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American Journal of Kidney Diseases

Novel Once-Daily Extended-Release Tacrolimus Versus Twice-Daily Tacrolimus in De Novo Kidney Transplant Recipients: Two-Year Results of Phase 3, Double-Blind, Randomized Trial

Open AccessPublished:December 22, 2015DOI:https://doi.org/10.1053/j.ajkd.2015.10.024

      Background

      1-year data from this trial showed the noninferiority of a novel once-daily extended-release tacrolimus (LCPT; Envarsus XR) to immediate-release tacrolimus (IR-Tac) twice daily after kidney transplantation.

      Study Design

      Final 24-month analysis of a 2-armed, parallel-group, randomized, double-blind, double-dummy, multicenter, phase 3 trial.

      Setting & Participants

      543 de novo kidney recipients randomly assigned to LCPT (n = 268) or IR-Tac (n = 275); 507 (93.4%) completed the 24-month study.

      Intervention

      LCPT tablets once daily at 0.17 mg/kg/d or IR-Tac twice daily at 0.1 mg/kg/d; subsequent doses were adjusted to maintain target trough ranges (first 30 days, 6-11 ng/mL; thereafter, 4-11 ng/mL). The intervention was 24 months; the study was double blinded for the entirety.

      Outcomes & Measurements

      Treatment failure (death, transplant failure, biopsy-proven acute rejection, or loss to follow up) within 24 months. Safety end points included adverse events, serious adverse events, new-onset diabetes, kidney function, opportunistic infections, and malignancies. Pharmacokinetic measures included total daily dose (TDD) of study drugs and tacrolimus trough levels.

      Results

      24-month treatment failure was LCPT, 23.1%; IR-Tac, 27.3% (treatment difference, −4.14% [95% CI, −11.38% to +3.17%], well below the +10% noninferiority criterion defined for the primary 12-month end point). Subgroup analyses showed fewer treatment failures for LCPT versus IR-Tac among black, older, and female recipients. Safety was similar between groups. From month 1, TDD was lower for LCPT; the difference increased over time. At month 24, mean TDD for LCPT was 24% lower than for the IR-Tac group (P < 0.001), but troughs were similar (means at 24 months: LCPT, 5.47 ± 0.17 ng/mL; IR-Tac, 5.8 ± 0.30 ng/mL; P = 0.4).

      Limitations

      Trial participant eligibility criteria may limit the generalizability of results to the global population of de novo kidney transplant recipients.

      Conclusions

      Results suggest that once-daily LCPT in de novo kidney transplantation has comparable efficacy and safety profile to that of IR-Tac. Lower TDD reflects LCPT’s improved bioavailability and absorption.

      Index Words

      Tacrolimus is overwhelmingly used as an immunosuppressant in kidney transplantation, both early posttransplantation and as part of long-term maintenance regimens.
      Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR)
      OPTN/SRTR 2012 Annual Data Report.
      While highly effective in preventing acute transplant rejection, tacrolimus has several limitations, including a narrow therapeutic window (necessitating drug monitoring and individual dose titration

      US Food and Drug Administration. Draft Guidance on Tacrolimus. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm181006.pdf. Accessed July 2, 2014.

      ), interindividual variation in absorption, and low bioavailability (17% ± 10%) of the currently widely used immediate-release tacrolimus (IR-Tac) twice-daily capsule formulation (Prograf; Astellas Pharma US, Inc).

      Prograf [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; September 2013.

      In addition, both the IR-Tac formulation and another extended-release once-daily tacrolimus formulation (Advagraf/Astagraf XL; Astellas Pharma US, Inc) are associated with similar peak concentrations
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      A randomized cross-over comparison of short-term exposure of once-daily extended release tacrolimus and twice-daily tacrolimus on renal function in healthy volunteers.
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      for the OLN-452 Study Group
      Neoral® rescue therapy in transplant patients with intolerance to tacrolimus.
      Additionally, the twice-daily formulation adds further pill burden to a patient population already encumbered with taking many long-term medications. Multiple daily drug dosing is associated with increased risk for nonadherence
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      ; this may result in acute rejection
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      Factors contributing to acute rejection in renal transplantation: the role of noncompliance.
      and, in severe cases, transplant failure.
      • Michelon T.
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      • et al.
      Kidney graft failure due to noncompliance.
      The medication LCP-Tacro (LCPT; Envarsus XR; Veloxis Pharmaceuticals) is an extended-release tablet formulation of tacrolimus with once-daily dosing that has been developed using a proprietary MeltDose drug delivery technology (Veloxis Pharmaceuticals), distinguishing LCPT from other once-daily extended-release tacrolimus products (eg, Astagraf XL). The MeltDose technology decreases a drug’s particle size to the smallest possible units as single molecules (ie, a “solid solution”).

      Life Cycle Pharma A/S, assignee. MeltDose® Technology. US patent 7,217,431. May 2007.

      Drug particle size critically affects drug dissolution and absorption; if particle size is smaller, the surface area of the drug increases and the drug will be dissolved more quickly, resulting in better absorption.

      US Food and Drug Administration. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070246.pdf. Accessed July 2, 2014.

      Results of the MeltDose technology are increased absorption and bioavailability associated with LCPT tablets compared with other extended-release and IR tacrolimus formulations currently available. Phase 1 and phase 2 trials confirmed that LCPT enables broader absorption throughout the gastrointestinal tract and sustains consistent tacrolimus concentrations.

      Nigro V, Glicklich A, Weinberg J. Improved bioavailability of MELTDOSE once-daily formulation of tacrolimus (LCP-Tacro) with controlled agglomeration allows for consistent absorption over 24 hrs: a scintigraphic and pharmacokinetic evaluation. Presented at: American Transplant Congress; May 18-22, 2013; Seattle, WA. Abstract B1034.

      In addition, LCPT showed a lack of diurnal variability

      Nigro V, Glicklich A, Weinberg J. Flexible dosing of once-daily LCP-Tacro tablets: morning vs. evening randomized crossover chronopharmacokinetic study. Presented at: AST/ESOT Joint Meeting; October 12-14, 2012; Nice, France.

      common with other formulations.

      Prograf [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; September 2013.

      ASTAGRAF XL tacrolimus capsule, coated, extended release.
      Phase 2 trials of de novo and stable kidney
      • Alloway R.
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      • Cohen D.
      • Kaplan B.
      A phase 2 randomized study of the pharmacokinetics, safety and efficacy of LCP-Tacro tablets once-a-day vs Prograf capsules twice-a-day in de novo kidney transplants.
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      Conversion from twice-daily tacrolimus capsules to once-daily extended-release tacrolimus (LCPT): a phase 2 trial of stable renal transplant recipients.
      and liver recipients
      • Alloway R.R.
      • Eckhoff D.E.
      • Washburn W.K.
      • Teperman L.W.
      Conversion from twice-daily tacrolimus capsules to once-daily extended-release tacrolimus (LCPT): phase II trial of stable liver transplant recipients.
      • DuBay D.A.
      • Alloway R.R.
      • Alsina A.E.
      • et al.
      A phase 2b, open-label, multicenter, prospective, randomized study to compare the pharmacokinetics and safety of LCP-Tacro™ tablets once-a-day to Prograf® capsules twice-a-day in de novo liver transplant patients.
      showed a steadier and more consistent concentration-time profile over 24 hours, with reduced peak and peak-to-trough fluctuations for LCPT compared to IR-Tac, increased bioavailability of ∼30%, and comparable efficacy and safety profiles. A robust correlation between the area under the curve at 24 hours and the minimum concentration was also shown, indicating that therapeutic drug monitoring of minimum concentration as a measure of tacrolimus exposure can be applied to LCPT. A phase 3 conversion trial showed that LCPT had noninferior efficacy and comparable safety profile to IR-Tac, with lower doses (∼20% lower than IR-Tac overall and 30% lower in white patients) of LCPT.
      • Bunnapradist S.
      • Ciechanowski K.
      • West-Thielke P.
      • et al.
      Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT Trial.
      Previously, the 12-month primary efficacy and safety outcomes were reported from this phase 3 double-blind double-dummy trial of de novo kidney transplant recipients randomly assigned to LCPT or IR-Tac.
      • Budde K.
      • Bunnapradist S.
      • Grinyo J.M.
      • et al.
      Once daily LCP-Tacro MeltDose® tacrolimus vs. twice daily tacrolimus in de novo kidney transplants: one-year results of phase 3, double-blind, randomized trial.
      Here, the prespecified blinded efficacy and safety outcomes at 24 months’ follow-up are reported from this same phase 3 trial. Efficacy was also analyzed within patient subgroups (ie, females, blacks, and recipients aged ≥ 65 years) in order to explore the consistency of results, or lack thereof, within specific patient populations.

      Methods

      Study Overview

      This was a 2-armed, parallel group, prospective, randomized, double-blind, double-dummy, multicenter, 24-month, phase 3 trial. The study design has been previously reported.
      • Budde K.
      • Bunnapradist S.
      • Grinyo J.M.
      • et al.
      Once daily LCP-Tacro MeltDose® tacrolimus vs. twice daily tacrolimus in de novo kidney transplants: one-year results of phase 3, double-blind, randomized trial.
      Both the 1- and the 2-year analyses were a priori planned as explicitly stated in the study protocol. The primary endpoint was based on the 1-year analysis and the 2-year analysis was the final analysis designed to assess long-term efficacy and safety outcomes; patients and investigators stayed blinded for the full 24 months. In brief, adult de novo recipients of a living or deceased donor kidney transplant were randomly assigned to receive LCPT tablets once daily on a starting dose of 0.17 mg/kg/d or IR-Tac twice-daily (Prograf) capsules at 0.1 mg/kg/d. Subsequent doses of each study drug were adjusted to maintain whole-blood trough concentrations within the target range of 6 to 11 ng/mL for the first 30 days, then 4 to 11 ng/mL for the rest of the study. All patients also received a matching double-dummy placebo to maintain the blind. All patients also received mycophenolate mofetil (1 g twice daily) or mycophenolic acid (720 mg twice daily), an interleukin 2 receptor antagonist, and corticosteroids per local practice.
      Key study exclusion criteria were as follows: receipt of an organ transplant other than kidney; panel-reactive antibody > 30%; body mass index < 18 or >40 kg/m2; receipt of sirolimus, everolimus, azathioprine, or cyclophosphamide within 3 months before enrollment; and abnormal laboratory values.
      Health authority, ethics committee, and institutional review board approval were obtained at each participating center, and informed consent was obtained from all patients. The study was undertaken in accordance with the ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) Harmonized Tripartite Guidelines for Good Clinical Practice and conformed to the Declaration of Helsinki.

      Study End Points

      Efficacy

      The incidence of treatment failures (any of the following: death, transplant failure, biopsy-proven acute rejection [BPAR; Banff grade ≥ 1A, using Banff 2007 criteria; based on centrally read biopsies], or loss to follow-up) within 24 months after randomization was compared between LCPT and IR-Tac for the overall sample and also stratified by the following subgroups: age (<65 and ≥65 years), race (black or nonblack), and sex (male or female).
      The incidence of each individual event (death, transplant failure, BPAR, or loss to follow-up) within 24 months after the randomization date was also assessed. Efficacy results are reported for the overall 24-month study period and separately for the 0- to 12-month and 13- to 24-month periods.

      Safety

      Safety end points at 24 months included the following: incidence of AEs, serious AEs (SAEs), and discontinuations due to AEs; incidence of predefined potentially clinically significant laboratory values; new-onset diabetes after transplantation (NODAT); incidence of posttransplantation lymphoproliferative disorder; mean change from baseline (day 30) in estimated glomerular filtration rate (MDRD7 [Modification of Diet in Renal Disease] Study equation); change in clinical laboratory values and vital signs; incidence of opportunistic infections; and any malignancy or BK virus diseases. As prespecified in the study protocol, NODAT analysis was restricted to patients without diabetes at baseline and patients with no medical history of diabetes, baseline fasting plasma glucose level < 126 mg/dL, no prior use of a hypoglycemic agent for diabetes conditions, no prior use of insulin for diabetes conditions, or hemoglobin A1c level < 6.5% before transplantation. Patients meeting the at-risk definition were considered to have NODAT if they met any of the following 4 criteria: fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c level ≥ 6.5% 90 days or later after randomization, new-onset oral hypoglycemic agent use, or new-onset insulin use for more than 30 days. In general, AEs and infections were spontaneously reported by the investigator and then mapped to MedDRA (Medical Dictionary for Regulatory Activities) preferred terms.

      Statistical Analysis

      Sample Size Determination

      Sample size determination was based on the 12-month primary end point. Based on an expected treatment failure rate of 15% at 1 year, 270 patients per group were required to have 90% power to reject the null hypothesis that LCPT was inferior to IR-Tac based on a 2-sided 95% confidence interval (CI) upper bound and a 10% noninferiority margin.
      The study design and vigorous 10% noninferiority margin used for the 12-month analysis were decided upon in pretrial collaboration with the US Food and Drug Administration. Subgroup analyses were prespecified in the Statistical Analysis Plan for the study for the 12-month outcomes; the same subgroup analyses were performed at 24 months for consistency check of the 12- and 24-month data.

      Analysis Method

      The total daily dose (TDD) the day before a trough sample recorded in the case report forms was used to compute the ratio of trough value to dose for each trough sample for each patient. The ratio was then tabulated by treatment group and time point; differences in ratios between groups at each time point were evaluated by 1-way analysis of variance with main effect of treatment.
      Treatment failure within 24 months was assessed using a 2-sided 95% CI for the difference (LCPT minus IR-Tac) in treatment failure rates between treatment groups. The incidence of clinically suspected and treated acute rejection episodes and the incidence of BPAR episodes was compared between treatment groups using Fisher exact test and 2-sided 95% CI for the difference. The 2-sided 95% CIs for the differences were calculated using the Newcombe-Wilson score method. In addition, the association between treatment and severity grade of the first BPAR episode was assessed using Cochran-Mantel-Haenszel test for general association.
      Differences between treatment groups in time-to-event distributions were evaluated using log-rank tests, displayed as Kaplan-Meier curves. Baseline characteristics and treatment-emergent AEs were tabulated by treatment. Change from baseline in lipid levels was compared using an analysis of covariance model with main effect of treatment and baseline as covariates.

      Results

      Study Overview

      The study was initiated on October 13, 2010. All randomly assigned participants completed the 24-month visit by March 26, 2014, at 68 sites (United States, n = 31; Latin America, n = 13; Europe, n = 15; and Asia Pacific, n = 9).

      Patient Disposition and Baseline Characteristics

      A total of 543 patients were randomly assigned to the study drug (intention-to-treat population; LCPT, n = 268; IR-Tac, n = 275). Overall, 507 (93.4%) patients completed the 24-month study period and 394 (72.6%) completed the 24-month study on study drug (LCPT, n = 195; IR-Tac, n = 199; Fig 1).
      Figure thumbnail gr1
      Figure 1Patient disposition. Abbreviations: AE, adverse event; LCPT, extended-release tacrolimus, once daily.
      Demographic characteristics were similar between treatment groups. The patient population was predominately white (76.8%) and male (65.4%); mean age was 45.8 years (Table 1).
      Table 1Patient Demographics and Baseline Characteristics
      LCPT (n = 268)IR-Tac (n = 275)
      Age, y44.8 ± 13.2946.9 ± 14.26
      Sex
       Male174 (64.9)181 (65.8)
       Female94 (35.1)94 (34.2)
      Race
       White203 (75.7)214 (77.8)
       Black10 (3.7)15 (5.5)
       Asian10 (3.7)10 (3.6)
       Other45 (16.8)36 (13.1)
      Previous transplant11 (4.1)11 (4.0)
      Donor type
       Living135 (50.4)129 (46.9)
       Deceased133 (49.6)145 (52.7)
       Missing0 (0.0)1 (0.4)
      PRA, %1.5 ± 5.101.5 ± 5.98
      PRA < 5%243 (90.7)253 (92.0)
      Diabetes at time of transplantation50 (18.7)56 (20.4)
      Time from transplantation to first study drug dose, h34.15 ± 8.934.38 ± 9.7
      Note: Values for categorical variables are given as number (percentage); for continuous variables, as mean ± standard deviation.
      Abbreviations and definitions: IR-Tac, immediate-release tacrolimus, twice-daily; LCPT, extended-release tacrolimus, once daily; PRA, panel-reactive antibody.

      Immunosuppression

      As a result of the higher starting dose for LCPT, initial TDDs were higher in patients in the LCPT group versus the IR-Tac group. From months 1 through 12, TDDs were lower in the LCPT group, and the difference between groups increased over time. At month 3, TDD for the LCPT group was ∼14% lower, and by month 12, ∼20% lower. At month 24, mean TDD for the LCPT group was 24.4% lower than that for the IR-Tac group (3.4 ± 0.15 [standard error] and 4.5 ± 0.22 mg, respectively; P < 0.001; Fig 2).
      Figure thumbnail gr2
      Figure 2Mean (± standard error) tacrolimus trough levels and tacrolimus daily dose over the 24-month study period. Abbreviations: LCPT, extended-release tacrolimus, once daily; TDD, total daily dose.
      Tacrolimus trough levels were notably higher in the LCPT group compared with the IR-Tac group in the first 2 weeks after dosing; thereafter, trough levels in the 2 groups were similar (Fig 2). Although a greater proportion of LCPT (67%) versus IR-Tac (25%) patients had tacrolimus trough levels ≥ 6 ng/mL by day 2,
      • Budde K.
      • Bunnapradist S.
      • Grinyo J.M.
      • et al.
      Once daily LCP-Tacro MeltDose® tacrolimus vs. twice daily tacrolimus in de novo kidney transplants: one-year results of phase 3, double-blind, randomized trial.
      the majority of patients in both treatment groups were within the post–30-day target range of 4 to 11 ng/mL from month 1.5 through month 24 (71.5%-84.5% for LCPT and 78.3%-87.0% for IR-Tac).
      Analysis of trough to dose ratio demonstrated an increasing ratio for LCPT throughout the 24 months (Fig 3); this reflected the improved absorption provided by the MeltDose formulation. This is apparent over time as the dose decreases but the trough level remains stable and similar to that of IR-Tac. Absorption (ie, bioavailability) per milligram was significantly higher in the LCPT group versus the IR-Tac group by month 12 (means for LCPT and IR-Tac of 2.3 ± 0.11 and 1.6 ± 0.07, respectively; P < 0.001) and month 24 (means for LCPT and IR-Tac of 2.2 ± 0.11 and 1.68 ± 0.07, respectively; P < 0.001).
      Figure thumbnail gr3
      Figure 3Mean (± standard error) tacrolimus trough level (ng/mL) achieved per total daily dose (TDD; mg). Abbreviation: LCPT, extended-release tacrolimus, once daily.

      Efficacy End Point

      Treatment failure at 24 months was 23.1% for patients in the LCPT group and 27.3% for patients in the IR-Tac group. The treatment difference was −4.14% (95% CI, −11.38% to +3.17%), well below the noninferiority margin of 10% that was used for the 12-month primary efficacy end point. No statistically significant difference was observed between the LCPT and IR-Tac groups for the incidence of all-cause mortality (P = 0.8), transplant failure (P = 0.5), BPAR (P = 0.8), or loss to follow-up (P = 0.4; Table 2).
      Table 2Efficacy Results During the First and Second 12 Months and Over the 24-Month Study Period
      LCPT (n = 268)IR-Tac (n = 275)Treatment Difference (95% CI)
      Two-sided 95% CIs were calculated using Newcombe-Wilson score intervals. For the primary efficacy end point (12-month treatment failure rate), difference between groups was assessed by a noninferiority approach with a noninferiority margin of 10%.
      Treatment failure
       0-12 mo49 (18.3)54 (19.6)−1.35% (−7.94% to 5.27%)
       13-24 mo
      Percentage was calculated based on persons who participated in the study during this period.
      13 (5.1)21 (8.0)−2.94% (−7.38% to 1.42%)
       0-24 mo62 (23.1)75 (27.3)−4.14% (−11.38% to 3.17%)
      Death
       0-12 mo8 (3.0)8 (2.9)0.08% (−3.02% to 3.21%)
       13-24 mo
      Percentage was calculated based on persons who participated in the study during this period.
      3 (1.2)5 (1.9)−0.74% (−3.33% to 1.73%)
       0-24 mo11 (4.1)13 (4.7)−0.62% (−4.29% to 3.03%)
      Transplant failure
       0-12 mo9 (3.4)11 (4.0)−0.64% (−4.05% to 2.75%)
       13-24 mo
      Percentage was calculated based on persons who participated in the study during this period.
      2 (0.78)4 (1.5)−0.75% (−3.15% to 1.48%)
       0-24 mo11 (4.1)15 (5.5)−1.35% (−5.15% to 2.40%)
      Loss to follow-up
       0-12 mo4 (1.5)5 (1.8)−0.33% (−2.86% to 2.18%)
       13-24 mo
      Percentage was calculated based on persons who participated in the study during this period.
      0 (0.0)3 (1.2)NA
       0-24 mo4 (1.5)8 (2.9)−1.42% (−4.29% to 1.27%)
      BPAR
       0-12 mo35 (13.1)37 (13.5)−0.39% (−6.14% to 5.38%)
       13-24 mo
      Percentage was calculated based on persons who participated in the study during this period.
      11 (4.3)13 (5.0)−0.66% (−4.50% to 3.16%)
       0-24 mo46 (17.2)50 (18.2)−1.02% (−7.44% to 5.43%)
      Note: Unless otherwise indicated, values are given as number (percentage). The prespecified noninferiority margin was 10%.
      Abbreviations: BPAR, biopsy-proven acute rejection; CI, confidence interval; IR-Tac, immediate-release tacrolimus, twice-daily; LCPT, extended-release tacrolimus, once daily; NA, not applicable.
      a Two-sided 95% CIs were calculated using Newcombe-Wilson score intervals. For the primary efficacy end point (12-month treatment failure rate), difference between groups was assessed by a noninferiority approach with a noninferiority margin of 10%.
      b Percentage was calculated based on persons who participated in the study during this period.
      No statistically significant difference was observed between the 2 treatment groups in time-to-event distribution during the 24-month study period by log-rank test: treatment failure (P = 0.3) and first episode of BPAR (P = 0.7). Overall patient survival was 95.9% versus 95.2% (P = 0.7), and transplant survival was 95.8% versus 94.4% (P = 0.4) for LCPT and IR-Tac, respectively. Both drug groups had more treatment failures in the first versus second 12 months of the study. In both study years, LCPT had fewer treatment failures; a larger difference between groups was seen between study years 1 and 2 compared to the first 12 months (Table 2; Fig 4).
      Figure thumbnail gr4
      Figure 4Kaplan-Meier analysis, proportion free of treatment failure over 24 months. Abbreviation: LCPT, extended-release tacrolimus, once daily.
      There were no statistically significant differences between the 2 treatment groups in incidence of patients with clinically suspected and treated rejections, number of BPAR episodes, or severity of the first BPAR episode (Table 3). There were more acute rejection episodes in the first year compared to the second study year in both groups (Tables 2 and 3).
      Table 3Incidence of Clinically Suspected and Treated Acute Rejection Episodes Within 24 Months After Randomization and Severity of First BPAR Episode
      ParameterLCPT (n = 268)IR-Tac (n = 275)LCPT – IR-Tac (95% CI)
      Two-sided Newcombe-Wilson score CIs are presented.
      P
      Patients with ≥1 rejection event
       0-12 mo37 (13.8)43 (15.6)−1.83% (−7.81% to 4.18%)0.6
      P value from 2-sided Fisher exact test.
       0-24 mo46 (17.2)48 (17.5)−0.29% (−6.66% to 6.11%)0.9
      P value from 2-sided Fisher exact test.
      Patients with rejections over 24-mo study
       1 episode39 (14.6)41 (14.9)
       2 episodes6 (2.2)6 (2.2)
       3 episodes1 (0.4)0 (0.0)
       ≥4 episodes0 (0.0)0 (0.0)
      Severity of first BPAR episode
      For BPAR severity, mild is acute T-cell–mediated rejection grade IA or IB; moderate is acute T-cell–mediated rejection grade IIA or grade IIB; and severe is acute T-cell–mediated rejection grade III using Banff 2007 criteria. BPAR events were based on the central biopsy reading. Events occurring prior to or on study day 404 or March 18, 2013, whichever is earlier, are included.
       Mild37 (13.8)39 (14.2)0.9
      P value from Cochran-Mantel-Haenszel test for general association.
       Moderate8 (3.0)10 (3.6)
       Severe1 (0.4)1 (0.4)
      BPAR treated with polyclonal antibodies9 (3.4)12 (4.4)0.6b
      Note: Unless otherwise indicated, values are given as number (percentage).
      Abbreviations: BPAR, biopsy-proven acute rejection; CI, confidence interval; IR-Tac, immediate-release tacrolimus, twice-daily; LCPT, extended-release tacrolimus, once daily.
      a Two-sided Newcombe-Wilson score CIs are presented.
      b P value from 2-sided Fisher exact test.
      c For BPAR severity, mild is acute T-cell–mediated rejection grade IA or IB; moderate is acute T-cell–mediated rejection grade IIA or grade IIB; and severe is acute T-cell–mediated rejection grade III using Banff 2007 criteria. BPAR events were based on the central biopsy reading. Events occurring prior to or on study day 404 or March 18, 2013, whichever is earlier, are included.
      d P value from Cochran-Mantel-Haenszel test for general association.
      Subgroup analyses showed that the LCPT group had fewer treatment failures compared to the IR-Tac group in females, blacks, and recipients 65 years or older (Fig 5).
      Figure thumbnail gr5
      Figure 5Forest plot of difference (95% confidence interval) in treatment failure for extended-release tacrolimus, once daily (LCPT) versus twice-daily tacrolimus by patient subgroups and overall.

      Safety

      Treatment-Emergent AEs

      Mean numbers of AEs per patient during the study were 14.3 and 14.4 for the LCPT and IR-Tac groups, respectively. The incidence of AEs was similar between the 2 treatment groups (Table 4). AEs reported in the second year tended to follow the same pattern as in the first study year; however, AEs tended to be fewer for the second year of the study compared to the first 12 months (percentages of patients with ≥1 AE in the first vs second year were 98% vs 74% and 99% vs 70% for the LCPT and IR-Tac groups, respectively).
      Table 4Summary of AEs, Potentially Clinically Significant Laboratory Values, and Kidney Function
      LCPT (n = 268)IR-Tac (n = 275)
      AEs
       No. of AEs3,8423,965
       No. of AEs suspected related to study drug493543
       Patients with ≥1 AE263 (98.1)269 (97.8)
       AEs occurring in ≥20% of overall patients
      Edema peripheral50 (18.7)66 (24.0)
      Constipation51 (19.0)68 (24.7)
      Diabetes mellitus55 (20.5)42 (15.3)
      Tremor59 (22.0)51 (18.5)
      Hypertension71 (26.5)73 (26.5)
      Anemia75 (28.0)84 (30.5)
      Urinary tract infection81 (30.2)80 (29.1)
      Diarrhea91 (34.0)102 (37.1)
       Malignancies
      0-12 mo4 (1.5)3 (1.1)
      0-24 mo8 (3.0)8 (2.9)
       Infections
      Any opportunistic
      The opportunistic designation was assigned by the physician.
      infection
      0-12 mo92 (34.3)84 (30.5)
      0-24 mo110 (41.0)99 (36.0)
      Cytomegalovirus infection
      0-12 mo31 (11.6)25 (9.1)
      0-24 mo33 (12.3)29 (10.5)
      BK virus infection
      0-12 mo24 (9.0)26 (9.5)
      0-24 mo32 (11.9)31 (11.3)
       No. of SAEs475519
       Patients with ≥1 SAE166 (61.9)185 (67.3)
       SAEs occurring in ≥5% of overall patients
      Urinary tract infection9.7%8.0%
      Kidney transplant rejection8.6%12.0%
      Complications of transplanted kidney
      Mostly delayed transplant function.
      3.0%6.5%
      Kidney function
      Calculated as month-24 value – baseline value for each patient.
       eGFR, mL/min/1.73 m2
      Baseline53.9 ± 1.2754.4 ± 1.30
      Month 2460.0 ± 1.4060.6 ± 1.46
      Change from baseline4.1 ± 1.185.1 ± 1.13
       Creatinine, mg/dL
      Baseline5.59 ± 0.1785.67 ± 0.168
      Month 241.46 ± 0.061.49 ± 0.07
      Change from baseline−3.84 ± 0.19−4.05 ± 0.19
      Lipids
       HDL cholesterol, mg/dL
      Baseline41.7 ± 0.8240.1 ± 0.80
      Month 2456.8 ± 1.2753.9 ± 1.20
      Change from baseline13.7 ± 1.1514.4 ± 1.04
       LDL cholesterol, mg/dL
      Baseline86.7 ± 2.2885.1 ± 2.11
      Month 24102.4 ± 2.01103.3 ± 2.12
      Change from baseline15.8 ± 3.0917.3 ± 2.67
       Total cholesterol, mg/dL
      Baseline151.2 ± 2.71148.9 ± 2.37
      Month 24185.7 ± 2.66186.0 ± 2.74
      Change from baseline34.0 ± 3.7036.6 ± 3.11
       Triglycerides, mg/dL
      Baseline98.8 ± 3.55102.7 ± 4.39
      Month 24152.6 ± 6.69167.5 ± 6.83
      Change from baseline57.2 ± 6.5465.1 ± 7.06
      Note: Unless otherwise indicated, values are given as number (percentage) or mean ± standard error. Conversion factors for units: cholesterol in mg/dL to mmol/L, ×0.02586; creatinine in mg/dL to μmol/L, ×88.4; triglycerides in mg/dL to mmol/L, ×0.01129.
      Abbreviations: AE, adverse event; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; IR-Tac, immediate-release tacrolimus, twice-daily; LCPT, extended-release tacrolimus, once daily; LDL, low-density lipoprotein; SAE, serious adverse event.
      a The opportunistic designation was assigned by the physician.
      b Mostly delayed transplant function.
      c Calculated as month-24 value – baseline value for each patient.
      The majority of patients had at least 1 mild (LCPT, 92.2%; IR-Tac, 93.8%) or moderate (LCPT, 82.8%; IR-Tac, 84.7%) AE. Eighty (29.9%) patients in the LCPT group and 95 (34.5%) in the IR-Tac group had at least 1 severe event.
      The majority of events (>80%) were not suspected to be related to study drug. However, 64.9% of patients in the LCPT group and 59.3% of patients in the IR-Tac group had at least 1 event suspected to be related to the study drug.
      The proportion of patients who had AEs resulting in discontinuation from study drug and/or withdrawal from the study was similar in the treatment groups (0-12 months: 8.6% in LCPT, 9.8% in IR-Tac; 0-24 months: 11.6% in LCPT, 12.7% in IR-Tac).

      Treatment-Emergent SAEs

      In the LCPT and IR-Tac groups, 61.9% and 67.3% of patients, respectively, had treatment-emergent SAEs. The frequency of SAEs tended to be fewer for the second year versus the first 12 months (percentages of patients with ≥1 SAE in the first vs second year were 53% vs 24% and 58% vs 24%, for LCPT and IR-Tac, respectively).
      Twenty-four deaths (11 in LCPT [first year, 8; second year, 3] and 13 in IR-Tac [first year, 8; second year, 5]) occurred during the study. Most causes of death were related to the cardiopulmonary system. None of the 11 fatal SAEs in the LCPT group were suspected to be related to the study drug. Three of the 13 patients who died in the IR-Tac group had events (sepsis) considered to be related to study drug.

      Potentially Clinically Significant Laboratory Values and Kidney Function

      No statistically significant difference was observed between treatment groups in the incidence of predefined potentially clinically significant laboratory measurements.
      Laboratory results most commonly reported as an AE were anemia, hypophosphatemia, leukopenia, hyperkalemia, increased blood creatinine level, hypokalemia, hypomagnesemia, hyperglycemia, and vitamin D deficiency. Most were mild or moderate in severity and most were not suspected to be related to study drug.
      Hematology, chemistry, hepatic profile, urinalysis, vital signs, physical examination, and estimated glomerular filtration rate results had minimal change from baseline for both tacrolimus formulations (Table 4).
      Within 24 months after randomization, 24 of 88 (27.3%) and 12 of 74 (16.2%) at-risk patients in the LCPT and IR-Tac groups, respectively, had developed NODAT (P = 0.1). Change from baseline in hemoglobin A1c level was similar for both treatment groups over the entire study.

      Discussion

      The results discussed here are from the blinded 24-month follow-up of a phase 3 trial assessing the efficacy and safety of once-daily LCPT MeltDose tablets versus IR-Tac capsules in de novo kidney transplant recipients. Consistent with the 12-month results,
      • Budde K.
      • Bunnapradist S.
      • Grinyo J.M.
      • et al.
      Once daily LCP-Tacro MeltDose® tacrolimus vs. twice daily tacrolimus in de novo kidney transplants: one-year results of phase 3, double-blind, randomized trial.
      this double-blind double-dummy study in 543 recipients showed that once-daily LCPT was associated with a comparable efficacy and safety profile as IR-Tac at 24 months postrandomization. The LCPT group had fewer treatment failures compared to the IR-Tac group over the duration of the study, including early posttransplantation (ie, at 3 months), when there is the greatest risk for rejection; noninferiority was demonstrated at 12 months posttransplantation. Lower LCPT doses were able to achieve similar trough levels compared to IR-Tac.
      Post hoc subgroup analyses showed that the LCPT group had fewer treatment failures among black recipients, older recipients, and females; each of these populations has been found to have higher risk for acute rejection, transplant loss, and/or death.
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      Outcomes in African American kidney transplant patients receiving tacrolimus and mycophenolic acid immunosuppression.
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      • Chan L.
      Long-term outcomes in African American kidney transplant recipients under contemporary immunosuppression: a four-yr analysis of the Mycophenolic acid Observational REnal transplant (MORE) study.
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      Clinical outcomes in elderly kidney transplant recipients are related to acute rejection episodes rather than pretransplant comorbidity.
      • Laging M.
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      Understanding the influence of ethnicity and socioeconomic factors on graft and patient survival after kidney transplantation.
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      Mortality after kidney transplant failure: the impact of non-immunologic factors.
      Lower tacrolimus bioavailability has been observed in females
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      A randomized, crossover pharmacokinetic study comparing generic tacrolimus vs. the reference formulation in subpopulations of kidney transplant patients.
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      • et al.
      Gender differences in pharmacokinetics of tacrolimus and their clinical significance in kidney transplant recipients.
      and African American kidney transplant recipients, largely due to variations in CYP3A5 gene expression
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      and polymorphism preponderance (CYP3A5*1 allele).
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      The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation.
      The improved bioavailability of LCPT may translate into improved clinical outcomes. Although older recipients generally have less acute rejection owing to immunosenescence,
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      Aging of the innate immune system: an update.
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      The combination of donor and recipient age is critical in determining host immunoresponsiveness and renal transplant outcome.
      early rejection episodes may be particularly detrimental to long-term clinical outcomes in older recipients.
      • Heldal K.
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      • et al.
      Clinical outcomes in elderly kidney transplant recipients are related to acute rejection episodes rather than pretransplant comorbidity.
      • de Fijter J.W.
      The impact of age on rejection in kidney transplantation.
      It has also been hypothesized that elderly transplant recipients are likely to have a greater degree of variability in tacrolimus pharmacokinetics compared with younger recipients.
      • Staatz C.E.
      • Tett S.E.
      Pharmacokinetic considerations relating to tacrolimus dosing in the elderly.
      Thus, it is reasonable to hypothesize that LCPT may be a particularly good option in older receipts due to improved pharmacokinetics and efficacy against rejection. The trends observed are consistent with a post hoc analysis performed on pooled 12-month data from de novo and stable kidney transplant recipients, where significant differences in treatment failure were found in both elderly and black patients for LCPT versus IR-Tac.

      Bunnapradist S, Alloway R, West-Thielke P, Denny J, Mulgaonkar S. Lower treatment failures in blacks and older denovo and stable kidney transplant recipients treated with Envarsus once-daily MeltDose tablets vs. twice-daily Prograf capsules: a pooled subgroup analysis of two phase 3 trials. Presented at: World Transplant Congress; July 26-31, 2014; San Francisco, CA. Abstract 50.

      The incidence of treatment-emergent AEs was similar between both tacrolimus formulations. Kidney function was similar between the 2 groups throughout the 24-month study period, as were incidences of malignancy, infections, and NODAT.
      During this 2-year outpatient therapy period, LCPT patients required lower doses than the IR-Tac group and the difference increased continually over time while trough levels remained similar, indicating the improved absorption by the MeltDose drug delivery technology. Absorption (ie, bioavailability) per milligram was significantly greater in the LCPT group versus the IR-Tac group. This result is consistent with data from phase 2 studies that demonstrated LCPT is associated with an increase in bioavailability
      • Alloway R.
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      • Ueda K.
      • Cohen D.
      • Kaplan B.
      A phase 2 randomized study of the pharmacokinetics, safety and efficacy of LCP-Tacro tablets once-a-day vs Prograf capsules twice-a-day in de novo kidney transplants.
      • Alloway R.R.
      • Mulgaonkar S.
      • Bowers V.D.
      • et al.
      A phase 2b, open-label, multi-center, prospective, randomized study to compare the pharmacokinetics and safety of LCP-Tacro™ tablets once-a-day to Prograf® capsules twice-a-day in de novo kidney transplant patients.
      and a phase 3 conversion study in which the required TDD of LCPT was ∼20% lower than the preconversion IR-Tac dose, whereas drug trough levels were stable.
      • Bunnapradist S.
      • Ciechanowski K.
      • West-Thielke P.
      • et al.
      Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT Trial.
      Currently, LCPT is the only extended-release once-daily tacrolimus formulation that requires a lower tacrolimus dose to achieve similar exposure levels and demonstrates comparable efficacy to IR-Tac capsules.
      There are conflicting data for the importance of tacrolimus peak concentrations. Although peak concentrations are important for cyclosporine-treated patients,
      • Grant D.
      • Kneteman N.
      • Tchervenkov J.
      • et al.
      Peak cyclosporine levels (Cmax) correlate with freedom from liver graft rejection: results of a prospective, randomized comparison of Neoral and Sandimmune for liver transplantation (NOF-8)1,2.
      • Nashan B.
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      Use of Neoral C2 monitoring: a European consensus.
      Undre et al
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      • Christiaans M.
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      Low systemic exposure to tacrolimus correlates with acute rejection.
      reported no association between peak concentration and rejection for tacrolimus-treated patients. Instead, overall exposure, as determined by area under the curve, is important for good rejection prophylaxis. Conversely, it has been hypothesized that peak calcineurin inhibitor levels may be associated with prevention of rejection.
      • Grant D.
      • Kneteman N.
      • Tchervenkov J.
      • et al.
      Peak cyclosporine levels (Cmax) correlate with freedom from liver graft rejection: results of a prospective, randomized comparison of Neoral and Sandimmune for liver transplantation (NOF-8)1,2.
      • Srinivas T.R.
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      • Meier-Kriesche H.U.
      The noninferiority trial: don't don't do it.
      However, results from the present study suggest that this is not the case because LCPT is associated with an ∼30% lower peak compared to IR-Tac, and it is the achievement of early therapeutic tacrolimus exposure that is likely more important in preventing rejection.
      An advantage of LCPT tablets is their once-a-day dosing. Multiple daily dosing could contribute to lack of adherence,
      • Eisen S.A.
      • Miller D.K.
      • Woodward R.S.
      • Spitznagel E.
      • Przybeck T.R.
      The effect of prescribed daily dose frequency on patient medication compliance.
      • Claxton A.J.
      • Cramer J.
      • Pierce C.
      A systematic review of the associations between dose regimens and medication compliance.
      • Saini S.D.
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      Effect of medication dosing frequency on adherence in chronic diseases.
      • Feldman H.I.
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      Potential utility of electronic drug compliance monitoring in measures of adverse outcomes associated with immunosuppressive agents.
      and posttransplantation drug regimens are frequently associated with high pill burden. Transplant recipients often have lack of treatment adherence
      • Germani G.
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      • Gnoato F.
      • et al.
      Nonadherent behaviors after solid organ transplantation.
      • Chisholm M.A.
      Issues of adherence to immunosuppressant therapy after solid-organ transplantation.
      • Laederach-Hofmann K.
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      Noncompliance in organ transplant recipients: a literature review.
      ; nonadherence is purported to be a major contributor to transplant failure
      • Sellarés J.
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      • Mengel M.
      • et al.
      Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence.
      and a barrier to improving long-term kidney transplantation outcomes. Once-daily tacrolimus has been shown to increase adherence.
      • Kuypers D.R.J.
      • Peeters P.C.
      • Sennesael J.J.
      • et al.
      Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring.
      • Doesch A.O.
      • Mueller S.
      • Akyol C.
      • et al.
      Increased adherence eight months after switch from twice daily calcineurin inhibitor based treatment to once daily modified released tacrolimus in heart transplantation.
      In this double-dummy trial, every patient was assigned to twice-daily dosing in order to not break the blind. Thus, it was beyond the scope of this trial to examine whether adherence is increased for LCPT versus IR-Tac twice daily.
      As for all clinical trials, these results and their generalizability are limited by the patients in a trial having to meet eligibility criteria to participate and might not necessarily be representative of the overall population of de novo kidney transplant recipients. In addition, trial participants are in a highly controlled environment and patient behavior (ie, dose adherence and return for clinical follow-up) and that of the treating clinicians might differ outside of the trial conditions, thus influencing clinical outcomes. Strengths of this trial include it being double blind with a titratable drug and blinded for 2 years.
      The MeltDose technology with its improved bioavailability, along with extended drug release, has resulted in a novel once-daily dosing version of tacrolimus. Results in this report confirm the benefit of a lower dose to achieve target trough levels. This trial offers evidence that LCPT demonstrates comparable efficacy to currently available tacrolimus in de novo kidney transplantation.

      Acknowledgements

      The members of the Envarsus study group are as follows: United States: Denny, Jason E., MD, Henry Ford Health System, Detroit, MI; Kulkarni, Sanjay, MD, Yale University, New Haven, CT; Hricik, Donald, MD, University Hospitals Case Medical Center, Cleveland, OH; Bresnahan, Barbara A., Medical College of Wisconsin, Milwaukee, WI; Bunnapradist, Suphamai, University of California Los Angeles Medical Center, Los Angeles, CA; El-Sabrout, Rafik A., Westchester Medical Center, Valhalla, NY; Chan, Laurence K., University of Colorado, Denver, CO; Ciancio, Gaetano, University of Miami, Miami, FL; El-Ghoroury, Mohamed A., St. Clair Specialty Physicians, Detroit, MI; Goldstein, Michael J., Mount Sinai Medical Center, New York, NY; Gaston, Robert S., University of Alabama at Birmingham, Birmingham, AL; Gohh, Reginald Y., Rhode Island Hospital, Providence, RI; Killackey, Mary T., Tulane University Medical Center, New Orleans, LA; King, Anne, Virginia Commonwealth University, Richmond, VA; Knight, Richard J., The Methodist Hospital, Houston, TX; Kore, Arputharaj H., Loma Linda University Health Care, Loma Linda, CA; Sudan, Debra L., Duke University Medical Center, Durham, NC; Chapochnick Friedmann, Javier, Montefiore Medical Center, Bronx, NY; Mulgaonkar, Shamkant P., Saint Barnabas Medical Center, Livingston, NJ; Nolan, Charles, University of Texas, San Antonio, TX; Pankewycz, Oleh G., Erie County Medical Center, Buffalo, NY; Pirsch, John D., University of Wisconsin, Madison, WI; Schaefer, Heidi M., Vanderbilt University Medical Center, Nashville, TN; Steinberg, Steven M., California Institute of Renal Research, San Diego, CA; Gelb, Bruce E., New York University Medical Center, New York, NY; True, Karin A., University of North Carolina at Chapel Hill, Chapel Hill, NC; West-Thielke, Patricia M., University of Illinois at Chicago, Chicago, IL; Waybill, Mary M., Central Pennsylvania Transplant Foundation, Harrisburg, PA; Wolf, Joshua H., Piedmont Healthcare Research Institute, Atlanta, GA; Ketel, Beverley L., Renal Care Associates, Peoria, IL; Harland, Robert C., East Carolina University, Greenville, NC; Shihab, Fuad S., University of Utah, Salt Lake City, UT. France: Cassuto, Elisabeth, Hôpital l'Archet, Nice; Le Meur, Yannick, Hôpital de La Cavale Blanche, Brest; Rostaing, Lionel, Hôpital de Rangueil, Toulouse; Mariat, Christophe, Association SRT, Saint-Etienne. Spain: Grinyó, Josep Maria, Hospital Universitari De Bellvitge, Cataluña; Puig, Jose, Hospital del Mar, Barcelona; Seron, Daniel, Hospital Vall D'Hebron Barcelona. Italy: Tisone, Giuseppe, Fondazione PTV Policlinico, Roma. Poland: Ciechanowski, Kazimierz, Samodzielny Publiczny Szpital Kliniczny, Szczecin; Foroncewicz, Bartosz, Szpital Kliniczny Dzieciatka Jezus, Warszawa; Wlodarczyk, Zbigniew, Szpital Uniwersytecki im. Dr A. Jurasza, Bydgoszcz. Germany: Budde, Klemens, Charitè Campus Mitte, Berlin; Witzke, Oliver, Universitätsklinikum Essen, Essen. Mexico: Mondragon, Guillermo A., Instituto Mexicano de Transplantes, Cuernavaca, Morelos; Mancilla Urrea, Eduardo, Instituto Nacional de Cardiologia “Dr. Ignacio Chavez”, Mexico City; Alberu Gomez, Josefina, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City; Reyes Acevedo, Rafael, Centenario Hospital Miguel Hidalgo, Aguascalientes. Argentina: Rial, Maria del Carmen, Instituto de Nefrología, Buenos Aires; Novoa, Pablo A., Hospital Cordoba, Cordoba. Brazil: Silva Jr, Helio T., Hospital do Rim e Hipertensão, São Paulo; Garcia, Valter D., Irmandade Santa Casa de Misericórdia de Porto Alegre, Rio Grande do Sul; Carvalho, Deise D., Hospital Geral de Bonsucesso, Rio de Janeiro; Santamaria Saber, Luciana T., Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto; Contieri, Fabiana L., Hospital Universitário Evangélico de Curitiba, Curitiba; Bastos, Marcos G., Fundacao IMEPEN, Juiz de Fora; Manfro, Roberto C., Hospital de Clínicas de Porto Alegre, Rio Grande do Sul. Australia: Kanellis, John, Monash Medical Centre, Clayton, VIC; Eris, Josette, Royal Prince Alfred Hospital, Camperdown NSW; O'Connell, Philip, Westmead Hospital, Westmead, NSW; Hughes, Peter, Royal Melbourne Hospital, Parkville, VIC; Russ, Graeme, Royal Adelaide Hospital, SA. New Zealand: Pidgeon, Grant B., Wellington Hospital, Wellington; Dittmer, Ian D., Auckland City Hospital, Grafton, Auckland. Singapore: Kee, Terence, Singapore General Hospital; Vathsala, Anantharaman, National University of Singapore. Serbia: Naumovic, Radomir, Clinical Center of Serbia, Belgrade; Mitic, Igor, Clinical Centre of Vojvodina, Novi Sad. Central reader: Parmjeet Randhawa, MD, University of Pittsburgh Medical Center.
      Portions of these data were presented at the 2013 European Society for Organ Transplantation (ESOT) in Vienna, Austria (September 8-11, 2013); the 2013 American Transplant Congress in Seattle, WA (May 18-22, 2013); the 2014 World Transplant Congress in San Francisco, CA (July 26-31, 2014); the 2014 ESOT in Madrid, Spain (October 17-19, 2014); the 2014 American Society of Nephrology Kidney Week in Philadelphia, PA (November 11-16, 2014); and the 2015 World Congress of Nephrology in Cape Town, South Africa (March 13-17, 2015).
      Support: Veloxis Pharmaceuticals provided funding for this manuscript, and contributed to study design. Collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication were done by the authors. Kristin Kistler, PhD, from Evidera, provided medical writing support.
      Financial Disclosure: Dr Budde: research funds and/or honoraria from AiCuris, Astellas, Bristol-Myers Squibb, Hexal, Effimune Pharma, Novartis, Pfizer, Roche, Siemens, Chiesi, Fresenius, Alexion, and Veloxis Pharma and on advisory board of Chiesi. Dr Bunnapradist: grant/research support from Veloxis, BMS, Novartis, and Genentech and on advisory board of Astellas and Alexion. Dr Grinyó: grant/research support from Veloxis and on advisory board of Chiesi. Dr Ciechanowski: participated in clinical trials with Veloxis as a principal investigator. Dr Denny: grant/research support from and on advisory board of Veloxis. Dr Silva Jr: participated in this clinical trial with Veloxis as a principal investigator and has received honoraria from Novartis and Pfizer; Dr Silva Jr’s institution has received research grants from Novartis, BMS, Pfizer, Roche, and Teraclone. Dr Rostaing: on advisory board of and consultancy with Veloxis.
      Contributions: Research idea and study design: LR, SB, JMG, KC, JED, HTS, KB; data acquisition: LR, SB, JMG, KC, JED, HTS, KB; data analysis/interpretation: LR, SB, JMG, KC, JED, HTS, KB; statistical analysis: LR, SB, JMG, KC, JED, HTS, KB. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. All authors take responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned and registered have been explained.
      Peer Review: Evaluated by 2 external peer reviewers, a Statistical Editor, a Co-Editor, and the Editor-in-Chief.

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