Title: Improved Renal Function After Early Conversion From a Calcineurin Inhibitor to Everolimus: a Randomized Trial in Kidney Transplantation
Abstract: American Journal of TransplantationVolume 12, Issue 10 p. 2744-2753 Free Access Improved Renal Function After Early Conversion From a Calcineurin Inhibitor to Everolimus: a Randomized Trial in Kidney Transplantation L. Mjörnstedt, Corresponding Author L. Mjörnstedt Transplant Institute, Sahlgrenska University Hospital, Göteborg, SwedenLars Mjörnstedt, [email protected] for more papers by this authorS. S. Sørensen, S. S. Sørensen Department of Nephrology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, DenmarkSearch for more papers by this authorB. von zur Mühlen, B. von zur Mühlen Department of Transplant Surgery, Uppsala University Hospital, Uppsala, SwedenSearch for more papers by this authorB. Jespersen, B. Jespersen Department of Nephrology, Aarhus University Hospital, Skejby, DenmarkSearch for more papers by this authorJ. M. Hansen, J. M. Hansen Department of Nephrology, Herlev Hospital, University of Copenhagen, Herlev, DenmarkSearch for more papers by this authorC. Bistrup, C. Bistrup Department of Nephrology, Odense University Hospital, Odense, DenmarkSearch for more papers by this authorH. Andersson, H. Andersson Department of Nephrology and Transplantation, Skåne University Hospital, Malmö, SwedenSearch for more papers by this authorB. Gustafsson, B. Gustafsson Transplant Institute, Sahlgrenska University Hospital, Göteborg, SwedenSearch for more papers by this authorL.H. Undset, L.H. Undset Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, NorwaySearch for more papers by this authorH. Fagertun, H. Fagertun Capturo AS, Oslo, NorwaySearch for more papers by this authorD. Solbu, D. Solbu Medical Department, Novartis Norge AS, Oslo, NorwaySearch for more papers by this authorH. Holdaas, H. Holdaas Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, NorwaySearch for more papers by this author L. Mjörnstedt, Corresponding Author L. Mjörnstedt Transplant Institute, Sahlgrenska University Hospital, Göteborg, SwedenLars Mjörnstedt, [email protected] for more papers by this authorS. S. Sørensen, S. S. Sørensen Department of Nephrology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, DenmarkSearch for more papers by this authorB. von zur Mühlen, B. von zur Mühlen Department of Transplant Surgery, Uppsala University Hospital, Uppsala, SwedenSearch for more papers by this authorB. Jespersen, B. Jespersen Department of Nephrology, Aarhus University Hospital, Skejby, DenmarkSearch for more papers by this authorJ. M. Hansen, J. M. Hansen Department of Nephrology, Herlev Hospital, University of Copenhagen, Herlev, DenmarkSearch for more papers by this authorC. Bistrup, C. Bistrup Department of Nephrology, Odense University Hospital, Odense, DenmarkSearch for more papers by this authorH. Andersson, H. Andersson Department of Nephrology and Transplantation, Skåne University Hospital, Malmö, SwedenSearch for more papers by this authorB. Gustafsson, B. Gustafsson Transplant Institute, Sahlgrenska University Hospital, Göteborg, SwedenSearch for more papers by this authorL.H. Undset, L.H. Undset Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, NorwaySearch for more papers by this authorH. Fagertun, H. Fagertun Capturo AS, Oslo, NorwaySearch for more papers by this authorD. Solbu, D. Solbu Medical Department, Novartis Norge AS, Oslo, NorwaySearch for more papers by this authorH. Holdaas, H. Holdaas Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, NorwaySearch for more papers by this author First published: 19 July 2012 https://doi.org/10.1111/j.1600-6143.2012.04162.xCitations: 72AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract In an open-label, multicenter trial, de novo kidney transplant recipients at low to medium immunological risk were randomized at week 7 posttransplant to remain on CsA (n = 100, controls) or convert to everolimus (n = 102), both with enteric-coated mycophenolate sodium and corticosteroids. The primary endpoint, change in measured GFR (mGFR) from week 7 to month 12, was significantly greater with everolimus than controls: 4.9 (11.8) mL/min versus 0.0 (12.9) mL/min (p = 0.012; analysis of covariance [ANCOVA]). Per protocol analysis demonstrated a more marked difference: an increase of 8.7 (11.2) mL/min with everolimus versus a decrease of 0.4 (12.0) mL/min in controls (p < 0.001; ANCOVA). There were no differences in graft or patient survival. The 12-month incidence of biopsy-proven acute rejection (BPAR) was 27.5% (n = 28) with everolimus and 11.0% (n = 11) in controls (p = 0.004). All but two episodes of BPAR in each group were mild. Adverse events occurred in 95.1% of everolimus patients and 90.0% controls (p = 0.19), with serious adverse events in 53.9% and 38.0%, respectively (p = 0.025). Discontinuation because of adverse events was more frequent with everolimus (25.5%) than controls (3.0%; p = 0.030). In conclusion, conversion from CsA to everolimus at week 7 after kidney transplantation was associated with a greater improvement in mGFR at month 12 versus CNI-treated controls but discontinuations and BPAR were more frequent. Abbreviations: ANCOVA analysis of covariance BPAR biopsy-proven acute rejection 51Cr-EDTA 51chromium-labeled ethylenediaminetetraacetic acid CENTRAL CErtican Nordic Trial in RenAL Transplantation CMV cytomegalovirus CNI calcineurin inhibitor CsA cyclosporine EC-MPS enteric-coated mycophenolate sodium eGFR estimated glomerular filtration rate IF/TA interstitial fibrosis/tubular atrophy ITT intent-to-treat mGFR measured glomerular filtration rate Introduction Although the potency of calcineurin inhibitors (CNIs) in preventing rejection of solid organ allografts is unquestionable, the disadvantages of long-term CNI therapy are becoming increasingly well recognized. These include acute and chronic nephrotoxicity characterized by arteriolar hyalinosis and tubulointerstitial fibrosis (1) and increased cardiovascular risk (2, 3) and malignancy (2, 4). Entirely CNI-free regimens, however, have frequently been associated with a higher rate of rejection in kidney transplant patients (5-7) except in low-risk individuals (8, 9), and generally it appears preferable to minimize CNI exposure instead of avoiding their use entirely (10, 11). The mTOR class of immunosuppressants offers an attractive option for minimizing CNI exposure. They are not associated with the nephrotoxicity observed with CNIs, and their antiproliferative properties inhibit the progression of interstitial fibrosis/tubular atrophy (IF/TA) in preclinical models (12, 13). Heart transplant patients treated with the mTOR inhibitors everolimus and sirolimus have shown a reduced incidence of cardiac allograft vasculopathy (14, 15), and there is a substantial body of evidence demonstrating that mTOR inhibitors exert antitumor properties (16, 17). Strategies to minimize CNI exposure by using mTOR inhibitors either exploit the synergistic mechanisms of the two classes (18) to permit maintenance of low-dose CNI (19-23), or introduce an mTOR inhibitor to facilitate complete CNI elimination (24-28). Typically, CNI withdrawal has taken place at 3–6 months after kidney transplant (24, 25, 27, 28). Early conversion to an mTOR inhibitor has been explored less frequently (26, 28), although this approach reduces the duration of damaging high-exposure CNI therapy (1) during the first weeks and months after transplantation. In a previous single-arm, single-center pilot study, kidney transplant patients without prior rejection were abruptly converted from cyclosporine (CsA) to everolimus at seven weeks posttransplant (28). In that population of 20 patients, the rate of biopsy-proven acute rejection (BPAR) was 15.0% at 7 weeks after conversion. All episodes were mild with subsequent recovery of renal function, and renal function improved significantly following conversion. CErtican Nordic Trial in RenAL Transplantation (CENTRAL) was undertaken using the same design as the pilot study, with the objective of evaluating whether early conversion from CsA to everolimus can improve long-term renal function in low- to medium-risk kidney transplant recipients. The 12-month results from this ongoing 3-year study are reported here. Methods Study design and conduct CENTRAL was an open-label, parallel-group study conducted at eight transplant centers in Sweden, Norway and Denmark (Clinicaltrials.gov NCT00634920). De novo kidney transplant recipients were randomized at week 7 posttransplant to remain on CsA or convert to everolimus, both in combination with enteric-coated mycophenolate sodium (EC-MPS) and corticosteroids. The study was undertaken in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki following approval by the institutional review board at each center. Written informed consent was obtained from all patients. Eligibility criteria Adult patients (>18 years) were eligible for the study if they received a first or second single kidney transplant from a deceased or living donor and if, at week 7 posttransplant, they were receiving CsA, EC-MPS at a target dose of 1440 mg/day (minimum 1080 mg/day) and corticosteroids at a dose of ≥10 mg/day with no previous acute rejection or treatment for acute rejection. All patients were to have received basiliximab induction therapy. Key exclusion criteria were multiorgan transplantation or a previous nonrenal transplant, panel reactive antibodies >30% at the most recent assessment, HLA-identical sibling donor, hemoglobin <8.0 g/dL, platelets <50 × 109/L and/or white blood cell count ≤2.5 × 109/L, total cholesterol ≥9 mmol/L and/or triglycerides ≥6 mmol/L despite lipid-lowering treatment, urinary protein/creatinine ratio ≥150 mg/mmol, ongoing wound healing problems or any other severe surgical complication, requirement for dialysis and/or estimated glomerular filtration rate (eGFR) <20 mL/min (Cockcroft-Gault formula) at week 7 posttransplant. Randomization and study medication Randomization was performed centrally at week 7 posttransplant in a 1: 1 ratio, stratified by center using a validated, automated system, with investigators notified of the randomization group via the electronic case record form system. On the day of randomization, patients in the everolimus group received everolimus 3 mg in the evening with a 50% reduction in their usual evening dose of CsA, followed the next day by everolimus 2 mg in the morning and evening and no CsA. Subsequently, everolimus dose was titrated to target a C0 concentration of 6–10 ng/mL. In this group, the target dose of EC-MPS was 1440 mg/day (minimum 720 mg/day) during the first 2 weeks, thereafter reduced to 1080 mg/day (minimum 720 mg/day). In the control group, CsA target concentration was C0 75–200 ng/mL (C2 700–900 ng/mL) from randomization to month 6, and C0 50–150 ng/mL (C2 600–800 ng/mL) after month 6. The target dose of EC-MPS in control patients was 1440 mg/day (minimum 720 mg/day). In both groups, corticosteroids were given at a minimum dose of 10 mg prednisolone daily until 10–12 weeks after transplantation (minimum 4 weeks after conversion to everolimus), thereafter as per local practice and at a minimum dose of 5 mg/day (or 10 mg every other day) throughout the first year. Prophylactic treatment for cytomegalovirus (CMV) and Pneumocystis jirovecii pneumonia was given according to local practice. Evaluation Study visits took place on the day of transplantation (±3 days), at week 7 posttransplant (baseline visit i.e. point of randomization), at least weekly for the next 3 weeks and then at 6, 9 and 12 months posttransplant. Measured GFR (mGFR) was recorded on, or a few days before, the day of randomization (before any switch in medication) and at 12 months based on iohexol or 51chromium-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) clearance. Blood concentrations of everolimus and CsA, laboratory measurements, hematology parameters and vital signs were obtained at each visit. eGFR was calculated using the Cockcroft-Gault and Nankivell formulae. Clinically mandated biopsies were assessed locally. Protocol biopsies were performed at month 12. All protocol biopsy samples were assessed centrally and graded according to the Banff 97 classification. Unscheduled biopsies were assessed locally. The key criteria for defining an adverse event as serious were fatal or life threatening, results in persistent or significant disability/incapacity, requires or prolongs inpatient hospitalization, requires treatment on an emergency outpatient basis, is medically significant (defined as an event that jeopardizes the patient or may require medical or surgical intervention to prevent one of the outcomes listed above) or graft loss. Statistical analysis The primary efficacy endpoint was the change in renal function from week 7 to month 12, evaluated by mGFR. Analysis of covariance (ANCOVA) with treatment and center as factors and baseline mGFR (i.e. mGFR at week 7) as covariate was used for analysis of this endpoint. Secondary endpoints included the occurrence of a composite efficacy endpoint (BPAR, graft loss or death), percentage of patients receiving lipid-lowering drugs and antihypertensive medication, lipid profile and safety and tolerability. Categorical variables were compared between treatment groups using the Fisher's exact test. Event data were assessed by Kaplan–Meier statistics and compared between treatment groups using the log rank test.The sample size calculation showed that a total of 100 randomized patients per group were required, based on the estimate that the difference in the 12-month mGFR between the everolimus and CsA group would be 8 ± 19 mL/min and using a two-sample unpaired t-test. This allowed for a 10% dropout rate after randomization. The safety population and the intent-to-treat (ITT) population consisted of all randomized patients who received ≥1 dose of study drug or CsA. The per protocol population was defined as all ITT patients who did not show major deviations from protocol that could have an impact on study outcome and who completed 12 months' treatment according to the protocol. Results Patient population and immunosuppression Study recruitment took place during March 2008 to April 2010, with the final patient visit in April 2011. Of 341 patients included at time of transplant, 204 (59.8%) met the inclusion criteria at week 7 and were randomized. Two patients did not receive any study medication, such that the ITT and safety populations comprised 202 patients (102 everolimus, controls 100). More patients in the everolimus group discontinued study medication (44 [43.1%] versus 14 [14%] in the control arm; p < 0.001), for which the primary reason was most frequently adverse events (everolimus 26, controls three; p = 0.030; Figure 1). Baseline characteristics were similar between groups other than a higher proportion of female donors in the control arm (Table 1). Figure 1Open in figure viewerPowerPoint Patient disposition. Table 1. Baseline characteristics Everolimus (n = 102) Controls (n = 100) p-Value Recipient characteristics Age (years) 55.5 (10.9) 53.8 (12.3) 0.21 Female gender, n (%) 32 (31.4) 26 (26.0) 0.44 Caucasian, n (%) 99 (97.1) 100 (100) 0.50 End-stage disease leading to transplantation, n (%) Glomerulonephritis/glomerular disease 39 (38.2) 23 (23.0) Polycystic disease 22 (21.6) 21 (21.0) Diabetes mellitus 12 (11.8) 9 (9.0) Hypertension/nephrosclerosis 6 (5.9) 10 (10.0) Interstitial nephritis 1 (1.0) 7 (7.0) Other 16 (15.7) 23 (23.0) Unknown 6 (5.9) 7 (7.0) Panel reactive antibodies 0, n (%) 95 (93.1) 95 (95.0) 0.95 Systolic blood pressure (mmHg) 138 (15) 138 (16) 0.72 Diastolic blood pressure (mmHg) 83 (10) 81 (11) 0.25 Weight (kg) 79.1 (14.8) 81.1 (14.7) 0.39 mGFR (mL/min) 47.0 (13.2) 47.9 (15.0) 0.55 Plasma creatinine (mmol/L) 124 (38) 131 (38) 0.17 Donor characteristics Age (years) 49.8 (16.6) 52.4 (14.5) 0.32 Female gender, n (%) 46 (45.1) 61 (61) 0.025 Deceased, n (%) 73 (71.6) 71 (71.0) 1.00 Transplant characteristics Cold ischemia time (h) 11.0 (7.3) 10.9 (7.5) 0.95 Retransplant, n (%) 9 (8.8) 6 (6.0) 0.59 0 HLA mismatch A, n (%) 14/100 (14.0) 24/99 (24.2) 0.18 B, n (%) 11/100 (11.0) 14/99 (14.1) 0.47 DR, n (%) 26/99 (26.3) 23/99 (23.2) 0.54 Immunosuppresssion at week 71 CsA C0 (ng/mL) 156 (45) 168 (45) 0.059 Corticosteroid dose (mg/day2; median [range]) 10 (7.5–20) 10 (7.5–20) 0.83 EC-MPS (mg/day) 1404 (141) 1418 (101) 0.37 1Point of randomization. 2Prednisolone equivalents. Continuous variables are shown as mean (SD) unless otherwise stated. mGFR = measured glomerular filtration rate; CsA = cyclosporine; EC-MPS = enteric-coated mycophenolate sodium. The two treatment groups were receiving similar immunosuppression at the point before randomization (Table 1). After randomization, mean (SD) everolimus C0 remained within target range (6–10 ng/mL) at all time points throughout the study (month 6: 8.2 [1.9] ng/mL, month 12: 7.4 [1.6] ng/mL). However, at weeks 1, 2 and 3 postrandomization, 40.7% (n = 37/91), 22.7% (n = 22/97) and 28.4% (n = 27/95) of patients had an everolimus C0 value below the minimum target of 6 ng/mL. Mean CsA C0 was also within target at all time points; values at months 6 and 12 were 117 (31) ng/mL and 105 (40) ng/mL. Mean EC-MPS dose at month 6 posttransplant was 992 (327) mg/day in the everolimus group versus 1211 (401) mg/day in the control group (p < 0.001), 929 (377) mg/day versus 1107 (479) mg/day, respectively, at month 12 (p = 0.004). Renal function In the ITT population, mGFR values at week 7 and month 12 were available in 92 everolimus patients and 90 controls. Ten patients in each group were not included in the ITT analyses, most frequently because of withdrawal of consent (five everolimus, four controls), death (two in each group) and missed follow-up (two in each group). There were no significant differences between groups at week 7 or month 12 (Figure 2A). The primary endpoint, change in mGFR from week 7 to month 12, was significantly greater in the everolimus group versus controls: 4.9 (11.8) mL/min versus 0.0 (12.9) mL/min (p = 0.012; ANCOVA). In a prespecified analysis, the primary endpoint was also assessed in the per protocol population, and showed that mGFR increased by 8.7 (11.2) mL/min in the everolimus cohort compared to a decrease of –0.4 (12.0) mL/min in controls (p < 0.001; Figure 2B). No significant differences were observed for the change from week 7 to month 12 using eGFR based on the Cockcroft-Gault equation or the Nankivell equation, or in plasma creatinine levels (Table 2). The mean urine albumin: creatinine ratio did not increase significantly from week 7 to month 12 in the everolimus group (p = 0.32) or in control patients (p = 0.58) and the between-group difference in the change from week 7 to month 12 was also nonsignificant (p = 0.125; Table 2). Figure 2Open in figure viewerPowerPoint Measured GFR (mGFR) in (A) the intent-to-treat population and (B) the per protocol population. Values are shown as mean ± SD. Table 2. Laboratory values Everolimus (n = 102) Controls (n = 100) p-Value1 Week 7 Month 12 Week 7 Month 12 mGFR (mL/min)2 46.2 (12.9) 51.2 (14.1) 47.8 (15.0) 47.8 (15.4) 0.012 eGFR2 Cockcroft-Gault (mL/min) 66.8 (20.5) 68.1 (21.5) 66.0 (18.4) 69.4 (22.9) 0.31 Nankivell (mL/min/1.73 m2) 71.2 (16.5) 73.9 (17.1) 69.9 (14.8) 71.3 (17.6) 0.48 Plasma creatinine (μmol/L)2 124 (39) 122 (35) 132 (39) 132 (45) 0.43 Urine albumin: creatinine ratio (mg/mmol)2 13.9 (25.3) 17.3 (29.4) 12.9 (28.1) 11.3 (22.9) 0.125 Alanine aminotransferase (IU/L) 27 (18) 27 (15) 27 (25) 22 (14) 0.019 Aspartate aminotransaminase (IU/L) 21 (7) 28 (10) 21 (7) 24 (12) 0.039 Plasma sodium (mmol/L) 141 (3) 142 (3) 141 (3) 142 (3) 0.39 Plasma potassium (mmol/L) 4.1 (0.4) 4.0 (0.4) 4.2 (0.4) 4.1 (0.4 0.002 Plasma calcium (mmol/L) 2.25 (0.44) 2.23 (0.40) 2.26 (0.38) 2.22 (0.42) 0.37 Total cholesterol (mmol/L) 6.8 (1.3) 6.1 (1.7) 6.5 (1.2) 5.3 (1.1) 0.003 LDL cholesterol (mmol/L) 4.2 (1.0) 3.5 (1.4) 4.0 (1.1) 3.2 (1.0) 0.18 HDL cholesterol (mmol/L) 1.5 (0.4) 1.5 (0.4) 1.5 (0.5) 1.4 (0.4) 0.29 LDL/HDL ratio 2.9 (1.0) 2.5 (1.1) 2.9 (1.2) 2.4 (1.2) 0.97 Triglycerides (mmol/L) 2.4 (1.3) 2.4 (1.6) 2.1 (1.1) 1.9 (0.9) 0.008 Hemoglobin (g/dL) 12.4 (1.2) 13.1 (1.5) 12.3 (1.4) 13.3 (1.7) 0.11 White blood cell count (× 109/mL) 8.2 (2.7) 6.9 (2.4) 8.8 (2.5) 7.7 (2.7) 0.077 Platelet count (× 109/mL) 290 (81) 257 (88) 312 (83) 284 (71) 0.023 1p-Value for difference in change from week 7 to month 12 between treatment groups. Values are shown as mean (SD). 2ITT population. eGFR = estimated glomerular filtraton rate; mGFR = measured glomerular filtration rate. Efficacy There were 75 unscheduled biopsies in the everolimus group compared to 44 in the control group, undertaken at the discretion of the investigator. The 12-month incidence of at least one episode of BPAR was 27.5% (n = 28) and 11.0% (n = 11) in the everolimus and control groups, respectively (p = 0.004), based on local biopsy readings. Kaplan–Meier estimates showed the time to first BPAR during the 12-month study differed significantly in disfavor of the everolimus group when compared to the control group (p = 0.02; Figure 3). There were 36 episodes of BPAR in 28 everolimus patients and 13 episodes of BPAR in 11 control patients as assessed locally. In total, 31 patients in the everolimus group and 13 patients in the CsA group were treated for rejection (either biopsy-proven or presumed), including use of lymphocyte-depleting antibodies in four everolimus-treated patients and two CsA-treated patients. All episodes responded to treatment, with a high proportion of mild rejections using Banff scoring, especially in the everolimus group (Table 3). Eleven borderline rejection episodes occurred in the everolimus arm (six of which were treated) and four episodes in the CsA arm (two of which were treated). No grade III rejections were reported in either arm. Figure 3Open in figure viewerPowerPoint Kaplan–Meier estimate of time to first biopsy-proven acute rejection (BPAR) from point of randomization (week 7 posttransplant) based on local biopsy readings. Table 3. Efficacy endpoints at month 12 posttransplant, n (%; ITT population) Everolimus (n = 102) Controls (n = 100) p-Value Composite efficacy endpoint1 29 (28.7) 12 (12.0) 0.005 Biopsy-proven acute rejection2 28 (27.5) 11 (11.0) 0.004 IA 17 6 IB 14 0 IIA 3 5 IIB 2 2 Total 36 13 Death-censored graft loss 0 0 – Death 2 (2.0) 2 (2.0) 1.0 1Biopsy-proven acute rejection, graft loss, death and loss to follow-up. 2Unscheduled biopsy results. Data on serum creatinine were obtained post hoc from all patients who underwent an unscheduled biopsy. Values were analyzed on the day of the first unscheduled biopsy and according to the most recent stable level recorded before that biopsy took place. The mean creatinine level at the day of biopsy was 164 μmol/L in the everolimus group (n = 41) and 195 μmol/L (n = 27) in the CsA group (p = 0.052). The mean increase from the preceding stable value to the day of biopsy was 33 μmol/L with everolimus compared to 53 μmol/L with CsA (p = 0.174). Protocol biopsies at 1 year were performed in 78 everolimus patients and 86 control patients. In the everolimus group, 15 biopsies (19.2%) indicated subclinical acute rejection (14 grade IA/IB and one grade II with suspected humoral rejection). Fourteen biopsies (16.3%) in the CsA group suggested the presence of subclinical rejection (12 grade IA/IB [one with suspected humoral rejection] and two grade IIA [one with suspected humoral rejection]). Four patients died during the study, two in the everolimus group (one intracerebral bleeding, one lung emboli or acute myocardial infarction) and two in the control arm (one intoxication with ethylene glycol, one pneumonia). There were no other graft losses. Safety The proportion of patients experiencing one or more adverse event was similar between groups (everolimus 95.1%, controls 90.0%; p = 0.19). The incidence of edema, acne, anemia, mouth ulceration and hypercholesterolemia was higher in the everolimus arm; nasopharyngitis and diarrhea were more frequent in controls (Table 4). The incidence of adverse events with a suspected relation to study drug was 80.4% (n = 82) and 52.0% (n = 52) in the everolimus and control arms, respectively (p < 0.001). Table 4. Most frequent adverse events and infections at month 12 posttransplant, n (%; safety population) Everolimus (n = 102) Controls (n = 100) p-Value Any adverse event 97 (95.1) 90 (90.0) 0.19 Any infection 59 (57.8) 52 (52.0) 0.48 Any serious adverse event 55 (53.9) 38 (38.0) 0.025 Adverse events Edema 30 (29.4) 21 (21.0) 0.20 Anemia 17 (16.7) 6 (6.0) 0.025 Leukopenia 14 (13.7) 11 (11.0) 0.67 Hyperlipidemia 13 (12.7) 9 (9.0) 0.50 Acne 13 (12.7) 2 (2.0) 0.006 Mouth ulceration 13 (12.7) 1 (1.0) 0.001 Hypercholesterolemia 10 (9.8) 2 (2.0) 0.033 Lymphocele 10 (9.8) 6 (6.0) 0.44 Dermatitis 9 (8.8) 5 (5.0) 0.41 Cough 7 (6.9) 4 (4.0) 0.54 Nasopharyngitis 7 (6.9) 12 (12.0) 0.24 Headache 6 (5.9) 4 (4.0) 0.75 Hypokalemia 6 (5.9) 0 0.029 Oral candidiasis 5 (4.9) 2 (2.0) 0.45 Venous thrombosis 6 (5.9) 3 (3.0) 0.50 Proteinuria present 5 (4.9) 0 0.060 Myalgia 5 (4.9) 2 (2.0) 0.45 Sinusitis 5 (4.9) 1 (1.0) 0.21 Diarrhea 5 (4.9) 11 (11.0) 0.12 Fatigue 2 (2.0) 7 (7.0) 0.10 Plasma creatinine increased 8 (7.8) 9 (9.0) 0.80 Hirsutism 1 (1.0) 6 (6.0) 0.064 Arthralgia 4 (3.9) 5 (5.0) 0.75 Dizziness 1 (1.0) 5 (5.0) 0.12 Infections Urinary tract infection 15 (14.7) 28 (28.0) 0.025 Polyoma virus infection 2 (2.0) 1 (1.0) 1.0 Cytomegalovirus 9 (8.8) 13 (13.0) 0.37 Herpes simplex 5 (4.9) 1 (1.0) 0.21 Pneumonia 12 (11.8) 2 (2.0) 0.010 Upper respiratory tract infection 5 (4.9) 4 (4.0) 1.0 Herpes zoster 1 (1.0) 6 (6.0) 0.064 Serious adverse events were reported more frequently in everolimus-treated patients (53.9%[n = 55] versus 38.0%[n = 38] of controls; p = 0.025). Serious adverse events or infections that occurred in more than two everolimus-treated patients comprised pneumonia (eleven), lymphocele (seven), increased plasma creatinine (five), sepsis (five), gastroenteritis (five), CMV infection (four), rejection (four) and hydronephrosis (three). In the control group, urinary tract infection (seven), CMV infection (five), lymphocele (three) pyelonephritis (three), increased plasma creatinine (three) and rejection (three) occurred as serious adverse events in more than two patients. Pneumonia was reported as a serious adverse event in one control patient. No cases of pneumonitis were diagnosed in either treatment group, although because pneumonitis is an exclusion diagnosis its absence cannot be confirmed. Infections occurred at a comparable rate in both treatment groups (everolimus 57.8%, controls 52.0%; p = 0.48). Urinary tract infection and CMV were more common in control patients (Table 4). BK virus nephropathy occurred in one patient in the everolimus arm and two control patients. Two malignant neoplasms occurred in each group (everolimus: malignant parathyroid tumor, adenocarcinoma of the prostate; controls: squamous cell carcinoma, testicular cancer). The proportion of patients receiving statin therapy increased from 30.4% (n = 31) at baseline to 73.5% (n = 75) at month 1 in the everolimus group, and from 19.0% (n = 19) to 64.0% (n = 64) in the control group; use of statin therapy at month 12 was not significantly different between groups (p = 0.17). Total cholesterol decreased in both treatment groups during the study, but to a significantly smaller extent in the everolimus arm (Table 2). Triglycerides remained stable in everolimus-treated patients but decreased in controls; the difference in the change was statistically significant (Table 2). The change in platelet count was also greater in the everolimus arm (Table 2). There were no between-group differences for the change in serum electrolytes or liver enzymes from randomization to month 12 other than a non-significant trend to a greater increase in alanine aminotransferase and a greater reduction in serum potassium in the everolimus group, neither of which were considered clinically relevant (Table 2). At randomization, 61.8% of everolimus patients and 82.0% of control patients were receiving beta blockers (p