vs 787), leading to a cost per functioning graft of US$38,033 (R$121,417). In conclusion, this analysis indicates that, despite the initial added cost associated with MP, the use of MP results in more functioning grafts (821 vs 787) and higher patient quality of life relative to SCS in Brazil.
•Machine perfusion results in more functioning kidney grafts vs static cold storage.•Machine perfusion is a cost-effective alternative for kidney preservation in Brazil.
Sotrastaurin, a novel selective protein‐kinase‐C inhibitor, inhibits early T cell activation via a calcineurin‐independent pathway. Efficacy and safety of sotrastaurin in a calcineurin inhibitor—free ...regimen were evaluated in this two‐stage Phase II study of de novo kidney transplant recipients. Stage 1 randomized 131 patients (2:1) to sotrastaurin 300 mg or cyclosporine A (CsA). Stage 2 randomized 180 patients (1:1:1) to sotrastaurin 300 or 200 mg or CsA. All patients received basiliximab, everolimus (EVR) and prednisone. Primary endpoint was composite efficacy failure rate of treated biopsy‐proven acute rejection, graft loss, death or lost to follow‐up. Main safety assessment was estimated glomerular filtration rate (eGFR) by MDRD‐4 at Month 12. Composite efficacy failure rates at 12 months were higher in sotrastaurin arms (Stage 1: 16.5% and 10.9% for sotrastaurin 300 mg and CsA; Stage 2: 27.2%, 34.5% and 19.4% for sotrastaurin 200 mg, 300 mg and CsA). eGFR was significantly better in sotrastaurin groups versus CsA at most time points, except at 12 months. Gastrointestinal and cardiac adverse events were more frequent with sotrastaurin. Higher treatment discontinuation, deaths and graft losses occurred with sotrastaurin 300 mg. Sotrastaurin combined with EVR showed higher efficacy failure rates and some improvement in renal allograft function compared to a CsA‐based therapy.
This non‐inferiority study showed that sotrastaurin plus reduced tacrolimus demonstrated comparable effi cacy to enteric‐coated mycophenolic acid plus standard tacrolimus in prevention of rejection with no signifi cant difference in renal function in de novo kidney transplant recipients receiving basiliximab induction and corticosteroids.
PDF
