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Keywords:

  • Acute allograft rejection;
  • delayed graft function (DGF);
  • mycophenolate mofetil;
  • renal function;
  • sirolimus;
  • tacrolimus

Abstract

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

Safety and efficacy of two sirolimus (SRL)-based regimens were compared with tacrolimus (TAC) and mycophenolate mofetil (MMF). Renal transplantation recipients were randomized to Group 1 (SRL+TAC; week 13 TAC elimination [n = 152]), Group 2 (SRL + MMF [n = 152]) or Group 3 (TAC + MMF [n = 139]). Group 2, with higher-than-expected biopsy-confirmed acute rejections (BCARs), was sponsor-terminated; therefore, Group 2 two-year data were limited. At 1 and 2 years, respectively, graft (Group 1: 92.8%, 88.5%; Group 2: 90.6%, 89.9%; Group 3: 96.2%, 95.4%) and patient (Group 1: 97.3%, 94.4%; Group 2: 95.2%, 94.5%; Group 3: 97.0%, 97.0%) survival rates were similar. One- and 2-year BCAR incidence was: Group 1, 15.2%, 17.4%; Group 2, 31.3%, 32.8%; Group 3, 8.2%, 12.3% (Group 2 vs. 3, p < 0.001). Mean 1- and 2-year modified intent-to-treat glomerular filtration rates (mL/min) were similar. Primary reason for discontinuation was adverse events (Group 1, 34.2%; Group 2, 33.6%; Group 3, 22.3%; p < 0.05). In Groups 1 and 2, delayed wound healing and hyperlipidemia were more frequent. One-year post hoc analysis of new-onset diabetes posttransplantation was greater in TAC recipients (Groups 1 and 3 vs. 2, 17% vs. 6%; p = 0.004). Between-group malignancy rates were similar. The SRL-based regimens were not associated with improved outcomes for kidney transplantation patients.


Abbreviations: 
AE

adverse event

AR

acute rejection

BCAR

biopsy-confirmed acute rejection

CMV

cytomegalovirus

CNI

calcineurin inhibitor

CS

corticosteroid

CsA

cyclosporine

DD

deceased donor

DGF

delayed graft function

Elim

elimination

GFR

glomerular filtration rate

HLA

human leukocyte antigen

LD

living donor

mITT

modified intent-to-treat

MMF

mycophenolate mofetil

NODAT

new-onset diabetes after transplantation

ORION

Optimizing Renal Transplant Immunosuppression to Overcome Nephrotoxicity

SCr

serum creatinine

SRL

sirolimus

TAC

tacrolimus

Introduction

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

The introduction of cyclosporine (CsA) in the 1980s greatly improved the rates of acute rejection (AR) and short-term renal allograft survival. However, the use of the calcineurin inhibitors (CNIs) CsA and tacrolimus (TAC) has been associated with both acute and chronic nephrotoxicity, which contribute to the development of interstitial fibrosis/tubular atrophy and late graft loss in renal transplant recipients (1–3). Recent studies have indicated that minimizing or eliminating CNIs from a regimen containing sirolimus (SRL) and corticosteroids (CS) may be beneficial with regard to long-term renal allograft function (4,5), as SRL appears to not have the same effect on the kidneys as CNIs (6). Approaches for using SRL in treatment regimens include use of SRL with lower doses of CNIs, CNI withdrawal/elimination or complete CNI avoidance (7–20). The purpose of this study was to evaluate the safety and efficacy of two SRL-based regimens, one with CNI elimination (SRL+TAC-Elim) and the other with complete CNI avoidance (SRL+mycophenolate mofetil [MMF]) compared with a CNI-based regimen containing TAC+MMF in de novo renal allograft recipients.

Materials and Methods

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

Study design

This was an open-label, randomized, comparative, multinational trial comparing 2 SRL-based regimens with TAC and MMF. Subjects were enrolled from March 2004 to May 2005. De novo renal allograft recipients (N = 469) were randomly assigned (1:1:1) to 1 of 3 treatment groups: SRL+TAC-Elim (Group 1), SRL+MMF (Group 2) and TAC+MMF (Group 3). All patients received CS and induction with daclizumab.

This study was conducted according to the Good Clinical Practice guidelines and the ethical principles of the Declaration of Helsinki. Approval for the study was obtained from the institutional review board or independent ethics committee of each participating center. All patients provided written informed consent upon enrollment. Safety was monitored on an ongoing basis by the sponsor (Wyeth).

Eligibility criteria

Patients eligible for enrollment were aged ≥18 years and scheduled to receive a primary or secondary renal allograft from a living donor (LD) or deceased donor (DD). Patients were excluded from participation if they had multiple organ transplants, body mass index >32 kg/m2, white cell count ≤3,000 per mm3, platelet count ≤100,000 mm3, fasting triglycerides ≥400 mg/dL, fasting total cholesterol ≥300 mg/dL and cold ischemia time (CIT) >30 h.

Two years after study initiation (June 2006, 1 year after all patients were accrued), Group 2 patients were discontinued from assigned therapy by the sponsor (not a data safety monitoring board) because of a higher-than-anticipated biopsy-confirmed AR (BCAR) rate. This decision was also based on higher-than-anticipated AR rates for a similar regimen in another clinical study conducted concurrently with this trial. Off-therapy adverse events (AEs) were collected for 1 month in these patients. Because of the termination, the mean on-therapy follow-up time for Group 2 (322 days) was less than the other groups (Group 1: 393 days, Group 3: 558 days). The protocol was subsequently amended to collect limited 2-year data in these patients, including patient and graft survival, renal function, ARs, serious infection, malignancy, delayed wound healing and lymphocele. Not all patients consented to this additional follow-up, further limiting data collection.

End points

The primary end point was Nankivell glomerular filtration rate (GFR) at 12 months after transplantation. Secondary end points included Nankivell GFR up to 2 years posttransplantation, serum creatinine (SCr), patient and graft survival, incidence and severity of BCAR and time to first BCAR. The incidence of AEs, including anemia, wound healing complications, hyperlipidemia, malignancy, delayed graft function (DGF) and urine protein–creatinine ratios, were included as secondary end points. Biopsies were required for suspected episodes of AR. The local pathologist used Banff 1997 criteria for diagnosis and severity grading of AR.

Treatment regimens

Within 48 h after transplantation, patients in Group 1 (SRL+TAC-Elim) received a loading dose of SRL up to 15 mg, followed by 5 mg/day to maintain trough concentrations of 8–15 ng/mL through week 13, then 12–20 ng/mL after TAC elimination. TAC was initiated within 24 h of transplantation with a dose up to 0.2 mg/kg/day (in divided doses) to maintain trough concentrations of 6–15 ng/mL through week 13, then decreased by 25% per week until fully eliminated. TAC was not eliminated if patients had Banff grade 3 AR or vascular rejection in the 4 weeks prior to week 13, dialysis dependency, SCr >4.5 mg/dL, inadequate renal function (in the opinion of the investigator) or SRL trough concentrations <8 ng/mL.

In Group 2 (SRL+MMF), a loading dose of up to 15 mg followed by 5 mg/day of SRL was initiated within 48 h after transplantation. The initial target trough concentrations of SRL were 10–15 ng/mL through week 13, 8–15 ng/mL through week 26, and 5–15 ng/mL thereafter. With an observed higher rate of AR during the study, the protocol was amended, approximately 4 months after the last patient was enrolled, to increase the lower limit for target SRL trough concentrations (10–15 ng/mL through week 26, and 8–15 ng/mL thereafter).

In Group 3 (TAC+MMF), an oral dose of up to 0.2 mg/kg/day of TAC was initiated within 24 h of transplantation. Target trough concentrations were 8–15 ng/mL through week 26 and 5–15 ng/mL thereafter.

MMF was initiated in Groups 2 and 3 within 24 h of transplantation, with an oral dose up to 2 g/day. MMF dose reductions were allowed; however, a minimum daily dose of 1 g was required.

All groups received CS tapered to 5 mg/day by week 13 and antibody induction with 2 doses of daclizumab 2 mg/kg (maximum of 100 mg) on the day of transplantation and on the day of hospital discharge (no later than 14 days after transplantation). Prophylaxis against Pneumocystis jiroveci pneumonia (based on local standards) was required in all patients during the first 12 months of the study. Also, all cytomegalovirus (CMV)-negative patients who received a kidney from a CMV-positive donor were required to receive prophylaxis with a nucleoside inhibitor for the first 3 months after transplantation.

Laboratory determinations

Study drug concentrations were determined using high-performance liquid chromatography (SRL) by a central laboratory or by standard monoclonal assays (TAC). Both SRL and TAC trough levels were obtained 5 to 7 days after the first dose, during TAC elimination (Group 1) at regular intervals throughout the study (months 1, 3, 6, 9, 12, 18 and 24) and during suspected rejection episodes.

Statistical methods

The primary end point was Nankivell GFR at 12 months. Two comparisons were planned: Group 1 versus 3 and Group 2 versus 3. To maintain an overall Type I error rate of 0.05, each of these comparisons had an alpha = 0.025 level. With 140 subjects per group, and assuming a standard deviation of 18 mL/min, there was approximately 90% power to detect differences of 8 mL/min in GFR between treatment groups (alpha = 0.025, two-sided).

Efficacy and safety analyses were conducted for the modified intent-to-treat (mITT) population, defined as all randomized patients who were transplanted and received at least 1 dose of study medication (SRL or TAC for Group 1, SRL for Group 2 and TAC for Group 3). The primary end point of Nankivell GFR at 12 months was analyzed with a one-way analysis of variance, with treatment group as a factor. Random coefficient models were used to assess Nankivell GFR over time. In the mITT population, GFR was imputed as zero for graft loss or death; last observation was carried forward for missing values. Comparisons between treatment groups of secondary end points, which were binary data, were made with Chi-square tests. Severity of AR was analyzed with a Cochran–Mantel–Haenszel row mean score test. Time-to-event end points were summarized using Kaplan–Meier statistics, with censoring at the last study visit.

Results

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

Patient demographics

A total of 469 patients were enrolled at 65 centers in Canada, United States, Europe and Australia. Of the 450 patients who underwent transplantation (19 patients were enrolled but not transplanted), 7 patients did not receive at least 1 dose of the assigned therapy. Thus, 443 patients were included in the study analysis (mITT population: n = 152 in SRL+TAC-Elim; n = 152 in SRL+MMF; n = 139 in TAC+MMF groups; Figure 1). Following study termination of Group 2, 68 patients consented to 2-year follow-up.

image

Figure 1. Patient disposition. BCAR = biopsy-confirmed acute rejection; Elim = elimination; MMF = mycophenilate mofetil; SRL = sirolimus; TAC = tacrolimus.

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Overall, baseline demographic characteristics were similar among treatment groups, with the exception of more males in the SRL groups compared with the TAC+MMF group (Table 1). The mITT population consisted of 443 patients (300 male and 143 female) between the ages of 19 and 76 years (mean, 49 years). The mean number of human leukocyte antigen mismatches, pretransplant (CMV) serologies and mean peak panel reactive antibodies were similar across the 3 groups. Mean cold ischemia time for all kidneys was 11 h, and 17 h for DD. The number of patients with panel reactive antibody levels of 20 or greater was similar across groups (11.3%). Approximately 60% of patients had received DD kidneys in all 3 groups (Table 1). The median donor age was also similar across the 3 groups; DD ages ranged in years from 1.9 to 82.0, with a median of 49; LD ages ranged in years from 19.6 to 66.5, with a median of 42.1. The number of donors aged 60 years or older was similar across groups (12.4%).

Table 1.  Baseline demographic characteristics
CharacteristicsGroup 1 SRL+TAC-Elim (n = 152)Group 2 SRL+MMF (n = 152)Group 3 TAC+MMF (n = 139)Total (N = 443)
  1. *p < 0.05.

  2. CMV = cytomegalovirus; DD = deceased donor; Elim = elimination; LD = living donor; HLA = human leukocyte antigen; MMF = mycophenilate mofetil; SRL = sirolimus; TAC = tacrolimus.

Age at transplant, mean (years) ± SD47.9 ± 13.350.4 ± 13.048.4 ± 13.248.9 ± 13.2
Gender, n (%)
 Male109 (71.7)110 (72.4)81 (58.3)*300 (67.7)
 Female43 (28.3)42 (27.6)58 (41.7)143 (32.3)
Ethnic origin, n (%)
 White114 (75.0)117 (77.0)102 (73.4)333 (75.2)
 Black14 (9.2)17 (11.2)15 (11.0)46 (10.4)
 Asian6 (4.0)4 (2.6)5 (3.6)15 (3.4)
 Other18 (11.8)14 (9.2)17 (12.2)49 (11.1)
Cause of renal failure, n (%)
 Hypertension22 (14.5)22 (14.5)17 (12.2)61 (13.8)
 Diabetes mellitus–Type I9 (6.0)10 (6.6)7 (5.0)26 (5.9)
 Diabetes mellitus–Type II18 (11.8)18 (11.8)10 (7.2)46 (10.4)
 Polycystic kidney disease11 (7.2)17 (11.2)21 (15.1)49 (11.1)
 Obstructive uropathy2 (1.3)4 (2.6)2 (1.4)8 (1.8)
 Glomerulonephritis38 (25.0)33 (21.7)27 (19.4)98 (22.1)
 Other52 (34.2)48 (31.6)55 (40.0)155 (35.0)
HLA-mismatches, class I and II, mean ± SD3.38 ± 1.543.36 ± 1.693.32 ± 1.693.35 ± 1.64
Transplant history
 Primary, n (%)141 (92.8)139 (91.5)128 (92.1) 
 Secondary, n (%)11 (7.2)13 (8.6)11 (7.9) 
Pretransplant CMV (IgG) recipient antibody status
 Negative65 (42.8)56 (36.8)44 (31.7)165 (37.3)
 Positive84 (55.3)94 (61.8)92 (66.2)270 (61.0)
 Unknown3 (2.0)2 (1.3)3. (2.2)8 (1.8)
Patients with peak panel of reactive antibodies ≥20% (%)11.211.810.811.3
Mean age of donor, years ± SD43.2 ± 13.645.5 ± 14.944.4 ± 13.944.4 ± 14.2
Median age of donor, years (range)
 DD47  (12–74)50 (2–82)49 (7–76)49 (2–82)
 LD41 (20–65)43 (21–65)41 (27–66)42 (20–66)
Donor age ≥60 years (%)8.615.113.712.4
Organ source, n (%)
 DD92  (60.5)96 (63.2)89 (64.0)277 (62.5)
 Living related36  (23.7)39 (25.7)31 (22.3)106 (23.9)
 Living unrelated24  (15.8)17 (11.2)19 (13.7)60 (13.5)
DD organ cold ischemia time, mean (hrs) ± SD17.7 ± 6.717.3 ± 5.717.4 ± 6.317.5 ± 6.2
Delayed graft function (%); DD18.527.122.5 
Delayed graft function (%); LD5.002.0 

The incidence of DGF, defined as the need for dialysis within the first 7 days after transplantation with subsequent recovery of renal function, was similar in all 3 groups for LD and DD (Table 1).

In patients who remained on assigned therapy, mean daily dosages at 6 and 12 months, respectively, were 5.9 to 7.6 mg of CS across all 3 groups at both time points and 1.4 to 1.6 g of MMF for Groups 2 and 3, in which MMF was coadministered. In the on-therapy populations in Groups 1, 2 and 3, respectively, the mean daily dosages of CS at 6 months were 6.9, 7.6 and 7.0 mg, and at 12 months were 6.5, 6.2 and 5.9 mg. In the on-therapy populations in Groups 2 and 3, respectively, the mean daily dosages of MMF were 1.62 and 1.48 g at 6 months and 1.57 and 1.41 g at 12 months. Daily doses of TAC and SRL were administered according to target blood level ranges (see Methods for target ranges and Results for BCAR for achieved).

Four-hundred six patients received 2 doses of daclizumab; the time to the second dose ranged from 2 to 18 days posttransplant, with a median of 8 days. In Group 1, 39/152 (25.7%) patients withdrew from assigned therapy prior to TAC withdrawal at week 13. TAC withdrawal was completed in 89/152 (58.6%) patients, with a mean time of 134 ± 35 days posttransplantation; 28 (31%) patients withdrew within 120 days and 77 (87%) withdrew within 168 days. The remaining patients, 24/152 (15.8%), did not complete withdrawal. Group 1 and 2 patients who discontinued assigned therapy (30.9% and 30.3%, respectively) went on a TAC-based regimen.

Primary and secondary efficacy outcomes

Renal function:  The primary end point of mean (±SD) Nankivell GFR for the mITT population at 1 year was 59.1 ± 23.9 and 59.3 ± 24.3 mL/min for Groups 1 and 2, respectively, and 62.0 ± 22.1 mL/min for Group 3 (Group 1 vs. 3; Group 2 vs. 3; p = NS). Mean Nankivell GFR was similar between Groups 1 and 3 (mITT) at weeks 26, 52, 78 and 104 (week 104: 58.3 mL/min vs. 62.2 mL/min; p = NS), and was also similar between Groups 2 and 3 at weeks 26 and 52 (mITT). The median Nankivell GFR was similar as well (Figure 3A). Because of Group 2 termination, the number of patients at weeks 78 and 104 was too small to make a comparison by mITT analysis. After Group 2 termination, 68 patients provided consent to collect data through 2 years; GFR was obtained in 57 of those patients at 2 years, with a mean of 63.4 mL/min.

image

Figure 3. (A) Estimated glomerular filtration rate in the modified intent-to-treat population.* (B) Estimated glomerular filtration rate in on-therapy patients.**GFR estimated by Nankivell formula. GFR = glomerular filtration rate.

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On-therapy Nankivell GFR at 1 year was 67.2 mL/min for Group 1 (n = 75), 68.2 mL/min for Group 2 (n = 77) and 66.8 mL/min for Group 3 (n = 101), with no significant differences at weeks 26, 52, 78 and 104 (week 104: Group 1: 67.2 mL/min [n = 55], Group 2: 70.6 mL/min [n = 4], Group 3: 67.7 mL/min [n = 83]; Figure 3B). Of note, only 4 patients were on therapy in Group 2 at week 104 prior to the termination. However, after the termination, GFR was obtained in 31 patients who were on SRL+MMF at 2 years. Mean GFR for the 31 patients and for the 4 patients on-therapy was 68.0 mL/min.

Similarly, mean SCr (mITT and on-therapy) at 26, 52, 78 and 104 weeks after transplantation was not significantly different in Groups 1 and 2 compared with Group 3.

Patient and graft survival:  At 1 and 2 years, no statistically significant differences in patient or graft survival between Groups 1 and 3 and Groups 2 and 3 occurred, with noted data limitations through 2 years in Group 2. In total, 39 graft losses (including death) occurred through 2 years: 17 in Group 1, 15 in Group 2 and 7 in Group 3. Kaplan–Meier estimates of graft survival at 2 years were 88.5%, 89.9% and 95.4% in Groups 1, 2 and 3, respectively (p = NS). The number of patients with technical (nonimmune) graft losses in Groups 1, 2 and 3 were 2, 4 and 0, respectively. Two patients in Group 1 underwent graft nephrectomy during the first week for renal vein thrombosis. In Group 2, two kidneys were removed, 1 for thrombosis related to donor disseminated intravascular coagulation and 1 for cortical necrosis. In addition, two Group 2 patients lost their grafts as a consequence of surgery, 1 for renal artery stenosis and 1 for ureteral stenosis.

In total, 21 deaths were reported through 2 years: 8 in Group 1, 8 in Group 2 and 5 in Group 3. Kaplan–Meier estimates of patient survival at 2 years were 94.4%, 94.5% and 97.0% in Groups 1, 2 and 3, respectively (p = NS). The causes of death for Group 1 were hepatic failure due to progression of hepatic cirrhosis (1), vascular disorder (1), respiratory distress syndrome (1), cerebrovascular accident (1), gastrointestinal disorder (1), sudden death (1), deep vein thrombophlebitis (1) and coronary artery disorder (1). In Group 2, the causes of death were cardiovascular disorder (2), pneumonia (2), sepsis (3) and hyperkalemia (1). The causes of death in Group 3 were death of unknown origin (1), cardiac arrest (2) and sepsis (2).

Biopsy-confirmed acute rejection:  The rate of BCAR was not significantly different between Groups 1 and 3 in the mITT population at 6 months, 1 year and 2 years (Table 2). Among Group 1 patients who completed TAC withdrawal, BCAR was reported in 11/89 (12.4%) patients following withdrawal. However, the rate of BCAR was significantly higher in Group 2 versus Group 3 in the mITT population at 6 months (25.7% vs. 6.5%, respectively; p < 0.001), 1 year and 2 years. Four of 45 (9%) Group 2 patients with 1-year BCAR were off SRL therapy when rejection was diagnosed. The severity of AR was not significantly different between groups, with most AR episodes being Banff Grade 1 (Table 2). Time to first BCAR (Figure 4) was significantly different between Groups 2 and 3 (p < 0.0001); however, time was not significantly different between Groups 1 and 3 (p = 0.233).

Table 2.  Summary of patient survival, overall graft survival1, and biopsy-confirmed acute rejection (mITT) at 1 and 2 years2
End PointGroup 1 SRL+TAC-Elim (n = 152)Group 2 SRL+MMF (n = 152)Group 3 TAC+MMF (n = 139)
  1. *p < 0.001, Group 2 versus Group 3.

  2. 1Graft loss including death.

  3. 2Note: Data limitations through 2 years in Group 2.

  4. 3Percentages are the proportion of acute rejection episodes, not the proportion of total patients.

  5. AR = acute rejection; BCAR = biopsy-confirmed acute rejection; CI = confidence interval; Elim = elimination; MMF = mycophenilate mofetil; SRL = sirolimus; TAC = tacrolimus.

Patient survival (%)
 1 year97.395.297.0
   95% CI93.0–99.090.2–97.792.2–98.9
 2 year94.494.597.0
   95% CI89.0–97.189.3–97.292.2–98.8
Overall graft survival (%)
 1 year92.890.696.2
   95% CI87.3–95.984.6–94.391.1–98.4
 2 year88.589.995.4
   95% CI82.2–92.783.8–93.890.1–97.9
BCAR, n (%)
 1 year315.231.38.2
   95% CI10.2–22.124.4–39.54.6–14.3
 2 year*17.432.812.3
   95% CI12.1–24.625.7–41.17.7–19.3
AR severity, n (%)*
Banff Grade 1
 1 year17/22 (77.3)32/45 (71.1)5/11 (45.5)
 2 year20/25 (80.0)34/47 (72.3)10/16 (62.5)
Banff Grade 2
 1 year5/22 (22.7)13/45 (28.9)6/11 (54.5)
 2 year5/25 (20.0)13/47 (27.7)6/16 (37.5)
image

Figure 4. Time to first biopsy-confirmed acute rejection in the modified intent-to-treat population.

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Group mean trough concentrations were within the protocol-specified target ranges at all time points for SRL (Groups 1 and 2) and TAC (Group 3); at 1 year, SRL was 14.4 ng/mL and 12.0 ng/mL and TAC was 8.9 ng/mL, respectively. However, as most episodes of BCAR occurred in the first 6 months in Group 2, individual patient levels were reviewed post hoc to determine whether they had trough levels within the target range. Specifically, SRL trough blood levels 10–15 ng/mL at week 1 and at months 1, 3 and 6 were reviewed. Patients with 2 or more SRL trough levels <10 ng/mL or 1 level <10 ng/mL within 14 days of BCAR were categorized as having SRL trough levels ‘below the target range’. In Group 2, 31% (47/152) of patients had SRL blood levels below the target range during the first 6 months. The percentage of patients with SRL levels below the target range was significantly higher in rejectors (56.4%) compared with nonrejectors (24.3%, p < 0.001; Figure 2). Therefore, more than half of Group 2 recipients with BCAR had levels of SRL below the target range during the first 6 months after transplantation. In addition, a center effect was apparent among the 7 centers that enrolled more than 5 patients in Group 2; these centers reported a lower mean 1-year BCAR rate of 17% compared with 29.6% for all centers.

image

Figure 2. Frequency of low sirolimus whole-blood trough concentrations in Group 2 patients.‘Within target range’ defined as sirolimus trough blood levels 10–15 ng/mL at week 1 and at months 1, 3 and 6. Two or more sirolimus trough levels <10 ng/mL, or 1 level <10 ng/mL within 14 days of biopsy-confirmed acute rejection, was considered ‘below target range’.

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Adverse events

The primary reason for discontinuation was AEs (34.2% in Group 1, 33.6% in Group 2, 22.3% in Group 3, p < 0.05; Figure 1). The most common AEs that led to discontinuation in Group 1 included: thrombocytopenia, pneumonia, infection, kidney tubular necrosis, urinary tract disorder; in Group 2: thrombocytopenia, pneumonia, infection and in Group 3: infection, abnormal kidney function, CNI toxicity. After Group 2 termination, patients in this group were followed for any AEs of special interest (AR, serious infection, life-threatening event, malignancy, death and graft loss) for up to 24 months after transplantation. As previously noted, only 68 patients provided consent for this follow-up. Thus, in Group 2, the duration of study drug exposure and AE monitoring was less than that in Groups 1 and 3.

The incidence of treatment-emergent AEs varied among groups and reflected previously described AEs most commonly associated with the specific agents (Table 3). Patients receiving SRL-containing therapy (Groups 1 and 2) experienced more peripheral edema, anemia, thrombocytopenia, hyperlipidemia, proteinuria, acne, delayed wound healing and lymphoceles. In contrast, patients receiving TAC-based therapy (Groups 1 and 3) experienced more hyperkalemia, tremor and new-onset diabetes. There were no differences in the rates of malignancy (Table 3) or infection (Group 1, 61.2%; Group 2, 63.8% and Group 3, 66.9%) between groups. There were no differences in mean systolic or diastolic blood pressure or in the use of antihypertensive therapy between groups at any time point.

Table 3.  Commonly reported treatment-related adverse events
 Group 1 SRL+TAC-Elim1 (n = 152)Group 2 SRL+MMF1 (n = 152)Group 3 TAC+MMF1 (n = 139)Total
  1. *Overall p < 0.05 between groups.

  2. **p < 0.05 SRL+TAC-Elim versus TAC+MMF.

  3. 1Data collected for 2 years in Groups 1 and 3, and to time of study termination in Group 2.

  4. 2One subject in Group 3 reported 2 events.

  5. Elim = elimination; MMF = mycophenilate mofetil; SRL = sirolimus; TAC = tacrolimus.

(N = 443)
Peripheral edema*78   (51.3)**75   (49.3)51   (36.7)204   (46.0)
Anemia62   (40.8)73   (48.0)50   (36.0)185   (41.8)
Diarrhea46   (30.3)63   (41.4)59   (42.4)**168   (37.9)
Hypertension62   (40.8)54   (35.5)48   (34.5)164   (37.0)
Hyperlipidemia*56   (36.8)**65   (42.8)28   (20.1)149   (33.6)
Tremor*33   (21.7)12   (7.9)34   (24.5)79   (17.8)
Hyperkalemia*36   (23.7)17   (11.2)25   (18.0)78   (17.6)
Delayed wound healing*25   (16.4)**35   (23.0)8   (5.8)68   (15.3)
Lymphoceles*25   (16.4)28   (18.4)12   (8.6)65   (14.7)
Thrombocytopenia*20   (13.2)**25   (16.4)4   (2.9)49   (11.1)
Proteinuria17   (11.2)22   (14.5)9   (6.5)48   (10.8)
Acne*19   (12.5)**14   (9.2)3   (2.2)36   (8.1)
All malignancies7   (4.6)5   (3.3)5   (3.6)217   (3.8)
 Lymphoma001   (0.7)1   (0.2)
 Skin6   (3.9)4   (2.6)1   (0.7)11   (2.5)
 Renal002   (1.4)2   (0.5)
 Urogenital1   (0.7)1   (0.7)2   (1.4)4   (0.9)

Laboratory determinations

The median urinary protein to creatinine ratio (UPr/Cr) was similar at week 13 between groups (Group 1: 0.21, range 0.06–17.43; Group 2: 0.28, range 0.02–3.05 and Group 3: 0.16, range 0.01–3.51; p = NS). At 1 year, the median UPr/Cr was significantly different in Group 1 versus 3 (Group 1: 0.20, range 0.01–2.46; Group 3: 0.15, range 0.00–0.89; p = 0.002) and Group 2 versus 3 (Group 2: 0.26, range 0.03–7.94; Group 3: 0.15, range 0.00–0.89; p < 0.001). At 2 years, the median UPr/Cr was significantly different between Groups 1 and 3 (Group 1: 0.21, range 0.04–1.78; Group 3: 0.13, range 0.00–1.33; p = 0.01); there were too few patients in Group 2 (n = 4) to make a conclusion. There was no significant difference through 1 year in the number of patients who had a UPr/Cr≥3 (2.2%, 4.9% and 4.3%; p = NS for Groups 1, 2 and 3, respectively) or when analyzed for UPr/Cr≥1 (13.5%, 12.3% and 8.5%; p = NS).

At 1 year, mean total cholesterol, low-density lipoprotein cholesterol and triglyceride values were significantly higher in Groups 1 and 2 versus Group 3. Similar results were observed at 2 years; however, data were limited in Group 2. Of note, most patients were receiving lipid-lowering therapy (Group 1, 61.2%; Group 2, 58.6% and Group 3, 50.4%; p = NS).

Mean hemoglobin values were not significantly different between Groups 1 and 3 at 1 year (132 g/L vs. 137 g/L; p = NS) or at 2 years (134 g/L vs. 139 g/L, p = NS). However, mean hemoglobin values were significantly lower in Group 2 versus 3 at 1 year (129 g/L vs. 137 g/L; p < 0.05); data were limited in Group 2 at 2 years. The use of erythropoiesis-stimulating agents was higher with SRL regimens (Group 1, 35.5%; Group 2, 42.1% and Group 3, 27.3%; overall p < 0.05).

In a post hoc analysis, new-onset diabetes mellitus after transplantation (NODAT, defined as requiring either oral hypoglycemic medication or insulin, or a combination of the 2, for more than 30 days total in patients not diagnosed with diabetes mellitus prior to enrollment) at 1 year was significantly greater in Group 1 (22.5%, 27/120) compared with Group 3 (10.9%, 12/110; p < 0.05). Of note, 21 of the 27 patients in Group 1 were receiving TAC at the time of diabetes onset. In Group 2 at 1 year, 6.0% (7/117) of patients developed NODAT compared with Group 3; p = 0.0232. However, the incidence of NODAT was significantly less in Group 2 (6.0%, 7/117) compared with those recipients receiving TAC (Groups 1 and 3: 17.0%, 39/230; p = 0.004).

Discussion

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

This randomized, open-label, multicenter study compared 3 immunosuppressive regimens in first or second renal allograft recipients. Treatments were administered for up to 2 years in Groups 1 and 3 and until sponsor termination in Group 2. No significant differences were noted between groups in the primary end point of Nankivell GFR. While the study demonstrated that the incidence of BCAR was significantly higher with a CNI-free strategy, there was no significant difference in patient survival, high-grade rejections or DGF. Although not statistically significant, rates of graft loss (including death with a functioning graft) were numerically higher in both SRL groups. Proteinuria, although significantly greater in SRL-treated patients at 1 year, was minimal in all groups. Additionally, the SRL groups had a greater number of discontinuations versus the TAC group. The safety profile for SRL-containing regimens differed from the TAC–MMF regimen.

Clinical trials that evaluated the combination of SRL and CNIs have shown a detrimental effect on renal function with full doses of CNIs (21–23). In a phase 2 trial, the combination of reduced-dose CsA with SRL+CS decreased AR rates compared with controls (CsA+CS), but had little effect on renal function (7). Improved renal function has been reported only when CNIs are withdrawn from a CNI plus SRL regimen (8–13,20). The Rapamune Maintenance Regimen (RMR) trial provided confirmation that early and complete withdrawal of CsA from the SRL+CsA+CS regimen is safe and effective in patients with mild to moderate immunologic risk. By 4 years, Nankivell GFR was significantly better with SRL+CS compared with SRL+CsA+CS (43.4 mL/min vs. 58.3 mL/min; p < 0.001), without a significant difference in BCAR (13). Most of the CNI withdrawal trials were based on SRL+CsA. In the ORION study, TAC was used with SRL before elimination beginning at 13 weeks, and at 1 and 2 years we found no significant difference in BCAR rates or GFR compared with patients receiving TAC and MMF. Although an increase in AR rates was observed following TAC withdrawal, the overall AR rate was comparable (15.2% vs. 8.2%; Table 2), which may be attributable to the use of an IL2R antibody for induction in ORION. With regard to GFR, a difference may not have been observed owing to the duration of follow-up not being long enough to permit differences to emerge. Another factor may be related to the higher number of patients who discontinued SRL, with many going on to TAC-based therapy, thus reducing the treatment regimen difference.

Prior randomized clinical trials have reported good outcomes, such as similar patient and graft survival, AR rates of 15% or less, and improved renal function with CNI-free regimens using a depleting or nondepleting induction antibody with SRL, MMF and CS maintenance therapy (15,17–19,24–26). Another large, single-center experience reported similar good results (27). In each of these trials, investigators targeted SRL C0 levels at 10–20 ng/mL during the first 6 months. A meta-analysis of CNI-free, SRL-based regimens confirmed a greater number of ARs with levels below this threshold (28). In the ORION study, we found increased AR rates in Group 2, which led to sponsor termination of that group. This outcome may be attributed in part to C0 levels of SRL below the target range, identified in 56% of Group 2 recipients with BCAR (Figure 2). In this study, an abbreviated dosing schedule of 2 doses of daclizumab was required per protocol and could have been a factor in the higher AR rates observed with a CNI-free regimen. Another open-label, randomized, multicenter study (Wyeth, Study 318) was designed to examine the safety and efficacy of SRL versus CsA in regimens containing basiliximab, MMF and CS in de novo renal transplant recipients. This study was terminated because of a significantly higher rate of BCAR observed in the group receiving SRL (SRL, 17.5% vs. CsA, 2.5%; unpublished data). Target SRL trough concentrations for the CNI-free regimen were similar to those in ORION.

Similar outcomes were seen in the SYMPHONY study that was conducted to determine whether the use of 2 g of MMF would permit lower-dose administration of SRL or CNIs to minimize toxicity (29). In this 4-arm study, initial SRL levels were targeted at 4–8 ng/mL. The 1-year rate of BCAR in the low-dose SRL group was higher than the other treatment groups (25.8%, standard dose CsA; 24.0%, low-dose CsA; 12.3%, low-dose TAC; 37.2%, low-dose SRL; p < 0.001) and similar to Group 2 of the ORION study (31.3%). Higher rates of BCAR may have resulted in renal dysfunction, thus leading to the lack of difference in renal function for de novo CNI-free immunosuppression, and may have been a major cause of discontinuation of patients in multicenter trials such as the ORION study.

The side effect profile of SRL with or without MMF is different from that observed with TAC+MMF. For example, peripheral edema and acne were reported more frequently in SRL+TAC patients, whereas delayed wound healing, lymphoceles and hyperlipidemia were reported more often in SRL+MMF patients, and in TAC+MMF patients, hyperkalemia and tremors were observed more frequently (Table 3). We found no significant differences between groups in the use of lipid-lowering agents, which was similar to that reported in a systematic review of SRL use (30). We did find a significantly higher rate of erythropoiesis-stimulating agent use for anemia in the SRL groups (35.5% and 42.1% vs. 27.3%; p < 0.05). Higher rates of NODAT at 1 year were seen in the TAC groups (Groups 1 and 3) compared with Group 2 (17% vs. 6%; p = 0.004), with the highest rate in Group 1, which is consistent with previously reported database analyses, suggesting an increased risk with a SRL+TAC combination (31).

In conclusion, this study provides 2-year outcome data using 2 SRL-based regimens compared with TAC+MMF in adult recipients of first or second kidney transplants. No significant differences in patient survival, Nankivell GFR or DGF were found between groups. Although not statistically significant, rates of graft loss (including death with a functioning graft) were numerically higher in both SRL groups. The SRL groups had a greater number of discontinuations, particularly related to AEs. In addition, the de novo regimen of SRL+MMF resulted in a greater number of BCAR episodes. The 2 SRL-based regimens used in this study were not associated with improved outcomes for kidney transplantation patients.

Acknowledgments

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

The authors would like to recognize Carolyn Hahn for her contributions to study coordination and data review, Qin Jiang for her assistance with biostatistics, and Joan Korth-Bradley for her assistance with pharmacokinetics; all are employees of Pfizer Inc, Collegeville, PA. The authors express gratitude to Sara Parambil (Pfizer Inc., Collegeville, PA) for assistance with preparation of the manuscript. We thank Albert Balkiewicz, MSc, of Peloton Advantage for editorial assistance with manuscript preparation, which was funded by Pfizer Inc. This study was sponsored by Wyeth, which was acquired by Pfizer Inc in October 2009.

The authors also thank the Sirolimus ORION Trial Study Group: N. Ahsan, Mayo Clinic of Jacksonville, Jacksonville, FL; E. Akalin, Recanati/Miller Transplantation Institute, Mount Sinai School of Medicine, New York, NY; W. Arns, Krankenhaus Merheim, Köln Merheim, Germany; A. Asderakis, University Hospital of Wales, Heath, Cardiff, UK; G. Burke, Jackson Memorial Hospital, Miami, FL; K. Butt, Westchester Medical Center, Valhalla, NY; S.B. Campbell, Princess Alexandra Hospital, Queensland, Australia; J.M. Campistol, Hospital Clinic i Provincial, Barcelona, Spain; M. Castagneto, Universita Cattolica Policlinico Gemelli, Rome, Italy; S. Chadban, Royal Prince Alfred Hospital, Camperdown, Australia; L. Chan, University of Colorado Hospital, Aurora CO; P.A. Clavien, Klinik fur Viszeral-Transplantationschirurgie, Zurich, Switzerland; S. Cockfield, University of Alberta, Edmonton, Alberta, Canada; A. Farney, Wake Forest University, Winston-Salem, NC; S.M. Flechner, Cleveland Clinic Foundation, Cleveland, OH; M. Glyda, Szpital Wojewodzki, Poznan, Poland; J.M. Grinyo, Hospital Bellvitge, Barcelona, Spain; R. Gohh, Rhode Island Hospital, Providence, RI; S. Goral, University of Pennsylvania Health System, Philadelphia, PA; A. Guasch, Emory University, Atlanta, GA; D.E. Hricik, University Hospitals of Cleveland, Cleveland, OH; T. Johnston, University of Kentucky, Lexington, KY; J. Jonsson, Inova Transplant Center, Fairfax, VA; C. Legendre, Hopital Necker, Paris, France; M. Klinger, Wroclaw Medical University, Wroclaw, Poland; S. Kulkarni (formerly A. Friedman, M. Lorber), Yale University School of Medicine, New Haven, CT; D. Kuypers, Univ. Hospital Gasthuisberg, Leuven, Belgium; P. Kuo, Duke University Medical Center, Durham, NC; J. Magee, University of Michigan Health System, Ann Arbor, MI; D. Mital, Rush University Medical Center, Chicago, IL; B. Mistry, Merit Care Medical Group, Fargo, ND; J.M. Morales, Hospital 12 de Octubre, Madrid, Spain; M. Mourad (formerly J.P. Squifflet), Cliniques Universitatires Saint-Luc, Brussels, Belgium; S. Mulgaonkar, St. Barnabas Medical Center, Livingston, NJ; N. Nezakatgoo (formerly O. Gaber), UTHSC/Methodist University Transplant Institute, Memphis, TN; O. Pankewycz, Buffalo General Hospital, Buffalo, NY; P. Patton, Shands Hospital, University of Florida, Gainesville, FL; F. Pietruck, University Essen, Essen, Germany; J. Pratschke, Charite Universitatsmedizin Berlin, Berlin, Germany; G. Russ, The Queen Elizabeth Hospital, Woodville South, Australia; C. Sanders, Lifelink Transplant Institute, Tampa, FL; G. Segoloni, Azienda Ospedaliera Le Molinette, Torino, Italy; F. Shihab, University of Utah, Salt Lake City, UT; A. Shoker, St. Paul's Hospital, Saskatoon, SK, Canada; S. Stefoni, Azienda Ospedaliera St Orsola Malpighi, Bologna, Italy; M. Stegall, Mayo Clinic, Rochester, MN; S. Steinberg, Sharp Memorial Hospital, San Diego, CA; D. Van Buren, Texas Tech University Health Sciences Center, UMC Transplant Clinic, Lubbock, TX; F. Vincenti, University of California, San Francisco, CA; R. Walker, Royal Melbourne Hospital, Parkville, VIC, Australia; C. Watson, Addenbrooke's Hospital, Cambridge, UK; K. West (formerly J. Lawen), Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada; J. Whelchel, Piedmont Hospital, Atlanta, GA; K.M. Wissing, Hopital Erasme, Brussels, Belgium; H. Wolters, Klinik und Poliklinik fur Allgemeine Chirurgie der Universitat Munster, Munster, Germany; A. Yoshida, Henry Ford Hospital, Detroit, MI; J. Zaltzman, St. Michael's Hospital, Toronto, ON, Canada.

Disclosure

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

Flechner SM: has received consulting income from Bristol-Myers Squibb Company, Novartis Pharmaceuticals Corporation, TcL Pharma SAS and Wyeth Pharmaceuticals.

Glyda M: declares no commercial associations that might pose a conflict of interest in connection with the submitted manuscript.

Cockfield S: declares no commercial associations that might pose a conflict of interest in connection with the submitted manuscript.

Grinyo J: declares no commercial associations that might pose a conflict of interest in connection with the submitted manuscript.

Legendre C: declares no commercial associations that might pose a conflict of interest in connection with the submitted manuscript.

Russ G: has received honoraria from Wyeth Pharmaceuticals, Novartis Pharmaceuticals Corporation, Bristol-Myers Squibb Company and Astellas Pharma Inc.

Steinberg S: declares no commercial associations that might pose a conflict of interest in connection with the submitted manuscript.

Wissing KM: has received research grants from Astellas Pharma Inc and lecture fees from Astellas Pharma Inc and Roche Pharmaceuticals.

See Tai S: an employee of Wyeth Pharmaceuticals, which was acquired by Pfizer Inc in October 2009.

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  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References
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