one-year results with extended-release tacrolimus/mmf, tacrolimus/mmf and cyclosporine/mmf in de...

American Journal of Transplantation 2007; 7: 595–608Blackwell Munksgaard

C© 2007 The AuthorsJournal compilation C© 2007 The American Society of

Transplantation and the American Society of Transplant Surgeons

doi: 10.1111/j.1600-6143.2007.01661.x

One-Year Results with Extended-Release Tacrolimus/MMF, Tacrolimus/MMF and Cyclosporine/MMF in DeNovo Kidney Transplant Recipients

H. T. Silva Jr.a, H. C. Yangb, M. Abouljoudc,

P. C. Kuod, K. Wisemandlee, P. Bhattacharyae,

S. Dhaddae, J. Holmane, W. Fitzsimmonse and

M. Roy Firste,∗ for the Tacrolimus

Extended-Release De Novo Kidney Study

Group†

aHospital do Rim E Hipertansa, Sao Paulo, BrazilbPinnacle Health, Polyclinic Hospital, Harrisburg, PAcTransplant Surgery, Henry Ford Hospital, Detroit, MIdTransplant Surgery, Duke University Medical Center,Durham, NCeAstellas Pharma US, Inc., Deerfield, IL†See Appendix 1 for a list of members of the TacrolimusExtended-Release De Novo Kidney Study Group.∗Corresponding author: M. Roy First,[email protected]

Once-daily tacrolimus extended-release formulation(Prograf XL, formerly referred to as MR or MR4)was compared with the twice-a-day tacrolimus for-mulation (TAC) and cyclosporine microemulsion (CsA),all administered in combination with mycophenolatemofetil (MMF), corticosteroids and basiliximab induc-tion, in a phase 3, randomized (1:1:1), open-label trialin 638 de novo kidney transplant recipients. In combi-nation with MMF and corticosteroids, XL had an effi-cacy profile comparable to TAC and CsA. XL/MMF andTAC/MMF were statistically noninferior at 1-year post-transplantation to CsA/MMF for the primary efficacyendpoint, efficacy failure (death, graft loss, biopsy-confirmed acute rejection (BCAR) or lost to follow-up). One-year patient and graft survival were 98.6%and 96.7% in the XL/MMF group, 95.7% and 92.9% inTAC/MMF group and 97.6% and 95.7% in CsA/MMFgroup. The safety profile of XL in comparison with CsAwas similar to that observed with TAC in this study andconsistent with previously published reports of TAC incomparison with CsA. The results support the safetyand efficacy of tacrolimus in combination with MMF,corticosteroids and basiliximab induction, as well asXL as a safe and effective once-daily dosing alterna-tive.

Key words: De novo kidney transplantation, tacrolimus

Received 28 April 2006, revised 27 October 2006 andaccepted for publication 4 November 2006

Introduction

The efficacy and safety profiles of tacrolimus (Prograf®,Astellas Pharma US, Inc., Deerfield, IL; TAC) as an im-munosuppressive agent to prevent graft rejection arewell-defined (1–8). Tacrolimus extended-release formula-tion (Prograf XL, formerly referred to as MR or MR4)has been developed as a once-daily tacrolimus dosing al-ternative that enables the same patient care strategiesand therapeutic monitoring techniques as used with TAC.Since noncompliance with dosing can be a significant fac-tor related to graft rejection and late graft loss, a once-daily dosing regimen could be a beneficial addition tothe existing treatment armamentarium (9,10). A large,randomized, open-label study was designed to evaluatethe efficacy and safety of XL and TAC compared to thatof cyclosporine microemulsion (Neoral®, PharmaceuticalsCorp., East Hanover, NJ; CsA) when administered in combi-nation with mycophenolate mofetil (MMF), corticosteroidsand basiliximab induction, in de novo kidney transplant re-cipients. Herein, we report the 1-year results of this study.

Materials and Methods

Study design

This was a phase 3, randomized (1:1:1), open-label, multicenter, three-arm(XL/MMF, TAC/MMF, CsA/MMF) noninferiority study conducted in 60 cen-ters in the United States, Canada and Brazil. Patient enrollment began inJuly 2003 and the last evaluation was performed in April 2005. Randomiza-tion was obtained by the principal investigator or designee via telephoneto the sponsor’s automated randomization system after informed consentwas obtained and after it was established that the patient met the eligibilitycriteria. Within each treatment group, patients were stratified by numberof previous transplants (primary or retransplant) and by donor type (livingor deceased). Study visits were scheduled for days 1, 2, 3, 4, 7, 10, 14,21, and months 1, 2, 4, 6, 8, 10 and 12 posttransplant. The study protocolwas approved by an Institutional and/or Regional Review Board at all partic-ipating study centers to ensure that study procedures were performed inaccordance with the Helsinki Declaration.

At the investigator’s discretion, patients were allowed to cross over to theother calcineurin inhibitor regimen to address adverse events or severerefractory rejection that led to discontinuation of randomized study drug;however, crossover to the XL/MMF arm was not permitted. Patients whocrossed over or discontinued primary study drug (but did not withdraw con-sent) were followed throughout the course of the study.

Inclusion criteria were male and female patients ≥12 years of age who re-ceived a primary or retransplanted deceased donor or non-HLA-identicalliving kidney transplant provided they received their first oral dose of

595

Silva et al.

Randomized n=668

CsA/MMF treated

n=212 (95.1%)

TAC/MMF treated

n=212 (96.8%)

XL/MMF treated

n=214 (94.7%)

Completed 1 year

n=183 (85.5%)

Completed 1 year

n=179 (84.4%) Completed 1 year

n=151 (71.2%)

Reason Patient Discontinued: Adverse events n=23 (10.8%) Rejection n=0 Noncompliance n=4 (1.9%) Graft failure n=3 (1.4%) Withdrew consent n=0 Lost to follow-up n=1 (0.5%) Other n=2 (0.9%)

Discontinued n=61 (28.8%)


Reason Patient Discontinued: Adverse events n=37 (17.5%) Rejection n=16 (7.5%) Noncompliance n=5 (2.4%) Graft failure n=1 (0.5%) Withdrew consent n=1 (0.5%) Lost to follow-up n=0 Other n=1 (0.5%)

Reason Patient Discontinued: Adverse events n=19 (8.9%) Rejection n=1 (0.5%) Noncompliance n=2 (0.9%) Graft failure n=2 (0.9%) Withdrew consent n=4 (1.9%) Lost to follow-up n=0 Other n=3 (1.4%)

CsA/MMF n=223 TAC/MMF n=219 XL/MMF n=226


Not Treated n=12 (5.3%) Not Treated n=7 (3.2%) Not Treated n=11 (4.9%)

Figure 1: Patient disposition.

XL = tacrolimus extended-releaseformulation; TAC = tacrolimustwice-a-day formulation; CsA =cyclosporine microemulsion; MMF= mycophenolate mofetil. Otherreasons for discontinuation from ran-domized therapy were investigatordiscretion/converted to rapamycin,acute tubular necrosis, incorrectstudy drug dispensed, investigatordiscretion/possible toxicity, improperabsorption of study drug and sub-sequent pancreas transplant. Thereasons for discontinuation fromthe study are those provided by theinvestigator for the patient’s finalassessment. A more conservativedata-driven number was used forgraft failure and lost to follow-up inefficacy failure analyses.

randomized study drug within 48 h of the transplant procedure. Exclu-sion criteria were: patients had previously received or were receiving anorgan transplant other than a kidney; receiving a kidney from a non-heart-beating or an ABO blood group incompatible donor or from a ≥60 yearsof age; or receiving a kidney with a cold ischemia time of ≥36 h. Patientswere excluded if they were known to be seropositive for HIV or if theyhad a current malignancy or a history of malignancy (previous 5 years)other than nonmetastatic basal or squamous cell carcinoma of the skinthat had been successfully treated. Patients were excluded who had sig-nificant liver disease (defined as continuously having serum glutamic ox-aloacetic or glutamate pyruvate transaminase levels more than three timesthe upper limit of normal during the 28 days prior to the transplant) or hadan uncontrolled concomitant infection or any unstable medical conditionthat could potentially interfere with study participation. Patients who had aknown sensitivity to TAC, CsA, MMF or corticosteroids; received everolimusor enteric-coated mycophenolic acid; received intravenous immunoglobu-lin therapy prior to randomization or within 48 h after randomization; andwho were taking or had previously taken another investigational drug within30 days prior to transplant were also excluded.

Primary immunosuppressive regimens

The three primary immunosuppressants were supplied to patients by thestudy sponsor, Astellas Pharma US, Inc., for the first year of the study.XL was administered as a single oral dose in the morning (initially 0.15–0.20 mg/kg/day) and TAC was administered in two equal oral doses 12 hapart (initially 0.075–0.10 mg/kg); target tacrolimus whole blood trough con-centrations were 7–16 ng/mL for the first 90 days posttransplant and 5–15ng/mL thereafter. Neoral was administered in two equal oral doses 12 hapart (initially 4–5 mg/kg); target cyclosporine whole blood trough concen-trations were 125–400 ng/mL for days 0–90, and 100–300 ng/mL thereafter.Whole blood target ranges for tacrolimus and cyclosporine were chosenbased on input from investigators. Dosing of XL, TAC and CsA was chosenbased on recommended ranges as described in the package insert for the

commercial products and was permitted to be adjusted by the investigatorbased on protocol-specified target whole blood trough concentrations andstandard clinical practice.

Adjunct immunosuppressants

Two 20-mg intravenous doses of basiliximab induction therapy were to beadministered, the first on day 0 (skin closure) and the second on days 3–5.Corticosteroid administration was initiated on day 0 (500–1000 mg methyl-prednisolone or equivalent intravenous bolus), with oral administration of200 mg methylprednisolone (or equivalent) on day 1 and subsequent ta-pering to achieve a targeted mean prednisone equivalent after the first3 months of 5–10 mg/day in each treatment group. MMF (1 g bid) wasadministered according to the CellCept® package insert (Roche Laborato-ries Inc., Nutley, NJ). MMF up to 1.5 g bid was permitted in black patients(11). Target levels for mycophenolic acid (MPA) were not specified in theprotocol.

Treatment of rejection episodes

All suspected rejection episodes were to be confirmed by a renal biopsybefore treatment for rejection was begun or within 48 h of initiation oftreatment for acute rejection. Initial rejection episodes were treated withoral or intravenous corticosteroids (dose not to exceed 1 g/day methylpred-nisolone or equivalent for a maximum of 3–5 days). Antilymphocyte anti-body treatment was allowed according to institutional practice for patientswith histologically proven Banff Grade II or III rejection or steroid-resistantrejection.

Endpoints and statistical analyses

Efficacy and safety analyses were performed using a modified intent-to-treat population of all randomized patients who received at least one doseof study drug (full analysis set). Within this full analysis set, select groups ofat-risk patients, defined as those who, at baseline, did not have the relevant

596 American Journal of Transplantation 2007; 7: 595–608

Extended-Release Tacrolimus/MMF in Kidney Transplantation

Table 1: Summary of patient demographics and baseline charac-teristics

XL/MM TAC/MMF CsA/MMF(n = 214) (n = 212) (n = 212)

SexMale 138 (64.5%) 136 (64.2%) 130 (61.3%)Female 76 (35.5%) 76 (35.8%) 82 (38.7%)

RaceWhite 160 (74.8%) 152 (71.7%) 163 (76.9%)Black 41 (19.2%) 51 (24.1%) 36 (17.0%)Asian 5 (2.3%) 5 (2.4%) 8 (3.8%)Other1 8 (3.7%) 4 (1.9%) 5 (2.4%)

EthnicityHispanic 31 (14.5%) 29 (13.7%) 31 (14.6%)Non-Hispanic 183 (85.5%) 183 (86.3%) 181 (85.4%)

Age (years)Mean ± SD 47.8 ± 13.0 48.6 ± 12.9 47.6 ± 13.0Median 48.00 50.50 48.50Range 17-77 19-74 17-77

Age group (years)<65 190 (88.8%) 189 (89.2%) 192 (90.6%)≥65 24 (11.2%) 23 (10.8%) 20 (9.4%)

Diabetes type I 50 (23.4%) 60 (28.3%) 58 (27.4%)or II2

HLA mismatches0 12 (5.6%) 6 (2.8%) 15 (7.1%)1 10 (4.7%) 7 (3.3%) 12 (5.7%)2 31 (14.5%) 27 (12.7%) 27 (12.7%)≥ 3 161 (75.2%) 172 (81.1%) 158 (74.5%)

Donor typeLiving 103 (48.1%) 106 (50.0%) 111 (52.4%)Deceased 111 (51.9%) 106 (50.0%) 101 (47.6%)

Cold ischemiatime (h)Number 110 103 101Mean ± SD 17.88 ± 7.732 19.41 ± 7.267 18.44 ± 7.109Median 17.87 19.57 18.00Range 0.8–34.8 0.5–37.3 2.3–38.0

Had a previous 8 (3.7%) 7 (3.3%) 9 (4.2%)transplant

Panel reactiveantibody (%)

Number 211 203 204Mean ± SD 2.49 ± 10.668 2.72 ± 11.343 4.09 ± 13.315Median 0.00 0.00 0.00Range 0.0–87.0 0.0–78.0 0.0–95.0

1Other: Brazilian Indian (4); East Indian (2); Indian (2); NativeHawaiian—Other Pacific Islander (2); Philippino (6) and IndianSubcontinent (1).2Not posttransplant diabetes mellitus (PTDM).MMF = mycophenolate mofetil; XL = tacrolimus extended-release formulation; TAC = tacrolimus twice-a-day formulation;CsA = cyclosporine microemulsion; SD = standard deviation.

condition or whose laboratory values did not meet the protocol-specifiedabnormal criterion (e.g. low-density lipoprotein cholesterol ≥200 mg/dL),were also identified for ‘new-onset’ safety analysis.

The primary efficacy endpoint for this study, developed in collaboration withthe Division of Special Pathogen and Transplant Products (FDA), was a com-posite endpoint, efficacy failure rate at 1 year, comprising any patient who

died, experienced graft failure (return to dialysis for >30 days or retrans-plant), had a biopsy-confirmed acute rejection (BCAR; Banff Grade ≥1) orwas lost to follow-up. Lost to follow-up was defined as any patient who didnot have at least 11 months (335 days) of follow-up information. Biopsieswere analyzed by the pathologist at each clinical site and were graded ac-cording to 1997 Banff criteria (12). Blinded central review of the biopsieswas also performed, but was not used in the primary analysis of the com-posite endpoint. The protocol-defined secondary endpoints included patientand graft survival rates at 1 year, incidence of BCAR (Banff Grade ≥1) at6 and 12 months, time to first acute rejection, incidence of antilympho-cyte antibody therapy for treatment of rejection, severity of acute rejection,number of patients experiencing multiple rejection episodes, number ofclinically treated acute rejection episodes, incidence of discontinuation ofrandomized drug for any reason and incidence of crossover. An evaluationof renal function (serum creatinine and calculated creatinine clearance) wasincluded as a secondary endpoint per the advice of the FDA. An analysisof the incidence of delayed graft function (defined as at least one dialysisepisode within the first 7 days posttransplant and included acute tubularnecrosis requiring dialysis in the first week after transplantation) was alsopreplanned.

All assessments of non-inferiority were made using a prespecified marginof 10%. Enrollment was targeted to provide at least 90% power to con-clude non-inferiority with respect to the primary endpoint, efficacy failure.The sample size calculation was adjusted for the two primary comparisons(XL/MMF vs. CsA/MMF, TAC/MMF vs. CsA/MMF). The achieved enrollmentwas found to provide greater than 99% power for patient and graft survival,89% power for BCAR at 6 months, and 84% power for BCAR at 12 monthsbased on the results in the CsA/MMF group. Adjustments were made formultiple comparisons for the primary, but not the secondary endpoints.Statistical tests regarding secondary endpoints should be interpreted withcaution.

Treatment group differences were calculated as the experimental regi-men minus the comparator (XL/MMF minus CsA/MMF; TAC/MMF minusCsA/MMF). For the primary analysis of efficacy failure rate, 95.2% confi-dence intervals (CI) of the treatment differences were constructed using anormal approximation in order to adjust for interim reviews of the data by aData Safety Monitoring Board. A procedure based on Hochberg’s methodwas used to adjust for the two primary treatment comparisons. Incidencerates were also compared using a chi-square test. Analysis of efficacy fail-ure rate was also compared across the treatment groups using a Cochran–Mantel–Haenszel test adjusting for donor type (living or deceased); the inter-action between treatment strata was examined by testing the homogeneityof the odds ratio using the Breslow–Day test. Analyses of the efficacy fail-ure rate for each donor type strata were also performed using a chi-squaretest.

Patient and graft survival were analyzed using Kaplan–Meier plots and treat-ment groups were compared for day 365 data using the log-rank test cen-soring patients at time of last follow-up. Patient survival included patientswho did not die and were not lost to follow-up; graft survival included pa-tients who did not die, did not experience graft failure (return to dialysis>30 days or retransplant), and were not lost to follow-up. Incidence ofBCAR, and antilymphocyte therapy were analyzed using a chi-square test.Renal function analysis was assessed based on worst case, highest serumcreatinine and lowest creatinine clearance (Cockcroft–Gault formula) valuesfor each visit window. The month 1 result was used as baseline for changein renal function analysis as graft function would be expected to have sta-bilized by month 1 posttransplant. Missing values were not imputed. Meanvalues over time were compared between groups using two-way analysisof variance (ANOVA) with treatment and center as factors. In addition, apost hoc analysis of change in estimated glomerular filtration rate (GFR)

American Journal of Transplantation 2007; 7: 595–608 597

Silva et al.

Table 2: Tacrolimus whole blood trough concentrations by visit

Above target Below target Mean trough concentration (ng/mL)

XL/MMF TAC/MMF XL/MMF TAC/MMF XL/MMF TAC/MMF

Day 3 n = 36 n = 47 n = 58 n = 48 n = 189 n = 17219.0% 27.3% 30.7% 27.9% 11.28 12.99

Month 2 n = 10 n = 11 n = 33 n = 29 n = 181 n = 1655.5% 6.7% 18.2% 17.6% 10.15 10.06

Month 4 n = 13 n = 7 n = 18 n = 20 n = 174 n = 1517.5% 4.6% 10.3% 13.2% 9.02 8.80

n = patients who had at least one dose of study drug and who had a trough blood concentration recorded within the protocol-definedtime window postdose for the indicated visit. MMF = mycophenolate mofetil; XL = tacrolimus extended-release formulation; TAC =tacrolimus twice-a-day formulation.

was performed using the Modification of Diet in Renal Disease (MDRD)formula (13).

Adverse events were coded using the Medical Dictionary for Regulatory Ac-tivities (MedDRA) version 6.1. Differences among treatment groups withrespect to adverse event incidence and the incidence of predefined poten-tially clinically significant laboratory values (glucose ≥200 mg/dL; platelets<100 × 109 cells/L; WBC <2.0 × 109 cells/L; transaminases ≥100 U/L;total cholesterol ≥300 mg/dL; LDL cholesterol ≥200 mg/dL; triglycerides≥500 mg/dL; serum creatinine ≥2.5 mg/dL) were assessed using Fisher’sexact test. A new onset glucose metabolism disorder was identified basedon the presence of a glucose intolerance or a diabetes-related treatment-emergent adverse event in the full analysis population, or a glucose intoler-ance parameter (i.e. fasting plasma glucose ≥126 mg/dL, insulin use ≥30days or oral hypoglycemic agent use) in the at-risk population.

Post hoc analyses using a one-way ANOVA with event status (with event vs.without event) as the only factor (significance at p < 0.050) were performedto evaluate the relationship between trough concentration and BCAR, and

Figure 2: Percentage of patients within the target study drug trough concentration range by visit. XL: tacrolimus extended-releaseformulation; TAC = tacrolimus twice-a-day formulation; CsA = cyclosporine microemulsion; MMF = mycophenolate mofetil.

renal dysfunction (creatinine clearance <40 mL/min). Creatinine clearance<40 mL/min was evaluated in patients who had the assessment at 1 monthposttransplant and did not meet the criteria, and had at least one value aftermonth 1.

Results

Patients

A total of 668 patients were randomized into one of threetreatment groups; 638 of these randomized patients re-ceived at least one dose of study drug and were includedin efficacy and safety analyses (Figure 1). A total of 30patients did not receive the study drug due to investiga-tor decision to use Thymoglobulin® induction therapy (n =6); not transplanted (n = 5); did not meet eligibility criteria(n = 4); discontinued or withdrew consent (n = 3); delayedgraft function (n = 2); acute tubular necrosis (n = 2); high



Table 3: Dose and tacrolimus whole blood trough concentrations by visit in white and black transplant recipients

XL/MMF TAC/MMF

White (n = 160) Black (n = 41) White (n = 152) Black (n = 51)

Mean Mean Mean Mean Mean Mean Mean Meandaily trough daily trough daily trough daily troughdose concentration dose concentration dose concentration dose concentration(mg/kg) (ng/mL) (mg/kg) (ng/mL) (mg/kg) (ng/mL) (mg/kg) (ng/mL)

Day 7 n = 159 n = 128 n = 41 n = 35 n = 150 n = 114 n = 49 n = 320.14 10.79 0.14 7.85 0.12 11.24 0.12 8.60

Month 1 n = 153 n = 138 n = 37 n = 32 n = 148 n = 124 n = 47 n = 340.14 11.11 0.18 10.83 0.11 11.28 0.15 10.79

Month 6 n = 148 n = 130 n = 31 n = 28 n = 137 n = 105 n = 45 n = 340.10 7.96 0.13 8.50 0.09 8.43 0.13 9.52

Month 12 n = 145 n = 129 n = 31 n = 26 n = 130 n = 109 n = 42 n = 330.09 7.54 0.12 7.52 0.08 7.66 0.12 7.95

n = patients who had at least one dose of study drug and had a trough blood concentration recorded within the protocol-definedtime window postdose for the indicated visit. MMF = mycophenolate mofetil; XL = tacrolimus extended-release formulation; TAC =tacrolimus twice-a-day formulation.

panel reactive antibody (n = 1); or received commercial Pro-graf (n = 1); 6 patients did not receive a first dose within48 h with no further explanation. Treatment groups werebalanced with regard to donor type and other baseline char-acteristics (Table 1). Eighty-five percent of patients in the

Table 4: Efficacy failure in de novo kidney transplant recipients at1-year posttransplant

XL/MMF TAC/MMF CsA/MMF(n = 214) (n = 212) (n = 212)

Efficacy failure1 30 (14.0%) 32 (15.1%) 36 (17.0%)Death 3 92 52

Graft failure 5 9 43

BCAR (local 224 16 29assessments)

Lost to follow-up 3 4 1Treatment difference5 −3.0% −1.9%95.2% confidence −9.9%, 4.0% −8.9%, 5.2%

interval6

1Efficacy failure comprised any patient who died, experiencedloss of a graft (return to dialysis for >30 days or retransplant), hada BCAR or was lost to follow-up. Patients could have met morethan one criterion; a patient was only counted once regardless ofhow many of the criteria were met.2One additional patient randomized to TAC/MMF and oneadditional patient randomized to CsA/MMF died after the 1-yearstudy period was completed.3One additional patient randomized to CsA/MMF experiencedgraft failure after the 1-year study period was completed.4Two additional patients randomized to XL/MMF had BCAR afterthe 1-year study period was completed.5Treatment differences are relative to CsA/MMF treatment group(XL minus CsA; TAC minus CsA).6Confidence interval adjusted for Data Safety Monitoring Boardinterim review.Lost to follow-up: any patient who did not have at least 11 months(335 days) of follow-up information. MMF = mycophenolatemofetil; XL = tacrolimus extended-release formulation; TAC= tacrolimus twice-a-day formulation; CsA = cyclosporinemicroemulsion.

XL/MMF and TAC/MMF groups completed 1 year of ran-domized treatment compared with 71% of patients in theCsA/MMF group; most of the patients who discontinuedrandomized therapy did so because of an adverse event(Figure 1).

Primary immunosuppressant blood trough

concentrations

Mean total daily doses of tacrolimus were similar be-tween the TAC/MMF and XL/MMF treatment groups

Table 5: Patient and graft survival (Kaplan–Meier estimates) in denovo kidney transplant recipients at 1-year posttransplant


Patient survival1 98.6% 95.7% 97.6%Kaplan–Meier 1.0% −1.9%estimate difference2

95% confidence −1.6%, 3.6% −5.3%, 1.5%interval

Graft survival 96.7% 92.9% 95.7%Death or graft failure 7 151 91

Kaplan–Meier 1.0% −2.9%estimate difference2

95%confidence −2.7%, 4.6% −7.3%, 1.6%interval

1One additional patient randomized to TAC/MMF and oneadditional patient randomized to CsA/MMF died after the 1-yearstudy period was completed. One additional patient randomizedto CsA/MMF experienced graft failure after the 1-year studyperiod was completed.2Kaplan–Meier estimate differences are relative to the CsA/MMFtreatment group (XL minus CsA; TAC minus CsA). Treatmentgroups were compared for day 365 data using the log-rank testcensoring patients at the time of the last follow-up.MMF = mycophenolate mofetil; XL = tacrolimus extended-release formulation; TAC = tacrolimus twice-a-day formulation;CsA = cyclosporine microemulsion.


Silva et al.

Table 6: Primary causes of death and reasons for graft failure1


Total deaths2 3 9 5Sepsis 3Pulmonary embolism/edema 1 2Cardiac arrest 1Cardiac arrest and 1respiratory arrestMyocardial infarction 2Subdural bleed after fall 1Homicide 1Tissue invasive 1strongyloidosisMiliary tuberculosis 1Lymphocytic 1choriomeningitis 1Stroke 1Diverticulitis 1

Total graft failures3 5 9 4Acute rejection 1 1Acute tubular necrosis 1 14 2Chronic allograft 1 1nephropathyRenal vein thrombosis 1 1 15

Vascular rejection, 1collapsing FSGNRecurrent disease 2Acute thrombosis of 1iliac arteryDelayed graft function 1Nephrectomy 1Primary nonfunctioning graft 1

1Investigator’s description of the primary cause of death andprimary reason for graft failure.2One additional patient randomized to TAC/MMF and oneadditional patient randomized to CsA/MMF died after the 1-yearstudy period was completed.3One additional patient randomized to CsA/MMF experiencedgraft failure after the 1-year study period was completed.4Acute tubular necrosis and noncompliance.5Renal artery and renal vein thrombosis.Graft failure: permanent return to dialysis (>30 days) or re-transplant. MMF = mycophenolate mofetil; XL = tacrolimusextended-release formulation; TAC = tacrolimus twice-a-dayformulation; CsA = cyclosporine microemulsion; FSGN = focalsegmental glomerulonephritis.

(e.g. month 1: 0.12 mg/kg vs. 0.14 mg/kg; month 6: 0.10mg/kg vs. 0.11 mg/kg and month 12: 0.08 mg/kg vs. 0.09mg/kg). Trough concentrations in whole blood were mostvariable during the first week of dosing for both tacrolimusformulations. There were no consistent trends betweenthe XL/MMF and TAC/MMF treatment groups with regardto patients above, below, or within the target trough con-centration range for tacrolimus during the course of the 1-year study (Figure 2). Slightly more patients in the XL/MMFgroup than in the TAC/MMF group had trough concentra-tions below target early posttransplant; however, the dif-ference was small (Table 2). For patients in the CsA/MMFgroup who had trough concentration data for the visit win-

dow, the mean trough concentrations at day 3, months2 and 4 were 272.4, 261.1 and 218.1 ng/mL. Regardlessof treatment group, mean trough concentrations of studydrug were generally at the middle to high end of the targetrange through the first month posttransplant and graduallydeclined toward the lower end of the target range there-after.

A high degree of interpatient variability in tacrolimus troughconcentrations was observed with administration of eitherthe extended-release or twice-a-day tacrolimus formulationin both black and white transplant recipients. Similar towhat has been previously reported for TAC (14), black pa-tients required a higher dose of XL or TAC to attain troughconcentrations comparable to those of white patients(Table 3).

Adjunct immunosuppressants

All but 10 patients received two 20-mg intravenous dosesof basiliximab induction therapy (1 XL, 1 TAC, 3 CsA didnot receive basiliximab; 2 XL, 3 TAC received one dose).At 1-year posttransplant, similar mean total daily doses ofprednisone or equivalent were administered in all threetreatment groups (XL/MMF 8.4 mg, TAC/MMF 6.9 mg,CsA/MMF 7.3 mg; p = 0.29, one-way ANOVA).

By 1-year posttransplant, administration of MMF had beendiscontinued in 10.7% (23/214) of patients in the XL/MMFgroup, 14.7% (31/211) in the TAC/MMF group and 8.1%(17/211) of patients in the CsA/MMF group. At 1-year post-transplant, mean total daily dose of MMF was significantlyhigher in the CsA/MMF group (1800.8 mg) compared withthe two tacrolimus groups (XL/MMF 1668.9 mg, TAC/MMF1655.8 mg) (p = 0.0012, one-way ANOVA). Mean month1 and 1-year plasma trough MPA levels were 3.3 and3.0 lg/mL in the XL/MMF group, 3.7 and 3.1 lg/mL in theTAC/MMF group, and 2.1 and 2.4 lg/mL in the CsA/MMFgroup.

Efficacy

At 1-year posttransplant, efficacy failure rates in both theXL/MMF and TAC/MMF groups were statistically non-inferior to that in the CsA group (Table 4); the results ofanalyses adjusting for donor type were similar. Kaplan–Meier estimates for 1-year patient and graft survival(XL/MMF 98.6% and 96.7%; TAC/MMF 95.7% and 92.9%;CsA/MMF 97.6% and 95.7%) were similar among treat-ment groups (Table 5). No trends with respect to primarycause of death or graft failure were identified (Table 6). Theincidence of BCAR at 6 months and 1 year was significantlylower in the TAC/MMF group than in the CsA/MMF group;no statistically significant differences were observed be-tween the XL/MMF and CsA/MMF groups (Table 7). TheKaplan–Meier curve for time to first BCAR through 1 yearis presented in Figure 3.

Although not defined a priori as an efficacy endpoint, theincidence of BCAR early posttransplant (month 1) also



Table 7: Other secondary endpoints

XL/MMF (n = 214) TAC/MMF (n = 212) CsA/MMF (n = 212)

BCAR (local assessment)At 6 months 17 (7.9%) 8 (3.8%)∗ 25 (11.8%)95% CI −9.5%, 1.8% −13.1%, −3.0%At 12 months 22 (10.3%) 16 (7.5%)∗ 29 (13.7%)95% CI −9.6%, 2.8% −12.0%, −0.3%

Maximum grade of acute rejection (Banff criteria)I-A 11 8 14I-B 3 4 6II-A 6 3 6II-B 1 1 1III 1 0 2BCAR (central assessment, 1 year) 10/207 (4.8%) 8/199 (4.0%) 14/200 (7.0%)95% CI −6.8%, 2.4% −7.4%, 1.5%Antilymphocyte antibody therapy (1 year) 8 (3.7%)∗ 6 (2.8%)∗ 18 (8.5%)95% CI −9.3%, −0.2% −10.0%, −1.3%Multiple acute rejection episodes (1 year) 4 (1.9%) 2 (0.9%) 8 (3.8%)95% CI −5.0%, 1.2% −5.7%, 0Clinically treated acute rejection (1 year) 39 (18.2%) 25 (11.8%)∗ 45 (21.2%)95% CI −10.6%, 4.6% −16.4%, −2.4%Discontinued randomized drug for any reason 31 (14.5%)∗∗ 33 (15.6%)∗∗ 61 (28.8%)95% CI −22.0%, −6.6% −21.0%, −5.4%Crossover 10 (4.7%)∗∗ 6 (2.8%)∗∗ 39 (18.4%)95% CI −19.7%, −7.8% −21.2%, −9.9%Delayed graft function (1 year) 38 (17.8%) 46 (21.7%) 38 (17.9%)95% CI −7.4%, 7.1% −3.8%, 11.4%

∗Statistically different from CsA/MMF group, p ≤ 0.04, chi-square test.∗∗Statistically different from CsA/MMF group, p ≤ 0.001, chi-square test.MMF = mycophenolate mofetil; XL = tacrolimus extended-release formulation; TAC = tacrolimus twice-a-day formulation; CsA =cyclosporine microemulsion; CI = confidence interval for treatment difference; BCAR = biopsy-confirmed acute rejection.

was not significantly different (p ≥ 0.9803, chi-squaretest) between either of the tacrolimus-based treatmentgroups and the CsA-based treatment group (TAC/MMF2.8%, 6/212 vs. CsA/MMF 6.1%, 13/212, treatment dif-ference −3.3%; 95% CI: −7.2%, 0.6%; XL/MMF 6.1%,13/214 vs. CsA/MMF 6.1%, 13/212, treatment difference

Figure 3: Kaplan–Meier estimate

of time to occurrence of first

biopsy-confirmed acute rejection.

XL: tacrolimus extended-release for-mulation; TAC = tacrolimus twice-a-day formulation; CsA = cyclosporinemicroemulsion; MMF = mycopheno-late mofetil; BCAR = biopsy con-firmed acute rejection. Kaplan–Meierplot of BCAR censored at time of lastfollow-up.

−0.1%; 95% CI: −4.6%, 4.5%). There was no statis-tically significant difference between the XL/MMF andTAC/MMF groups in the incidence of BCAR early post-transplant (treatment difference −3.2%; 95% CI: −7.1%,0.7%). In all three treatment groups, mean trough con-centrations (ng/mL) were similar between patients with


Silva et al.

Table 8: Trough concentrations (ng/mL) at days 3 and 30 in patients with and without BCAR during the first 30 days posttransplant

Patients with BCAR Patients without BCARTreatment Visitgroup (day) n Mean ± SD n Mean ± SD p-value

XL/MMF 3 10 11.2 ± 9.10 179 11.3 ± 7.17 0.745730 10 10.5 ± 4.11 172 11.2 ± 4.96 0.8434

TAC/MMF 3 4 10.8 ± 4.88 168 13.0 ± 8.86 0.875130 8 10.3 ± 3.81 166 11.2 ± 4.65 0.6206

CsA/MMF 3 10 218.9 ± 95.84 162 275.7 ± 154.8 0.438230 7 271.6 ± 108.3 159 311.7 ± 126.1 0.4167

p-value from a one-way ANOVA with even status (with event vs. without event) as the only factor.n in the table reflects patients who had or did not have event by day 30 and who had a trough blood concentration recorded within theprotocol-defined time window postdose for the indicated visit.BCAR = biopsy-confirmed acute rejection; MMF = mycophenolate mofetil; XL = tacrolimus extended-release formulation; TAC =tacrolimus twice-a-day formulation; CsA = cyclosporine microemulsion; SD = standard deviation.

and without BCAR during the first 30 days posttransplant(Table 8).

The incidence of BCAR at 1 year in patients who receivedgrafts from deceased donors was significantly lower(p ≤ 0.015) in the XL/MMF (9.0%, 10/111) and TAC/MMF(7.5%, 8/106) groups than in the CsA/MMF group (20.8%,21/101). Both XL/MMF and TAC/MMF groups had simi-lar relative incidence of BCAR compared with CsA/MMFwhen biopsies were assessed by a central, blinded re-viewer (Table 7). Proportion of patients receiving antilym-phocyte antibody therapy for the treatment of rejection,the distribution of the maximum grade of acute rejection,the incidence of multiple acute rejection episodes, the in-cidence of discontinuations from randomized drug for anyreason, the incidence of crossovers, and the incidence ofdelayed graft function are presented in Table 7. Regardlessof treatment group, >90% of episodes of delayed graftfunction occurred in patients who received grafts from de-ceased donors.

Renal function parameters are presented in Table 9. Therobustness of the renal function findings was evaluated byestimating the GFR using MDRD. This analysis showedconsistent results with the Cockroft Gault estimates ofcreatinine clearance with significantly higher GFR in theXL/MMF and TAC/MMF groups as compared to CsA/MMFat 1-year posttransplant. Similar mean tacrolimus troughconcentrations were observed throughout the study forpatients with or without creatinine clearance <40 mL/minin both tacrolimus-based treatment groups (e.g. day 365,XL/MMF: 8.5 ± 2.58 ng/mL vs. 7.4 ± 3.85 ng/mL;TAC/MMF: 7.3 ± 2.57 ng/mL vs. 7.9 ± 3.13 ng/mL; p ≥0.075, one-way ANOVA with event status as only factor).Within each category (with or without creatinine clearance<40 mL/min), mean tacrolimus trough concentrations ap-peared similar between the two tacrolimus-based treat-ment groups throughout the study.

Safety

The overall safety profile of TAC/MMF and the differ-ences in adverse event incidence between TAC/MMF andCsA/MMF observed in this study were consistent with

those previously reported (1–8). XL/MMF and TAC/MMFpresented similar overall safety profiles. A summaryof adverse events with a statistically significant differ-ence between tacrolimus/MMF treatment group and theCsA/MMF group is presented in Table 10. There were nostatistically significant differences in the incidence of bac-terial, fungal or viral infections, or adverse events reportedby the investigator as cytomegalovirus infection, or cy-tomegalovirus viremia, or human polyomavirus infectionin the XL/MMF compared with the CsA/MMF treatmentgroups (Table 11).

The incidence of new onset diabetes as defined by theAmerican Diabetes Association (ADA) as a single fastingplasma glucose ≥126 mg/dL during the 1-year treatmentperiod was significantly higher for patients at risk in theTAC/MMF group than in the CsA/MMF (Table 12), consis-tent with previous reports (5–7); the incidence was notstatistically significantly different between the XL/MMFand CsA/MMF groups. The incidence of new onset oralhypoglycemic agent use was significantly higher in bothtacrolimus groups compared with the CsA/MMF group(Table 12). However, the incidence of new onset use ofinsulin ≥30 days was not significantly different betweeneither of the tacrolimus-based treatment groups and theCsA/MMF group.

Mean values for total cholesterol, LDL cholesterol, HDLcholesterol and triglycerides at the day 21, and months 6and 12 visits are summarized in Table 13. There was a sta-tistically significant (p = 0.011) difference among treatmentgroups with respect to incidence of patients at risk who hadtotal serum cholesterol levels ≥300 mg/dL (XL/MMF 8/168,4.8%; TAC/MMF 6/176, 3.4%; CsA/MMF 18/166, 10.8%).During the course of the 1-year study, 50.9% (109/214) ofpatients in the XL/MMF group, 44.8% (95/212) of patientsin the TAC/MMF group, and 60.8% (129/212) of patientsin the CsA/MMF treatment group received some form oflipid-lowering medication.

There were no significant differences among treatmentgroups with respect to incidence of glucose ≥200 mg/dL,platelets <100 × 109 cells/L, WBCs <2.0 × 109 cells/L,



Table 9: Renal function


Serum creatinine (mg/dL)Month 1n 199 202 195Mean ± SD 1.63 ± 1.14 1.62 ± 1.17 1.68 ± 0.99

Month 6n 188 186 173Mean ± SD 1.46 ± 0.55 1.42∗ ± 0.43 1.51 ± 0.50

Month 12n 185 175 150Mean ± SD 1.39∗ ± 0.44 1.42 ± 0.56 1.48 ± 0.51

Incidence of patients with serum creatinine <2.5 mg/dL at month1 and ≥2.5 mg/dL at months 6 and 12Month 6 1/179 (0.6%) 4/188 (2.1%) 6/177 (3.4%)Month 12 1/179 (0.6%) 4/188 (2.1%) 3/177 (1.7%)

Creatinine clearance (mL/min) 1

Month 1n 199 202 193Mean ± SD 55.4 ± 20.61 55.1 ± 20.73 53.5 ± 21.01

Month 6n 188 186 171Mean ± SD 56.7∗ ± 18.24 56.8∗ ± 17.25 53.6 ± 15.92

Month 12n 185 175 148Mean ± SD 58.7∗∗ ± 18.26 57.7∗ ± 18.81 54.6 ± 17.60

Estimated GFR (mL/min per 1.73 m2) 2

Month 1n 199 201 193Mean ± SD 53.2 ± 18.62 54.1 ± 19.78 51.5 ± 21.46

Month 6n 188 185 171Mean ± SD 56.8∗ ± 17.86 58.8∗∗ ± 17.29 53.5 ± 16.69

Month 12n 184 174 149Mean ± SD 58.6∗ ± 17.64 59.7∗∗ ± 18.24 55.0 ± 17.34

Incidence of decrease in estimated GFR (mL/min per 1.73 m2)2

from months 1–12≥10% 36/181 (19.9%) 44/172 (25.6%) 40/145 (27.6%)≥15% 25/181 (13.8%) 38/172 (22.1%) 32/145 (22.1%)≥20% 22/181 (12.2%) 29/172 (16.9%) 24/145 (16.6%)≥25% 14/181 (7.7%) 17/172 (9.9%) 17/145 (11.7%)

All patients who received at least one dose of study drug and had a result at each study visit according to predefined visit windows wereincluded; visit windows were days 26–45 for month 1, days 152–212 for month 6 and days ≥335 for month 12.Statistically different from CsA/MMF group, ∗p < 0.05, ∗∗ p < 0.01; two-way ANOVA with treatment and center as factors.1Based on Cockcroft–Gault formula using ideal body weight.2MDRD study prediction equation (13); 170 × [serum creatinine (mg/dL)](−0.999) × [age](−0.176) × [0.762 if patient is female] × [1.180if patient is black] × [BUN (mg/dL)](−0.170) × [albumin (g/dL)](0.318). Percent decrease was calculated only for patients with all valuesrequired for the MDRD calculation available at both months 1 and 12. The month 1 result was used as baseline for analysis of change inrenal function as graft function was expected to have stabilized by month 1 posttransplant.MMF = mycophenolate mofetil; XL = tacrolimus extended-release formulation; TAC = tacrolimus twice-a-day formulation; CsA =cyclosporine microemulsion; SD = standard deviation; GFR = glomerular filtration rate.

transaminases ≥100 U/L, LDL cholesterol ≥200 mg/dL ortriglycerides ≥500 mg/dL.

Discussion

Based on the results of this comparative study in denovo renal transplant recipients, XL/MMF is as effectiveas TAC/MMF and CsA/MMF when used in combination

with corticosteroids and basiliximab induction. Tacrolimusextended-release formulation used in combination withMMF provided a safety profile consistent with that his-torically established for twice-a-day tacrolimus (1–8) andsimilar to that observed for TAC/MMF in this study.

Tacrolimus administered as a twice-a-day formulation incombination with steroids has been associated with a


Silva et al.

Table 10: Summary of statistically significant treatment-emergent adverse events regardless of relationship to study drug

MedDRA (v. 6.1) system organ class preferred term XL/MMF (n = 214) TAC/MMF (n = 212) CsA/MMF (n = 212)

Gastrointestinal disordersDiarrhoea 97 (45.3%)∗∗∗ 94 (44.3%)∗∗∗ 54 (25.5%)Loose stools 11 (5.1%) 15 (7.1%)∗ 4 (1.9%)Gingival hyperplasia 1 (0.5%)∗∗ 0∗∗ 10 (4.7%)

Injury, poisoning and procedural complicationsAV fistula thrombosis 0∗ 1 (0.5%) 5 (2.4%)

Metabolism and nutrition disordersHyperlipidaemia 35 (16.4%)∗ 37 (17.5%) 52 (24.5%)Diabetes mellitus 30 (14.0%)∗ 24 (11.3%) 14 (6.6%)Hyponatraemia 6 (2.8%) 2 (0.9%)∗ 10 (4.7%)

Infections and infestationsSinusitis 15 (7.0%)∗ 7 (3.3%) 5 (2.4%)Gastroenteritis 14 (6.5%)∗ 1 (0.5%) 4 (1.9%)

General disorders and administration site conditionsOedema peripheral 76 (35.5%)∗ 74 (34.9%)∗ 97 (45.8%)

Nervous system disordersTremor 75 (35.0%)∗∗∗ 73 (34.4%)∗∗ 42 (19.8%)Paraesthesia 12 (5.6%) 3 (1.4%)∗ 13 (6.1%)

Vascular disordersOrthostatic hypotension 15 (7.0%)∗ 10 (4.7%) 5 (2.4%)Lymphocele 1 (0.5%)∗ 2 (0.9%) 7 (3.3%)

Psychiatric disordersInsomnia 55 (25.7%) 64 (30.2%)∗ 45 (21.2%)

Skin and subcutaneous tissue disordersAlopecia 14 (6.5%)∗ 15 (7.1%)∗ 4 (1.9%)Hypertrichosis 0∗∗ 0∗ 7 (3.3%)

Renal and urinary disordersHydronephrosis 1 (0.5%)∗ 2 (0.9%) 9 (4.2%)Nephropathy toxic 3 (1.4%) 1 (0.5%)∗ 8 (3.8%)

Reproductive system and breast disordersBenign prostatic hyperplasia 1 (0.5%)∗ 4 (1.9%) 7 (3.3%)

Endocrine disordersHirsutism 0∗∗∗ 0∗∗∗ 18 (8.5%)

Eye disordersVisual acuity reduced 2 (0.9%) 0∗ 6 (2.8%)

All randomized patients who received at least one dose of study drug. Within a MedDRA system organ class, patients may haveexperienced more than one adverse event. The sum of the terms may exceed 100% Statistical significance was determined usingFisher’s exact test (two-tailed) vs. CsA/MMF. ∗p ≤ 0.05, ∗∗p ≤ 0.01, ∗∗∗p ≤ 0.001.MMF = mycophenolate mofetil; XL = tacrolimus extended-release formulation; TAC = tacrolimus twice-a-day formulation; CsA =cyclosporine microemulsion; AV = arteriovenous.

higher risk of glucose metabolism disorders than cy-closporine (4–7); this was also observed in the presentstudy. In recent years, the incidence of new onset diabetesmellitus posttransplant has been lower, possibly reflective

Table 11: Summary of infections

XL/MMF (n = 214) TAC/MMF (n = 212) CsA/MMF (n = 212)

Bacterial infections 18 (8.4%) 25 (11.8%) 17 (8.0%)Fungal infections 33 (15.4%) 28 (13.2%) 32 (15.1%)Viral infections 50 (23.4%) 56 (26.4%) 45 (21.2%)Cytomegalovirus infection 15 (7.0%) 17 (8.0%) 16 (7.5%)Cytomegalovirus viremia 3 (1.4%) 6 (2.8%) 3 (1.4%)Human polyomavirus infection 6 (2.8%) 9 (4.2%) 5 (2.4%)

MMF = mycophenolate mofetil; XL = tacrolimus extended-release formulation; TAC = tacrolimus twice-a-day formulation; CsA =cyclosporine microemulsion.

of better patient management including lower targetedblood levels of tacrolimus, steroid tapering and new ad-junctive agents (4–7). The incidence of insulin dependencyin the present study in both the XL/MMF and TAC/MMF



Table 12: Summary of glucose metabolism disorders other than those considered an adverse event at any time during 1-year study

Parameter XL/MMF (n = 214) TAC/MMF (n = 212) CsA/MMF (n = 212)

Fasting plasma glucose ≥126 mg/dL 92/163 (56.4%) 96/150 (64.0%)∗ 80/152 (52.6%)Treatment difference 3.8% 11.4%95% donfidence interval −7.2%, 14.8% 0.3%, 22.4%Fasting plasma glucose ≥126 mg/dL at ≥2 visits 48/157 (30.6%) 47/143 (32.9%)∗ 32/145 (22.1%)Treatment difference 8.5% 10.8%95% confidence interval −1.4%, 18.4% 0.6%, 21.0%Insulin use ≥30 days 9/163 (5.5%) 9/150 (6.0%) 4/152 (2.6%)Treatment difference 2.9% 3.4%95% confidence interval −1.4%, 7.2% −1.2%, 7.9%Oral hypoglycemic agent use 23/163 (14.1%)∗∗ 15/150 (10.0%)∗ 5/152 (3.3%)Treatment difference 10.8% 6.7%95% confidence interval 4.8%, 16.9% 11.1%, 12.3%

All randomized patients who received at least one dose of study drug and had no history of diabetes at baseline were included in theanalyses.Statistical significance was determined using Fisher’s exact test (two-tailed) vs. Neoral/MMF.∗p ≤ 0.05, ∗∗p ≤ 0.001.MMF = mycophenolate mofetil; XL = tacrolimus extended-release formulation; TAC = tacrolimus twice-a-day formulation; CsA =cyclosporine microemulsion.

groups was lower than that previously reported for twice-a-day tacrolimus (3–6). The incidence of fasting plasma glu-cose ≥126 mg/dL was not significantly different betweenXL/MMF and CsA/MMF treatment groups.

The incidence of polyomavirus events in our study, basedon adverse events reported by the study investigators,is consistent with the 1–8% incidence of polyomavirusnephropathy reported by Trofe and colleagues in re-nal transplant recipients (15). The incidence of humanpolyomavirus infection was similar in the XL/MMF andCsA/MMF groups.

The open-label aspect of the trial is recognized as a designlimitation. As with many trials in the past (1–8), technicaldifficulties made double-blinding impractical. However, thistrial was a large (>200 per arm), multicenter randomizedtrial adequately powered to demonstrate noninferiority forthe primary composite endpoint, as well as for the sec-ondary endpoints of patient and graft survival and BCAR. Inaddition, the comparative acute rejection rates were con-sistent with those previously reported in other trials (2–5,7,8).

Dosing for the primary immunosuppressants and MMFwas based on commercial product recommendations andthe investigators were allowed to adjust doses accordingto their clinical judgment. Target blood concentrations forthe primary immunosuppressants in this study also werebased on investigator input and are consistent with clin-ical practice (5). Therefore, the exposure to the primaryimmunosuppressants and MPA observed in this study re-flects clinical practice.

An earlier pharmacokinetic study of conversion fromPrograf-based to XL-based immunosuppression in stable

kidney transplant recipients showed equivalence of expo-sure between the two formulations (16). In the presentstudy, interpatient variability in trough concentrations washigh in both tacrolimus-based groups as has been previ-ously reported for TAC (17). Based on the results of a one-way ANOVA, there was no statistically significant associ-ation between early tacrolimus trough concentration andthe incidence of BCAR, or between trough concentrationsobserved later during the study and renal dysfunction (cre-atinine clearance <40 mL/min), in either tacrolimus-basedtreatment group. This would support the ability of cliniciansto achieve appropriate patient management for XL/MMFand TAC/MMF groups using techniques established forTAC.

As observed previously (8,18,19), a higher dose of MMFwas used in the CsA/MMF group compared with the twotacrolimus groups. The requirement for higher doses ofMMF with cyclosporine is consistent with reports that cy-closporine in combination with MMF is associated withlower MPA levels than tacrolimus in combination withMMF (18–21). A relationship has been reported betweenhigh MPA levels and anemia, leukopenia, thrombocytope-nia, upper gastrointestinal complaints, diarrhea and viralinfection in kidney transplant recipients (18,21–23).

A potential design flaw was the absence of a protocol-specified target level for plasma MPA levels. However, theobserved MPA levels in the CsA/MMF group at month 1suggest that in the early period posttransplant MPA lev-els were at least equal to those reported by Borrowset al. (18) and van Gelder et al. (21) as being associated withlow acute rejection rates in kidney transplant recipients.Despite the difference in MPA exposure with cyclosporinecompared with that of noncyclosporine regimens, fixeddoses of MMF are typically used in combination with


Silva et al.

Table 13: Summary of lipid profile over time


Total cholesterol (mg/dL)Baselinen 180 182 178Mean ± SD 143.4 ± 41.06 143.4 ± 39.28 143.7 ± 39.88

Day 21n 172 173 168Mean ± SD 197.7 ± 44.10∗ 195.3 ± 43.46∗ 227.2 ± 54.29

Month 6n 179 175 164Mean ± SD 187.6 ± 46.16∗ 184.7 ± 43.04∗ 205.2 ± 48.83

Month 12n 178 172 144Mean ± SD 188.7 ± 45.98∗ 182.2 ± 41.60∗ 202.3 ± 55.45

LDL (mg/dL)Baselinen 174 177 172Mean ± SD 80.1 ± 34.16 79.9 ± 32.33 80.6 ± 33.96

Day 21n 162 155 151Mean ± SD 106.2 ± 35.40∗ 101.9 ± 36.93∗ 125.0 ± 43.17

Month 6n 169 165 146Mean ± SD 100.9 ± 39.30∗ 100.0 ± 33.99∗ 116.9 ± 42.59

Month 12n 171 163 137Mean ± SD 102.4 ± 37.88∗ 97.1 ± 30.53∗ 113.4 ± 46.44

HDL (mg/dL)Baselinen 177 179 174Mean ± SD 42.3 ± 13.28 44.4 ± 13.14 42.5 ± 14.67

Day 21n 166 163 161Mean ± SD 59.1 ± 17.61 58.2 ± 17.45 62.6 ± 20.20

Month 6n 173 170 155Mean ± SD 52.1 ± 17.40 53.2 ± 17.60 51.8 ± 17.25

Month 12n 174 170 141Mean ± SD 51.5 ± 15.85 52.2 ± 17.12 51.9 ± 16.73

Triglycerides (mg/dL)Baselinen 181 182 178Mean ± SD 111.4 ± 84.17 99.2 ± 79.88 96.6 ± 62.78

Day 21n 173 171 164Mean ± SD 171.4 ± 92.49 171.5 ± 101.99 185.3 ± 111.69

Month 6n 177 174 162Mean ± SD 182.2 ± 114.15 166.6 ± 97.04∗ 192.3 ± 100.76

Month 12n 177 170 144Mean ± SD 183.9 ± 117.09 176.8 ± 153.35 195.7 ± 170.96

Statistical significance vs. CsA/MMF was determined fromcontrasts in a two-way ANOVA, with treatment and center asfactors. ∗p ≤ 0.020.MMF = mycophenolate mofetil; XL = tacrolimus extended-release formulation; TAC = tacrolimus twice-a-day formulation;CsA = cyclosporine microemulsion; SD = standard deviation;HDL = high density lipoprotein; LDL = low density lipoprotein.

cyclosporine or tacrolimus. In several prospective studiesusing a starting dose of MMF 2 g/day with tacrolimus,the mean daily dose was approximately 1.6–1.7 g/day by6 months posttransplant as was observed in our study(3,24,25).

Tacrolimus extended-release formulation/MMF affords aconvenient, once-daily dosing option. Therapeutic regi-mens for transplant recipients are often complex, con-tributing to a high incidence of medication non-complianceand its consequences of increased mortality and morbidity.In a prospective cohort study of 278 adult recipients of de-ceased donor renal transplants, Weng and colleagues (10)found a statistically significant association for adherence tomedication regimen with daily dosing versus twice-a-daydosing, suggesting that compliance in transplant recipientscould be improved with a once-daily regimen. Tacrolimusextended-release formulation, by virtue of its once-dailyregimen, may improve compliance while enabling the useof the same patient care strategies, total daily dose, tar-get trough concentrations and therapeutic monitoring tech-niques as currently used with the twice-a-day formulationof tacrolimus. In conclusion, XL/MMF was noninferior toCsA/MMF, and had similar efficacy and safety profiles toTAC/MMF, when administered in combination with corti-costeroids and basiliximab induction with respect to effi-cacy failure, patient and graft survival, and BCAR, and ap-pears to be a safe and effective addition to the existingtreatment armamentarium.

Appendix

The Tacrolimus Modified-release Formulation De Novo Kid-ney Study Group who contributed data to this study were,in the US, Marwan Abouljoud, Henry Ford Hospital; RitaAlloway, University of Cincinnati; Scott Ames, Mount SinaiSchool of Medicine; Kenneth Andreoni, University of NorthCarolina at Chapel Hill; Iman Bajjoka, Henry Ford Hospital;William M. Bennett, Legacy Transplant Services, LegacyGood Samaritan Hospital; Roy D. Bloom, University ofPennsylvania Medical Center; Barbara Bresnahan, MedicalCollege of Wisconsin; Stephan Busque, Stanford Univer-sity Medical Center; Khalid M. H. Butt, New York Medi-cal College; Jose Castillo-Lugo, Dallas Nephrology Asso-ciates; Laurence Chan, University of Colorado Health Sci-ences Center; Diane Cibrik, University of Michigan; DavidJ. Conti, Albany Medical College; A. Benedict Cosimi, Mas-sachusetts General Hospital; James D. Eason, OchanerClinic Foundation Multi-Organ Transplant Center; GeorgeC. Francos, Thomas Jefferson University; Mahendra Gov-ani, Indiana University Medical Center; Robert Harland, Uni-versity of Chicago Medical Center; Marquis E. Hart, Univer-sity of California at San Diego Medical Center; Stephen Jen-sik, University Transplant; Johann Jonsson, Inova Trans-plant Center; Bruce Kaplan, University of Florida; CliftonE. Kew, II, University of Alabama at Birmingham; PaulC. Kuo, Duke University Medical Center; David Laskow,



Robert Wood Johnson University Hospital; Jimmy A. Light,Washington Hospital Center; Martin L. Mai, Mayo ClinicJacksonville; Rodrigo Mateo, University of Southern Cali-fornia Keck School of Medicine; Joseph Keith Melancom,Johns Hopkins Hospital; Larry B. Melton, Baylor UniversityMedical Center; Rafael Mendez, National Institute of Trans-plantation; Shamkant Mulgaonkar, Saint Barnabas MedicalCenter; Laura Lyngby Mulloy, Medical College of Georgia;Charles R. Nolan, III, The University of Texas Health Sci-ence Center at San Antonio; Douglas J. Norman, OregonHealth & Science University; William A. Nylander, Vander-bilt University Medical Center; Okechukwu Ojogho, LomaLinda University Medical Center Transplantation Institute;Oleh G. Pankewycz, Kaleida Health—Buffalo General Hos-pital; V. Ram Peddi, California Pacific Medical Center; Al-ice Peng, Cedars-Sinai Medical Center; Phuong-Thu Pham,University of California at Los Angeles School of Medicine;John D. Pirsch, University of Wisconsin; Velma P. Scantle-bury, University of South Alabama; Fuad Shihab, Universityof Utah; Douglas Slakey, Tulane Center of Abdominal Trans-plant; Steven Marc Steinberg, California Institute of RenalResearch; Stephen J. Tomlanovich, University of Californiaat San Francisco; Charles T. Van Buren, St. Luke’s Episco-pal Hospital; Thomas Wald, University of Kentucky MedicalCenter; Harold C. Yang, Pinnacle Health at Polyclinic Hos-pital; in Canada, Dr. Anne Boucher, Hopital Maisonneuve—Rosemont; Patricia Campbell, University of Alberta Hospi-tals; Michel R. Paquet, CHUM Hopital Notre Dame; JeanShapiro, BC Transplant Society; Dr. Jeffrey Zaltzman, St.Michael’s Hospital; in Brazil, Deise R. De Boni Monteirode Carvalho, Hospital Geral de Bonsucesso; Gentil AlvesFilho, Hospital das Clinicas—UNICAMP; Valter Duro Garcia,Irmandade da Santa Casa de Misericordia de Porto Alegre;Maria Cristina Ribeiro de Castro, Hospital das Clinicas daFaculdade de Medicina da USP; Helio Tedesco Silva Junior,Hospital do Rim E Hipertansa—Fundacao Oswaldo Ramos;and, from Astellas Pharma US, Inc., Kathleen Wiseman-dle, Pranob Bhattacharya, Shobha Dhadda, John Holman,William Fitzsimmons and M. Roy First.

Acknowledgments

The design and results of this study have been presented in an abstract atthe World Transplant Congress in Boston, July 2006.

This study was supported by Astellas Pharma US, Inc., Deerfield, IL. Themanuscript was drafted by the medical writing department of AstellasPharma US, Inc. (Ellen Hodosh and Kathy Stoffel), which also provided ed-itorial assistance to the authors. The authors made a substantial contribu-tion to the study’s conception and design, acquisition of data, and analysisand interpretation of data; participated in the drafting and review of themanuscript; and approved the final version.

References

1. Artz MA, Boots JMM, Ligtenberg G et al. Improved cardiovas-cular risk profile and renal function in renal transplant patientsafter randomized conversion from cyclosporine to tacrolimus. JAm Soc Nephrol 2003; 14: 1880–1888.

2. Vincenti F, Jensik SC, Filo RS, Miller J, Pirsch J. A long-term com-parison of tacrolimus (FK506) and cyclosporine in kidney trans-plantation: Evidence for improved allograft survival at five years.Transplantation 2002; 73: 775–782.

3. Johnson C, Ahsan N, Gonwa T et al. Randomized trial oftacrolimus (Prograf) in combination with azathioprine or my-cophenolate mofetil versus cyclosporine (Neoral) with mycophe-nolate mofetil after cadaveric kidney transplantation. Transplan-tation 2000; 69: 834–841.

4. Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS for the FK506Kidney Transplant Study Group. A comparison of tacrolimus(FK506) and cyclosporine for immunosuppression after cadav-eric renal transplantation. Transplantation 1997; 63: 977–983.

5. Webster AC, Woodroffe R, Taylor RS, Chapman JR, CraigJC. Tacrolimus versus cyclosporin as primary immunosuppres-sion for kidney transplant recipients: Meta-analysis and meta-regression of randomized trial data. Br Med J 2005;331: 810–814.

6. Heisel O, Heisel R, Balshaw R, Keown P. New onset dia-betes mellitus in patients receiving calcineurin inhibitors: A sys-temic review and meta-analysis. Am J Transplant 2004;4: 583–595.

7. Knoll GA, Bell RC. Tacrolimus versus cyclosporin for immunosup-pression in renal transplantation: Meta-analysis of randomizedtrials. Br Med J 1999;318: 1104–1107.

8. Gonwa T, Johnson C, Ahsan N et al. Randomized trial oftacrolimus + mycophenolate mofetil or azathioprine versuscyclosporine + mycophenolate mofetil after cadaveric kidneytransplantation: Results at three years. Transplantation 2003;75:2048–2053.

9. Didlake RH, Dreyfus K, Kerman RH, Van Buren CT, Kahan BD.Patient noncompliance: A major cause of late graft failure incyclosporine-treated renal transplants. Transplant Proc 1988;20:63–69.

10. Weng FL, Israni AK, Joffe MM et al. Race and electronicallymeasured adherence to immunosuppressive medications afterdeceased donor renal transplantation. J Am Soc Nephrol 2005;16: 1839–1848.

11. Neylan JF. Immunosuppressive therapy in high-risk transplantpatients: Dose-dependent efficacy of mycophenolate mofetil inAfrican-American renal allograft recipients. Transplantation 1997;64: 1277–1282.

12. Racusen LC, Solez K, Colvin RB et al. The Banff 97 workingclassification of renal allograft pathology. Kidney Int 1999; 55:713–723.

13. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth Dfor the Modification of Diet in Renal Disease Study Group. Amore accurate method to estimate glomerular filtration rate fromserum creatinine: A new prediction equation. Ann Intern Med1999; 130: 461–470.

14. Fitzsimmons WE, Bekersky I, Dressler D, Raye K, Hodosh E,Mekki Q. Demographic considerations in tacrolimus pharmacoki-netics. Transplant Proc 1998; 30: 1359–1364.

15. Trofe J, Gordon J, Roy-Chaudhury P et al. Polyomavirusnephropathy in kidney transplantation. Prog Transplant 2004; 14:130–140.

16. Alloway R, Steinberg S, Khalil K et al. Conversion of stable kidneytransplant recipients from a twice daily Prograf-based regimen toa once daily modified release tacrolimus-based regimen. Trans-plant Proc 2005; 37: 867–870.

17. Ihara H, Shinkuma D, Ichikawa Y, Nojima M, Nagano S, IkomaF. Intra- and inter-individual variation in the pharmacokinetics oftacrolimus (FK506) in kidney transplant recipients—Importance


Silva et al.

of trough level as a practical indicator. Int J Urol 1995; 2: 151–155.

18. Borrows R, Chusney G, Loucaidou M et al. Mycophenolic acid12-h trough level monitoring in renal transplantation: Associationwith acute rejection and toxicity. Am J Transplant 2006; 6: 121–128.

19. Zucker K, Rosen A, Tsaroucha A et al. Augmentation ofmycophenolate mofetil pharmacokinetics in renal transplant pa-tients receiving Prograf and Cellcept [sp] in Combination Ther-apy. Transplant Proc 1997; 29: 334–336.

20. van Hest RM, Mathot RAA, Pescovitz MD, Gordon R, MamelokRD, Van Gelder T. Explaining variability in mycophenolic acidexposure to optimize mycophenolate mofetil dosing: A popula-tion pharmacokinetic meta-analysis of mycophenolic acid in renaltransplant recipients. J Am Soc Nephrol 2006; 17: 871–880.

21. van Gelder T, Meur YL, Shaw LM et al. Therapeutic drug mon-itoring of mycophenolate mofetil in transplantation. Ther DrugMonit 2006; 28: 145–154.

22. Mourad M, Malaise J, Eddour DC et al. Correlation of mycophe-nolic acid pharmacokinetic parameters with side effects in kid-ney transplant patients treated with mycophenolate mofetil. ClinChem 2001; 47: 88–94.

23. Mourad M, Malaise J, Eddour DC et al. Pharmacokinetic basis forthe efficient and safe use of low-dose mycophenolate mofetil incombination with tacrolimus in kidney transplantation. Clin Chem2001; 47: 1241–1248.

24. Gonwa T, Mendez R, Yang HC, Weinstein S, Jensik S, SteinbergS, for the Prograf Study Group. Randomized trial of tacrolimus incombination with sirolimus or mycophenolate mofetil in kidneytransplantation: Results at 6 months. Transplantation 2003; 75:1213–1220.

25. Miller J, Mendez R, Pirsch JD, Jensik SC for the FK506/MMFDose-Ranging Kidney Transplant Study Group. Safety and effi-cacy of tacrolimus in combination with mycophenolate mofetil(MMF) in cadaveric renal transplant recipients. Transplantation2000; 69: 875–880.


one-year results with extended-release tacrolimus/mmf, tacrolimus/mmf and cyclosporine/mmf in de...

Documents