ORIGINAL PAPER

e-ISSN 2329-0358
© Ann Transplant, 2024; 29: e942167
DOI: 10.12659/AOT.942167

Received:
Accepted:
2023.08.14
2024.02.09 Long-Term Outcomes with Prolonged-
Available online:
Published:
2024.03.07
2024.03.19 Release Tacrolimus in Kidney Transplantation:
A Retrospective Real-World Data Analysis

Authors’ Contribution: ABDE 1 Wilfried Gwinner 1 Department of Nephrology, Hannover Medical School, Hannover, Germany
Study Design A ACDE 2 Swapneel Anaokar 2 Astellas Pharma Europe Ltd., Addlestone, United Kingdom
Data Collection B 3 Astellas Pharma GmbH, Munich, Germany
Statistical Analysis C ACDE 2 Martin Blogg 4 Department of Nephrology and Hypertension, Universitätsklinikum Erlangen
Data Interpretation D ACDE 3 Birgit Hermann und Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
Manuscript Preparation E CDE 2 Carola del Pilar Repetur
Literature Search F
Funds Collection G ABDE 4 Mario Schiffer

Corresponding Author: Wilfried Gwinner, e-mail: gwinner.wilfried@mh-hannover.de

Financial support: This study was funded by Astellas Pharma, Inc. Medical writing and editorial support were funded by Astellas Pharma, Inc.
Conflict of interest: All authors report non-financial support from Astellas during the conduct of the study. WG received consulting fees from Novartis
and Bayer. MS received an unrestricted grant from Novartis, and consulting fees for advisory boards from Novartis and Bayer. SA,
MB, and CPR are employees of Astellas Pharma Europe. BH is an employee of Astellas Pharma GmbH

Background: Long-term real-world outcomes data for kidney transplant recipients (KTRs) converting from immediate-release
tacrolimus (IRT) to prolonged-release tacrolimus (PRT) are limited.
Material/Methods: A retrospective, non-interventional review of adult KTRs treated with PRT for ³1 month was conducted in
Germany. Data were extracted from time of transplant (2008-2014) to 2018. Primary composite endpoints
(graft loss, biopsy-confirmed acute rejection, graft dysfunction) and secondary endpoints (all-cause mortality,
kidney function course, and tacrolimus dose/trough levels) were analyzed for sub-cohorts: de novo PRT, early
conversion from IRT (within 6 months post-transplant), and late conversion (7 months to 3 years).
Results: Analysis included 163 patients (101 de novo, 12 early converters, and 50 late converters). The overall Kaplan-Meier
estimate of freedom from efficacy failure through 5 years was 0.537, (95% confidence interval (CI) 0.455-0.612)
(de novo: 0.512 [0.407-0.608]; early converters: 0.500 [0.208-0.736]; late converters: 0.594 [0.443-0.717]). The
overall survival rate was 0.925 (95% CI 0.872-0.957) (de novo: 0.900 [0.823-0.945]; early converters: 0.917
[0.539-0.988]; late converters: 0.977 [0.846-0.997]). During follow-up, there was a gradual reduction in tacro-
limus dose and trough levels; kidney function remained stable in all cohorts. Multivariable analysis found re-
transplantation, organ donor quality, best estimated glomerular filtration rate 8-12 weeks after transplant, and
treatment center (between-center differences in age, sex, donor status/quality) were significantly associated
with efficacy failure.
Conclusions: There was no difference in long-term survival profiles between KTRs who received PRT de novo vs those who
converted from IRT, with 5-year survival remaining high in both groups.
Keywords: Immunosuppression Therapy • Tacrolimus • Kidney Transplantation • Retrospective Studies •
Clinical Study
Abbreviations: BCAR – biopsy-confirmed acute rejection; CKD-EPI – Chronic Kidney Disease Epidemiology Collaboration;
CMV – cytomegalovirus; CI – confidence interval; ECD – expanded criteria donor; eGFR – estimated glo-
merular filtration rate; FAC – full analysis cohort; HLA – human leukocyte antigen; HR – hazard ratio;
IgG – immunoglobulin; IRT – immediate-release tacrolimus; KM – Kaplan-Meier; KTR – kidney transplant
recipient; MDRD-4 – modification of diet in renal disease-4; NE – not estimable; PRT – prolonged-release
tacrolimus; SCD – standard criteria donor; SD – standard deviation; SE – standard error

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Introduction
Despite advances in immunosuppressive therapy and im-
provements in 1-year transplant survival rates over several
decades [1,2], long-term survival after kidney transplantation
remains challenging, with data from the US and Europe sug-
gesting that 10-year graft survival is less than 60% [3].
Tacrolimus is the mainstay of post-kidney transplant immuno-
suppression, commonly used with other immunosuppressants
as dual- or triple-drug regimens to prevent acute kidney rejec-
tion [4,5]. While short-term patient and graft survival rates af-
ter kidney transplant are high, longer-term graft survival may be
jeopardized by nonadherence to immunosuppressive regimens
[5,6]. A prospective study following kidney transplant recipients
(KTRs) for 18 years found nonadherence to be a major cause of
graft loss, with most nonadherence occurring 3 years or more af-
ter transplantation [6]. For tacrolimus, which has a narrow thera-
peutic index, adherence and maintenance of stable blood levels
are important [5]. Variability in systemic tacrolimus exposure is
a risk factor for graft loss in the early and late post-transplanta-
tion period [7,8] and reducing intra-patient variability in tacroli-
mus exposure has been shown to improve graft survival [9,10].
In addition to the traditional twice-daily immediate-release ta-
crolimus (IRT) formulation, a once-daily prolonged-release ta-
crolimus (PRT) formulation has been developed to provide a
more consistent level of total tacrolimus exposure and more
convenient dosing regimen [5,11-13]. Benefits of PRT over IRT
include improved patient adherence [14] and reduced intra-pa-
tient variability in tacrolimus exposure [11,12], both of which
are determinants of long-term graft outcome, with no differ-
ence in exposure [7,8,15-19]; however, there could be some for-
mulation and pharmacokinetic differences between PRT med-
ications. Additionally, the benefit of switching to PRT may be
impacted by the exact formulation used; recent data showed
differences in intestinal absorption between 2 formulations
of PRT, leading to differences in variability of exposure [20].
The efficacy and safety of PRT is well established with respect to
short-term outcomes, in both de novo KTRs and those switch-
ing from IRT [21]. Longer-term outcomes with PRT are less well
characterized, but the limited trial data that are available are
encouraging [22,23]. A 5-year, non-interventional, prospec-
tive follow-up study of KTRs randomized to de novo PRT in
the Phase IV, open-label, ADHERE (1-year) study revealed pa-
tient and graft survival rates of 91.9% and 89.3%, respectively
[22]. Similar 5-year patient and graft survival rates (94.4% and
88.1%) were seen in a follow-up of KTRs receiving de novo PRT
in the Phase IV, open-label, 24-week ADVANCE trial [24]. In a
5-year open-label, single-center, prospective study of KTRs in
Japan, the patient survival rate with de novo PRT was 96.7%
at 5 years after transplantation, with 6.8% of patients having
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© Ann Transplant, 2024; 29: e942167
graft loss and a 5-year Kaplan-Meier (KM) estimated rejection
rate of 26.9% [23]. In the ADMIRAD follow-up study, a retro-
spective non-interventional chart review of KTRs treated with
PRT following conversion from IRT, the KM survival rate with-
out efficacy failure (defined as transplantation, nephrectomy,
death or return to dialysis) from randomization to year 5 was
74.1%, and overall patient survival was 98.1% and 88.0% at
5 and 10 years after transplant, respectively [25].
There is a need to further characterize long-term clinical out-
comes with PRT in both de novo patients and those converting
from IRT. The aim of this retrospective study was to assess the
long-term outcomes of PRT-based immunosuppressive ther-
apy in de novo KTRs or those converting from IRT to PRT in a
real-world clinical practice setting.
Material and Methods
Study Design and Population
This was a retrospective, non-interventional, observational chart
review conducted at 2 kidney transplant centers in Germany:
Universitätsklinikum Erlangen (Center 1) and Medizinische
Hochschule Hannover (Center 2).
Patients were included if they were ³18 years of age, had re-
ceived a kidney transplant between 2008 and 2014 from a de-
ceased or living donor, and had received PRT-based therapy
(Advagraf®, Astellas Pharma Europe BV, Leiden, the Netherlands)
for ³1 month either de novo or after conversion from IRT
(Prograf®, Astellas Pharma Europe BV, Leiden, the Netherlands).
PRT-based therapy was defined as PRT at a strength of 0.5 mg,
1 mg, 3 mg, and 5 mg; capsules were administered orally once
daily, either de novo or after conversion from IRT. Patients were
excluded if they had contraindications for tacrolimus treat-
ment, had received IRT >3 years prior to conversion to PRT,
had switched from a non-tacrolimus-based immunosuppres-
sive regimen, or had received a multi-organ transplant. Patients
could have received a kidney from a deceased or living donor.
Minimum thresholds for inclusion based on estimated glomer-
ular filtration rate (eGFR) at baseline were not defined.
The study was conducted in compliance with national and
European Union requirements for ensuring the rights of par-
ticipants in non-interventional studies and followed the reg-
ulations of the Declaration of Helsinki and the Declaration of
Istanbul. Approval was obtained from the Institutional Ethics
Commission at both centers. Patients who were alive at the
time of data extraction provided written informed consent.
The requirement for informed consent was waived for patients
who had died before the start of the study. The reporting of
this study conforms to the STROBE statement [26].
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© Ann Transplant, 2024; 29: e942167
Data Extraction
Data were sourced from the medical charts of transplant re-
cipients at Center 1 and Center 2. For each eligible patient,
retrospective data from time of transplant (2008-2014) until
the date of the last follow-up visit prior to December 31, 2018
(maximum 11-year period) were extracted from existing medi-
cal records by center personnel using an electronic case report
form. Data were recorded as part of routine care and no spe-
cific patient visits were required as part of the study. Collected
data included: date of PRT initiation or conversion from IRT;
reason for conversion to PRT from IRT; drug dose; tacrolimus
blood trough level; date of graft loss and type of graft loss (re-
transplantation, death, or first day of dialysis); date of biopsy-
confirmed acute rejection (BCAR); date of occurrence of graft
dysfunction, defined as eGFR of <40 mL/min/1.73 m2 accord-
ing to the modification of diet in renal disease-4 (MDRD-4) for-
mula; renal parameters from laboratory assessment, includ-
ing serum creatinine, Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) and baseline eGFR, defined as best
eGFR 8-12 weeks post-transplant (MDRD-4); and cause of pa-
tient death. Missing data were requested from the treating
nephrologists by center personnel.
Endpoints
The primary composite endpoint of efficacy failure was the ear-
liest occurrence of any of the following: (1) graft loss, includ-
ing re-transplantation, death or dialysis; (2) BCAR, determined
by the investigator and regarded as acute antibody-mediated
rejection (grade I, II or III) or acute T-cell-mediated rejection
(grade IA, IB, IIA, IIB or III), according to Banff criteria valid at
the time of biopsy [27]; or (3) graft dysfunction, defined previ-
ously. Patients who never had eGFR ³40 mL/min/1.73 m2 were
considered to have graft dysfunction on the day of first occur-
rence of eGFR <40 mL/min/1.73 m2, which could be on day 1.
Secondary endpoints included all-cause mortality, kidney func-
tion over time, and prescribed tacrolimus dosing and trough
levels. In addition, exploratory analyses assessed independent
risk factors for impact on the composite endpoint.
Sub-group and Post Hoc Analyses
Primary analyses of endpoints were conducted for the full anal-
ysis cohort (FAC), comprising all eligible patients who received
³1 month of continuous PRT following kidney transplantation,
and 3 sub-groups as follows:
• De novo – PRT treatment initiated within the first month
post-transplant
• Early conversion – received de novo IRT and subsequently
converted to PRT within 6 months post-transplant
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• Late conversion – received de novo IRT and subsequently con-
verted to PRT between 7 months and 3 years post-transplant.
Post hoc analyses included comparison of the primary endpoint
(and individual components of the composite) between Center
1 and Center 2 and the association of further variables with
the primary endpoint including; cohort (de novo vs combined
conversion [early plus late conversion sub-groups]), baseline
kidney function (8-12 weeks after transplantation), and the im-
pact on kidney function in patients who had converted from
IRT (combined conversion sub-group) versus the de novo PRT
sub-group. Post-transplant prescribed tacrolimus doses and
trough levels from time of transplant were also assessed in
the FAC and combined conversion cohorts.
Statistical Analysis
Continuous data were reported as mean (standard devia-
tion [SD]), median (lower quartile [Q1], upper quartile [Q3]).
Categorical data were reported as frequencies and percent-
ages. Patients with missing data were not excluded, and each
variable was summarized based on the available data. Primary
and secondary endpoint and post hoc analyses were conduct-
ed on all study cohorts.
Analysis of the primary composite endpoint provided KM es-
timates and 95% confidence intervals (95% CIs) of the time
from transplant to the first incidence of the components of the
endpoint, using Greenwood’s formula to estimate the standard
error of survival. Statistical significance was determined using
log-rank testing of all events captured over the follow-up pe-
riod. KM estimates (with 95% CI, calculated as defined above)
of the composite endpoint at 5 years (the primary objective)
and for each year of follow-up were calculated, as well as the
estimated median time to composite endpoint (with 95% CI).
Patients who were lost to follow-up or were alive at the end of
the study without occurrence of the endpoint were censored
on the day of the last available follow-up visit. For the sec-
ondary endpoints, all-cause mortality was analyzed using KM
methods as per the primary composite endpoint. Other second-
ary endpoints were analyzed using descriptive statistics, with
baseline measurements performed on the date of transplan-
tation. Post hoc analyses compared the KM estimates of free-
dom from efficacy failure between the de novo and combined
conversion (early plus late) cohorts and the primary composite
endpoint by eGFR at baseline (8-12 weeks post-transplant) us-
ing fixed thresholds for eGFR categories (<30 mL/min/1.73 m2,
³30-<45 mL/min/1.73 m2, ³45-<60 mL/min/1.73 m2, and ³60
mL/min/1.73 m2). Descriptive graphs plotting means and stan-
dard errors of eGFR over time from time of transplant were plot-
ted for the de novo and combined conversion cohort. Patients
with graft loss were included in the analysis of subsequent vis-
its and assigned an eGFR of 0. Sensitivity analyses, conducted
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ORIGINAL PAPER
to test the robustness of the primary composite endpoint, in-
cluded KM estimates of the individual components of the com-
posite endpoint and patients with and without BCAR or kid-
ney dysfunction prior to conversion.
In the exploratory analysis, independent risk factors were
modeled using a Cox regression model adjusting for potential
confounders. Univariate models were used to determine the
variables associated with PRT effectiveness and a final mul-
tivariable model was developed to quantify the contribution
of each variable to the between-patient variation in outcome.
The models used eGFR according to the MDRD-4 formula. The
Cox multivariable models (exploratory and post hoc analyses)
used forward selection (P value threshold 0.05) due to con-
vergence issues observed for the models that included all po-
tential covariates. All variables with P<0.2 in univariate Cox re-
gression were considered for model entry. Statistical analyses
were performed using SAS® software, version 9.4.1 or higher.
Results
Among 243 patients eligible for the study, 163 met the inclu-
sion criteria and were included in the FAC (Figure 1). More pa-
tients were treated with PRT de novo (n=101) than converted
from IRT (n=62; early n=12, late n=50). The majority (71.8%)
of patients were male and the median (Q1-Q3) age was 52.0
(42-62) years (Table 1). In the de novo and early conversion
cohorts, around three-quarters of transplants were from de-
ceased donors, whereas the late conversion cohort had a com-
paratively higher proportion of living donors (56% living/44%
deceased). Furthermore, patients in the late conversion cohort
had a median (Q1-Q3) time from transplant to conversion of
21.41 (15-27) months. Median (Q1-Q3) time from initiation
of PRT to discontinuation, censoring or loss-to-follow-up was
55.26 (33.58-85.19) months. Significant between-center dif-
ferences in baseline patient and donor characteristics were
evident. Patients at Center 1 were older and included a high-
er proportion with comorbidities, a lower proportion of trans-
plants from living donors, and a higher proportion with ex-
panded criteria donor (ECD) status (Table 2).
Primary Composite Endpoint
Overall, 76 (46.6%) patients had a primary composite end-
point event (de novo 49 [48.5%]; early converters 6 [50.0%];
late converters 21 [42.0%]), and 87 (53.4%) patients were
censored. Post hoc analysis revealed 60.5% of patients had
a primary composite endpoint event at Center 1 vs 32.9% at
Center 2 (Table 3).
KM estimates of time from transplant to first primary composite
endpoint event are presented in Figure 2. The KM estimate of
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Eligible in site databases, n=243
Not participated, n=80
• Not reached, n=17
• Not consented, n=62
• Died before consenting, n=1
Included in analyses, n=163
• Consented, n=137
• Included without consent (died), n=26
Figure 1. Patient flow through the study.
median time to primary endpoint event was 7.11 years (95% CI
3.87-not estimable [NE]). There was no clear difference in the
5-year time-to-event profile between the cohorts (log-rank test
P=0.744) and the KM estimate of freedom from efficacy fail-
ure through 5 years was 0.537 (95% CI 0.455-0.612) (Table 4).
Sensitivity Analyses of the Primary Composite Endpoint
The KM estimates of individual components of the primary
composite endpoint are presented only as a sensitivity analy-
sis owing to potential bias due to the competing risks of occur-
rence of the other primary endpoint components. When each
component was analyzed individually, there was no major dif-
ference between the de novo, early conversion, and late con-
version cohorts (Table 5). The survival rate without experienc-
ing graft loss in the FAC was 0.862 (95% CI 0.794-0.909) at 5
years. When combining early and late conversion cohorts into
a single ‘conversion’ cohort in the post hoc analysis, there was
also no significant difference between the cohorts (log-rank test
P=0.603; Figure 3). The KM estimate of freedom from efficacy
failure through 5 years was 0.512 (95% CI 0.407-0.608) in the
de novo PRT cohort and 0.576 (95% CI 0.442-0.689) in the com-
bined (early plus late) conversion cohort. The crude incidence of
primary endpoint event by the end of the study (date of the last
available follow-up visit) was 48.5% (49/101) in the de novo PRT
cohort and 43.5% (27/62) in the combined conversion cohort.
There were 22 patients in the primary analysis who had graft
dysfunction or BCAR prior to conversion to PRT (17 of whom
were included in the late conversion cohort). Sensitivity anal-
ysis of the primary composite endpoint for the remaining 141
patients after exclusion of these patients revealed a KM esti-
mate of freedom from efficacy failure through 5 years of 0.622
(95% CI 0.533-0.698).
Survival
Overall, 18 (11.0%) patients died over the maximum post-
transplant study period (11 years). The KM estimate of surviv-
al rate at 5 years was 0.925 (95% CI 0.872-0.957) in the FAC
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ORIGINAL PAPER

Table 1. Baseline characteristics of patients.

Cohort
Parameter De novo Early conversion Late conversion Full analysis
(n=101) (n=12) (n=50) (N=163)

Study site, n (%)

Center 1 57 (56.4) 7 (58.3) 17 (34.0) 81 (49.7)

Center 2 44 (43.6) 5 (41.7) 33 (66.0) 82 (50.3)

Age, years

Mean (SD) 51.3 (13.7) 53.1 (13.9) 48.3 (13.3) 50.5 (13.6)

53.0 49.0 51.0 52.0

Median (Q1-Q3)
(42.0-63.0) (42.5-63.5) (40.0-58.0) (42.0-62.0)

Age group, n (%)

³18 to <65 years 81 (80.2) 9 (75.0) 45 (90.0) 135 (82.8)

³65 years 20 (19.8) 3 (25.0) 5 (10.0) 28 (17.2)

Sex, n (%)

Male 71 (70.3) 9 (75.0) 37 (74.0) 117 (71.8)

Female 30 (29.7) 3 (25.0) 13 (26.0) 46 (28.2)

Race/ethnicity, n (%)

White/Caucasian 55 (54.5) 8 (66.7) 43 (86.0) 106 (65.0)

Black/African-American/Caribbean 1 (1.0) 1 (8.3) 1 (2.0) 3 (1.8)

Middle Eastern 1 (1.0) 1 (2.0) 2 (1.2)

Other 2 (2.0) 2 (1.2)

Not available 42 (41.6) 3 (25.0) 5 (10.0) 50 (30.7)

Number of previous transplants, n (%)

0 100 (99.0) 8 (66.7) 45 (90.0) 153 (93.9)

1 1 (1.0) 4 (33.3) 4 (8.0) 9 (5.5)

2 1 (2.0) 1 (0.6)

Donor vital status

Living 24 (23.8) 3 (25.0) 28 (56.0) 55 (33.7)

Deceased 77 (76.2) 9 (75.0) 22 (44.0) 108 (66.3)

Time from transplant to PRT conversion, months

Mean (SD) 0.02 (0.09) 3.80 (1.56) 21.02 (7.47) 6.74 (10.43)

0.00 3.67 21.41 0.00

Median (Q1-Q3)
(0.00-0.00) (2.40-5.05) (14.72-26.71) (0.00-12.98)

Time from PRT conversion to discontinuation,

censoring or loss-to-follow-up, months

Mean (SD) 65.22 (35.84) 55.86 (26.12) 42.85 (16.27) 57.67 (31.99)

77.47 52.24 41.27 55.26

Median (Q1-Q3)
(35.94-89.63) (44.81-64.13) (31.97-50.89) (33.58-85.19)

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Table 1 continued. Baseline characteristics of patients.

Cohort
Parameter De novo Early conversion Late conversion Full analysis
(n=101) (n=12) (n=50) (N=163)

Reason for conversion to PRT

Adherence issues 2 (4.0) 2 (1.2)

Trough variability 1 (1.0) 4 (33.3) 18 (36.0) 23 (14.1)

Patient preference 1 (1.0) 3 (6.0) 4 (2.5)

Other clinical preference 7 (14.0) 7 (4.3)

Study participation 93 (92.1) 93 (57.1)

Not available 6 (5.9) 8 (66.7) 20 (40.0) 34 (20.9)

PRT – prolonged-release tacrolimus; Q – quartile; SD – standard deviation. Center 1, Universitätsklinikum Erlangen;

Center 2, Medizinische Hochschule Hannover.

Table 2. Patient demographics per transplant center.

Center 1 Center 2
Parameter P value
(n=81) (n=82)

Age, mean (SD) 54.6 (12.3) 46.6 (13.7) <0.001

Age ³65 years, n (%) 20 (24.7) 8 (9.8) 0.011

Male, n (%) 62 (76.5) 55 (67.1) 0.179

Living donor, n (%) 20 (24.7) 35 (42.7) 0.015

ECD status, n (%) 36 (44.4) 9 (11.0) <0.001

Comorbidities at baseline (type 2 diabetes), n (%) 18 (22.2) 6 (7.3) 0.007

CMV donor IgG positive/recipient IgG negative, n (%) 25 (30.9) 19 (23.2) 0.269

CMV – cytomegalovirus; ECD – expanded criteria donor; IgG – immunoglobulin G; SD – standard deviation. Center 1, Universitäts-
klinikum Erlangen; Center 2, Medizinische Hochschule Hannover.

Table 3. Post hoc analysis of outcomes per transplant center.

Center 1 Center 2
Parameter
(n=81) (n=82)

Endpoint, n (%)

Primary composite endpoint 49 (60.5) 27 (32.9)

Graft loss 20 (24.7) 6 (7.3)

BCAR 26 (32.1) 19 (23.2)

Graft dysfunction 35 (43.2) 6 (7.3)

Death 17 (21.0) 1 (1.2)

BCAR – biopsy-confirmed acute rejection. Center 1, Universitätsklinikum Erlangen; Center 2, Medizinische Hochschule Hannover.

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ORIGINAL PAPER

1.0
Proportion of patients surviving without reaching the composite endpoint + Censored

0.8

0.6

0.4

0.2
De novo cohort
Early conversion
Late conversion
All patients

0.0 P value=0.744

0 1 2 3 4 5 6 7 8 9 10 11
Follow-up (years)

De novo cohort, n: 101 67 60 56 48 43 38 31 12 8 6 0

Early conversion, n: 12 7 6 6 6 3 2 1 0
Late conversion, n: 50 35 32 30 27 16 11 3 1 1 0
All patients, n: 163 109 98 92 81 62 51 35 13 9 6 0

Figure 2. Kaplan-Meier plot of time from transplant to primary composite endpoint event in the full analysis cohort and
the 3 tacrolimus conversion cohorts. P-value is based on time to event though 5 years.

and remained high in all cohorts: (0.900 (95% CI 0.823-0.945) Tacrolimus Dose and Trough Levels
for the de novo cohort, 0.917 (95% CI 0.539-0.988) for the ear-
ly conversion cohort, and 0.977 (95% CI 0.846-0.997) for the Tacrolimus doses prescribed over time were captured in a
late conversion cohort (Table 6). descriptive plot stratified by conversion cohorts (Figure 4A),
which shows that mean prescribed doses were similar for the
Impact of Independent Variables on Composite de novo and late conversion cohorts throughout the follow-
Primary Endpoint up period. Mean doses in the early conversion cohort, which
had considerably fewer patients (n=12 vs n=101 and n=50, in
All variables with P<0.2 in the univariate analysis (results shown the de novo and late conversion cohorts, respectively) were
in Table 7) were considered for multivariable model entry. The comparatively lower. The tacrolimus dose curves in all 3 co-
multivariable Cox proportional hazards analysis revealed vari- horts followed a downward gradient, indicating a gradual ta-
ables significantly associated with the primary composite end- pering of dosage over time before the dose became stable.
point (P£0.001) including: number of previous transplants (1 Similarly, in all 3 cohorts, tacrolimus trough levels gradually
vs 0; hazard ratio [HR] 6.592; 95% CI 2.331-18.639); donor decreased over time before whole blood tacrolimus trough lev-
quality (ECD vs standard criteria donor [SCD] status: HR 2.931; els reached a stable level (Figure 4B). At baseline, the mean
95% CI 1.554-5.526); baseline eGFR (best eGFR 8-12 weeks tacrolimus trough levels ranged from 10-12 ng/mL in all co-
post-transplant, time-dependent variable: HR 0.933; 95% CI horts. The mean levels in all cohorts remained generally sim-
0.894-0.974); as well as study site (Center 2 vs Center 1: HR ilar throughout the duration of follow-up.
0.196; 95% CI 0.078-0.494) (Table 7).

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Table 4. Kaplan-Meier estimates of freedom from the primary composite endpoint stratified by population cohort (first 5 years
post-transplant).

Cohort
KM rate estimate
Year De novo Early conversion Late conversion Full analysis
(95% CI)
(n=101) (n=12) (n=50) (N=163)

Composite 1 0.691 (0.591-0.772) 0.500 (0.208-0.736) 0.680 (0.532-0.790) 0.673 (0.595-0.739)

2 0.638 (0.535-0.724) 0.500 (0.208-0.736) 0.640 (0.491-0.756) 0.628 (0.549-0.698)

3 0.616 (0.512-0.704) 0.500 (0.208-0.736) 0.620 (0.471-0.738) 0.608 (0.528-0.679)

4 0.547 (0.442-0.641) 0.500 (0.208-0.736) 0.620 (0.471-0.738) 0.567 (0.486-0.640)

5 0.512 (0.407-0.608) 0.500 (0.208-0.736) 0.594 (0.443-0.717) 0.537 (0.455-0.612)

CI – confidence interval; KM – Kaplan-Meier. The KM estimates of individual components are presented only as a sensitivity analysis of
the primary endpoint owing to potential bias due to the competing risks of occurrence of the other primary endpoint components.

Table 5. Sensitivity analysis of primary endpoint: Kaplan-Meier estimates of the individual components of the composite endpoint
stratified by population cohort (first 5 years post-transplant).

Cohort
KM rate estimate
Year
(95% CI) De novo Early conversion Late conversion Full analysis
(n=101) (n=12) (n=50) (N=163)

Graft loss 1 0.959 (0.895-0.985) 1.000 (1.000-1.000) 1.000 (1.000-1.000) 0.975 (0.935-0.991)

2 0.927 (0.852-0.964) 0.917 (0.539-0.988) 0.980 (0.866-0.997) 0.943 (0.892-0.970)

3 0.916 (0.838-0.957) 0.917 (0.539-0.988) 0.960 (0.848-0.990) 0.929 (0.876-0.960)

4 0.868 (0.778-0.923) 0.917 (0.539-0.988) 0.939 (0.822-0.980) 0.894 (0.832-0.934)

5 0.842 (0.748-0.904) 0.815 (0.435-0.951) 0.912 (0.780-0.966) 0.862 (0.794-0.909)

BCAR 1 0.818 (0.726-0.881) 0.583 (0.270-0.801) 0.740 (0.595-0.840) 0.775 (0.702-0.832)

2 0.759 (0.660-0.833) 0.583 (0.270-0.801) 0.720 (0.574-0.824) 0.734 (0.658-0.797)

3 0.759 (0.660-0.833) 0.583 (0.270-0.801) 0.720 (0.574-0.824) 0.734 (0.658-0.797)

4 0.733 (0.630-0.812) 0.583 (0.270-0.801) 0.720 (0.574-0.824) 0.719 (0.641-0.783)

5 0.733 (0.630-0.812) 0.583 (0.270-0.801) 0.720 (0.574-0.824) 0.719 (0.641-0.783)

Graft 1 0.780 (0.686-0.850) 0.750 (0.408-0.912) 0.900 (0.776-0.957) 0.815 (0.746-0.867)

dysfunction
2 0.769 (0.674-0.840) 0.750 (0.408-0.912) 0.900 (0.776-0.957) 0.808 (0.739-0.861)

3 0.746 (0.648-0.821) 0.750 (0.408-0.912) 0.880 (0.751-0.944) 0.788 (0.716-0.844)

4 0.723 (0.622-0.801) 0.667 (0.337-0.860) 0.880 (0.751-0.944) 0.767 (0.693-0.826)

5 0.710 (0.608-0.791) 0.667 (0.337-0.860) 0.854 (0.716-0.928) 0.752 (0.676-0.812)

BCAR – biopsy-confirmed acute rejection; CI – confidence interval; KM – Kaplan-Meier. The KM estimates of individual components are
presented only as a sensitivity analysis of the primary endpoint owing to potential bias due to the competing risks of occurrence of
the other primary endpoint components.

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1.0
+ Censored
Proportion of patients surviving without reaching the composite endpoint

0.8

0.6

0.4

0.2
De novo cohort
Conversion cohort
All patients

0.0 P value=0.603

0 1 2 3 4 5 6 7 8 9 10 11
Follow-up (years)

De novo cohort, n: 101 67 60 56 48 43 38 31 12 8 6 0

Conversion cohort, n: 62 42 38 36 33 19 13 4 1 1 0
All patients, n: 163 109 98 92 81 62 51 35 13 9 6 0

Figure 3. Kaplan-Meier plot of time from transplant to primary composite endpoint event in the full analysis cohort, de novo, and
tacrolimus conversion (combined early and late conversion) cohorts. P-value is based on time to event through 5 years.

Table 6. Kaplan-Meier estimates of patient survival stratified by population cohort (first 5 years post-transplant).

Cohort
KM rate estimate
Year
(95% CI) De novo Early conversion Late conversion Full analysis
(n=101) (n=12) (n=50) (N=163)

Patient 1 0.980 (0.923-0.995) 1.000 (1.000-1.000) 1.000 (1.000-1.000) 0.988 (0.952-0.997)

survival
2 0.941 (0.873-0.973) 0.917 (0.539-0.988) 1.000 (1.000-1.000) 0.957 (0.912-0.979)

3 0.941 (0.873-0.973) 0.917 (0.539-0.988) 1.000 (1.000-1.000) 0.957 (0.912-0.979)

4 0.921 (0.848-0.960) 0.917 (0.539-0.988) 1.000 (1.000-1.000) 0.945 (0.897-0.971)

5 0.900 (0.823-0.945) 0.917 (0.539-0.988) 0.977 (0.846-0.997) 0.925 (0.872-0.957)

CI – confidence interval; KM – Kaplan-Meier.

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Table 7. Multivariable analysis of independent variables associated with the primary composite endpoint for all patients.

Hazard ratio* Univariate hazard ratio**

Parameter P value
(95% CI) (95% CI)

Transplant center

Center 2 vs 1 0.196 (0.078-0.494) <0.001 0.372 (0.232-0.596)

Patient race/ethnicity

Black/African-American/Caribbean vs Caucasian 2.389 (0.487-11.715) 0.283 1.807 (0.435-7.503)

Middle Eastern vs Caucasian 13.519 (1.257-145.392) 0.032 1.647 (0.226-12.007)

Other vs Caucasian 6.048 (0.784-46.635) 0.084 3.760 (0.904-15.648)

Not available vs Caucasian 0.96 (0.45-2.048) 0.916 2.621 (1.641-4.187)

No. previous transplants

1 vs 0 6.592 (2.331-18.639) <0.001 2.286 (1.047-4.990)

2 vs 0 0.000 (0.000-NE) 0.994 0.000 (0.000-0.000)

Donor SCD/ECD status

ECD vs SCD 2.931 (1.554-5.526) <0.001 3.500 (2.158-5.677)

Not available vs SCD 0.394 (0.134-1.158) 0.090 0.883 (0.409-1.907)

Best eGFR***,# (mL/min/1.73 m2) 0.933 (0.894-0.974)## 0.001 0.950 (0.929-0.971)

Best serum creatinine*** (mg/dL) 0.892 (0.474-1.680) ##

0.724 2.024 (1.539-2.662)

CI – confidence interval; ECD – expanded criteria donor; eGFR – estimated glomerular filtration rate; NE – not estimable;
SCD – standard criteria donor. Proportional hazards were assumed, hazard ratio <1 indicates a reduction in hazard rate.
Center 1, Universitätsklinikum Erlangen; Center 2, Medizinische Hochschule Hannover.
* Hazard ratio generated through multivariate analysis; variables were selected using a forward selection model (P value threshold
0.05); eligible for model entry were all variables with a P value of <0.2 in univariate analysis.** Hazard ratio based on univariate Cox
regression model including the parameter as the only covariate. *** 8-12 weeks after transplant. # Estimated using modification of diet
in renal disease-4 (MDRD-4) method. ## Hazard ratio stated in relation to increases/decreases of 1 mL.

Kidney Function (crude incidence 75.0% vs 31.0-50.0% for eGFR categories

In the FAC, mean serum creatinine was 1.67 mg/mL at 8-12
weeks post-transplant. While all laboratory assessments were
similar in the de novo and late conversion cohorts, metrics dif-
fered in the early conversion cohort, including decreased se-
rum creatinine and tacrolimus trough level and increased eGFR
and CKD-EPI (Table 8).
³30 mL/min/1.73 m2). The KM estimates of freedom from
efficacy failure increased across the eGFR categories, with
the lowest event-free rate through 5 years of 0.208 (95% CI
0.044-0.455) in the eGFR <30 mL/min/1.73 m2 category and
highest rate of 0.690 (95% CI 0.488-0.825) in the eGFR ³60
mL/min/1.73 m2 category (Table 9).

When the early conversion cohort was combined with the
late conversion cohort, mean eGFR values were similar to the
de novo cohort and remained stable through 5 years and be-
yond (Figure 5).
Post hoc analysis of the primary composite endpoint by eGFR
at baseline (8-12 weeks post-transplant) showed that the low-
est category of eGFR (<30 mL/min/1.73 m2) was associated
with the highest cumulative proportion of patients reporting
primary composite endpoint event at 5 years post-transplant
Discussion
This retrospective real-world analysis of KTRs from 2 study cen-
ters in Germany was conducted to address the evidence gap in
long-term outcomes with PRT. Data were collected from trans-
plant recipients receiving PRT who were also stratified into 3
sub-cohorts depending on the time from kidney transplant
to initiation of PRT: within the first month (de novo), within
6 months (early conversion from IRT), or within 3 years (late
conversion from IRT). In this way, outcomes could be explored

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A 10.0 De novo cohort

Early conversion cohort
9.0 Late conversion cohort

8.0
Mean (SE) tacrolimus prescribed dose (mg)

7.0

6.0

5.0

4.0

3.0

2.0

1.0

0.0
0 1 2 3 4 5 6 7 8 9 10
Time from transplant (years)
De novo cohort, n: 85 83 57 69 48 68 43 62 36 58 29 57 30 40 17 14 2 8 1 5
Early conversion cohort, n: 11 10 10 11 5 8 7 7 5 6 1 2 1 1 0 0 0 0 0 1
Late conversion cohort, n: 48 46 43 43 38 42 40 36 30 26 14 17 4 5 1 3 1 – – –

B 16.0 De novo cohort

Early conversion cohort
Late conversion cohort
14.0

12.0
Mean (SE) tacrolimus through level (mg/ml)

10.0

8.0

6.0

4.0

2.0

0.0
0 1 2 3 4 5 6 7 8 9 10
Time from transplant (years)
De novo cohort, n: 92 89 83 56 69 48 68 42 63 36 59 29 57 30 40 19 16 2 9 1 6
Early conversion cohort, n: 12 11 12 10 11 5 8 7 7 5 6 1 2 1 1 0 0 0 0 0 1
Late conversion cohort, n: 47 49 44 43 42 39 42 39 36 30 26 14 17 5 5 1 3 1 – – –

Figure 4. (A) Mean prescribed tacrolimus dosages from time of transplant, stratified by de novo, early- and late-conversion cohorts.
Error bars denote standard error. (B) Mean tacrolimus trough levels from time of transplant, stratified by de novo, early- and
late-conversion cohorts. Error bars denote standard error.

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Table 8. Laboratory assessments at 8-12 weeks after transplant by population cohort.

Cohort
Parameter
De novo Early conversion Late conversion All patients
(n=92) (n=12) (n=48) (N=152)

Mean (SD) serum creatinine (mg/mL) 1.70 (0.74) 1.43 (0.64) 1.66 (0.46) 1.67 (0.65)

Mean (SD) eGFR* (mL/min/1.73 m2) 43.45 (12.37) 50.73 (19.73) 44.94 (13.04) 44.49 (13.32)

Mean (SD) CKD-EPI (mL/min/1.73 m2) 49.10 (18.52) 62.13 (24.47) 50.18 (17.47) 50.47 (18.91)

Mean (SD) tacrolimus trough level (ng/mL) 10.00 (3.04) 12.13 (5.84) 10.75 (3.12) 10.41 (3.39)

CKD-EPI – Chronic Kidney Disease Epidemiology Collaboration; eGFR – estimated glomerular filtration rate; SD – standard deviation.
* Estimated using modification of diet in renal disease-4 (MDRD-4) method.

100.0
De novo cohort
90.0 Conversion cohort

80.0

70.0
Mean (SE) eGFR (ml/min/1.73 m2)

60.0

50.0

40.0

30.0

20.0

10.0

0.0
0 1 2 3 4 5 6 7 8 9 10
Time from transplant (years)
De novo cohort, n: 92 92 89 85 54 65 45 63 34 61 27 56 20 50 21 35 14 13 0 8 0
Conversion cohort, n: 59 58 60 56 52 44 42 45 41 36 29 26 13 16 6 6 0 3 0 0 1

Figure 5. Mean (SE) eGFR values from time of transplant, stratified by de novo and combined conversion cohorts (early plus late
conversion). Patients with graft loss were included in the analysis of subsequent visits and assigned an eGFR of 0. eGFR –
estimated glomerular filtration rate; SE – standard error.
across patients with a broad spectrum of transplant-related 0.925 (95% CI 0.872-0.957), respectively, and there was no
medical histories (eg, renal impairment or rejection events pri- difference in 5-year time-to-event profiles between de novo
or to initiating PRT). The maximum period a patient could be and conversion patients. The KM estimate of median time
followed post-transplantion was 11 years and median time to primary endpoint event was 7.11 years (95% CI 3.87-NE).
between initiating PRT to discontinuation, censoring, or loss- Previous studies of IRT to PRT conversion over shorter-term ob-
to-follow-up was ~4.6 years. servation periods (1-2 years) have presented similar findings,
with no marked differences observed between early and late
For the entire population, the KM estimates of freedom from stages of conversion [28,29]. Further, a meta-analysis explor-
efficacy failure (primary composite endpoint) and overall sur- ing outcomes across 9 randomized controlled trials compar-
vival through 5 years were 0.537 (95% CI 0.455-0.612) and ing IRT or PRT in de novo KTRs found similar between-group

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Table 9. Kaplan-Meier estimates of primary composite endpoint stratified by baseline eGFR.

KM rate estimate (95% CI)

Year eGFR <30 ³30-<45 ³45-<60 ³60 Missing All patients
N=16 N=60 N=46 N=29 N=12 N=163
n=11 n=19 n=11 n=9 n=3 n=53
1 0.313 0.681 0.761 0.690 0.741 0.673
(0.114-0.536) (0.547-0.784) (0.610-0.860) (0.488-0.825) (0.391-0.909) (0.595-0.739)
n=11 n=23 n=14 n=9 n=3 n=60
2 0.313 0.610 0.694 0.690 0.741 0.628
(0.114-0.536) (0.473-0.721) (0.538-0.806) (0.488-0.825) (0.391-0.909) (0.549-0.698)
n=11 n=24 n=15 n=9 n=4 n=63
3 0.313 0.591 0.671 0.690 0.648 0.608
(0.114-0.536) (0.454-0.705) (0.514-0.787) (0.488-0.825) (0.310-0.852) (0.528-0.679)
n=11 n=28 n=17 n=9 n=4 n=69
4 0.313 0.516 0.623 0.690 0.648 0.567
(0.114-0.536) (0.380-0.636) (0.464-0.746) (0.488-0.825) (0.310-0.852) (0.486-0.640)
n=12 n=30 n=18 n=9 n=4 n=73
5 0.208 0.471 0.599 0.690 0.648 0.537
(0.044-0.455) (0.334-0.596) (0.440-0.726) (0.488-0.825) (0.310-0.852) (0.455-0.612)

CI – confidence interval; eGFR – estimated glomerular filtration rate in mL/min/1.73 m2; KM – Kaplan-Meier.

rates of acute rejection, graft failure, death, and adverse events
after 12 months, suggesting comparable efficacy and safe-
ty of these 2 regimens [30]. However, the current retrospec-
tive analyses aimed to assess the longer-term outcomes in a
real-world setting in kidney transplant patients in Germany.
Three previous studies have also reported 5-year patient and
graft survival with PRT, but not for patients converting from
IRT to PRT or using a stringent composite primary endpoint
[22,23]. The first study, an open-label, prospective, observa-
tional, multicenter, post-marketing surveillance study in Japan
[23], reported higher 5-year patient survival and graft survival
rates (96.7% and 93.2%, respectively) than those reported in
the current study (92.5% and 86.2% [graft survival from sen-
sitivity analysis]). However, 94% of patients in the Japanese
study received a kidney from a living donor (compared with
34% in the current study), 59% of recipients were male (com-
pared with 72% in the current study), and only 7% were aged
³65 years (compared with 17% in the current study). Post hoc
analysis comparing the demographic characteristics and out-
comes between Center 1 and Center 2 in our study, as well as
previous reports [31,32], show that these factors can marked-
ly influence outcomes. Incidence of graft loss was more than
3 times greater at Center 1 versus Center 2 (25% vs 7%); of
which, Center 1 had a recipient population with a smaller pro-
portion of living donors (29% vs 43%) and a larger proportion
with ECD status (44% vs 11%), more patients were aged ³65
years (25% vs 10%), and with comorbidities (22% vs 7%). These
results suggest that there may be further variables affecting
outcomes between the 2 centers that were not considered in
the multivariable analysis, such as donor serum creatinine.
The second study, a prospective multicenter 5-year follow-up
of the ADHERE study in a European population with a demo-
graphic profile that was similar to the current study in terms
of age, sex, and donor type, demonstrated patient survival
(91.9%) and graft survival (89.3%) rates with PRT that were
similar to those observed in the current study [22]. More re-
cent data from the ADVANCE follow-up trial, a 5-year follow-
up of KTRs receiving de novo PRT, reported higher patient sur-
vival rates (94.4%) versus the present study, but lower graft
survival rates (88.1%) [24]. However, the prevalence of key
factors that can influence outcomes [31,32] varied versus the
present study; at most, 14.6% of patients received a kidney
from a living donor in each study arm, and 65.1% of recipi-
ents were male. There were also some differences in the def-
inition of endpoints versus the present study.
Additionally, the ADMIRAD retrospective chart analysis study
explored long-term outcomes up to 10 years for KTRs convert-
ing from IRT to PRT [25]. In contrast to the present study, re-
sults for 5-year follow-up from ADMIRAD showed that the KM
survival rate without efficacy failure (defined as transplanta-
tion, nephrectomy, death or return to dialysis) in ADMIRAD was
74.1% for the PRT group and 66.7% for the IRT group and re-
mained higher for PRT throughout follow-up (P=0.041), sug-
gesting a benefit for patients switching from IRT to PRT [25].
In both the de novo and conversion cohorts in the present
study, there was a gradual reduction of mean tacrolimus daily
dose and trough levels before doses, and trough levels became
more stable around 18 months to 2 years post-transplantation.

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Nevertheless, stable kidney function was observed in the full
patient cohort and sub-cohorts of de novo and conversion PRT
throughout the entire period. This is consistent with previous
observations where eGFR values were unaffected by reduced
tacrolimus dose and trough levels after IRT to PRT conver-
sion [33,34]. Multivariable analysis showed that donor quali-
ty, previous transplantation, and the eGFR value 8-12 weeks
post-transplant were significantly associated with the com-
posite endpoint for efficacy failure (P<0.001). This was also
confirmed in the post hoc analysis where rates of event-free
survival 8-12 weeks post-transplant increased across the eGFR
categories from <30 mL/min/1.73 m2 to ³60 mL/min/1.73 m2.
Key strengths of the current study include the long post-trans-
plantation period over which patient data extraction could
take place. However, the study also has several potential lim-
itations: selection of patients from 2 clinical sites in Germany
potentially introduces selection bias and may not be represen-
tative of the wider population of kidney transplant patients;
only descriptive analyses were conducted, although this ap-
proach aligns with the lack of a comparator group; and adher-
ence with immunosuppressive therapy was not assessed, de-
spite being a known factor impacting long-term graft survival.
There were also few patients in the early conversion cohort
and the attrition rate in the late conversion cohort resulted
in a low sample size by year 5, which limits the generalizabil-
ity of findings for these data; one possibility for this attrition
rate may be due to graft loss experienced by patients, and
who were then no longer in the care of the transplant center
(data censored). However, this graft loss would be included in
the time to composite endpoint and time to graft loss analy-
ses. Despite these limitations, the current study provides cli-
nicians with real-world long-term information about the use
of PRT in a diverse group of recipients.
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transplantation. Nephrol Dial Transplant. 2010;25:2757-63
This work is licensed under Creative Common Attribution-
NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) e942167-14
Gwinner W. et al:
Long-term outcomes with prolonged-release tacrolimus in kidney transplantation…
© Ann Transplant, 2024; 29: e942167
Conclusions
In this retrospective study of KTRs treated with PRT in Germany,
over 50% of patients had event-free survival through 5 years,
and overall survival was over 90%. There was no difference in
5-year time-to-event profiles between de novo and conversion
cohorts, and kidney function remained stable for both cohorts,
with no new safety findings observed. These results support
existing data demonstrating the effectiveness and safety of
long-term PRT use in KTRs.
Acknowledgments
This study was sponsored by Astellas Pharma Europe Ltd. Rhian
Harper Owen, PhD, for Lumanity, assisted in drafting the man-
uscript under the direction of the authors and provided edito-
rial support throughout its development. S. Kadah, N.S. Heinz,
and I. Scheffner from the Hannover Medical School (MHH), and
M. Streubert (UK-Erlangen) also assisted with data manage-
ment and study organization. Medical and editorial support
was funded by Astellas Pharma, Inc.
Data Statement
Researchers may request access to anonymized participant-lev-
el data, trial-level data, and protocols from Astellas-sponsored
clinical trials at www.clinicalstudydatarequest.com. For the
Astellas criteria on data sharing see: https://clinicalstudyda-
tarequest.com/Study-Sponsors/Study-Sponsors-Astellas.aspx.
Declaration of Figures’ Authenticity
All figures submitted have been created by the authors who
confirm that the images are original with no duplication and
have not been previously published in whole or in part.
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