American Journal of Transplantation 2007; 7: 595–608
Blackwell Munksgaard
One-Year Results with Extended-Release Tacrolimus/
MMF, Tacrolimus/MMF and Cyclosporine/MMF in De
Novo 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†
a has been developed as a once-daily tacrolimus dosing al-
Hospital do Rim E Hipertansã, São Paulo, Brazil
b ternative that enables the same patient care strategies
Pinnacle Health, Polyclinic Hospital, Harrisburg, PA
c
Transplant Surgery, Henry Ford Hospital, Detroit, MI
d
Transplant Surgery, Duke University Medical Center,
Durham, NC
e daily dosing regimen could be a beneficial addition to
Astellas Pharma US, Inc., Deerfield, IL
†
See Appendix 1 for a list of members of the Tacrolimus
Extended-Release De Novo Kidney Study Group.
∗
Corresponding author: M. Roy First,
roy.first@us.astellas.com
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 mycophenolate
mofetil (MMF), corticosteroids and basiliximab induc-
tion, in a phase 3, randomized (1:1:1), open-label trial
in 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 and
TAC/MMF were statistically noninferior at 1-year post-
transplantation to CsA/MMF for the primary efficacy
endpoint, 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% in
TAC/MMF group and 97.6% and 95.7% in CsA/MMF
group. The safety profile of XL in comparison with CsA
was similar to that observed with TAC in this study and
consistent with previously published reports of TAC in
comparison with CsA. The results support the safety
and efficacy of tacrolimus in combination with MMF,
corticosteroids and basiliximab induction, as well as
XL 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 and
accepted for publication 4 November 2006

C 2007 The Authors
Journal compilation

C 2007 The American Society of
Transplantation and the American Society of Transplant Surgeons
doi: 10.1111/j.1600-6143.2007.01661.x
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 are
well-defined (1–8). Tacrolimus extended-release formula-
tion (Prograf XL, formerly referred to as MR or MR4)
and 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-
the existing treatment armamentarium (9,10). A large,
randomized, open-label study was designed to evaluate
the efficacy and safety of XL and TAC compared to that
of cyclosporine microemulsion (Neoral® , Pharmaceuticals
Corp., East Hanover, NJ; CsA) when administered in combi-
nation with mycophenolate mofetil (MMF), corticosteroids
and 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 in
July 2003 and the last evaluation was performed in April 2005. Randomiza-
tion was obtained by the principal investigator or designee via telephone
to the sponsor’s automated randomization system after informed consent
was obtained and after it was established that the patient met the eligibility
criteria. Within each treatment group, patients were stratified by number
of previous transplants (primary or retransplant) and by donor type (living
or 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 protocol
was approved by an Institutional and/or Regional Review Board at all partic-
ipating study centers to ensure that study procedures were performed in
accordance with the Helsinki Declaration.
At the investigator’s discretion, patients were allowed to cross over to the
other calcineurin inhibitor regimen to address adverse events or severe
refractory rejection that led to discontinuation of randomized study drug;
however, crossover to the XL/MMF arm was not permitted. Patients who
crossed 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-identical
living kidney transplant provided they received their first oral dose of
595
Silva et al.

Randomized n=668

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

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

Figure 1: Patient disposition.

XL/MMF treated
n=214 (94.7%)
Completed 1 year
n=183 (85.5%)
Discontinued
n=31 (14.5%)
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%)
XL = tacrolimus extended-release
TAC/MMF treated CsA/MMF treated formulation; TAC = tacrolimus
n=212 (96.8%) n=212 (95.1%) twice-a-day formulation; CsA =
cyclosporine microemulsion; MMF
= mycophenolate mofetil. Other
Completed 1 year Completed 1 year reasons for discontinuation from ran-
n=179 (84.4%) n=151 (71.2%) domized therapy were investigator
discretion/converted to rapamycin,
acute tubular necrosis, incorrect
Discontinued Discontinued study drug dispensed, investigator
n=33 (15.6%) n=61 (28.8%) discretion/possible toxicity, improper
absorption of study drug and sub-
Reason Patient Discontinued: Reason Patient Discontinued: sequent pancreas transplant. The
Adverse events n=23 (10.8%) Adverse events n=37 (17.5%) reasons for discontinuation from
Rejection n=0 Rejection n=16 (7.5%) the study are those provided by the
Noncompliance n=4 (1.9%) Noncompliance n=5 (2.4%)
investigator for the patient’s final
Graft failure n=3 (1.4%) Graft failure n=1 (0.5%)
Withdrew consent n=0 Withdrew consent n=1 (0.5%) assessment. A more conservative
Lost to follow-up n=1 (0.5%) Lost to follow-up n=0 data-driven number was used for
Other n=2 (0.9%) Other n=1 (0.5%) graft failure and lost to follow-up in
efficacy failure analyses.

randomized study drug within 48 h of the transplant procedure. Exclu-
sion criteria were: patients had previously received or were receiving an
organ transplant other than a kidney; receiving a kidney from a non-heart-
beating or an ABO blood group incompatible donor or from a ≥60 years
of age; or receiving a kidney with a cold ischemia time of ≥36 h. Patients
were excluded if they were known to be seropositive for HIV or if they
had a current malignancy or a history of malignancy (previous 5 years)
other than nonmetastatic basal or squamous cell carcinoma of the skin
that 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 times
the upper limit of normal during the 28 days prior to the transplant) or had
an uncontrolled concomitant infection or any unstable medical condition
that could potentially interfere with study participation. Patients who had a
known sensitivity to TAC, CsA, MMF or corticosteroids; received everolimus
or enteric-coated mycophenolic acid; received intravenous immunoglobu-
lin therapy prior to randomization or within 48 h after randomization; and
who were taking or had previously taken another investigational drug within
30 days prior to transplant were also excluded.
Primary immunosuppressive regimens
The three primary immunosuppressants were supplied to patients by the
study 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 h
apart (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 5–15
ng/mL thereafter. Neoral was administered in two equal oral doses 12 h
apart (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 chosen
based on input from investigators. Dosing of XL, TAC and CsA was chosen
based on recommended ranges as described in the package insert for the
commercial products and was permitted to be adjusted by the investigator
based on protocol-specified target whole blood trough concentrations and
standard clinical practice.
Adjunct immunosuppressants
Two 20-mg intravenous doses of basiliximab induction therapy were to be
administered, 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 of
200 mg methylprednisolone (or equivalent) on day 1 and subsequent ta-
pering to achieve a targeted mean prednisone equivalent after the first
3 months of 5–10 mg/day in each treatment group. MMF (1 g bid) was
administered 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 the
protocol.
Treatment of rejection episodes
All suspected rejection episodes were to be confirmed by a renal biopsy
before treatment for rejection was begun or within 48 h of initiation of
treatment for acute rejection. Initial rejection episodes were treated with
oral 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 patients
with histologically proven Banff Grade II or III rejection or steroid-resistant
rejection.
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 dose
of study drug (full analysis set). Within this full analysis set, select groups of
at-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- died, experienced graft failure (return to dialysis for >30 days or retrans-
teristics plant), had a biopsy-confirmed acute rejection (BCAR; Banff Grade ≥1) or
XL/MM TAC/MMF CsA/MMF was lost to follow-up. Lost to follow-up was defined as any patient who did
(n = 214) (n = 212) (n = 212) not have at least 11 months (335 days) of follow-up information. Biopsies
were analyzed by the pathologist at each clinical site and were graded ac-
Sex cording to 1997 Banff criteria (12). Blinded central review of the biopsies
Male 138 (64.5%) 136 (64.2%) 130 (61.3%) was also performed, but was not used in the primary analysis of the com-
Female 76 (35.5%) 76 (35.8%) 82 (38.7%) posite endpoint. The protocol-defined secondary endpoints included patient
Race and graft survival rates at 1 year, incidence of BCAR (Banff Grade ≥1) at
White 160 (74.8%) 152 (71.7%) 163 (76.9%) 6 and 12 months, time to first acute rejection, incidence of antilympho-
Black 41 (19.2%) 51 (24.1%) 36 (17.0%) cyte antibody therapy for treatment of rejection, severity of acute rejection,
Asian 5 (2.3%) 5 (2.4%) 8 (3.8%) number of patients experiencing multiple rejection episodes, number of
Other1 8 (3.7%) 4 (1.9%) 5 (2.4%) clinically treated acute rejection episodes, incidence of discontinuation of
Ethnicity randomized drug for any reason and incidence of crossover. An evaluation
Hispanic 31 (14.5%) 29 (13.7%) 31 (14.6%) of renal function (serum creatinine and calculated creatinine clearance) was
Non-Hispanic 183 (85.5%) 183 (86.3%) 181 (85.4%) included as a secondary endpoint per the advice of the FDA. An analysis
Age (years) of the incidence of delayed graft function (defined as at least one dialysis
Mean ± SD 47.8 ± 13.0 48.6 ± 12.9 47.6 ± 13.0 episode within the first 7 days posttransplant and included acute tubular
Median 48.00 50.50 48.50 necrosis requiring dialysis in the first week after transplantation) was also
Range 17-77 19-74 17-77 preplanned.
Age group (years)
<65 190 (88.8%) 189 (89.2%) 192 (90.6%)
All assessments of non-inferiority were made using a prespecified margin
≥65 24 (11.2%) 23 (10.8%) 20 (9.4%)
of 10%. Enrollment was targeted to provide at least 90% power to con-
Diabetes type I 50 (23.4%) 60 (28.3%) 58 (27.4%)
clude non-inferiority with respect to the primary endpoint, efficacy failure.
or II2
The sample size calculation was adjusted for the two primary comparisons
HLA mismatches
(XL/MMF vs. CsA/MMF, TAC/MMF vs. CsA/MMF). The achieved enrollment
0 12 (5.6%) 6 (2.8%) 15 (7.1%)
was found to provide greater than 99% power for patient and graft survival,
1 10 (4.7%) 7 (3.3%) 12 (5.7%)
89% power for BCAR at 6 months, and 84% power for BCAR at 12 months
2 31 (14.5%) 27 (12.7%) 27 (12.7%)
based on the results in the CsA/MMF group. Adjustments were made for
≥3 161 (75.2%) 172 (81.1%) 158 (74.5%)
multiple comparisons for the primary, but not the secondary endpoints.
Donor type
Statistical tests regarding secondary endpoints should be interpreted with
Living 103 (48.1%) 106 (50.0%) 111 (52.4%)
caution.
Deceased 111 (51.9%) 106 (50.0%) 101 (47.6%)
Cold ischemia
Treatment group differences were calculated as the experimental regi-
time (h)
men minus the comparator (XL/MMF minus CsA/MMF; TAC/MMF minus
Number 110 103 101
CsA/MMF). For the primary analysis of efficacy failure rate, 95.2% confi-
Mean ± SD 17.88 ± 7.732 19.41 ± 7.267 18.44 ± 7.109
dence intervals (CI) of the treatment differences were constructed using a
Median 17.87 19.57 18.00
normal approximation in order to adjust for interim reviews of the data by a
Range 0.8–34.8 0.5–37.3 2.3–38.0
Data Safety Monitoring Board. A procedure based on Hochberg’s method
Had a previous 8 (3.7%) 7 (3.3%) 9 (4.2%)
was used to adjust for the two primary treatment comparisons. Incidence
transplant
rates were also compared using a chi-square test. Analysis of efficacy fail-
Panel reactive
ure rate was also compared across the treatment groups using a Cochran–
antibody (%)
Mantel–Haenszel test adjusting for donor type (living or deceased); the inter-
Number 211 203 204
action between treatment strata was examined by testing the homogeneity
Mean ± SD 2.49 ± 10.668 2.72 ± 11.343 4.09 ± 13.315
of the odds ratio using the Breslow–Day test. Analyses of the efficacy fail-
Median 0.00 0.00 0.00
ure rate for each donor type strata were also performed using a chi-square
Range 0.0–87.0 0.0–78.0 0.0–95.0
test.
1 Other: Brazilian Indian (4); East Indian (2); Indian (2); Native
Hawaiian—Other Pacific Islander (2); Philippino (6) and Indian Patient and graft survival were analyzed using Kaplan–Meier plots and treat-
Subcontinent (1). ment groups were compared for day 365 data using the log-rank test cen-
2 Not posttransplant diabetes mellitus (PTDM).
soring patients at time of last follow-up. Patient survival included patients
MMF = mycophenolate mofetil; XL = tacrolimus extended- who did not die and were not lost to follow-up; graft survival included pa-
release formulation; TAC = tacrolimus twice-a-day formulation; tients who did not die, did not experience graft failure (return to dialysis
CsA = cyclosporine microemulsion; SD = standard deviation. >30 days or retransplant), and were not lost to follow-up. Incidence of
BCAR, and antilymphocyte therapy were analyzed using a chi-square test.
Renal function analysis was assessed based on worst case, highest serum
condition or whose laboratory values did not meet the protocol-specified creatinine and lowest creatinine clearance (Cockcroft–Gault formula) values
abnormal criterion (e.g. low-density lipoprotein cholesterol ≥200 mg/dL), for each visit window. The month 1 result was used as baseline for change
were also identified for ‘new-onset’ safety analysis. in renal function analysis as graft function would be expected to have sta-
bilized by month 1 posttransplant. Missing values were not imputed. Mean
The primary efficacy endpoint for this study, developed in collaboration with values over time were compared between groups using two-way analysis
the Division of Special Pathogen and Transplant Products (FDA), was a com- of variance (ANOVA) with treatment and center as factors. In addition, a
posite endpoint, efficacy failure rate at 1 year, comprising any patient who post 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 = 172
19.0% 27.3% 30.7% 27.9% 11.28 12.99
Month 2 n = 10 n = 11 n = 33 n = 29 n = 181 n = 165
5.5% 6.7% 18.2% 17.6% 10.15 10.06
Month 4 n = 13 n=7 n = 18 n = 20 n = 174 n = 151
7.5% 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-defined
time 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 with
respect 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’s
exact test. A new onset glucose metabolism disorder was identified based
on 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 ≥30
days 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 performed
to evaluate the relationship between trough concentration and BCAR, and
renal dysfunction (creatinine clearance <40 mL/min). Creatinine clearance
<40 mL/min was evaluated in patients who had the assessment at 1 month
posttransplant and did not meet the criteria, and had at least one value after
month 1.
Results
Patients
A total of 668 patients were randomized into one of three
treatment groups; 638 of these randomized patients re-
ceived at least one dose of study drug and were included
in efficacy and safety analyses (Figure 1). A total of 30
patients 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); delayed
graft function (n = 2); acute tubular necrosis (n = 2); high

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

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

 Extended-Release Tacrolimus/MMF in Kidney Transplantation

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 Mean
daily trough daily trough daily trough daily trough
dose 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 = 32
0.14 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 = 34
0.14 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 = 34
0.10 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 = 33
0.09 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-defined
time 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 within
48 h with no further explanation. Treatment groups were
balanced with regard to donor type and other baseline char-
acteristics (Table 1). Eighty-five percent of patients in the
XL/MMF and TAC/MMF groups completed 1 year of ran-
domized treatment compared with 71% of patients in the
CsA/MMF group; most of the patients who discontinued
randomized therapy did so because of an adverse event
(Figure 1).

Table 4: Efficacy failure in de novo kidney transplant recipients at Primary immunosuppressant blood trough
1-year posttransplant concentrations
XL/MMF TAC/MMF CsA/MMF Mean total daily doses of tacrolimus were similar be-
(n = 214) (n = 212) (n = 212) tween the TAC/MMF and XL/MMF treatment groups
Efficacy failure1 30 (14.0%) 32 (15.1%) 36 (17.0%)
Death 3 92 52
Graft failure 5 9 43 Table 5: Patient and graft survival (Kaplan–Meier estimates) in de
BCAR (local 224 16 29 novo kidney transplant recipients at 1-year posttransplant
assessments)
Lost to follow-up 3 4 1 XL/MMF TAC/MMF CsA/MMF
Treatment difference5 −3.0% −1.9% (n = 214) (n = 212) (n = 212)
95.2% confidence −9.9%, 4.0% −8.9%, 5.2% Patient survival1 98.6% 95.7% 97.6%
interval6 Kaplan–Meier 1.0% −1.9%
1 Efficacy estimate difference2
failure comprised any patient who died, experienced
95% confidence −1.6%, 3.6% −5.3%, 1.5%
loss of a graft (return to dialysis for >30 days or retransplant), had
interval
a BCAR or was lost to follow-up. Patients could have met more
Graft survival 96.7% 92.9% 95.7%
than one criterion; a patient was only counted once regardless of
Death or graft failure 7 151 91
how many of the criteria were met.
2 One additional patient randomized to TAC/MMF and one Kaplan–Meier 1.0% −2.9%
estimate difference2
additional patient randomized to CsA/MMF died after the 1-year
95%confidence −2.7%, 4.6% −7.3%, 1.6%
study period was completed.
3 One additional patient randomized to CsA/MMF experienced interval
graft failure after the 1-year study period was completed. 1 One additional patient randomized to TAC/MMF and one
4 Two additional patients randomized to XL/MMF had BCAR after additional patient randomized to CsA/MMF died after the 1-year
the 1-year study period was completed. study period was completed. One additional patient randomized
5 Treatment differences are relative to CsA/MMF treatment group to CsA/MMF experienced graft failure after the 1-year study
(XL minus CsA; TAC minus CsA). period was completed.
6 Confidence interval adjusted for Data Safety Monitoring Board 2 Kaplan–Meier estimate differences are relative to the CsA/MMF

interim review.
Lost to follow-up: any patient who did not have at least 11 months
(335 days) of follow-up information. MMF = mycophenolate
mofetil; XL = tacrolimus extended-release formulation; TAC
= tacrolimus twice-a-day formulation; CsA = cyclosporine
microemulsion.
treatment group (XL minus CsA; TAC minus CsA). Treatment
groups were compared for day 365 data using the log-rank test
censoring 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.

American Journal of Transplantation 2007; 7: 595–608 599

Silva et al.

Table 6: Primary causes of death and reasons for graft failure1 dow, the mean trough concentrations at day 3, months
XL/MMF TAC/MMF CsA/MMF 2 and 4 were 272.4, 261.1 and 218.1 ng/mL. Regardless
(n = 214) (n = 212) (n = 212) of treatment group, mean trough concentrations of study
drug were generally at the middle to high end of the target
Total deaths2 3 9 5
Sepsis 3
range through the first month posttransplant and gradually
Pulmonary embolism/edema 1 2 declined toward the lower end of the target range there-
Cardiac arrest 1 after.
Cardiac arrest and 1
respiratory arrest A high degree of interpatient variability in tacrolimus trough
Myocardial infarction 2 concentrations was observed with administration of either
Subdural bleed after fall 1 the extended-release or twice-a-day tacrolimus formulation
Homicide 1 in both black and white transplant recipients. Similar to
Tissue invasive 1 what has been previously reported for TAC (14), black pa-
strongyloidosis
tients required a higher dose of XL or TAC to attain trough
Miliary tuberculosis 1
Lymphocytic 1
concentrations comparable to those of white patients
choriomeningitis 1 (Table 3).
Stroke 1
Diverticulitis 1
Adjunct immunosuppressants
Total graft failures3 5 9 4 All but 10 patients received two 20-mg intravenous doses
Acute rejection 1 1 of basiliximab induction therapy (1 XL, 1 TAC, 3 CsA did
Acute tubular necrosis 1 14 2 not receive basiliximab; 2 XL, 3 TAC received one dose).
Chronic allograft 1 1 At 1-year posttransplant, similar mean total daily doses of
nephropathy prednisone or equivalent were administered in all three
Renal vein thrombosis 1 1 15 treatment groups (XL/MMF 8.4 mg, TAC/MMF 6.9 mg,
Vascular rejection, 1 CsA/MMF 7.3 mg; p = 0.29, one-way ANOVA).
collapsing FSGN
Recurrent disease 2
By 1-year posttransplant, administration of MMF had been
Acute thrombosis of 1
iliac artery
discontinued in 10.7% (23/214) of patients in the XL/MMF
Delayed graft function 1 group, 14.7% (31/211) in the TAC/MMF group and 8.1%
Nephrectomy 1 (17/211) of patients in the CsA/MMF group. At 1-year post-
Primary nonfunctioning graft 1 transplant, mean total daily dose of MMF was significantly
1 Investigator’s higher in the CsA/MMF group (1800.8 mg) compared with
description of the primary cause of death and
primary reason for graft failure. the two tacrolimus groups (XL/MMF 1668.9 mg, TAC/MMF
2 One additional patient randomized to TAC/MMF and one 1655.8 mg) (p = 0.0012, one-way ANOVA). Mean month
additional patient randomized to CsA/MMF died after the 1-year 1 and 1-year plasma trough MPA levels were 3.3 and
study period was completed. 3.0 lg/mL in the XL/MMF group, 3.7 and 3.1 lg/mL in the
3 One additional patient randomized to CsA/MMF experienced TAC/MMF group, and 2.1 and 2.4 lg/mL in the CsA/MMF
graft failure after the 1-year study period was completed. group.
4 Acute tubular necrosis and noncompliance.
5 Renal artery and renal vein thrombosis.

Graft failure: permanent return to dialysis (>30 days) or re-

transplant. MMF = mycophenolate mofetil; XL = tacrolimus
extended-release formulation; TAC = tacrolimus twice-a-day
formulation; CsA = cyclosporine microemulsion; FSGN = focal
segmental glomerulonephritis.
(e.g. month 1: 0.12 mg/kg vs. 0.14 mg/kg; month 6: 0.10
mg/kg vs. 0.11 mg/kg and month 12: 0.08 mg/kg vs. 0.09
mg/kg). Trough concentrations in whole blood were most
variable during the first week of dosing for both tacrolimus
formulations. There were no consistent trends between
the XL/MMF and TAC/MMF treatment groups with regard
to 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/MMF
group 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/MMF
group who had trough concentration data for the visit win-
Efficacy
At 1-year posttransplant, efficacy failure rates in both the
XL/MMF and TAC/MMF groups were statistically non-
inferior to that in the CsA group (Table 4); the results of
analyses 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 primary
cause of death or graft failure were identified (Table 6). The
incidence of BCAR at 6 months and 1 year was significantly
lower 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). The
Kaplan–Meier curve for time to first BCAR through 1 year
is presented in Figure 3.
Although not defined a priori as an efficacy endpoint, the
incidence of BCAR early posttransplant (month 1) also

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

 Extended-Release Tacrolimus/MMF in Kidney Transplantation

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 14
I-B 3 4 6
II-A 6 3 6
II-B 1 1 1
III 1 0 2
BCAR (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%, 0
Clinically 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-square
test) between either of the tacrolimus-based treatment
groups and the CsA-based treatment group (TAC/MMF
2.8%, 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
−0.1%; 95% CI: −4.6%, 4.5%). There was no statis-
tically significant difference between the XL/MMF and
TAC/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

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 = cyclosporine
microemulsion; MMF = mycopheno-
late mofetil; BCAR = biopsy con-
firmed acute rejection. Kaplan–Meier
plot of BCAR censored at time of last
follow-up.

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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
Treatment Visit
group (day) n Mean ± SD
XL/MMF 3 10 11.2 ± 9.10
30 10 10.5 ± 4.11
TAC/MMF 3 4 10.8 ± 4.88
30 8 10.3 ± 3.81
CsA/MMF 3 10 218.9 ± 95.84
30 7 271.6 ± 108.3
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 the
protocol-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 received
grafts 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/MMF
when 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 any
reason, the incidence of crossovers, and the incidence of
delayed graft function are presented in Table 7. Regardless
of treatment group, >90% of episodes of delayed graft
function occurred in patients who received grafts from de-
ceased donors.
Renal function parameters are presented in Table 9. The
robustness of the renal function findings was evaluated by
estimating the GFR using MDRD. This analysis showed
consistent results with the Cockroft Gault estimates of
creatinine clearance with significantly higher GFR in the
XL/MMF and TAC/MMF groups as compared to CsA/MMF
at 1-year posttransplant. Similar mean tacrolimus trough
concentrations were observed throughout the study for
patients with or without creatinine clearance <40 mL/min
in 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 and
CsA/MMF observed in this study were consistent with
602
Patients without BCAR
n Mean ± SD p-value
179 11.3 ± 7.17 0.7457
172 11.2 ± 4.96 0.8434
168 13.0 ± 8.86 0.8751
166 11.2 ± 4.65 0.6206
162 275.7 ± 154.8 0.4382
159 311.7 ± 126.1 0.4167
those previously reported (1–8). XL/MMF and TAC/MMF
presented similar overall safety profiles. A summary
of adverse events with a statistically significant differ-
ence between tacrolimus/MMF treatment group and the
CsA/MMF group is presented in Table 10. There were no
statistically significant differences in the incidence of bac-
terial, fungal or viral infections, or adverse events reported
by the investigator as cytomegalovirus infection, or cy-
tomegalovirus viremia, or human polyomavirus infection
in the XL/MMF compared with the CsA/MMF treatment
groups (Table 11).
The incidence of new onset diabetes as defined by the
American Diabetes Association (ADA) as a single fasting
plasma glucose ≥126 mg/dL during the 1-year treatment
period was significantly higher for patients at risk in the
TAC/MMF group than in the CsA/MMF (Table 12), consis-
tent with previous reports (5–7); the incidence was not
statistically significantly different between the XL/MMF
and CsA/MMF groups. The incidence of new onset oral
hypoglycemic agent use was significantly higher in both
tacrolimus groups compared with the CsA/MMF group
(Table 12). However, the incidence of new onset use of
insulin ≥30 days was not significantly different between
either of the tacrolimus-based treatment groups and the
CsA/MMF group.
Mean values for total cholesterol, LDL cholesterol, HDL
cholesterol and triglycerides at the day 21, and months 6
and 12 visits are summarized in Table 13. There was a sta-
tistically significant (p = 0.011) difference among treatment
groups with respect to incidence of patients at risk who had
total 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) of
patients in the XL/MMF group, 44.8% (95/212) of patients
in the TAC/MMF group, and 60.8% (129/212) of patients
in the CsA/MMF treatment group received some form of
lipid-lowering medication.
There were no significant differences among treatment
groups with respect to incidence of glucose ≥200 mg/dL,
platelets <100 × 109 cells/L, WBCs <2.0 × 109 cells/L,
American Journal of Transplantation 2007; 7: 595–608
 Extended-Release Tacrolimus/MMF in Kidney Transplantation

Table 9: Renal function

XL/MMF TAC/MMF CsA/MMF
(n = 214) (n = 212) (n = 212)
Serum creatinine (mg/dL)
Month 1
n 199 202 195
Mean ± SD 1.63 ± 1.14 1.62 ± 1.17 1.68 ± 0.99
Month 6
n 188 186 173
Mean ± SD 1.46 ± 0.55 1.42∗ ± 0.43 1.51 ± 0.50
Month 12
n 185 175 150
Mean ± SD 1.39∗ ± 0.44 1.42 ± 0.56 1.48 ± 0.51
Incidence of patients with serum creatinine <2.5 mg/dL at month
1 and ≥2.5 mg/dL at months 6 and 12
Month 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 1
n 199 202 193
Mean ± SD 55.4 ± 20.61 55.1 ± 20.73 53.5 ± 21.01
Month 6
n 188 186 171
Mean ± SD 56.7∗ ± 18.24 56.8∗ ± 17.25 53.6 ± 15.92
Month 12
n 185 175 148
Mean ± SD 58.7∗∗ ± 18.26 57.7∗ ± 18.81 54.6 ± 17.60
Estimated GFR (mL/min per 1.73 m2 ) 2
Month 1
n 199 201 193
Mean ± SD 53.2 ± 18.62 54.1 ± 19.78 51.5 ± 21.46
Month 6
n 188 185 171
Mean ± SD 56.8∗ ± 17.86 58.8∗∗ ± 17.29 53.5 ± 16.69
Month 12
n 184 174 149
Mean ± 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 were
included; 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.
1 Based on Cockcroft–Gault formula using ideal body weight.
2 MDRD study prediction equation (13); 170 × [serum creatinine (mg/dL)](−0.999) × [age](−0.176) × [0.762 if patient is female] × [1.180

if patient is black] × [BUN (mg/dL)](−0.170) × [albumin (g/dL)](0.318) . Percent decrease was calculated only for patients with all values
required for the MDRD calculation available at both months 1 and 12. The month 1 result was used as baseline for analysis of change in
renal 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 or
triglycerides ≥500 mg/dL.
Discussion
Based on the results of this comparative study in de
novo renal transplant recipients, XL/MMF is as effective
as TAC/MMF and CsA/MMF when used in combination
with corticosteroids and basiliximab induction. Tacrolimus
extended-release formulation used in combination with
MMF provided a safety profile consistent with that his-
torically established for twice-a-day tacrolimus (1–8) and
similar to that observed for TAC/MMF in this study.
Tacrolimus administered as a twice-a-day formulation in
combination with steroids has been associated with a

American Journal of Transplantation 2007; 7: 595–608 603

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 disorders
Diarrhoea 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 complications
AV fistula thrombosis 0∗ 1 (0.5%) 5 (2.4%)
Metabolism and nutrition disorders
Hyperlipidaemia 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 infestations
Sinusitis 15 (7.0%)∗ 7 (3.3%) 5 (2.4%)
Gastroenteritis 14 (6.5%)∗ 1 (0.5%) 4 (1.9%)
General disorders and administration site conditions
Oedema peripheral 76 (35.5%)∗ 74 (34.9%)∗ 97 (45.8%)
Nervous system disorders
Tremor 75 (35.0%)∗∗∗ 73 (34.4%)∗∗ 42 (19.8%)
Paraesthesia 12 (5.6%) 3 (1.4%)∗ 13 (6.1%)
Vascular disorders
Orthostatic hypotension 15 (7.0%)∗ 10 (4.7%) 5 (2.4%)
Lymphocele 1 (0.5%)∗ 2 (0.9%) 7 (3.3%)
Psychiatric disorders
Insomnia 55 (25.7%) 64 (30.2%)∗ 45 (21.2%)
Skin and subcutaneous tissue disorders
Alopecia 14 (6.5%)∗ 15 (7.1%)∗ 4 (1.9%)
Hypertrichosis 0∗∗ 0∗ 7 (3.3%)
Renal and urinary disorders
Hydronephrosis 1 (0.5%)∗ 2 (0.9%) 9 (4.2%)
Nephropathy toxic 3 (1.4%) 1 (0.5%)∗ 8 (3.8%)
Reproductive system and breast disorders
Benign prostatic hyperplasia 1 (0.5%)∗ 4 (1.9%) 7 (3.3%)
Endocrine disorders
Hirsutism 0∗∗∗ 0∗∗∗ 18 (8.5%)
Eye disorders
Visual 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 have
experienced more than one adverse event. The sum of the terms may exceed 100% Statistical significance was determined using
Fisher’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- of better patient management including lower targeted
closporine (4–7); this was also observed in the present blood levels of tacrolimus, steroid tapering and new ad-
study. In recent years, the incidence of new onset diabetes junctive agents (4–7). The incidence of insulin dependency
mellitus posttransplant has been lower, possibly reflective in the present study in both the XL/MMF and TAC/MMF

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.

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

 Extended-Release Tacrolimus/MMF in Kidney Transplantation

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 the
analyses.
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 between
XL/MMF and CsA/MMF treatment groups.
The incidence of polyomavirus events in our study, based
on adverse events reported by the study investigators,
is consistent with the 1–8% incidence of polyomavirus
nephropathy reported by Trofe and colleagues in re-
nal transplant recipients (15). The incidence of human
polyomavirus infection was similar in the XL/MMF and
CsA/MMF groups.
The open-label aspect of the trial is recognized as a design
limitation. As with many trials in the past (1–8), technical
difficulties made double-blinding impractical. However, this
trial was a large (>200 per arm), multicenter randomized
trial adequately powered to demonstrate noninferiority for
the primary composite endpoint, as well as for the sec-
ondary endpoints of patient and graft survival and BCAR. In
addition, 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 MMF
was based on commercial product recommendations and
the investigators were allowed to adjust doses according
to their clinical judgment. Target blood concentrations for
the primary immunosuppressants in this study also were
based on investigator input and are consistent with clin-
ical practice (5). Therefore, the exposure to the primary
immunosuppressants and MPA observed in this study re-
flects clinical practice.
An earlier pharmacokinetic study of conversion from
Prograf-based to XL-based immunosuppression in stable
kidney transplant recipients showed equivalence of expo-
sure between the two formulations (16). In the present
study, interpatient variability in trough concentrations was
high 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 and
the incidence of BCAR, or between trough concentrations
observed later during the study and renal dysfunction (cre-
atinine clearance <40 mL/min), in either tacrolimus-based
treatment group. This would support the ability of clinicians
to achieve appropriate patient management for XL/MMF
and TAC/MMF groups using techniques established for
TAC.
As observed previously (8,18,19), a higher dose of MMF
was used in the CsA/MMF group compared with the two
tacrolimus groups. The requirement for higher doses of
MMF with cyclosporine is consistent with reports that cy-
closporine in combination with MMF is associated with
lower MPA levels than tacrolimus in combination with
MMF (18–21). A relationship has been reported between
high MPA levels and anemia, leukopenia, thrombocytope-
nia, upper gastrointestinal complaints, diarrhea and viral
infection 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, the
observed MPA levels in the CsA/MMF group at month 1
suggest that in the early period posttransplant MPA lev-
els were at least equal to those reported by Borrows
et al. (18) and van Gelder et al. (21) as being associated with
low acute rejection rates in kidney transplant recipients.
Despite the difference in MPA exposure with cyclosporine
compared with that of noncyclosporine regimens, fixed
doses of MMF are typically used in combination with

American Journal of Transplantation 2007; 7: 595–608 605

Silva et al.

Table 13: Summary of lipid profile over time cyclosporine or tacrolimus. In several prospective studies
XL/MMF TAC/MMF CsA/MMF using a starting dose of MMF 2 g/day with tacrolimus,
(n = 214) (n = 212) (n = 212) the mean daily dose was approximately 1.6–1.7 g/day by
Total cholesterol (mg/dL) 6 months posttransplant as was observed in our study
Baseline (3,24,25).
n 180 182 178
Mean ± SD 143.4 ± 41.06 143.4 ± 39.28 143.7 ± 39.88 Tacrolimus extended-release formulation/MMF affords a
Day 21 convenient, once-daily dosing option. Therapeutic regi-
n 172 173 168 mens for transplant recipients are often complex, con-
Mean ± SD 197.7 ± 44.10∗ 195.3 ± 43.46∗ 227.2 ± 54.29 tributing to a high incidence of medication non-compliance
Month 6 and its consequences of increased mortality and morbidity.
n 179 175 164
In a prospective cohort study of 278 adult recipients of de-
Mean ± SD 187.6 ± 46.16∗ 184.7 ± 43.04∗ 205.2 ± 48.83
ceased donor renal transplants, Weng and colleagues (10)
Month 12
n 178 172 144 found a statistically significant association for adherence to
Mean ± SD 188.7 ± 45.98∗ 182.2 ± 41.60∗ 202.3 ± 55.45 medication regimen with daily dosing versus twice-a-day
LDL (mg/dL) dosing, suggesting that compliance in transplant recipients
Baseline could be improved with a once-daily regimen. Tacrolimus
n 174 177 172 extended-release formulation, by virtue of its once-daily
Mean ± SD 80.1 ± 34.16 79.9 ± 32.33 80.6 ± 33.96 regimen, may improve compliance while enabling the use
Day 21 of the same patient care strategies, total daily dose, tar-
n 162 155 151 get trough concentrations and therapeutic monitoring tech-
Mean ± SD 106.2 ± 35.40∗ 101.9 ± 36.93∗ 125.0 ± 43.17
niques as currently used with the twice-a-day formulation
Month 6
of tacrolimus. In conclusion, XL/MMF was noninferior to
n 169 165 146
Mean ± SD 100.9 ± 39.30∗ 100.0 ± 33.99∗ 116.9 ± 42.59 CsA/MMF, and had similar efficacy and safety profiles to
Month 12 TAC/MMF, when administered in combination with corti-
n 171 163 137 costeroids and basiliximab induction with respect to effi-
Mean ± SD 102.4 ± 37.88∗ 97.1 ± 30.53∗ 113.4 ± 46.44 cacy failure, patient and graft survival, and BCAR, and ap-
HDL (mg/dL) pears to be a safe and effective addition to the existing
Baseline treatment armamentarium.
n 177 179 174
Mean ± SD 42.3 ± 13.28 44.4 ± 13.14 42.5 ± 14.67
Day 21
n 166 163 161
Appendix
Mean ± SD 59.1 ± 17.61 58.2 ± 17.45 62.6 ± 20.20
Month 6 The Tacrolimus Modified-release Formulation De Novo Kid-
n 173 170 155 ney Study Group who contributed data to this study were,
Mean ± SD 52.1 ± 17.40 53.2 ± 17.60 51.8 ± 17.25 in the US, Marwan Abouljoud, Henry Ford Hospital; Rita
Month 12 Alloway, University of Cincinnati; Scott Ames, Mount Sinai
n 174 170 141 School of Medicine; Kenneth Andreoni, University of North
Mean ± SD 51.5 ± 15.85 52.2 ± 17.12 51.9 ± 16.73 Carolina at Chapel Hill; Iman Bajjoka, Henry Ford Hospital;
Triglycerides (mg/dL) William M. Bennett, Legacy Transplant Services, Legacy
Baseline Good Samaritan Hospital; Roy D. Bloom, University of
n 181 182 178
Pennsylvania Medical Center; Barbara Bresnahan, Medical
Mean ± SD 111.4 ± 84.17 99.2 ± 79.88 96.6 ± 62.78
Day 21
College of Wisconsin; Stéphan Busque, Stanford Univer-
n 173 171 164 sity Medical Center; Khalid M. H. Butt, New York Medi-
Mean ± SD 171.4 ± 92.49 171.5 ± 101.99 185.3 ± 111.69 cal College; Jose Castillo-Lugo, Dallas Nephrology Asso-
Month 6 ciates; Laurence Chan, University of Colorado Health Sci-
n 177 174 162 ences Center; Diane Cibrik, University of Michigan; David
Mean ± SD 182.2 ± 114.15 166.6 ± 97.04∗ 192.3 ± 100.76 J. Conti, Albany Medical College; A. Benedict Cosimi, Mas-
Month 12 sachusetts General Hospital; James D. Eason, Ochaner
n 177 170 144 Clinic Foundation Multi-Organ Transplant Center; George
Mean ± SD 183.9 ± 117.09 176.8 ± 153.35 195.7 ± 170.96 C. Francos, Thomas Jefferson University; Mahendra Gov-
Statistical significance vs. CsA/MMF was determined from ani, Indiana University Medical Center; Robert Harland, Uni-
contrasts in a two-way ANOVA, with treatment and center as versity of Chicago Medical Center; Marquis E. Hart, Univer-
factors. ∗ p ≤ 0.020. sity of California at San Diego Medical Center; Stephen Jen-
MMF = mycophenolate mofetil; XL = tacrolimus extended- sik, University Transplant; Johann Jonsson, Inova Trans-
release formulation; TAC = tacrolimus twice-a-day formulation;
plant Center; Bruce Kaplan, University of Florida; Clifton
CsA = cyclosporine microemulsion; SD = standard deviation;
E. Kew, II, University of Alabama at Birmingham; Paul
HDL = high density lipoprotein; LDL = low density lipoprotein.
C. Kuo, Duke University Medical Center; David Laskow,

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

 Extended-Release Tacrolimus/MMF in Kidney Transplantation
Robert Wood Johnson University Hospital; Jimmy A. Light,
Washington Hospital Center; Martin L. Mai, Mayo Clinic
Jacksonville; Rodrigo Mateo, University of Southern Cali-
fornia Keck School of Medicine; Joseph Keith Melancom,
Johns Hopkins Hospital; Larry B. Melton, Baylor University
Medical Center; Rafael Mendez, National Institute of Trans-
plantation; Shamkant Mulgaonkar, Saint Barnabas Medical
Center; 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, Oregon
Health & Science University; William A. Nylander, Vander-
bilt University Medical Center; Okechukwu Ojogho, Loma
Linda 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, University
of Utah; Douglas Slakey, Tulane Center of Abdominal Trans-
plant; Steven Marc Steinberg, California Institute of Renal
Research; Stephen J. Tomlanovich, University of California
at San Francisco; Charles T. Van Buren, St. Luke’s Episco-
pal Hospital; Thomas Wald, University of Kentucky Medical
Center; Harold C. Yang, Pinnacle Health at Polyclinic Hos-
pital; in Canada, Dr. Anne Boucher, Hôpital Maisonneuve—
Rosemont; Patricia Campbell, University of Alberta Hospi-
tals; Michel R. Pâquet, CHUM Hôpital Notre Dame; Jean
Shapiro, BC Transplant Society; Dr. Jeffrey Zaltzman, St.
Michael’s Hospital; in Brazil, Deise R. De Boni Monteiro
de Carvalho, Hospital Geral de Bonsucesso; Gentil Alves
Filho, Hospital das Clinicas—UNICAMP; Valter Duro Garcia,
Irmandade da Santa Casa de Misericórdia de Porto Alegre;
Maria Cristina Ribeiro de Castro, Hospital das Clinicas da
Faculdade de Medicina da USP; Helio Tedesco Silva Junior,
Hospital do Rim E Hipertansã—Fundação 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 at
the World Transplant Congress in Boston, July 2006.
This study was supported by Astellas Pharma US, Inc., Deerfield, IL. The
manuscript was drafted by the medical writing department of Astellas
Pharma 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 analysis
and interpretation of data; participated in the drafting and review of the
manuscript; and approved the final version.
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