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    Clinical Trial Results:
    Planned Transition to Sirolimus-based Therapy Versus Continued Tacrolimus-based Therapy in Renal Allograft Recipients.

    Summary
    EudraCT number
    		 2008-006840-20
    Trial protocol
    		 ES   IT   DE  
    Global end of trial date
    31 Jul 2013

    Results information
    Results version number
    		 v1
    This version publication date
    30 May 2016
    First version publication date
    31 Jul 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    0468E8-4500
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00895583
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 1800 7181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 1800 7181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Apr 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate whether planned transition between 90 and 150 days post-transplantation to Sirolimus (SRL) based therapy from Tacrolimus (TAC) based therapy was associated with a clinically relevant degree of improvement in renal function greater than or equal to [≥] 5 Milliliters Per Minute Per 1.73 Square Meters (mL/Min/m^2) compared to continuation of TAC-based therapy.
    Protection of trial subjects
    The study was in compliance with with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 Subjects remained on an inosine monophosphate dehydrogenase (IMPDH) inhibitor (mycophenolate mofetil [MMF] or mycophenolate sodium [MPS]; switching between the two was permitted). Subjects taking corticosteroids at the time of randomization had to be maintained on a minimum of 2.5 mg/day of prednisone (or the equivalent thereof); withdrawal which was not completed at least 30 days prior to randomization was prohibited.Subjects could be on study drug for up to maximum of 21 months.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Jun 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 55
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    United States: 140
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    Brazil: 34
    Worldwide total number of subjects
    254
    EEA total number of subjects
    61
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    217
    From 65 to 84 years
    37
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Study started on 05 June 2009 and ended on 31 July 2013. Subjects enrolled from Spain, Italy, United States, Argentina, Australia, Brazil.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sirolimus
    Arm description
    		 Subjects received tacrolimus (extended release formulation not permitted) within 30 days of transplant, dosed according to center’s standard of care. At 3-5 months post-transplant, subjects were randomized, tacrolimus was discontinued (withdrawal was to be completed within 2 weeks [maximum of 4 weeks] of sirolimus initiation).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sirolimus
    Investigational medicinal product code
    Other name
    Rapamune
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received sirolimus tablets, orally, at a dose to achieve trough levels of 7-15 nanograms per milliliter (ng/mL) during the first year post-transplant, then 5-15 ng/mL. Subjects received study drug during the post-randomization period for up to a maximum of 21months post-transplant.

    Arm title
    		 Tacrolimus
    Arm description
    		 Subjects received tacrolimus (extended-release formulation not permitted) within 30 days of transplant, dosed according to center’s standard of care. At 3-5 months post-transplant, subjects were randomized and tacrolimus continued.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects had to maintain the TAC-based immunosuppression therapy started prior to randomization, as per the center’s standard of care. The use of TAC extended release formulations was not permitted.

    Number of subjects in period 1
    		Sirolimus Tacrolimus
    Started
    131
    123
    Completed
    87
    111
    Not completed
    44
    12
         Consent withdrawn by subject
    4
    2
         Physician decision
    3
    1
         Death
    2
    1
         Not specified
    -
    1
         Adverse event
    28
    4
         Protocol Violation
    1
    -
         Lost to follow-up
    1
    3
         Lack of efficacy
    5
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sirolimus
    Reporting group description
    		 Subjects received tacrolimus (extended release formulation not permitted) within 30 days of transplant, dosed according to center’s standard of care. At 3-5 months post-transplant, subjects were randomized, tacrolimus was discontinued (withdrawal was to be completed within 2 weeks [maximum of 4 weeks] of sirolimus initiation).

    Reporting group title
    Tacrolimus
    Reporting group description
    		 Subjects received tacrolimus (extended-release formulation not permitted) within 30 days of transplant, dosed according to center’s standard of care. At 3-5 months post-transplant, subjects were randomized and tacrolimus continued.

    Reporting group values
    		 Sirolimus Tacrolimus Total
    Number of subjects
    		 131 123 254
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.7 ( 13.03 ) 52.4 ( 12.05 ) -
    Gender categorical
    Units: Subjects
        Female
    		 42 46 88
        Male
    		 89 77 166

    End points

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    End points reporting groups
    Reporting group title
    Sirolimus
    Reporting group description
    		 Subjects received tacrolimus (extended release formulation not permitted) within 30 days of transplant, dosed according to center’s standard of care. At 3-5 months post-transplant, subjects were randomized, tacrolimus was discontinued (withdrawal was to be completed within 2 weeks [maximum of 4 weeks] of sirolimus initiation).

    Reporting group title
    Tacrolimus
    Reporting group description
    		 Subjects received tacrolimus (extended-release formulation not permitted) within 30 days of transplant, dosed according to center’s standard of care. At 3-5 months post-transplant, subjects were randomized and tacrolimus continued.

    Primary: Percentage of Subjects With Improvement of Greater Than or Equal to [≥]5 Milliliters Per Minute Per 1.73 Square Meters (mL/Min/m^2) in Calculated Glomerular Filtration Rate (GFR) at 24 Months Post-Transplantation (On-Therapy Analysis)

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    End point title
    		 Percentage of Subjects With Improvement of Greater Than or Equal to [≥]5 Milliliters Per Minute Per 1.73 Square Meters (mL/Min/m^2) in Calculated Glomerular Filtration Rate (GFR) at 24 Months Post-Transplantation (On-Therapy Analysis)
    End point description
    GFR was calculated using the Modified Diet in Renal Disease (MDRD) equation using either serum creatinine traceable to isotope dilution mass spectrometry (IDMS) or serum creatinine not traceable to IDMS. On-Therapy Population (24 Months): all randomised subjects who remained on assigned study therapy through 24 months post-transplantation.
    End point type
    Primary
    End point timeframe
    Baseline, Month 24
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    86
    109
    Units: percentage of subjects
        number (not applicable)
    33.7
    42.2
    Statistical analysis title
    		 GFR at 24 months
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.239 [1]
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.3
    Notes
    [1] - Two-sided alpha equals (=) 0.05.

    Secondary: Percentage of Subjects With Improvement of ≥5 mL/Min/m^2 in Calculated GFR at 12 Months Post-Transplantation (On-Therapy Analysis)

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    End point title
    		 Percentage of Subjects With Improvement of ≥5 mL/Min/m^2 in Calculated GFR at 12 Months Post-Transplantation (On-Therapy Analysis)
    End point description
    GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS (isotope dilution mass spectrometry) or serum creatinine not traceable to IDMS. On-Therapy Population (12 Months): all randomized subjects who remained on assigned study therapy through 12 months post-transplantation.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    109
    116
    Units: percentage of subjects
        number (not applicable)
    39.4
    44.8
    Statistical analysis title
    		 GFR at 12 months
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.422 [2]
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.4
    Notes
    [2] - Alpha was unadjusted.

    Secondary: Percentage of Subjects With Improvement of ≥5 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation (Intent-to-Treat [ITT] Analysis)

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    End point title
    		 Percentage of Subjects With Improvement of ≥5 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation (Intent-to-Treat [ITT] Analysis)
    End point description
    GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS. ITT Population: all randomized subjects who received at least 1 dose of the assigned therapy after randomization. Missing GFR was imputed as follows: 1) GFR equals (=)0 after graft loss and 2) last observed value prior to missing was carried forward for death (with functioning graft), early termination or skipped assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12 and 24
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: percentage of subjects
    number (not applicable)
        Month 12
    38.2
    42.3
        Month 24
    33.6
    40.7
    Statistical analysis title
    		 GFR at 12 month
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.524 [3]
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.4
    Notes
    [3] - Alpha was unadjusted.
    Statistical analysis title
    		 GFR at 24 Month
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.298 [4]
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.2
    Notes
    [4] - Alpha was unadjusted.

    Secondary: Percentage of Subjects With Improvement of ≥7.5 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation

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    End point title
    		 Percentage of Subjects With Improvement of ≥7.5 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation
    End point description
    GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS. ITT Population. Missing GFR was imputed as follows: 1) GFR=0 after graft loss and 2) last observed value prior to missing was carried forward for death (with functioning graft), early termination or skipped assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12 and 24
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: percentage of subjects
    number (not applicable)
        Month 12
    24.4
    35.8
        Month 24
    25.2
    30.9
    Statistical analysis title
    		 GFR at 12 month
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.055 [5]
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 1
    Notes
    [5] - Alpha was unadjusted.
    Statistical analysis title
    		 GFR at 24 Month
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33 [6]
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.3
    Notes
    [6] - Alpha was unadjusted.

    Secondary: Percentage of Subjects With Improvement of ≥10 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation

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    End point title
    		 Percentage of Subjects With Improvement of ≥10 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation
    End point description
    GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS. ITT Population. Missing GFR was imputed as follows: 1) GFR=0 after graft loss and 2) last observed value prior to missing was carried forward for death (with functioning graft), early termination or skipped assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12 and 24
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: percentage of subjects
    number (not applicable)
        Month 12
    19.8
    23.6
        Month 24
    22.1
    22
    Statistical analysis title
    		 GFR at 12 month
    Comparison groups
    Tacrolimus v Sirolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.543 [7]
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.5
    Notes
    [7] - Alpha was unadjusted.
    Statistical analysis title
    		 GFR at 24 month
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [8]
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.8
    Notes
    [8] - Alpha was unadjusted.

    Secondary: Calculated GFR Using MDRD (On-Therapy Analysis)

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    End point title
    		 Calculated GFR Using MDRD (On-Therapy Analysis)
    End point description
    GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS. Baseline was defined as the last nonmissing assessment before or on the date of the first dose of test article. On-Therapy Population: all subjects who remained on assigned study therapy up to the point of discontinuation. n=number of subjects assessed for the specified parameter at a given visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12, 18, and 24
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: mL/min/1.73 m^2
    arithmetic mean (standard deviation)
        Baseline (n=131,123)
    58.5 ( 14.3 )
    57.4 ( 14.1 )
        Month 6 (n=125,120)
    61.6 ( 14.9 )
    57.6 ( 14.2 )
        Month 12 (n=109,116)
    59.6 ( 16.4 )
    61.3 ( 14.3 )
        Month 18 (n=99,111)
    60 ( 15 )
    59.8 ( 17.1 )
        Month 24 (n=86,109)
    59.4 ( 18 )
    58.4 ( 14.9 )
    No statistical analyses for this end point

    Secondary: Change From Randomization in Calculated GFR Using MDRD (On-Therapy Analysis)

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    End point title
    		 Change From Randomization in Calculated GFR Using MDRD (On-Therapy Analysis)
    End point description
    GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS. Baseline was defined as the last nonmissing assessment before or on the date of the first dose of test article. On-Therapy Population; n=number of subjects assessed for the specified parameter at a given visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12, 18, and 24
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: [units: mL/min/1.73 m^2]
    arithmetic mean (standard error)
        Month 6 (n=125,120)
    2.7 ( 1.1 )
    0 ( 0.8 )
        Month 12 (n=109,116)
    1.5 ( 1.2 )
    3.4 ( 1.1 )
        Month 18 (n=99,111)
    2.2 ( 1.2 )
    1.5 ( 1.3 )
        Month 24 (n=86,109)
    1.2 ( 1.6 )
    0.6 ( 1.3 )
    Statistical analysis title
    		 Change from randomization at Month 6
    Statistical analysis description
    Change from randomization at Month 6. Analysis of covariance (ANCOVA) with treatment as a factor and baseline GFR as a covariate.
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.019 [9]
    Method
    		 ANCOVA
    Parameter type
    		 Least square (LS) mean difference
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 5.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.3
    Notes
    [9] - Alpha was unadjusted.
    Statistical analysis title
    		 Change from randomization at Month 12
    Statistical analysis description
    Change from randomization at Month 12. ANCOVA with treatment as a factor and baseline GFR as a covariate.
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.215 [10]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.8
         upper limit
    		 1.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.5
    Notes
    [10] - Alpha was unadjusted.
    Statistical analysis title
    		 Change from randomization at Month 18
    Statistical analysis description
    Change from randomization at Month 18. ANCOVA with treatment as a factor and baseline GFR as a covariate.
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.722 [11]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 3.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.7
    Notes
    [11] - Alpha was unadjusted.
    Statistical analysis title
    		 Change from randomization at Month 24
    Statistical analysis description
    Change from randomization at Month 24. ANCOVA with treatment as a factor and baseline GFR as a covariate.
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.71 [12]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 4.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.9
    Notes
    [12] - Alpha was unadjusted.

    Secondary: Slope of Calculated GFR (MDRD) From Randomization to 24 Months Post-Transplantation (On-Therapy Analysis)

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    End point title
    		 Slope of Calculated GFR (MDRD) From Randomization to 24 Months Post-Transplantation (On-Therapy Analysis)
    End point description
    GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS. Timepoints were calculated as study days, relative to the time of randomization of study medication. All available on-therapy values were included. Observed data were multiplied by a scale factor of 365, expressing the slope as an annual change. On-Therapy analysis of the slope comprised the data collected from the on-therapy evaluations for all the subjects in the ITT population; data collected from subjects receiving sirolimus during the first 3 weeks post-randomization for safety monitoring were excluded from the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 24
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: mL/min/1.73 m^2 per year
        arithmetic mean (confidence interval 95%)
    -0.9 (-2.7 to 0.8)
    0.9 (-0.7 to 2.5)
    Statistical analysis title
    		 Slope of calculated GFR
    Statistical analysis description
    Slope difference (sirolimus [SRL] minus tacrolimus [TAC]). Random coefficient model with GFR as the dependent variable and study day as the independent variable.
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.131
    Method
    		 Random coefficient model
    Parameter type
    		 Slope difference (SRL-TAC)
    Point estimate
    -1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.2
         upper limit
    		 0.5

    Secondary: Serum Creatinine (On-Therapy Analysis)

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    End point title
    		 Serum Creatinine (On-Therapy Analysis)
    End point description
    Serum creatinine was measured in micromillimoles per liter (mcmol/L). Baseline was defined as the last nonmissing assessment before or on the date of the first dose of test article. On-Therapy Population: all subjects who remained on assigned study therapy up to the point of discontinuation. n=number of subjects assessed for the specified parameter at a given visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12, 18, and 24
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: mcmol/L
    arithmetic mean (standard deviation)
        Baseline (n=131,123)
    118.3 ( 24.8 )
    117.7 ( 27.9 )
        Month 6 (n=125,120)
    113.9 ( 27.6 )
    117 ( 28.2 )
        Month 12 (n=109,116)
    119.6 ( 37.5 )
    109.4 ( 24.6 )
        Month 18 (n=99,111)
    116.9 ( 37.5 )
    114.2 ( 30.4 )
        Month 24 (n=86,109)
    122.9 ( 48.8 )
    117.5 ( 42.8 )
    No statistical analyses for this end point

    Secondary: Change From Randomization in Serum Creatinine (On-Therapy Analysis)

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    End point title
    		 Change From Randomization in Serum Creatinine (On-Therapy Analysis)
    End point description
    Serum creatinine was measured in mcmol/L. Baseline was defined as the last assessment prior to first administration of study drug. On-Therapy Population: all subjects who remained on assigned study therapy up to the point of discontinuation. n=number of subjects assessed for the specified parameter at a given visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12, 18, and 24
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: mcmol/L
    arithmetic mean (standard error)
        Month 6 (n=125,120)
    -4.1 ( 2 )
    0 ( 1.4 )
        Month 12 (n=109,116)
    -0.3 ( 2.9 )
    -7 ( 1.9 )
        Month 18 (n=99,111)
    -3 ( 2.5 )
    -1.9 ( 2.3 )
        Month 24 (n=86,109)
    3.2 ( 4.6 )
    0.5 ( 3.7 )
    Statistical analysis title
    		 Change from randomization at Month 6
    Statistical analysis description
    ANCOVA with treatment as a factor and baseline serum creatinine as a covariate.
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.105 [13]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -3.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.6
         upper limit
    		 0.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.4
    Notes
    [13] - Alpha was unadjusted.
    Statistical analysis title
    		 Change from randomization at Month 12
    Statistical analysis description
    ANCOVA with treatment as a factor and baseline serum creatinine as a covariate.
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.023 [14]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    7.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 14.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.3
    Notes
    [14] - Alpha was unadjusted.
    Statistical analysis title
    		 Change from randomization at Month 18
    Statistical analysis description
    ANCOVA with treatment as a factor and baseline serum creatinine as a covariate.
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.955 [15]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.8
         upper limit
    		 6.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4
    Notes
    [15] - Alpha was unadjusted.
    Statistical analysis title
    		 Change from randomization at Month 24
    Statistical analysis description
    ANCOVA with treatment as a factor and baseline serum creatinine as a covariate.
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.582 [17]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.2
         upper limit
    		 14.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.8
    Notes
    [16] - Change from randomization at Month 24. ANCOVA with treatment as a factor and baseline serum creatinine as a covariate.
    [17] - Alpha was unadjusted.

    Secondary: Percentage of Subjects With Biopsy-Confirmed Acute Rejection (BCAR), Graft Loss, or Death From Randomization to 24 Months Post-Transplantation

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    End point title
    		 Percentage of Subjects With Biopsy-Confirmed Acute Rejection (BCAR), Graft Loss, or Death From Randomization to 24 Months Post-Transplantation
    End point description
    Biopsy-confirmed acute rejection was defined according to updated Banff criteria (2007) for renal allograft rejection. Graft loss was defined as physical loss (nephrectomy or retransplantation), functional loss (requiring dialysis for greater than or equal to [≥]56 days with no return of graft function), or death. ITT Population.
    End point type
    Secondary
    End point timeframe
    Post-randomization to Month 24 post-transplantation
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: percentage of subjects
        number (not applicable)
    11.5
    2.4
    Statistical analysis title
    		 Randomization to 24 Months
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.006 [19]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [18] - Alpha was unadjusted.
    [19] - Alpha was unadjusted.

    Secondary: Percentage of Subjects With Graft Loss (Including Death) at 12 and 24 Months Post-Randomization

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    End point title
    		 Percentage of Subjects With Graft Loss (Including Death) at 12 and 24 Months Post-Randomization
    End point description
    Graft loss was defined as physical loss (nephrectomy or retransplantation), functional loss (requiring dialysis for ≥56 days with no return of graft function), or death. ITT Population
    End point type
    Secondary
    End point timeframe
    Post-randomization to Months 12 and 24 Post-Transplantation
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: percentage of subjects
    number (not applicable)
        Month 12
    0.8
    0
        Month 24
    3.8
    0.8
    Statistical analysis title
    		 Post-randomization to Month 12
    Statistical analysis description
    Post-randomization to Month 12 Post-transplantation.
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [20]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [20] - Alpha was unadjusted.
    Statistical analysis title
    		 Post-randomization to Month 24
    Statistical analysis description
    Post-randomization to Month 24 post-transplantation.
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.215 [22]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [21] - Post-randomization to Month 24 post-transplantation. Alpha was unadjusted.
    [22] - Alpha was unadjusted.

    Secondary: Percentage of Subjects With BCAR Post-Randomization to 6, 12, 18, and 24 Months Post-Transplantation

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    End point title
    		 Percentage of Subjects With BCAR Post-Randomization to 6, 12, 18, and 24 Months Post-Transplantation
    End point description
    BCAR was defined according to updated Banff criteria (2007) for renal allograft rejection. ITT Population.
    End point type
    Secondary
    End point timeframe
    Post-Randomization to 6, 12, 18, and 24 months Post-Transplantation
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: Subjects
    number (not applicable)
        Month 6
    1.5
    0
        Month 12
    5.3
    0.8
        Month 18
    6.9
    1.6
        Month 24
    8.4
    1.6
    Statistical analysis title
    		 BCAR at Month 6
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.499 [23]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [23] - Alpha was unadjusted.
    Statistical analysis title
    		 BCAR at Month 12
    Comparison groups
    Tacrolimus v Sirolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.067 [24]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [24] - Alpha was unadjusted.
    Statistical analysis title
    		 BCAR at Month 18
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.061 [25]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [25] - Alpha was unadjusted
    Statistical analysis title
    		 BCAR at Month 24
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02 [26]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [26] - Alpha was unadjusted

    Secondary: Percentage of Subjects With First On-Therapy BCAR From Transplantation Occurring at 12 and 24 Months

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    End point title
    		 Percentage of Subjects With First On-Therapy BCAR From Transplantation Occurring at 12 and 24 Months
    End point description
    Defined as the first BCAR occurring during the On-Therapy period based on the ITT population. Time to first BCAR was the days from transplantation to the date of BCAR. ITT Population.
    End point type
    Secondary
    End point timeframe
    Months 12 and 24
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: percentage of subjects
    number (not applicable)
        Month 12
    5.1
    0
        Month 24
    9.3
    0.9
    No statistical analyses for this end point

    Secondary: Number of Subjects With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant

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    End point title
    		 Number of Subjects With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant
    End point description
    BCAR was categorized as antibody-mediated (AM) or T-cell. AM BCAR severity was graded as Grade I (mild), Grade II (moderate), and Grade III (severe). T-cell BCAR severity was graded as 'Grade Ia, Ib (mild), Grade IIa, IIb (moderate), and Grade III (severe). If a Subject had both T-cell BCAR and antibody-mediated BCAR on the first rejection, the subject was counted in each category. ITT Population.
    End point type
    Secondary
    End point timeframe
    Months 6, 12, 18, and 24
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: subjects
    number (not applicable)
        Month 6, AM Grade I
    0
    0
        Month 6, AM Grade II
    0
    0
        Month 6, AM Grade III
    0
    0
        Month 6, T-cell Grade Ia, Ib
    2
    0
        Month 6, T-cell Grade IIa, IIb
    0
    0
        Month 6, T-cell Grade III
    0
    0
        Month 12, AM Grade I
    1
    0
        Month 12, AM Grade II
    0
    0
        Month 12, AM Grade III
    1
    0
        Month 12, T-cell Grade Ia, Ib
    5
    0
        Month 12, T-cell Grade IIa, IIb
    1
    1
        Month 12, T-cell Grade III
    0
    0
        Month 18, AM Grade I
    1
    1
        Month 18, AM Grade II
    0
    0
        Month 18, AM Grade III
    1
    0
        Month 18, T-cell Grade Ia, Ib
    7
    1
        Month 18, T-cell Grade IIa, IIb
    1
    1
        Month 18, T-cell Grade III
    0
    0
        Month 24, AM Grade I
    2
    1
        Month 24, AM Grade II
    1
    0
        Month 24, AM Grade III
    1
    0
        Month 24, T-cell Grade Ia, Ib
    8
    1
        Month 24, T-cell Grade IIa, IIb
    1
    1
        Month 24, T-cell Grade III
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Antibody Use in Treatment of Acute Rejection

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    End point title
    		 Percentage of Subjects With Antibody Use in Treatment of Acute Rejection
    End point description
    Number of subjects who experienced an adverse event (AE) of rejection was used as the denominator in the determination of percentage of subjects with antibody use in treatment of acute rejection. Safety Population; only subjects with an AE of rejection were included in the analysis.
    End point type
    Secondary
    End point timeframe
    On Therapy Period (up to 21 months post-randomization) and Off-Therapy Period (up to 24 months post-transplantation)
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    15
    4
    Units: percentage of subjects
    number (not applicable)
        On-therapy Period
    60
    50
        Off-therapy Period
    40
    25
    Statistical analysis title
    		 On-therapy Period
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [27]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [27] - Alpha was unadjusted.
    Statistical analysis title
    		 Off-therapy Period
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [28]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [28] - Alpha was unadjusted.

    Secondary: Percentage of Subjects With Anemia, Thrombocytopenia, or Leukopenia

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    End point title
    		 Percentage of Subjects With Anemia, Thrombocytopenia, or Leukopenia
    End point description
    Anemia was defined as hemoglobin less than or equal to (≤)10 grams per deciliter (g/dL); leukopenia was defined as white blood cell (WBC) count ≤2000 per cubic millimeters (/mm^3); and thrombocytopenia was defined as platelets ≤100,000/mm^3. Baseline was defined as the last nonmissing assessment before or on the date of the first dose of test article. Safety Population; n=number of subjects assessed for the specified parameter at a given visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12 and 24
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    122
    Units: percentage of subjects
    number (not applicable)
        Baseline (n=131,122)
    4.6
    1.6
        Month 12 (n=110,116)
    9.1
    2.6
        Month 24 (n=89,112)
    3.4
    4.5
    Statistical analysis title
    		 Baseline
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.284 [29]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [29] - Alpha was unadjusted.
    Statistical analysis title
    		 Month 12
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.046 [30]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [30] - Alpha was unadjusted.
    Statistical analysis title
    		 Month 24
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [31]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [31] - Alpha was unadjusted.

    Secondary: Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L])

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    End point title
    		 Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L])
    End point description
    Parameters assessed included total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C); collected when subject was in a fasting state. Safety Population; n=number of subjects assessed for the specified parameter at a given visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12 and 24
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    96
    107
    Units: units: mmol/L
    arithmetic mean (standard error)
        TC, Change at Month 12 (n=96,107)
    0.66 ( 0.1 )
    -0.12 ( 0.07 )
        TC, Change at Month 24 (n=74,88)
    0.51 ( 0.14 )
    -0.08 ( 0.09 )
        HDL-C, Change at Month 12 (n=90,99)
    0 ( 0.03 )
    0.01 ( 0.02 )
        HDL-C, Change at Month 24 (n=69,81)
    0.01 ( 0.04 )
    0.01 ( 0.03 )
        LDL-C, Change at Month 12 (n=87,98)
    0.43 ( 0.09 )
    -0.06 ( 0.07 )
        LDL-C, Change at Month 24 (n=66,78)
    0.34 ( 0.13 )
    -0.06 ( 0.08 )
        Triglycerides, Change at Month 12 (n=94,104)
    0.47 ( 0.11 )
    -0.18 ( 0.07 )
        Triglycerides, Change at Month 24 (n=73,86)
    0.43 ( 0.1 )
    0.07 ( 0.12 )
    Attachments
    		 Statistical analysis
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimulating Agents (ESAs)

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    End point title
    		 Percentage of Subjects Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimulating Agents (ESAs)
    End point description
    ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12 and 24
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: percentage of subjects
    number (not applicable)
        Baseline, Anti-hypertensives
    95.4
    92.7
        Month 12, Anti-hypertensives
    75.6
    69.9
        Month 24, Anti-hypertensives
    61.8
    65.9
        Baseline, Diabetes agents (insulin)
    46.6
    47.2
        Month 12, Diabetes agents (insulin)
    26
    26
        Month 24, Diabetes agents (insulin)
    18.3
    25.2
        Baseline, Diabetes agents (non-insulin)
    14.5
    17.9
        Month 12, Diabetes agents (non-insulin)
    10.7
    13.8
        Month 24, Diabetes agents (non-insulin)
    9.2
    13
        Baseline, Lipid-lowering agents
    46.6
    60.2
        Month 12, Lipid-lowering agents
    55.7
    54.5
        Month 24, Lipid-lowering agents
    47.3
    49.6
        Baseline, ESAs
    50.4
    43.1
        Month 12, ESAs
    7.6
    2.4
        Month 24, ESAs
    3.8
    2.4
    Statistical analysis title
    		 Anti-hypertensives, Baseline
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.429 [32]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [32] - Alpha was unadjusted.
    Statistical analysis title
    		 Anti-hypertensives, Month 12
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.326 [33]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [33] - Alpha was unadjusted.
    Statistical analysis title
    		 Anti-hypertensives, Month 24
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.517 [34]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [34] - Alpha was unadjusted.
    Statistical analysis title
    		 Diabetes agents (insulin), Baseline
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [35]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [35] - Alpha was unadjusted.
    Statistical analysis title
    		 Diabetes agent (insulin), Month 12
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [36]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [36] - Alpha was unadjusted.
    Statistical analysis title
    		 Diabetes agent (non-insulin), Baseline
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.498 [37]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [37] - Alpha was unadjusted.
    Statistical analysis title
    		 Diabetes agent (non-insulin), Month 12
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.566 [38]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [38] - Alpha was unadjusted.
    Statistical analysis title
    		 Diabetes agent (non-insulin), Month 24
    Statistical analysis description
    Diabetes agent (non-insulin), Month 24.
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.423 [39]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [39] - Alpha was unadjusted.
    Statistical analysis title
    		 Lipid-lowering agents, Baseline
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.033 [40]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [40] - Alpha was unadjusted.
    Statistical analysis title
    		 Lipid-lowering agents, Month 12
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9 [41]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [41] - Alpha was unadjusted.
    Statistical analysis title
    		 Lipid-lowering agents, Month 24
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.802 [42]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [42] - Alpha was unadjusted.
    Statistical analysis title
    		 ESAs, Baseline
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.26 [43]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [43] - Alpha was unadjusted.
    Statistical analysis title
    		 ESAs, Month 12
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.086 [44]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [44] - Alpha was unadjusted.
    Statistical analysis title
    		 ESAs, Month 24
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.723 [45]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [45] - Alpha was unadjusted.

    Secondary: Spot and 24 Hour Urine Protein to Creatinine Ratio (UPr/Cr)

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    End point title
    		 Spot and 24 Hour Urine Protein to Creatinine Ratio (UPr/Cr)
    End point description
    Baseline was defined as the last nonmissing assessment before or on the date of the first dose of test article. Safety Population; n=number of subjects assessed for the specified parameter at a given visit.
    End point type
    Secondary
    End point timeframe
    Baseline and Months 12 and 24
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    127
    120
    Units: UPr/Cr
    arithmetic mean (standard deviation)
        Baseline (n=127,120)
    0.18 ( 0.1413 )
    0.195 ( 0.1477 )
        Month 12 (n=112,108)
    0.353 ( 0.3677 )
    0.208 ( 0.2234 )
        Month 24 (n=102,106)
    0.51 ( 0.7887 )
    0.3 ( 0.6154 )
    Statistical analysis title
    		 Change from pre-randomization at Month 12
    Statistical analysis description
    Treatment ratio (SRC/TAC) in adjusted geometric mean fold-change from baseline. ANCOVA model with change in the logarithmic Upr/Cr as dependent variable, treatment and logarithmic pre-randomization value as covariate.
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [46]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment ratio
    Point estimate
    1.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.38
         upper limit
    		 2.11
    Notes
    [46] - Alpha was unadjusted.
    Statistical analysis title
    		 Change from pre-randomization at Month 24
    Statistical analysis description
    Treatment ratio (SRC/TAC) in adjusted geometric mean fold-change from baseline. ANCOVA model with change in the logarithmic Upr/Cr as dependent variable, treatment and logarithmic pre-randomization value as covariate.
    Comparison groups
    Tacrolimus v Sirolimus
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [47]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment ratio
    Point estimate
    1.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.39
         upper limit
    		 2.26
    Notes
    [47] - Alpha was unadjusted.

    Secondary: Percentage of Subjects With Angiotensin Converting Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Block (ARB) Use

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    End point title
    		 Percentage of Subjects With Angiotensin Converting Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Block (ARB) Use
    End point description
    Included ACEI or ARB use prior to randomization, during the on-therapy period (up to 19 to 21 months post randomization) and the off-therapy period (up to 24 months post-transplantation). ITT Population.
    End point type
    Secondary
    End point timeframe
    Pre-randomization, On-Therapy Period (up to 21 months post-randomization), and Off-Therapy Period (up to 24 months post-transplantation)
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: percentage of subjects
    number (not applicable)
        Pre-randomization
    46.6
    46.3
        On-Therapy Period
    43.5
    29.3
        Off-Therapy Period
    32.1
    18.7
    Statistical analysis title
    		 Pre-randomization
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [48]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [48] - Alpha was unadjusted.
    Statistical analysis title
    		 On-Therapy Period
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02 [49]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [49] - Alpha was unadjusted.
    Statistical analysis title
    		 Off-Therapy Period
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.021 [50]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [50] - Alpha was unadjusted.

    Secondary: Percentage of Subjects With Stomatitis

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    End point title
    		 Percentage of Subjects With Stomatitis
    End point description
    Includes adverse events based on categorization by the investigator as stomatitis, regardless of the event preferred term in Medical Dictionary for Regulatory Activities (MedDRA). Safety Population.
    End point type
    Secondary
    End point timeframe
    From randomization up to 24 months after transplantation (On-Therapy)
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: percentage of subjects
        number (not applicable)
    28.2
    1.6
    Statistical analysis title
    		 Subjects with Stomatitis
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [51]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [51] - Alpha was unadjusted.

    Secondary: Percentage of Subjects Requiring Treatment for Stomatitis by Treatment Type

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    End point title
    		 Percentage of Subjects Requiring Treatment for Stomatitis by Treatment Type
    End point description
    Included treatments (analgesics, dental paste, topical antifungal, topical steroids, or other) prior to randomization, during the on-therapy period (up to 19 to 21 months post-randomization) and the off-therapy period (up to 24 months post-transplantation). ITT Population
    End point type
    Secondary
    End point timeframe
    On-Therapy Period (up to 21 months post-randomization) and Off-Therapy Period (up to 24 months post-transplantation).
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: percentage of subjects
    number (not applicable)
        On-Therapy Period, any treatment
    17.6
    2.4
        Off-Therapy Period, any treatment
    3.1
    1.6
        On-Therapy, analgesics
    0.8
    0
        On-Therapy, dental paste
    3.8
    0.8
        On-Therapy, topical steroids
    5.3
    0
        On-Therapy, other
    10.7
    2.4
        Off-Therapy, topical steroids
    1.5
    0
        Off-Therapy, other
    1.5
    1.6
    Statistical analysis title
    		 On-Therapy Period
    Statistical analysis description
    On-Therapy Period, any treatment.
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [52]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [52] - Alpha was unadjusted.
    Statistical analysis title
    		 Off-Therapy Period
    Statistical analysis description
    Off-Therapy Period, any treatment.
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.685 [53]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [53] - Alpha was unadjusted.

    Secondary: Change From Pre-Randomization to 12 Months Post-Transplantation in Hemoglobin A1C (Liter Per Liter [L/L])

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    End point title
    		 Change From Pre-Randomization to 12 Months Post-Transplantation in Hemoglobin A1C (Liter Per Liter [L/L])
    End point description
    Ratio of hemoglobin A1c to normal hemoglobin. Safety Population.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    86
    98
    Units: L/L
        arithmetic mean (standard error)
    0 ( 0 )
    0 ( 0 )
    Attachments
    		 Statistical analysis
    No statistical analyses for this end point

    Secondary: Change From Pre-Randomization to 12 Months Post-Transplantation in Fasting Glucose (mmol/L)

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    End point title
    		 Change From Pre-Randomization to 12 Months Post-Transplantation in Fasting Glucose (mmol/L)
    End point description
    Safety Population.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    101
    112
    Units: mmol
        arithmetic mean (standard error)
    -0.5 ( 0.31 )
    -0.23 ( 0.2 )
    Attachments
    		 Statistical attachment
    No statistical analyses for this end point

    Secondary: Change From Pre-Randomization to 12 Months Post-Transplantation in Fasting Insulin (Picomoles Per Liter [Pmol/L])

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    End point title
    		 Change From Pre-Randomization to 12 Months Post-Transplantation in Fasting Insulin (Picomoles Per Liter [Pmol/L])
    End point description
    Safety Population.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    71
    84
    Units: pmol/L
        arithmetic mean (standard error)
    27.25 ( 21.97 )
    17.14 ( 11.85 )
    Attachments
    		 Statistical analysis
    No statistical analyses for this end point

    Secondary: Change From Pre-Randomization to 12 Months Post-Transplantation in Weight (Kilograms [kg])

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    End point title
    		 Change From Pre-Randomization to 12 Months Post-Transplantation in Weight (Kilograms [kg])
    End point description
    Safety Population.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    104
    113
    Units: kg
        arithmetic mean (standard error)
    1.61 ( 0.51 )
    2.03 ( 0.44 )
    Attachments
    		 Statistical analysis
    No statistical analyses for this end point

    Secondary: Change From Pre-Randomization to 12 Months Post-Transplantation in Waist Circumference(Centimeters [cm])

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    End point title
    		 Change From Pre-Randomization to 12 Months Post-Transplantation in Waist Circumference(Centimeters [cm])
    End point description
    Safety Population.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    98
    105
    Units: cm
        arithmetic mean (standard error)
    1.13 ( 0.73 )
    2.21 ( 1 )
    Attachments
    		 Statistical analysis
    No statistical analyses for this end point

    Secondary: Change From Pre-Randomization to 12 Months Post-Transplantation in Homeostasis Model Assessment Insulin Resistance (HOMA-IR; Fasting)

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    End point title
    		 Change From Pre-Randomization to 12 Months Post-Transplantation in Homeostasis Model Assessment Insulin Resistance (HOMA-IR; Fasting)
    End point description
    The HOMA-IR measures insulin resistance based on fasting glucose and insulin measurements: HOMA-IR = fasting plasma glucose (mmol/L) multiplied by (*) fasting plasma insulin in microunits per liter (µU/L) divided by (/) 22.5. Subjects taking insulin within 12 hours were excluded from the analysis. Safety Population.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    66
    77
    Units: insulin resistance score
        arithmetic mean (standard error)
    1.14 ( 1.37 )
    1.1 ( 0.7 )
    Attachments
    		 Statistical analysis
    No statistical analyses for this end point

    Secondary: Change From Pre-Randomization to 12 Months Post-Transplantation in HOMA-Beta Cell (HOMA-B; Fasting)

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    End point title
    		 Change From Pre-Randomization to 12 Months Post-Transplantation in HOMA-Beta Cell (HOMA-B; Fasting)
    End point description
    The Homeostasis Model Assessment (HOMA) estimates steady state beta cell function (%B) as a percentage of a normal reference population. HOMA-B = 20 * insulin (µU/L) / fasting plasma glucose (mmol/L) minus (-) 3.5 Subjects taking insulin within 12 hours were excluded from the analysis. Safety Population.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    66
    77
    Units: percentage beta cell function
        arithmetic mean (standard error)
    230.23 ( 214.68 )
    26.05 ( 21.99 )
    Attachments
    		 Statistical analysis
    No statistical analyses for this end point

    Secondary: Change From Pre-Randomization to 12 Months Post-Transplantation in Body Mass Index (BMI; in Kilograms Per Square Meter [kg/m^2])

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    End point title
    		 Change From Pre-Randomization to 12 Months Post-Transplantation in Body Mass Index (BMI; in Kilograms Per Square Meter [kg/m^2])
    End point description
    BMI = Weight (kg)/(Height*Height) (square meters [m^2]). Safety Population.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    101
    109
    Units: kg/m^2
        arithmetic mean (standard error)
    0.53 ( 0.18 )
    0.75 ( 0.15 )
    Attachments
    		 Statistical analysis
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With New-Onset Diabetes

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    End point title
    		 Percentage of Subjects With New-Onset Diabetes
    End point description
    Subjects were considered as having new onset diabetes during the On-therapy period if any of the below events emerged from baseline to Month 24: 1) at least 30 days continuous, or at least 25 days non-stop (without gap) use of any diabetic treatment after randomization; 2) a fasting glucose greater than or equal to (≥)126 milligrams per deciliter (mg/dL) after randomization; or 3) a non-fasting glucose ≥200 mg/dL after randomization, were included in the new-onset diabetes population. Events at Months 12 or 24 occurred from baseline to On-therapy Month 12 and from On-therapy Months 12 to 24, respectively. Safety Population. n=number of subjects assessed for the specified parameter at a given visit.
    End point type
    Secondary
    End point timeframe
    From Baseline to On-Therapy Month 12, from Baseline to On-Therapy Month 24, and from On-Therapy Month 12 up to On-Therapy Month 24
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    82 [54]
    72 [55]
    Units: percentage of subjects
    number (not applicable)
        New onset (n=82,72)
    18.3
    5.6
        New onset at 1 year (n=82,72)
    14.6
    2.8
        New onset at 2 years (n=70,70)
    4.3
    2.9
    Notes
    [54] - Number of subjects analyzed
    [55] - Number of subjects analyzed
    Statistical analysis title
    		 From Baseline up to On-Therapy Month 24
    Statistical analysis description
    New onset (from baseline up to On-Therapy Month 24).
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.025 [56]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [56] - Alpha was unadjusted.
    Statistical analysis title
    		 From Baseline up to On-Therapy Month 12
    Statistical analysis description
    New onset at 1 year (from baseline up to On-Therapy Month 12).
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012 [57]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [57] - Alpha was unadjusted.
    Statistical analysis title
    		 From On-Therapy Month 12 to On-Therapy Month 24
    Statistical analysis description
    New onset at 2 years (from On-Therapy Month 12 to On-Therapy Month 24).
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [58]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [58] - Alpha was unadjusted.

    Secondary: Percentage of Subjects With New-Onset Diabetes Receiving Treatment for Diabetes (Insulin and Non-Insulin)

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    End point title
    		 Percentage of Subjects With New-Onset Diabetes Receiving Treatment for Diabetes (Insulin and Non-Insulin)
    End point description
    Subjects were considered as having new onset diabetes during the On-therapy period if any of the below events emerged between baseline and Month 12 or Month 24: 1) at least 30 days continuous, or at least 25 days non-stop (without gap) use of any diabetic treatment after randomization; 2) a fasting glucose ≥126 mg/dL after randomization; or 3) a non-fasting glucose ≥200 mg/dL after randomization. Safety Population. Only subjects with new-onset diabetes mellitus at the beginning of the analysis interval were included; those with pre-existing diabetes were excluded from the analysis.
    End point type
    Secondary
    End point timeframe
    12 Months and 24 Months
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    15
    4
    Units: percentage of subjects
    number (not applicable)
        Insulin (12-Month)
    13.3
    0
        Insulin (24-Month)
    6.7
    25
        Non-insulin (12-Month)
    13.3
    0
        Non-Insulin (24-Month)
    13.3
    0
    Statistical analysis title
    		 Insulin (12-Month)
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [59]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [59] - Alpha was unadjusted.
    Statistical analysis title
    		 Non-insulin (12-Month)
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [60]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [60] - Alpha was unadjusted.
    Statistical analysis title
    		 Non-insulin (24-Month)
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.386 [61]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [61] - Alpha was unadjusted.
    Statistical analysis title
    		 Insulin (24-Month)
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [62]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [62] - Alpha was unadjusted.

    Secondary: Percentage of Subjects With Infection

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    End point title
    		 Percentage of Subjects With Infection
    End point description
    Includes adverse events based on categorization by the investigator as 'infection', regardless of the event preferred term in MedDRA. Safety Population.
    End point type
    Secondary
    End point timeframe
    From randomization up to 24 months after transplantation (On-Therapy)
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: percentage of subjects
        number (not applicable)
    61.8
    52
    Statistical analysis title
    		 Subjects with infection
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.129
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Percentage of Subjects With Cytomegalovirus (CMV) Infection

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    End point title
    		 Percentage of Subjects With Cytomegalovirus (CMV) Infection
    End point description
    Includes adverse event terms reported by the investigator to be attributed to the organism 'cytomegalovirus', regardless of the preferred term in MedDRA. Safety Population.
    End point type
    Secondary
    End point timeframe
    From randomization up to 24 months after transplantation (On-Therapy)
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: percentage of subjects
        number (not applicable)
    3.1
    3.3
    Statistical analysis title
    		 Subjects with CMV infection
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Percentage of Subjects With Polyomavirus Infection

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    End point title
    		 Percentage of Subjects With Polyomavirus Infection
    End point description
    Includes adverse event terms reported by the investigator to be attributed to the organism 'polyomavirus', regardless of the preferred term in MedDRA. Safety Population
    End point type
    Secondary
    End point timeframe
    From randomization up to 24 months after transplantation (On-Therapy)
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: percentage of subjects
        number (not applicable)
    3.8
    7.3
    Statistical analysis title
    		 Subjects with Polyomavirus Infection
    Comparison groups
    Tacrolimus v Sirolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.276
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Percentage of Subjects With Malignancy

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    End point title
    		 Percentage of Subjects With Malignancy
    End point description
    Includes any adverse events based on categorization by the investigator as 'malignancy', regardless of the event preferred term in MedDRA. Safety Population.
    End point type
    Secondary
    End point timeframe
    From randomization up to 24 months after transplantation (On-Therapy)
    End point values
    		 Sirolimus Tacrolimus
    Number of subjects analysed
    131
    123
    Units: percentage of subjects
        number (not applicable)
    3.1
    7.3
    Statistical analysis title
    		 Subjects With Malignancy
    Comparison groups
    Sirolimus v Tacrolimus
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.158
    Method
    		 Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization up to 24 months after transplantation (plus [+]4 weeks) for adverse events (AEs) and serious AEs (SAEs).
    Adverse event reporting additional description
    The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    v16.0
    Reporting groups
    Reporting group title
    Sirolimus
    Reporting group description
    		 Subjects received tacrolimus (extended-release formulation not permitted) within 30 days of transplant, dosed according to center’s standard of care. At 3-5 months post-transplant, participants were randomized, tacrolimus was discontinued (withdrawal was to be completed within 2 weeks [maximum of 4 weeks] of sirolimus initiation) and participants received sirolimus tablets, orally, at a dose to achieve trough levels of 7-15 nanograms per milliliter (ng/mL) during the first year post-transplant, then 5-15 ng/mL. subjects remained on an inosine monophosphate dehydrogenase (IMPDH) inhibitor (mycophenolate mofetil [MMF] or mycophenolate sodium [MPS]; switching between the two was permitted). Corticosteroids were maintained at a minimum of 2.5 milligrams per day (mg/day) of prednisone (or equivalent); withdrawal was prohibited after randomization. subjects received study drug during the post-randomization period for up to a maximum of 18 months post-transplant.

    Reporting group title
    Tacrolimus
    Reporting group description
    		 Subjects received tacrolimus (extended-release formulation not permitted) within 30 days of transplant, dosed according to center’s standard of care. At 3-5 months post-transplant, participants were randomized and tacrolimus continued. Subjects remained on an IMPDH inhibitor (MMF or MPS; switching between the two was permitted). Corticosteroids were maintained at a minimum of 2.5 mg/day of prednisone (or equivalent); withdrawal was prohibited after randomization. Subjects received study drug during the post-randomization period for up to a maximum of 18 months post-transplant.

    Serious adverse events
    		 Sirolimus Tacrolimus
    Total subjects affected by serious adverse events
         subjects affected / exposed
    50 / 131 (38.17%)
    38 / 123 (30.89%)
         number of deaths (all causes)
    4
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 131 (0.76%)
    3 / 123 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm of unknown primary site
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Metastatic uterine cancer
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 131 (0.00%)
    4 / 123 (3.25%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 131 (1.53%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Granuloma
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 131 (1.53%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudopolyp
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 131 (3.05%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney transplant rejection
         subjects affected / exposed
    3 / 131 (2.29%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant rejection
         subjects affected / exposed
    11 / 131 (8.40%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    5 / 13
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 131 (0.76%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immunosuppressant drug level increased
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    1 / 131 (0.76%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft dysfunction
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 131 (1.53%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polycythaemia
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 131 (0.76%)
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flatulence
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingivitis ulcerative
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal artery stenosis
         subjects affected / exposed
    3 / 131 (2.29%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst ruptured
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 131 (0.76%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 131 (0.00%)
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vesicoureteric reflux
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperparathyroidism tertiary
         subjects affected / exposed
    0 / 131 (0.00%)
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site infection
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis staphylococcal
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 131 (0.76%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    2 / 131 (1.53%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 131 (0.76%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis bacterial
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 131 (4.58%)
    3 / 123 (2.44%)
         occurrences causally related to treatment / all
    4 / 6
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia cryptococcal
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyomavirus-associated nephropathy
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 131 (1.53%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    5 / 131 (3.82%)
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    2 / 10
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 131 (0.00%)
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 131 (0.76%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sirolimus Tacrolimus
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    116 / 131 (88.55%)
    86 / 123 (69.92%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    8 / 131 (6.11%)
    5 / 123 (4.07%)
         occurrences all number
    8
    5
    Weight increased
         subjects affected / exposed
    7 / 131 (5.34%)
    4 / 123 (3.25%)
         occurrences all number
    7
    5
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 131 (8.40%)
    11 / 123 (8.94%)
         occurrences all number
    12
    11
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 131 (12.21%)
    7 / 123 (5.69%)
         occurrences all number
    21
    8
    Tremor
         subjects affected / exposed
    0 / 131 (0.00%)
    8 / 123 (6.50%)
         occurrences all number
    0
    10
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    11 / 131 (8.40%)
    9 / 123 (7.32%)
         occurrences all number
    12
    10
    Polycythaemia
         subjects affected / exposed
    2 / 131 (1.53%)
    7 / 123 (5.69%)
         occurrences all number
    3
    7
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    25 / 131 (19.08%)
    9 / 123 (7.32%)
         occurrences all number
    29
    10
    Pyrexia
         subjects affected / exposed
    13 / 131 (9.92%)
    6 / 123 (4.88%)
         occurrences all number
    23
    6
    Gastrointestinal disorders
    Aphthous stomatitis
         subjects affected / exposed
    13 / 131 (9.92%)
    1 / 123 (0.81%)
         occurrences all number
    17
    1
    Diarrhoea
         subjects affected / exposed
    22 / 131 (16.79%)
    12 / 123 (9.76%)
         occurrences all number
    28
    16
    Mouth ulceration
         subjects affected / exposed
    16 / 131 (12.21%)
    0 / 123 (0.00%)
         occurrences all number
    18
    0
    Nausea
         subjects affected / exposed
    7 / 131 (5.34%)
    9 / 123 (7.32%)
         occurrences all number
    8
    10
    Stomatitis
         subjects affected / exposed
    11 / 131 (8.40%)
    1 / 123 (0.81%)
         occurrences all number
    14
    1
    Vomiting
         subjects affected / exposed
    4 / 131 (3.05%)
    7 / 123 (5.69%)
         occurrences all number
    4
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 131 (6.87%)
    6 / 123 (4.88%)
         occurrences all number
    9
    6
    Oropharyngeal pain
         subjects affected / exposed
    7 / 131 (5.34%)
    3 / 123 (2.44%)
         occurrences all number
    13
    3
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    19 / 131 (14.50%)
    1 / 123 (0.81%)
         occurrences all number
    23
    1
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    19 / 131 (14.50%)
    2 / 123 (1.63%)
         occurrences all number
    24
    2
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    6 / 131 (4.58%)
    9 / 123 (7.32%)
         occurrences all number
    8
    10
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 131 (5.34%)
    6 / 123 (4.88%)
         occurrences all number
    8
    8
    Upper respiratory tract infection
         subjects affected / exposed
    22 / 131 (16.79%)
    13 / 123 (10.57%)
         occurrences all number
    25
    13
    Urinary tract infection
         subjects affected / exposed
    14 / 131 (10.69%)
    8 / 123 (6.50%)
         occurrences all number
    23
    10
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    15 / 131 (11.45%)
    3 / 123 (2.44%)
         occurrences all number
    18
    3
    Hypercholesterolaemia
         subjects affected / exposed
    7 / 131 (5.34%)
    2 / 123 (1.63%)
         occurrences all number
    7
    3
    Hyperglycaemia
         subjects affected / exposed
    8 / 131 (6.11%)
    1 / 123 (0.81%)
         occurrences all number
    10
    1
    Hyperlipidaemia
         subjects affected / exposed
    14 / 131 (10.69%)
    4 / 123 (3.25%)
         occurrences all number
    16
    4
    Hypokalaemia
         subjects affected / exposed
    8 / 131 (6.11%)
    1 / 123 (0.81%)
         occurrences all number
    10
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2009
    Subjects with known allergy to iothalamate or any of its components were excluded from the study because subjects in this trial were required to receive subcutaneous injection of iothalamate for measured renal clearance.
    22 Apr 2010
    1. Instructions for iothalamate testing were added in the protocol. 2. To in line with current clinical practice, updated requirement for PCP prophylaxis to specify that all subjects must have received PCP prophylaxis for 6 months post-transplantation. 3.Clarified requirement for CMV prophylaxis to specify that subjects should have received prophylaxis for CMV infection according to local standard of care.
    24 Feb 2011
    1. Total bilirubin test was added to the blood chemistry profile to be collected at Visits 4, 5, 9, 10, 12, 14, 16 and 98. In addition, any subjects with suspected drug-induced liver injury should have had the following tests performed: albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase (GGT), international normalized ratio (INR), and alkaline phosphatase. 2. Replaced the AE reporting sections of the protocol to reflect Pfizer requirements.
    12 Dec 2011
    1. Revisions were made to change the terminology regarding project specific events that should have been handled as SAEs. 2. Clarified that drug abuse and drug dependency were to be considered AEs and not only signs and symptoms resulting from these. 3. Clarifications were made to SAE reporting requirements throughout the protocol to align with “US Food and Drug Administration Final Rule:” Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans’ dated September 2010 and the European Union “CT-3” guidance dated July 2011: Communication from the Commission Detailed Guidance on the Collection, Verification and Presentation of Adverse Event/Reaction Reports Arising From Clinical Trials on Medicinal Products for Human Use. 4. The criteria for further evaluation for subjects who presented with laboratory abnormalities that might be potentially associated with potential drug-induced liver injury were rewritten to provide greater clarity. The recommended list of repeated laboratory tests was updated to include prothrombin time (PT). 5. Clarified that generally the facts (evidence) or arguments to suggest a causal relationship with an AE should have been provided by the investigator to align with CT-3 guidance. 6. Added a new section to clarify the need for immediate notification if there was a clinical hold or similar issue taken for purposes of safety so that the sponsor was able to fulfill its reporting obligations in accordance with local legislation.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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