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Keywords:

  • Cytomegalovirus;
  • everolimus;
  • kidney transplant;
  • mycophenolate mofetil;
  • rejection

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Appendix
  8. Acknowledgments
  9. References

Everolimus 1.5 or 3 mg/day was compared with mycophenolate mofetil (MMF) 2 g/day in a randomized, multicenter 36-month trial in de novo renal allograft recipients (n = 588) receiving cyclosporine microemulsion (CsA) and corticosteroids. The study was double-blind until all patients had completed 12 months, then open-label. By 36 months, graft loss occurred in 7.2, 16.7 and 10.7% of patients in the everolimus 1.5, 3 mg/day, and MMF groups, respectively (p = 0.0048 for everolimus 1.5 mg/day vs. 3 mg/day); efficacy failure (biopsy-proven acute rejection (BPAR), graft loss, death or lost to follow-up) occurred in 33.0, 38.9 and 37.2% of patients (p = 0.455 overall), respectively. Mortality and incidence of BPAR were comparable in all groups. Creatinine values were higher in everolimus groups, requiring a protocol amendment that recommended lower CsA exposure. Diarrhea, lymphocele, peripheral edema and hyperlipidemia were more common among everolimus-treated patients, whereas viral infections, particularly cytomegalovirus infection, increased in the MMF group. Overall safety and tolerability were better with MMF and everolimus 1.5 mg/day than with everolimus 3 mg/day. In conclusion, at 36 months, an immunosuppressive regimen containing everolimus 1.5 mg/day had equivalent patient, and graft survival and rejection rates compared with MMF in de novo renal transplant recipients, whereas everolimus 3 mg/day had inferior graft survival. Renal dysfunction in everolimus cohorts necessitates close monitoring.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Appendix
  8. Acknowledgments
  9. References

The goal of immunosuppressive therapy is to deliver effective protection against rejection with minimal morbidity. Immunosuppressive regimens that combine drugs that act synergistically via complementary mechanisms of action offer the best opportunity to achieve high efficacy while minimizing adverse effects. The proliferation signal inhibitor everolimus exerts its effect at a different physiological target to cyclosporine microemulsion (CsA), raising interest in an immunosuppressive strategy that optimizes exposure of both agents such that the side effects of either everolimus or CsA are reduced. Everolimus inhibits growth-factor-dependent proliferation of cells through a calcium-independent signal (2,3), whereas CsA inhibits T-cell-dependent growth factors through a calcium-dependent signal. In animal models of organ transplantation, combination therapy using 10% of full everolimus dose with 30% of full CsA dose was as effective as administering either drug alone at full dose (4). Everolimus can also decrease vascular remodeling by preventing growth-factor-mediated smooth muscle cell proliferation and attenuating vascular neointimal formation in animal models (3) and humans (5). Chronic allograft dysfunction is the major barrier to long-term patient and graft survival after renal transplantation. This is a multifactorial process in which the primary causes are acute rejection, vascular remodeling, calcineurin inhibitor (CNI)-induced nephrotoxicity and cytomegalovirus (CMV) infection (6,7). Because it can target several of these contributory factors, everolimus has the potential to improve long-term outcomes in renal transplantation (8).

Mycophenolate mofetil (MMF) has been shown to reduce graft rejection and prolong death-censored graft survival after renal transplantation (9–12). As a consequence, triple therapy comprising CNI, MMF and corticosteroids evolved as the most prevalent immunosuppressive regimen employed in de novo kidney transplant recipients in the late 1990s (13). This combination was therefore selected as the control group for a randomized, prospective 36-month trial that compared the efficacy and safety of two doses of everolimus with that of MMF, each in combination with CsA and steroids, in a population of de novo renal transplant patients. The 12-month findings were reported previously (14); here we present the full 3-year results of the trial.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Appendix
  8. Acknowledgments
  9. References

Study design

This was a 36-month, multicenter, randomized, parallel-group equivalence trial of two oral doses of everolimus (1.5 or 3 mg/day) versus MMF in combination with CsA microemulsion (Neoral) and corticosteroids in de novo renal transplant recipients. The primary objective of the trial was to compare the efficacy of two doses of everolimus with that of MMF as measured by the incidence of a composite endpoint of efficacy failure (biopsy-proven acute rejection (BPAR), graft loss or death) in the first 6 months of treatment (14).

The objectives of the protocol-prespecified 36-month analysis were (1) to compare allograft and patient survival, (2) to compare the efficacy of everolimus with that of MMF as measured by the incidence of acute and chronic rejection and (3) to assess safety and tolerability of the everolimus regimens versus the MMF regimen. Additionally, two composite endpoints for efficacy failure (graft loss, death and loss to follow-up with or without BPAR), which were not specified in the protocol, were also assessed. Allograft loss was presumed to occur if a patient started dialysis and could not subsequently be removed from dialysis. Safety assessments included the frequency of deaths, serious adverse events, early discontinuations, malignancies, infections and serial laboratory results from a central laboratory. Renal function was assessed with creatinine levels and calculated creatinine clearance (Cockroft–Gault formula).

Patient selection and treatment have been described previously (14). In brief, the trial was conducted at 54 centers (4 in Australia, 48 in Europe, and 2 in South Africa), and patients were recruited between August 1998 and August 1999. Within 48 h after transplantation, patients were randomly assigned (ratio of 1:1:1, stratified by center) to receive everolimus 0.75 mg b.i.d., everolimus 1.5 mg b.i.d. or MMF 2 g/day in a double-blind, double-dummy format for 12 months. Both investigators and patients remained blinded until all patients completed the first year of the study. In October 2000, after the last patient had completed the 12-month visit and the database was locked, investigators were unblinded and the remainder of the study was open-label. Patients were randomized according to a computer-generated schedule that ensured equal distribution among the three treatment groups within each center. Patients were 18–68 years old and had received a donor kidney (cadaveric or living related) with an ischemic time <40 h. The study was approved by the Ethics Committee at all participating institutions and conducted according to the recommendations of Good Clinical Practice and the Declaration of Helsinki. All patients gave written informed consent to participate in the study. A Safety Monitoring Board, established at the start of the study, reviewed serious adverse events. The protocol required extensive external monitoring in accordance with strict regulatory requirements over the entire 36-month period.

Whole blood trough levels of everolimus and CsA were assessed in a central laboratory at all visits. Neoral dosing after the first year was adjusted to achieve a CsA trough-level target of 100–300 ng/mL. In January 2001, when data from the 12-month double-blind phase were analyzed and reviewed by investigators and Safety Monitoring Board, an amendment to the protocol allowed a reduction of CsA trough levels to 50–75 ng/mL (while maintaining everolimus trough levels of ≥3 ng/mL) in patients who had suboptimal renal function. Corticosteroid doses were tapered from a minimum of 20 mg/day initially to ≥5 mg/day for at least 6 months; the steroid regimen was uniform within each center. The study protocol provided guidelines for lipid-lowering therapy and prophylaxis for Pneumocystis carinii infection. CMV prophylaxis with ganciclovir, CMV hyperimmune globulin or acyclovir was mandatory for all CMV-negative recipients of a transplant from a CMV-positive donor and was recommended after antibody treatment of an acute rejection episode. Guidelines for discontinuing, interrupting or lowering the dose of study medications were also prespecified in the protocol. Patients who prematurely discontinued the study drug continued to be followed up for the 3-year study period.

Allograft biopsy was required for all suspected cases of rejection within 24 h of suspected rejection episode, and biopsy specimens were assessed locally. Acute rejection was treated with methylprednisolone, minimally, at a total dose of 750 mg. In cases of vascular rejection, or if there was continuing evidence of acute rejection, treatment with antithymocyte globulin or antilymphocyte antibodies (OKT3) was permitted. A Biopsy Reviewing Board was established before the start of the study to ensure that evaluation of biopsy specimens was standardized and adhered to Banff 1997 criteria. Furthermore, the Biopsy Board performed a blinded review of a representative selection of all biopsy specimen slides.

Statistical analysis

The statistical analysis focused on summarizing long-term efficacy and safety data, including renal function, over the 36-month study period. Efficacy analysis was performed on the intention-to-treat (ITT) population (all randomized patients) and safety analyses on the safety population (all randomized patients who received at least one dose of study medication and had at least one safety assessment). All analyses were prespecified in the protocol.

The study was powered for the 6-month analysis with a sample size of 188 patients per treatment arm based on the following assumptions: a type 1 error of 2.5% (two-sided), a power of 80% in claiming equivalence, efficacy failure rate of 20% for MMF and a true failure rate for everolimus is 2.5% better than that of MMF. Furthermore, by assuming that the chronic allograft nephropathy rate at 3 years was 70% and 50% for MMF and everolimus groups, respectively; a sample size of 123 per arm was required to detect a difference of 20% between everolimus and MMF (two-sided type 1 error of 2.5% and power of 80%).

Efficacy failure (BPAR, graft loss, death, lost to follow-up) and its components were assessed using Kaplan–Meier survival analysis, Fisher's exact test, confidence intervals based on Z-test statistics and Cochran–Mantel–Haenszel tests stratified by center. Comparisons of the two everolimus dose groups with the MMF group were made using Z-test statistics. The Bonferroni and modified-Bonferroni (Hochberg) procedures were used to maintain the overall type 1 error rate of 0.05 for the two comparisons. Safety variables were evaluated by descriptive statistics, and between-group comparisons were made using the Wilcoxon rank sum test and Fisher's exact test, as appropriate. Creatinine values were analyzed for both on-treatment and ITT populations; the on-treatment analysis included values up to discontinuation of study medication and the ITT analysis used all available values, including off-treatment values. The analysis of drug trough levels used descriptive statistics and included results only of assays performed at Novartis Pharmaceuticals.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Appendix
  8. Acknowledgments
  9. References

Patient population and immunosuppressive therapy

Figure 1 shows the distribution of patients through the trial at 36 months. Of 588 patients who were enrolled, 194 were randomized to the everolimus 1.5 mg/day group, 198 to the everolimus 3 mg/day group and 196 to the MMF group. All patients received treatment. After 3 years overall, 88.1% of the patients completed the study and 50% completed 36 months of the study treatment (Figure 1). Significantly more patients discontinued study medication in the everolimus 3 mg/day group (113/198, 57.1% compared with MMF (81/196, 41.3%) (p = 0.002), mainly because of increased frequency of adverse events.

image

Figure 1. Disposition of patients in the trial. Patients who discontinued the study due to death or loss to follow-up included those who discontinued study treatment due to reasons other than death or loss to follow-up.

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Demographic and baseline clinical characteristics were similar across the groups except for a significantly lower proportion of male patients in the everolimus 1.5 mg/day group compared with the MMF group (14). Delayed graft function (defined as need for dialysis within 7 days post-transplant) was observed in a similar proportion of patients in each treatment group (everolimus 1.5 mg/day, 23%; 3 mg/day, 21%; MMF, 20%; p = NS).

Mean daily doses and plasma concentrations of immunosuppressive agents at 36 months are shown in Table 1. At month 36, the mean daily dose of all three immunosuppressants was lower than planned. The main reason for dose reductions was adverse events. CsA trough concentrations during year 3 were 10–25% lower in the everolimus groups compared with the MMF group, reflecting the lower target CsA concentrations recommended in the protocol amendment. At month 30, CSA levels were 113 and 101 ng/mL in the everolimus 1.5 and 3 mg/day groups, respectively, compared with 135 ng/mL in the MMF group. There were no significant between-group differences in mean steroid dose during the trial.

Table 1.  Dose and plasma levels of immunosuppressive agents at 36 months
 Everolimus 1.5 mg/dayEverolimus 3 mg/dayMMF 2 g/day
  1. NA = not applicable.

  2. Values are expressed as mean ± SD.

  3. ap < 0.0001, everolimus 1.5 mg/day vs. MMF.

  4. bp < 0.0001, everolimus 3 mg/day vs. MMF.

  5. cp = 0.019, everolimus 1.5 mg/day vs. everolimus 3 mg/day.

Mean daily dose of everolimus (mg)1.4 ± 0.32.3 ± 0.93NA
(n = 96)(n = 86) 
Mean daily dose of MMF (g)NANA1.7 ± 0.4 (n = 117)
Mean daily dose of CsA (mg/kg)2.1 ± 0.9a1.8 ± 0.84b,c2.6 ± 1.0
(n = 96)(n = 86)(n = 117)
Mean daily dose of steroids (mg/kg)0.1 ± 0.10.1 ± 0.10.1 ± 0.1
(n = 96)(n = 86)(n = 117)
Mean everolimus trough level (ng/mL)4.5 ± 2.47.4 ± 5.0NA
(n = 51)(n = 45) 
Mean CsA trough level (ng/mL)106 ± 70109 ± 74120 ± 42
(n = 55)(n = 45)(n = 56)

Efficacy

At 36 months, graft loss had occurred in 14 out of 194 (7.2%) patients in the everolimus 1.5 mg/day group compared with 33 out of 198 (16.7%) patients in the everolimus 3 mg/day and 21 out of 196 (10.7%) patients in the MMF (p = 0.2879, everolimus 1.5 mg/day vs. MMF; p = 0.1067 for everolimus 3 mg/day vs. MMF; p = 0.0048 for everolimus 1.5 mg/day vs. everolimus 3 mg/day) (Table 2). The incidence of death and BPAR was similar in all groups at 36 months. Figures 2 and 3 show Kaplan–Meier estimates of the incidence of BPAR and graft loss or death over the 36-month study period. The log-rank test showed no significant differences between the everolimus and MMF groups in rates of BPAR. Although the difference was not significant, the incidence of graft loss or death was higher in the everolimus 3 mg/day group compared with the MMF group. The reasons for graft loss are shown in Table 2. The groups showed similar rates of antibody-treated acute rejection (p = 0.9433 overall) and biopsy-proven chronic allograft nephropathy (p = 0.612 overall) (Table 2).

Table 2.  Efficacy assessments at 12 and 36 months (ITT population)
 Everolimus 1.5 mg/dayEverolimus 3 mg/dayMMF 2g/day
  1. Subcategories are not mutually exclusive.

  2. ap = 0.0048, everolimus 1.5 mg/day vs. everolimus 3 mg/day; p = 0.1067, everolimus 3 mg/day vs. MMF; p = 0.2879, everolimus 1.5 mg/day vs. MMF (Fisher's exact test).

  3. bp = 0.0103, everolimus 1.5 mg/day vs. everolimus 3 mg/day (Fisher's exact test).

  4. cp = 0.0347, everolimus 3 mg/day vs. MMF; p = 0.0052, everolimus 1.5 mg/day vs. everolimus 3 mg/day; p = 0.5725, everolimus 1.5 mg/day vs. MMF (Fisher's exact test).

12 months post-transplant
Graft loss9 (4.6%)21 (10.6%)18 (9.2%)
Death10 (5.2%)8 (4.0%)5 (2.6%)
Graft loss/death18 (9.3%)29 (14.6%)21 (10.7%)
BPAR45 (23.2%)39 (19.7%)47 (24.0%)
Antibody-treated acute rejection15 (7.7%)13 (96.6%)14 (97.1%)
Biopsy-proven chronic allograft nephropathy21 (10.8%)17 (8.6%)15 (7.7%)
Efficacy failure (BPAR episode, graft loss, death, or lost to follow-up)58 (29.9%)60 (30.3%)61 (31.1%)
Efficacy failure (graft loss, death, or lost to follow-up)21 (10.8%)33 (16.7%)23 (11.7%)
36 months post-transplant
Graft lossa14 (7.2%)33 (16.7%)21 (10.7%)
 Acute rejection3 (1.5%)6 (3.0%)5 (2.6%)
 Chronic rejection1 (0.5%)6 (3.0%)2 (1.0%)
 Infection1 (0.5%)5 (2.5%)2 (1.0%)
 Renal vein thrombosis01 (0.5%)4 (2.0%)
 Infarcted kidney1 (0.5%)2 (1.0%)0
 Renal artery thrombosis01 (0.5%)0
 Primary non-function002 (1.0%)
 Other8 (4.1%)11 (5.6%)6 (3.1%)
Death15 (7.7%)18 (9.1%)16 (8.2%)
Graft loss/deathb27 (13.9%)48 (24.2%)32 (16.3%)
BPAR47 (24.2%)49 (24.7%)52 (26.5%)
Antibody-treated acute rejection15 (7.7%)16 (8.1%)14 (7.1%)
Biopsy-proven chronic allograft nephropathy26 (13.4%)22 (11.1%)20 (10.2%)
Efficacy failure (BPAR episode, graft loss, death, or lost to follow-up)64 (33.0%)77 (38.9%)73 (37.2%)
Efficacy failure (graft loss, death, or lost to follow-up)c27 (13.9%)50 (25.3%)32 (16.3%)
image

Figure 2. Incidence of BPAR over 36 months in patients treated with everolimus 1.5 mg/day, everolimus 3 mg/day or MMF (p = 0.581 for everolimus 1.5 mg/day vs. MMF and p = 0.565 for everolimus 3 mg/day vs. MMF, log-rank test).

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image

Figure 3. Incidence of graft loss or death over 36 months in patients treated with everolimus 1.5 mg/day, everolimus 3 mg/day or MMF (p = 0.534 for everolimus 1.5 mg/day vs. MMF and p = 0.053 for everolimus 3 mg/day vs. MMF, log-rank test).

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At 36 months, the incidence of a composite endpoint of efficacy failure (BPAR, graft loss, death or loss to follow-up) did not differ significantly among the three treatment groups (p = 0.455 overall) (Table 2). The incidence of the combined endpoint consisting of graft loss, death or loss to follow-up was comparable for the everolimus 1.5 mg/day and MMF groups (p = 0.5725) but was significantly higher in the everolimus 3 mg/day group (p = 0.0347 vs. MMF and p = 0.0052 vs. everolimus 1.5 mg/day) (Table 2).

Renal function

Renal function in the ITT and on-treatment populations at 12, 24 and 36 months is shown in Table 3. In both populations, mean serum creatinine values were higher in the everolimus groups, particularly in the 3 mg/day cohort, compared with the MMF group. As a consequence this issue was addressed by a protocol amendment. Correspondingly, creatinine clearance values over 36 months were lower among patients treated with everolimus; in patients who received everolimus 3 mg/day, creatinine clearance was decreased significantly at 12, 24 and 36 months. At 12 and 36 months, a significantly higher proportion of patients treated with everolimus had high serum creatinine levels (defined as ≥354 μmol/L from day 8 to week 4 or ≥265 μmol/L after week 4) compared with those treated with MMF.

Table 3.  Renal function at 12, 24 and 36 months post-transplant (safety population)
ITT analysisaEverolimus 1.5 mg/dayEverolimus 3 mg/dayMMF 2 g/day
  1. aITT analysis includes all values, including those observed after treatment discontinuation; on-treatment analysis includes only values observed up to treatment discontinuation.

  2. bSignificant difference (p < 0.05) everolimus 1.5 mg/day vs MMF.

  3. cSignificant difference (p < 0.05) everolimus 3 mg/day vs MMF.

  4. dSignificant difference (p <0.05) everolimus 1.5 mg/day vs everolimus 3 mg/day.

  5. eHigh serum creatinine was defined as ≥354 μmol/L from day 8 to week 4 or ≥265 μmol/L after week 4.

Mean serum creatinine levels (μmol/L)
 12 months175 ± 82 (n = 168)216 ± 191 (n = 167)c,d183 ±171 (n = 180)
 24 months178 ± 136 (n = 160)b185 ± 92 (n = 151)c,d168 ± 131 (n = 161)
 36 months166 ± 86 (n = 164)196 ± 137 (n = 151)c,d173 ± 145 (n = 161)
Mean creatinine clearance (mL/min)
 12 months52 ± 21 (n = 168)47 ± 19 (n = 167)c54 ± 18 (n = 180)
 24 months55 ± 24 (n = 160)50 ± 20 (n = 151)c58 ± 22 (n = 161)
 36 months55 ± 23 (n = 164)50 ± 21 (n = 151)c57 ± 21 (n = 161)
% of patients with high serum creatinine levelse
 During 36-month study period128/194 (66.0%)b143/198 (72.2%)c104/196 (53.1%)
 At 36 months22/158 (13.9%)25/148 (16.9%)16/159 (10.1%)
On-treatment analysisa
Mean serum creatinine levels (μmol/L)
 12 months175 ± 78 (n = 124)b185 ± 77 (n = 120)c149 ± 36 (n = 138)
 24 months163 ± 63 (n = 100)b192 ± 96 (n = 89)c,d149 ± 71 (n = 118)
 36 months165 ± 75 (n = 92)199 ± 128 (n = 83)c,d146 ± 49 (n = 108)
Mean creatinine clearance (mL/min)
 12 months53 ± 21 (n = 124)b49 ± 17 (n = 120)c57 ± 15 (n = 138)
 24 months58 ± 22 (n = 100)52 ± 19 (n = 89)c62 ± 20 (n = 118)
 36 months58 ± 23 (n = 92)53 ± 20 (n = 83)c62 ± 20 (n = 108)
% of patients with high serum creatinine levelse
 During 36-month study period119 /193 (61.7%)b129/198 (65.2%)c92/195 (47.2%)
 At 36 months10/92 (10.9%)10/83 (12.1%)c4/108 (3.7%)

Safety

There were no significant differences in rates of death among the three treatment groups at 36 months (Table 2). Primary causes of death were myocardial infarction (three patients in the everolimus 1.5 mg/day group), sepsis (two patients in each group) and pneumonia (two patients in the everolimus 3 mg/day group).

All but four patients reported an adverse event during the 36-month study. Diarrhea, lymphocele and peripheral edema were significantly more common among at least one group of everolimus-treated patients compared with MMF, whereas CMV infection occurred more frequently in MMF-treated patients (Table 4). The incidence of malignancies was also similar for all three groups (5% of patients in each group); four cases of post-transplant lymphoproliferative disease (PTLD) were reported, all in the everolimus 1.5 mg/day group.

Table 4.  Adverse events at 36 months (safety population)
 Everolimus 1.5 mg/dayEverolimus 3 mg/dayMMF 2 g/day
  1. ap = 0.0002 and p = 0.025 for MMF vs. everolimus 1.5 mg/day and MMF vs. everolimus 3 mg/day, respectively.

  2. bp = 0.0001 for MMF vs. everolimus 1.5 mg/day and MMF vs. everolimus 3 mg/day.

Deaths15 (7.7%)18 (9.1%)16 (8.2%)
Infections
 Bacterial96 (49.5%)89 (44.9%)80 (40.8%)
 Viral26 (13.4%)38 (12.6%)57 (29.1%)a
 Fungal18 (9.3%)25 (12.6%)15 (7.7%)
CMV infection11 (5.7%)16 (8.1%)40 (19.9%)b
Malignancies10 (5.2%)9 (4.5%)9 (4.6%)
Lymphocele17 (9%)24 (12%)8 (4%)
Adverse events reported in ≥10% of patients
 Anemia54 (27.8%)71 (35.9%)59 (30.1%)
 Leukopenia20 (10.3%)24 (12.1%)30 (15.3%)
 Thrombocytopenia20 (10.3%)23 (11.6%)11 (5.6%)
 Diarrhea48 (24.7%)41 (20.7%)32 (16.3%)
 Edema38 (19.6%)44 (22.2%)34 (17.3%)
 Peripheral edema43 (22.2%)37 (18.7%)26 (13.3%)
 Diabetes mellitus13 (6.7%)25 (12.6%)11 (5.6%)

Nonfatal serious adverse events occurred more frequently with everolimus treatment (71 and 75% in the everolimus 1.5 and 3 mg/day groups, respectively) than with MMF treatment (62%) (p = 0.0540 for everolimus 1.5 mg/day vs. MMF and p = 0.0067 for everolimus 3 mg/day vs. MMF). The frequency of discontinuation of study medication because of adverse events was similar in the everolimus 1.5 mg/day and MMF groups (31 and 28%, respectively) but higher in the everolimus 3 mg group (39%) (p = 0.5792, everolimus 1.5 mg/day vs. MMF; p = 0.0327, everolimus 3 mg/day vs. MMF; p = 0.1376, everolimus 1.5 mg/day vs. everolimus 3 mg/day). The most common adverse event leading to discontinuation was hemolytic uremic syndrome (4% in the everolimus 3 mg/day group).

The overall incidence of infections did not differ significantly among the three groups, but the incidence of viral infection was significantly higher after treatment with MMF compared with everolimus 1.5 mg/day (p = 0.0002) or everolimus 3 mg/day (p = 0.025) (Table 4). In particular, CMV infection was reported significantly more frequently with MMF than with everolimus 1.5 mg/day (p = 0.0001) or everolimus 3 mg/day (p = 0.0001); there were no differences in the type or duration of CMV prophylaxis between groups. Urinary tract infection with Escherichia coli was more frequent in everolimus-treated patients (24 and 25%, respectively, vs. 18% with MMF; p = 0.1706, everolimus 1.5 mg/day vs. MMF; p = 0.1099, everolimus 3 mg/day vs. MMF).

Biochemical and hematologic abnormalities at 36 months are summarized in Table 5. Leukopenia (leukocyte count < 2.8 × 109/L) and neutropenia (neutrophil count < 1.5 × 109/L) were reported significantly more frequently in the MMF group than in the everolimus 3 mg/day group. Low platelet counts were associated more frequently with everolimus 3 mg/day and mean hemoglobin levels were significantly lower in both the everolimus groups. At 36 months, mean total cholesterol and triglyceride levels were significantly higher after treatment with either dose of everolimus than with MMF, although both cholesterol and triglyceride levels remained stable after 12 months. The frequency of patients with notably high cholesterol levels (≥9.1 mmol/L) was increased significantly in both everolimus groups, whereas the frequency of patients with notably high triglyceride levels (≥8.5 mmol/L) did not differ between groups. Levels of LDL-cholesterol and HDL-cholesterol did not differ significantly between the three groups at 36 months. Lipid-lowering agents, in general and HMG-CoA-reductase inhibitors in particular were used more frequently in patients treated with everolimus (Table 5). The incidence of hypertension was similar in the three groups at all time points.

Table 5.  Lipid and hematologic abnormalities over 36 months (safety population)
 Everolimus 1.5 mg/dayEverolimus 3 mg/dayMMF 2 g/day
  1. aSignificant difference (p < 0.05) everolimus 1.5 mg/day vs. MMF.

  2. bSignificant difference (p < 0.05) everolimus 3 mg/day vs. MMF.

Mean total cholesterol level (mmol/L)5.8 ± 1.0a6.0 ± 1.3b5.5 ± 1.0
(n = 87)(n = 80)(n = 104)
% of patients with total cholesterol level ≥9.1 mmol/L45 (23.1%)a57 (28.8%)b13 (6.6%)
(n = 194)(n = 198)(n = 196)
Mean triglyceride level (mmol/L)2.6 ± 1.7a2.8 ± 1.8b2.0 ± 1.2
(n = 87)(n = 81)(n = 105)
% of patients with triglyceride level ≥8.5 mmol/L11 (5.6%)13 (6.6%)3 (1.5%)
(n = 194)(n = 198)(n = 196)
Mean hemoglobin level (g/dL)12.9 ± 1.6a12.7 ± 2.2b13.5 ± 1.6
(n = 79)(n = 76)(n = 101)
% of patients receiving any lipid-lowering therapy126 (64.9%)a114 (57.6%)b86 (43.9%)
(n = 194)(n = 198)(n = 196)
% of patients receiving HMG CoA reductase inhibitors122 (62.8%)a110 (55.5%)b80 (40.8%)
(n = 194)(n = 198)(n = 196)
% of patients with leukocyte count <2.8 × 109/L11 (6%)10 (5%)b20 (10%)
(n = 194)(n = 198)(n = 196)
% of patients with platelet count ≤75 × 109/L8 (4%)14 (7%)5 (3%)
(n = 194)(n = 198)(n = 196)

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Appendix
  8. Acknowledgments
  9. References

We report the 3-year data of a large prospective randomized study that compared two doses of everolimus with MMF in combination with CsA and steroids in de novo renal transplant recipients. The 36-month results confirm and extend the 12-month findings, which demonstrated that everolimus, particularly the 1.5 mg/day dose, was as effective as MMF in preventing acute rejection and efficacy failure, and that the 1.5 mg/day dose of everolimus was better tolerated than the 3 mg/day dose (14). At 6 and 12 months, the primary composite endpoint of efficacy failure (BPAR, graft loss or death) of both doses of everolimus was equivalent to that of MMF, but at 36 months, graft failure rates were higher with everolimus 3 mg/day, supporting the need of long-term follow-up for more complete evaluation of any immunosuppressive strategy (15). Interestingly, compared with MMF the 1.5 mg/day dose of everolimus resulted in similar rejection rates and hard endpoints such as patient and graft survival in renal transplant recipients when administered in combination with CsA and steroids. CMV infections and leucopenia were more prominent in MMF-treated patients, renal dysfunction and hyperlipidemia were more common after treatment with everolimus; the 3 mg/day everolimus dose clearly had a worse safety profile and poor long-term tolerability. Because inferior renal function in both the everolimus groups led to concern over long-term outcome, the protocol was amended to recommend lower CsA levels for both the everolimus groups. Despite this safety intervention, renal function in both the everolimus arms was inferior in this 36-month analysis, suggesting that long-term administration of high doses of everolimus, especially in combination with regular doses of CsA, should be avoided.

Overall long-term outcomes of this large prospective trial were in line with previous studies with other immunosuppressive protocols. Rates of graft loss or death at 36 months with everolimus 1.5 mg/day (14%) and MMF (16%) were similar to those reported for MMF 2 g/day in the 3-year follow-up analyses (15.2–18.1%) (11,16) and sirolimus (14.9%) (17). In a parallel trial conducted in the United States with the same two doses of everolimus vs. MMF, rates of graft loss after 3 years were 11.9% (everolimus 1.5 mg/day), 7.7% (everolimus 3 mg/day) and 7.1% (MMF) (18). Another 3-year open-label trial of everolimus in de novo renal transplant has demonstrated good tolerability and excellent graft survival (96.6%) in patients receiving everolimus and reduced-exposure CsA (19).

Rates of BPAR, which may seem rather high today, were similar in all the three groups at both 12 and 36 months. Nearly identical 36-month rates of BPAR were observed in the sister trial of everolimus versus MMF conducted in the United States (19). Data from this study, as well as other pharmacokinetic analyses of everolimus (20–22), have revealed that in combination therapy with CsA an everolimus exposure above a threshold of 3 ng/mL is sufficient for excellent rejection prophylaxis. This goal was achieved in the majority of patients in the 1.5 mg/day dosing group; thus increased exposure in the 3 mg/day cohort resulted in similar efficacy but increased toxicity, as evidenced by the fact that everolimus 1.5 mg/day was better tolerated than everolimus 3 mg/day. The incidence of treatment discontinuation and serious adverse events, as well as the percentage of renal dysfunction, were higher in patients receiving everolimus 3 mg/day than those receiving 1.5 mg/day or MMF.

Consistent with the known side-effect profile of this class of immunosuppressants, both doses were associated with an increased incidence of hypercholesterolemia, hypertriglyceridemia and thrombocytopenia, compared with MMF. Levels of total cholesterol and triglycerides in both everolimus groups were elevated compared with those in the MMF group at 36 months, although lipid levels stabilized after 6 months posttransplant, probably through use of lipid-lowering agents. Interestingly, levels of LDL-cholesterol were similar in all groups, and the higher lipid levels in the everolimus groups did not translate into an increased incidence of major adverse cardiac events, although the relatively small number of patients does not permit firm conclusions. Further prospective long-term studies as well as observational analysis from large databases are needed to determine whether the hyperlipidemia associated with mTor-inhibitors increases risk for cardiovascular events, or whether the detrimental effects are offset by the well-described antiproliferative effects, which may lead to less intimal proliferation (5,23).

As pointed out, increasing evidence suggests that everolimus therapy should be guided by therapeutic drug monitoring (TDM) (21). As a consequence, a theoretical shortcoming of the present study was to omit TDM, but any double-blind design makes TDM rather difficult. Further approaches to optimize everolimus therapy in future trials are the reduction, avoidance or withdrawal of CsA. Due to the synergy between CsA and everolimus, similar low rejection rates have been achieved with much lower CsA exposure, which was better tolerated and resulted in better renal function (19). A CsA-sparing approach using C2 monitoring (24,25) results in acceptable rejection rates and may mitigate the nephrotoxicity of full-dose CsA. So far these regimens have not been compared directly with the CsA-MMF combination, and it is therefore difficult to draw any firm conclusions. The results of this and other studies conducted with everolimus underscore the need for additional investigations of concentration-controlled low-dose everolimus in combination with low-dose CsA or even CsA withdrawal to further improve the efficacy and safety with everolimus.

Immunosuppressive therapy in general is associated with an increased incidence of malignancy and infections, particularly opportunistic infections. At 36 months, the incidence of malignancy was 5% in each treatment group. The risk of viral infections, particularly CMV infection was significantly higher in the MMF group (20%) compared with either everolimus dose groups (6–7%). There is ongoing debate whether this reflects a beneficial effect of everolimus on viral infections, as has also been reported in heart transplant recipients (5), or whether MMF specifically increased the risk for viral and CMV infections. Because CMV infection is associated with increased morbidity and mortality (26,27), the avoidance of CMV infection is certainly an important goal in transplant medicine.

Renal function was consistently lower in both everolimus groups than in the MMF group, particularly in the 3 mg/day cohort. This observation parallels previous findings on the combined use of sirolimus and CsA (1,17), which was not foreseen at the beginning of the study. Aggravated CsA toxicity is the most likely cause of renal dysfunction observed in patients treated with CsA and mTOR-inhibitors, because mTOR-inhibitors themselves are devoid of nephrotoxicity. In response to this important safety concern a protocol amendment targeted lower CsA trough levels. This maneuver neither resulted in increased rejection rates, nor led to normalization of renal function when compared with the MMF–CsA group. Probably because of the fear of rejection with this novel regimen, many investigators in this trial were reluctant to lower CsA levels below 75 ng/mL, as was suggested in the protocol amendment. Importantly a recent report demonstrated that reduced-exposure CsA (trough level of 100 ng/mL initially, later 60–70 ng/mL) in combination with everolimus retains effective rejection prophylaxis while reducing renal toxicity (19). As in previous studies (10,11,16–19), renal function was defined as a safety parameter in this study, but today many physicians consider renal function an important efficacy parameter that has been shown to be an acceptable surrogate parameter for long-term graft function (28). During the course of the study it became evident that protocols of mTOR-inhibitor in combination with full-dose CNI-therapy are inferior with respect to renal function and long-term outcome when compared with a MMF-CsA regimen (29). Thus, today many physicians consider mTOR-inhibitors an effective means to spare CNI or to avoid them altogether (30,31).

In conclusion, the results of this study demonstrate that a regimen containing everolimus 1.5 mg/day, CsA and steroids was associated with equivalent rates of acute rejection and patient and graft survival compared with MMF plus CsA and steroids over the first 3 years after renal transplantation. In contrast, a higher dose of everolimus (3 mg/day) in combination with CsA resulted in inferior graft survival compared with the MMF-CsA regimen. CsA with either dose of everolimus was associated with inferior renal function compared with a regimen of CsA and MMF. It is important to note that the inferior renal function in everolimus-treated patients compared with MMF-treated patients requires close attention, especially with regard to CsA exposure. Further trials are needed to better define the role of everolimus in renal transplantation.

Appendix

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Appendix
  8. Acknowledgments
  9. References

Appendix: Study B201 Investigators

Australia: S.B. Campbell, Princess Alexandra Hospital and District Health Service, Woolloongabba; J.M. Eris, Royal Prince Alfred Hospital, Camperdown; G.R. Russ, The Queen Elisabeth Hospital, Woodville South; R.G. Walker, Royal Melbourne Hospital, Parkville. Austria: R. Margreiter, Universitätsklinik für Chirurgie, Innsbruck; F. Mühlbacher, Universitätsklinik für Chirurgie, Wien. Belgium: D. Abramowicz, Hôpital Erasme, Bruxelles; J. Malaise, Cliniques Universitaires St Luc, Bruxelles; Prof. Van Renterghem and D. Kuypers, University Hospital Gasthuisberg, Leuven. Czech Republic: A. Martinek, University Hospital, Ostrava-Poruba; S. Vitko, Institute of Clinical and Experimental Medicine, Praha. France: Y. Berland, Hôpital Sainte-Marguerite, Marseilles; F. Berthoux, Hôpital Nord, Saint-Etienne; B. Bourbigot, Hôpital de la Cavale Blanche, Brest; B. Charpentier, Hôpital Kremlin Bicêtre, Le Kremlin Bicêtre; J. Dantal, Hôpital Hôtel-Dieu, Nantes; D. Durand, Hôpital Rangueil, Toulouse; H. Kreis, Hôpital Necker, Paris; P. Lang, Hôpital Henri Mondor, Créteil; Y. Lebranchu, Hôpital Bretonneau, Tours; N. Lefrançois, Hôpital Edouard Herriot, Lyon; M. Kessler, CHR Brabois, Vandoeuvre les Nancy; C. Legendre, Hôpital Saint-Louis, Paris. Germany: B. Grabensee, Universitätsklinikum Klinik für Nephrologie und Rheumatologie, Düsseldorf; U. Heemann, Universitätsklinikum Abteilung für Nieren und Hochdruckkranke, Essen; J. Klempnauer, Kliniken der Medizinischen Hochschule Hannover, Hannover; U. Kunzendorf, Universität Erlangen-Medizinische Klinik I u. Poliklinik, Erlangen; H.-H. Neumayer, Universitätsklinik Charité Zentrum für Innere Medizin, Berlin; G. Offermann, Medizinische Klinik und Poliklinik, Berlin. Italy: E. Ancona, Policlinico—Università degli Studi, Padova; C. Ponticelli, Ospedale Maggiore—IRCCS, Milano; G. Rizzo, Az. Osp. Ospedali Riuniti S. Chiara, Pisa; S. Scolari, Policlinico S. Orsola-Malpighi, Bologna; U. Valente, Az. Osp. Ospedale S. Martino, Genova. Netherlands: J. de Fijter, Leiden Universitair Medisch Cemtrum, Leiden; R. Hene, Academisch Ziekenhuis Utrecht, Utrecht; A. Hoitsma, Academisch Ziekenhuis Nijmegen, Nierziekten; A. Tegzess, Academisch Ziekenhuis Groningen, Groningen; R.J.M. ten Berge, Academisch Medisch Centrum, Amsterdam; W. Weimar, Academisch Ziekenhuis Rotterdam/Dijkzight, Rotterdam. Norway: O. Øyen, Rikshospitalet, Oslo. Russia: P. Filiptsev, City Center for Kidney Transplantation, Moscow; V. Gorbounov, Clinical Hospital No. 119, Moscow Rerion; I. Moissiouk, Research Institute of Transplantology and Artificial Organs, Moscow. South Africa: M.R. Moosa, Tygerburg Hospital, Cape Town; H.G. Viljoen, Garden City Clinic, Johannesburg. Spain: J.J. Amenabar, Hospital de Cruces, Baracaldo; J.M. Grinyo, Hospital de Bellvitge, Barcelona; J.-M. Morales, Hospital 12 de Octubre, Madrid; M.A.A. Rodriguez, Hospital Marquis de Valdecilla, Santander; F.O. Salinas, Hospital Clinic I Provincial de Barcelona, Barcelona. Switzerland: P. Ambühl, Universitätspital Zürich, Zürich. United Kingdom: S.H. Sacks, Guy's Hospital, London; S.A. Sadek, St. Mary's Hospital, Portsmouth.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Appendix
  8. Acknowledgments
  9. References

This study was supported by Novartis Pharma AG.

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  4. Methods
  5. Results
  6. Discussion
  7. Appendix
  8. Acknowledgments
  9. References
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