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    Clinical Trial Results:
    Inmunosupresión óptima en pacientes con alto riesgo de diabetes de novo tras el trasplante renal: Un estudio prospectivo, multicéntrico, controlado y randomizado

    Summary
    EudraCT number
    		 2008-005617-22
    Trial protocol
    		 ES  
    Global end of trial date
    08 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Oct 2021
    First version publication date
    30 Oct 2021
    Other versions
    Summary report(s)
    		 Publication of the trial

    Trial information

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    Trial identification
    Sponsor protocol code
    01DMPT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01002339
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC)
    Sponsor organisation address
    Bco Ballena s/n, Edificio Anexo Hospital Dr Negrin, Las Palmas de Gran Canaria, Spain, 35019
    Public contact
    Armando Torres Ramírez, Unidad de Investigación. Hospital Universitario de Canarias. Ofra s/n, 38320 La Laguna, Tenerife, 34 630989515, atorres@ull.edu.es
    Scientific contact
    Armando Torres Ramírez, Unidad de Investigación. Hospital Universitario de Canarias. Ofra s/n, 38320 La Laguna, Tenerife, 34 922679123, nlorenzo@fciisc.org
    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
    23 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jun 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Comparar la incidencia de diabetes de novo e intolerancia a la glucosa post-trasplante renal de un régimen inmunosupresor basado en Tacrolimus (Tacro) y supresión rápida de esteroides frente a Tacro o CsA con dosis reducidas de esteroides y supresión a los 6 meses, en pacientes con riesgo elevado de desarrollar DMPT.
    Protection of trial subjects
    This is a Phase 4 RCT and all participants received standard of care to minimize pain and stress. In addition, a Contracted Insurance Policy was operative during the trial.
    Background therapy
    		 Immunosuppressants apart from the calcineurin inhibitor (corticosteroids and mycophenolate mofetil); CMV prophylaxis (valganciclovir), Pneumocystis jirovecii prevention (cotrimoxazole), antihypertensives (RAS inhibitors), lipid-lowering drugs (statins).
    Evidence for comparator
    		 Cyclosporine A (CsA) is less diabetogenic than Tacrolimus, specifically in renal transplant recipients at risk of post-transplant diabetes (older age, insulin resistance phenotype). In addition, early corticosteroid withdrawal has been shown to reduce the incidence of post-transplant diabetes in patients treated with Tacrolimus. We investigated whether CsA or Tacrolimus with rapid steroid withdrawal, are superior in terms of one-year post-transplant incidence of diabetes, than Tacrolimus and corticosteroid minimization.
    Actual start date of recruitment
    23 Feb 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 128
    Worldwide total number of subjects
    128
    EEA total number of subjects
    128
    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)
    85
    From 65 to 84 years
    43
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eight transplant centers in Spain participated in the study, which began on February 23, 2010. The Safety Committee decided to stop recruitment in the intermediate analysis but continue with the patients already recruited until the end of the study. Therefore, until February 5, 2014, a total of 128 patients were recruited.

    Pre-assignment
    Screening details
    		 -Assessed for eligibility(n = 211): Scheduled delay of CNI initiationn = 51 Logistic problems n = 26 Randomized(n = 134) Excluded: Error in the assigned study medication n = 1; Unjustified change of study medication n = 1; Randomized but not transplanted n = 1; Violation of I.C. n = 3 -Randomized and included (n = 128)

    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
    		 Tac-SW
    Arm description
    		 Tacrolimus-based immunosuppression and rapid steroid withdrawal (SW) within 1 week (Tac-SW) Basiliximab induction. Tacrolimus plus Mycophenolate mofetil (MMF), and corticosteroids with rapid withdrawal after one week.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tacrolimus-based immunosuppresion and rapid steroid withdrawal
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet, Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Tac-SW arm: tacrolimus (Prograf) 0.15 mg/kg per day p.o. in 2 separate doses to maintain trough levels of 8 to 12 ng/ml in the first month, and mycophenolate mofetil (MMF; Cell Cept) 2 g/d p.o. Methyl-prednisolone 0.5 g i.v. intraoperatively and 125 mg on day 1; prednisone 30 mg p.o. on days 2 and 3, 20 mg on day 4, 15 mg on day 5, 10 mg on day 6, 5 mg on day 7, and then discontinuation.

    Arm title
    		 Tac-SM
    Arm description
    		 Tacrolimus with steroids minimization (Tac-SM) Basiliximab induction.Tacrolimus plus Mycophenolate mofetil (MMF) and low-dose corticosteroids for 6 months with subsequent removal
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tacrolimus with Steroid Minimization
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tac-SM arm: tacrolimus and MMF following the same schedule as in arm 1. Intraoperative and day 1 methyl-prednisolone as in arm 1; prednisone 0.3 mg/kg per day p.o. from day 2 to 7 (never >20 mg/d), 0.2 mg/kg per day from day 8 to 14 (never >15 mg/d), 0.15 mg/kg per day from day 15 to 21 (never >10 mg/d), 0.1 mg/kg per day from day 22 to 28 (never >7.5 mg/d), and then 5 mg/d until 5 months, with subsequent gradual discontinuation over 4 weeks.

    Arm title
    		 CsA-SM
    Arm description
    		 CsA with steroid minimization (CsA-SM) Basiliximab induction. Ciclosporin A (CsA) plus Mycophenolate mofetil (MMF) and low-dose corticosteroids for 6 months with subsequent removal
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cyclosporine A with Steroid Minimization
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    CsA-SM arm: Cyclosporine A microemulsion (Neoral) (CsA) 5 mg/kg per day p.o. to maintain C0 levels of 150–200 ng/ml the first month, and MMF and steroids following the same schedule as arm 2.

    Investigational medicinal product name
    Tacrolimus-based immunosuppresion and rapid steroid withdrawal
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tac-SW arm: tacrolimus (Prograf) 0.15 mg/kg per day p.o. in 2 separate doses to maintain trough levels of 8 to 12 ng/ml in the first month, and mycophenolate mofetil (MMF; Cell Cept) 2 g/d p.o. Methyl-prednisolone 0.5 g i.v. intraoperatively and 125 mg on day 1; prednisone 30 mg p.o. on days 2 and 3, 20 mg on day 4, 15 mg on day 5, 10 mg on day 6, 5 mg on day 7, and then discontinuation.

    Number of subjects in period 1
    		Tac-SW Tac-SM CsA-SM
    Started
    44
    42
    42
    Completed
    41
    39
    38
    Not completed
    3
    3
    4
         Adverse event, serious fatal
    2
    1
    2
         Adverse event, non-fatal
    1
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tac-SW
    Reporting group description
    		 Tacrolimus-based immunosuppression and rapid steroid withdrawal (SW) within 1 week (Tac-SW) Basiliximab induction. Tacrolimus plus Mycophenolate mofetil (MMF), and corticosteroids with rapid withdrawal after one week.

    Reporting group title
    Tac-SM
    Reporting group description
    		 Tacrolimus with steroids minimization (Tac-SM) Basiliximab induction.Tacrolimus plus Mycophenolate mofetil (MMF) and low-dose corticosteroids for 6 months with subsequent removal

    Reporting group title
    CsA-SM
    Reporting group description
    		 CsA with steroid minimization (CsA-SM) Basiliximab induction. Ciclosporin A (CsA) plus Mycophenolate mofetil (MMF) and low-dose corticosteroids for 6 months with subsequent removal

    Reporting group values
    		 Tac-SW Tac-SM CsA-SM Total
    Number of subjects
    		 44 42 42 128
    Age categorical
    There were no specific criteria for age in general. All patients from 18 years and over were eligible to participate. However, given the characteristics of renal disease, the participants were subject to the following metabolic inclusion and exclusion criteria inter alia: Age Inclusion Criteria: Recipient age >or =60 or Recipient age between 45 and 59 years and at least one of specific metabolic criteria defined in the criteria section study participants. Age Exclusion Criteria: Recipient age under 45 years.
    Units: Subjects
        18 years and over
    		 44 42 42 128
    Age continuous
    The Overall Number of Baseline Participants was a mean of 61.0 (7.7) years. Attending to the arm assigned mean age was: - Tacrolimus With Rapid Steroid Withdrawal: 61.2 (7.6) years. - Tacrolimus With Steroids Minimization: 61.6 (7.3) years. - CsA With Steroid Minimization: 60.2 (8.3) years.
    Units: years
        arithmetic mean (standard deviation)
    		 61.2 ± 7.6 61.6 ± 7.3 60.2 ± 8.3 -
    Gender categorical
    100% of Participants (128) of whom 27.34% (35) were female and 72.66% (93) were male. Attending to each arm, the average of each gender was: - Tac-SW : Female = 25.0% (11) Male= 75.0% (33) - Tac-SM : Female = 28.6% (12) Male=  71.4% (30) - CsA-SM: Female = 28.6% (12) Male=  71.4% (30)
    Units: Subjects
        Female
    		 11 12 12 35
        Male
    		 33 30 30 93

    End points

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    End points reporting groups
    Reporting group title
    Tac-SW
    Reporting group description
    		 Tacrolimus-based immunosuppression and rapid steroid withdrawal (SW) within 1 week (Tac-SW) Basiliximab induction. Tacrolimus plus Mycophenolate mofetil (MMF), and corticosteroids with rapid withdrawal after one week.

    Reporting group title
    Tac-SM
    Reporting group description
    		 Tacrolimus with steroids minimization (Tac-SM) Basiliximab induction.Tacrolimus plus Mycophenolate mofetil (MMF) and low-dose corticosteroids for 6 months with subsequent removal

    Reporting group title
    CsA-SM
    Reporting group description
    		 CsA with steroid minimization (CsA-SM) Basiliximab induction. Ciclosporin A (CsA) plus Mycophenolate mofetil (MMF) and low-dose corticosteroids for 6 months with subsequent removal

    Primary: New Onset Diabetes After Renal Transplantation

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    End point title
    		 New Onset Diabetes After Renal Transplantation
    End point description
    American Diabetes Association criteria (ADA) including an oral glucose tolerance test.
    End point type
    Primary
    End point timeframe
    1 year
    End point values
    		 Tac-SW Tac-SM CsA-SM
    Number of subjects analysed
    41
    39
    38
    Units: percentage of participants
        number (confidence interval 95%)
    34.1 (21.6 to 49.5)
    23.1 (12.7 to 38.3)
    7.9 (2.7 to 20.8)
    Statistical analysis title
    		 New Onset Diabetes After Renal Transplantation
    Comparison groups
    Tac-SW v Tac-SM v CsA-SM
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Chi-squared
    Confidence interval

    Primary: Patients Treated With Insulin or Oral Antidiabetic Drugs

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    End point title
    		 Patients Treated With Insulin or Oral Antidiabetic Drugs
    End point description
    End point type
    Primary
    End point timeframe
    1 year
    End point values
    		 Tac-SW Tac-SM CsA-SM
    Number of subjects analysed
    41
    39
    38
    Units: percentage of participants
        number (confidence interval 95%)
    20 (10.5 to 34.8)
    15.4 (7.3 to 29.7)
    2.6 (0.5 to 13.5)
    Statistical analysis title
    		 Patients Treated With Insulin or Oral Antidiabetic
    Comparison groups
    Tac-SW v Tac-SM v CsA-SM
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06
    Method
    		 Chi-squared
    Confidence interval

    Primary: Primary Outcome Measure (Glucose Intolerance)

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    End point title
    		 Primary Outcome Measure (Glucose Intolerance)
    End point description
    Glycemia >=140 and <200 mg/dl, 2 hours after a standard oral glucose tolerance test. Measured values: glucose intolerance at 1 year defined by ADA criteria. Participants included are those that did not develop NODAT based on not reporting the use of antidiabetic drugs plus a fasting plasma glucose < 126 mg/dl.
    End point type
    Primary
    End point timeframe
    1 year
    End point values
    		 Tac-SW Tac-SM CsA-SM
    Number of subjects analysed
    26
    29
    30
    Units: percentage of participants
        number (confidence interval 95%)
    26.9 (13.7 to 46.1)
    31 (17.3 to 49.2)
    33.3 (19.2 to 51.2)
    Statistical analysis title
    		 Primary Outcome Measure (Glucose Intolerance)
    Comparison groups
    Tac-SW v Tac-SM v CsA-SM
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Rejection

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    End point title
    		 Rejection
    End point description
    Biopsy proven acute rejection. Measured variable: Rate of Biopsy proven acute rejection.
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Tac-SW Tac-SM CsA-SM
    Number of subjects analysed
    44
    42
    42
    Units: percentage of participants
        number (confidence interval 95%)
    11.4 (4.95 to 24)
    4.8 (1.3 to 15.8)
    21.4 (11.7 to 36)
    Statistical analysis title
    		 Rejection
    Comparison groups
    Tac-SW v Tac-SM v CsA-SM
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.07
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Renal Function

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    End point title
    		 Renal Function
    End point description
    Estimated Glomerular Filtration Rate (ml/min/1.73 m^2)
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Tac-SW Tac-SM CsA-SM
    Number of subjects analysed
    41
    39
    38
    Units: percentage of participants
        number (confidence interval 95%)
    51.9 (45.2 to 58.5)
    47.4 (42.9 to 52.0)
    44.6 (37.8 to 51.3)
    Statistical analysis title
    		 Renal Function
    Comparison groups
    Tac-SW v Tac-SM v CsA-SM
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2
    Method
    		 ANOVA
    Confidence interval

    Secondary: Proteinuria

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    End point title
    		 Proteinuria
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Tac-SW Tac-SM CsA-SM
    Number of subjects analysed
    39
    36
    36
    Units: mg/day
        number (confidence interval 95%)
    208 (121 to 296)
    241 (110 to 373)
    343.2 (154 to 532)
    Statistical analysis title
    		 Proteinuria
    Statistical analysis description
    Participants analyzed: participants living with a functioning graft at study end.
    Comparison groups
    Tac-SW v Tac-SM v CsA-SM
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4
    Method
    		 ANOVA
    Confidence interval

    Secondary: Blood Pressure

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    End point title
    		 Blood Pressure
    End point description
    Systolic pressure (mmHg)
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Tac-SW Tac-SM CsA-SM
    Number of subjects analysed
    39
    39
    36
    Units: mmHg
        arithmetic mean (standard deviation)
    135.36 ± 15.75
    133.97 ± 13.67
    36 ± 17.27
    Statistical analysis title
    		 Blood Pressure
    Comparison groups
    Tac-SW v Tac-SM v CsA-SM
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8
    Method
    		 ANOVA
    Confidence interval

    Secondary: Blood Pressure

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    End point title
    		 Blood Pressure
    End point description
    Diastolic pressure (mmHg)
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Tac-SW Tac-SM CsA-SM
    Number of subjects analysed
    39
    39
    36
    Units: mmHg
        arithmetic mean (standard deviation)
    76.67 ± 8.93
    74.59 ± 9.83
    76.64 ± 10.27
    Statistical analysis title
    		 Blood Pressure
    Statistical analysis description
    Diastolic pressure (mmHg)
    Comparison groups
    Tac-SW v Tac-SM v CsA-SM
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.56
    Method
    		 ANOVA
    Confidence interval

    Secondary: Number of Antihypertensive Drugs Patients Reported Taking.

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    End point title
    		 Number of Antihypertensive Drugs Patients Reported Taking.
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Tac-SW Tac-SM CsA-SM
    Number of subjects analysed
    41
    39
    38
    Units: Number of Antihypertensive Drugs
        median (inter-quartile range (Q1-Q3))
    2 (1 to 3)
    2 (1 to 2)
    2 (1 to 2)
    Statistical analysis title
    		 Number of Antihypertensive Drugs Patients Reported
    Comparison groups
    Tac-SW v Tac-SM v CsA-SM
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: Lipidic Profile (Triglycerides)

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    End point title
    		 Lipidic Profile (Triglycerides)
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Tac-SW Tac-SM CsA-SM
    Number of subjects analysed
    39
    37
    37
    Units: mg/dl
        arithmetic mean (standard deviation)
    159.44 ± 93.68
    145.59 ± 52.97
    160.78 ± 84.26
    Statistical analysis title
    		 Lipidic Profile (Triglycerides)
    Comparison groups
    Tac-SW v Tac-SM v CsA-SM
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.66
    Method
    		 ANOVA
    Confidence interval

    Secondary: Lipidic Profile (Cholesterol)

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    End point title
    		 Lipidic Profile (Cholesterol)
    End point description
    Lipidic Profile (total cholesterol)
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Tac-SW Tac-SM CsA-SM
    Number of subjects analysed
    39
    37
    38
    Units: mg/dl
        arithmetic mean (standard deviation)
    169.05 ± 30.57
    178.24 ± 33.64
    168.89 ± 33.38
    Statistical analysis title
    		 Lipidic Profile (cholesterol)
    Comparison groups
    Tac-SW v Tac-SM v CsA-SM
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 ANOVA
    Confidence interval

    Secondary: Lipidic Profile (HDL-c)

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    End point title
    		 Lipidic Profile (HDL-c)
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Tac-SW Tac-SM CsA-SM
    Number of subjects analysed
    38
    35
    34
    Units: mg/dl
        arithmetic mean (standard deviation)
    44.84 ± 13.89
    49.29 ± 16.90
    48.35 ± 16.59
    Statistical analysis title
    		 Lipidic Profile (HDL-c)
    Comparison groups
    Tac-SW v Tac-SM v CsA-SM
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.45
    Method
    		 ANOVA
    Confidence interval

    Secondary: Lipidic Profile (LDL-c)

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    End point title
    		 Lipidic Profile (LDL-c)
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Tac-SW Tac-SM CsA-SM
    Number of subjects analysed
    37
    35
    34
    Units: mg/dl
        arithmetic mean (standard deviation)
    94.00 ± 27.04
    95.43 ± 26.54
    88.65 ± 25.73
    Statistical analysis title
    		 Lipidic Profile (LDL-c)
    Comparison groups
    Tac-SW v Tac-SM v CsA-SM
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5
    Method
    		 ANOVA
    Confidence interval

    Secondary: Percentage of Patients Using Statins

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    End point title
    		 Percentage of Patients Using Statins
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Tac-SW Tac-SM CsA-SM
    Number of subjects analysed
    41
    39
    38
    Units: percentage of participants
        number (confidence interval 95%)
    56 (41 to 70)
    61.5 (45.9 to 75.1)
    73.7 (58 to 85)
    Statistical analysis title
    		 Percentage of Patients Using Statins
    Comparison groups
    Tac-SW v Tac-SM v CsA-SM
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Changes of Carotid Intima-media Thickness Over Time

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    End point title
    		 Changes of Carotid Intima-media Thickness Over Time
    End point description
    The absolute difference between carotid intima-media thickness at study end versus baseline.
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Tac-SW Tac-SM CsA-SM
    Number of subjects analysed
    9
    8
    10
    Units: mm
        arithmetic mean (confidence interval 95%)
    0.12 (0.09 to 0.15)
    0.04 (-0.15 to 0.23)
    0.01 (-0.01 to 0.03)
    Statistical analysis title
    		 Changes of Carotid Intima-media Thickness Over Tim
    Comparison groups
    Tac-SW v Tac-SM v CsA-SM
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5
    Method
    		 ANOVA
    Confidence interval

    Secondary: Percentage of Patients Using Acetylsalicylic Acid (ASA)

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    End point title
    		 Percentage of Patients Using Acetylsalicylic Acid (ASA)
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Tac-SW Tac-SM CsA-SM
    Number of subjects analysed
    39
    37
    36
    Units: percentage of participants
        number (confidence interval 95%)
    53.9 (38.6 to 68.4)
    48.7 (33.5 to 64.1)
    52.8 (37 to 68)
    Statistical analysis title
    		 Percentage of Patients Using Acetylsalicylic Acid
    Comparison groups
    Tac-SW v Tac-SM v CsA-SM
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Time frame, 1 year.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    2010
    Reporting groups
    Reporting group title
    Tac-SW
    Reporting group description
    		 Tacrolimus-based immunosuppression and rapid steroid withdrawal (SW) within 1 week (Tac-SW) Basiliximab induction. Tacrolimus plus Mycophenolate mofetil (MMF), and corticosteroids with rapid withdrawal after one week Tacrolimus with rapid steroid withdrawal: Tacrolimus 0.15 mg/Kg/day to achieve target trough levels of 8-12 ng/ml for the first month, and MMF 2 gr/day; steroids: 0.5 gr of Methylprednisolone (MP) intraoperatively and 125 mg on the first day, followed by oral doses of prednisone rapidly tapered from 30 mg/day to complete discontinuation by postoperative day 7. Basiliximab induction (4 mg, days 0 and 4).

    Reporting group title
    Tac-SM
    Reporting group description
    		 Tacrolimus with steroids minimization (Tac-SM) Basiliximab induction.Tacrolimus plus Mycophenolate mofetil (MMF) and low-dose corticosteroids for 6 months with subsequent removal. Tacrolimus with steroids minimization: Tacrolimus 0.15 mg/Kg/day to achieve target trough levels of 8-12 ng/ml for the first month, and MMF 2 gr/day; steroids: 0.5 gr of MP intraoperatively and 60 mg day 1; followed by oral doses of prednisone and gradual tapering to complete discontinuation over 6 months. Basiliximab induction (4 mg, days 0 and 4).

    Reporting group title
    CsA-SM
    Reporting group description
    		 CsA with steroid minimization (CsA-SM) Basiliximab induction. Ciclosporin A (CsA) plus Mycophenolate mofetil (MMF) and low-dose corticosteroids for 6 months with subsequent removal. CsA with steroid minimization: CsA 5 mg/Kg/day to achieve target trough of 150-200 ng/ml the first month, and similar pattern with MMF and steroids as group 2. Basiliximab induction (4 mg, days 0 and 4).

    Serious adverse events
    		 Tac-SW Tac-SM CsA-SM
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 44 (18.18%)
    5 / 42 (11.90%)
    12 / 42 (28.57%)
         number of deaths (all causes)
    2
    1
    2
         number of deaths resulting from adverse events
    2
    1
    2
    Cardiac disorders
    Heart Attack resulting in death event
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock resulting in death event
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    1 / 5
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Immune system disorders
    Acute Rejection
         subjects affected / exposed
    5 / 44 (11.36%)
    2 / 42 (4.76%)
    9 / 42 (21.43%)
         occurrences causally related to treatment / all
    5 / 8
    2 / 5
    9 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Graft Loss
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 42 (4.76%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    1 / 8
    2 / 5
    2 / 12
         deaths causally related to treatment / all
    2 / 2
    1 / 1
    2 / 2
    Infections and infestations
    Pneumonia resulting in death
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 5
    1 / 12
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    Sepsis resulting in death event
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
    1 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Tac-SW Tac-SM CsA-SM
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 44 (27.27%)
    17 / 42 (40.48%)
    18 / 42 (42.86%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    2 / 42 (4.76%)
         occurrences all number
    12
    17
    18
    Vascular disorders
    Stroke
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
         occurrences all number
    12
    17
    18
    Cardiac disorders
    Acute Miocardial Infarction or Coronary Revascularization
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    2 / 42 (4.76%)
         occurrences all number
    12
    17
    18
    Infections and infestations
    Acute Pyelonephritis of the graft
         subjects affected / exposed
    2 / 44 (4.55%)
    6 / 42 (14.29%)
    1 / 42 (2.38%)
         occurrences all number
    12
    17
    18
    BK Virus Infection
         subjects affected / exposed
    4 / 44 (9.09%)
    2 / 42 (4.76%)
    3 / 42 (7.14%)
         occurrences all number
    12
    17
    18
    CMV Infection
         subjects affected / exposed
    7 / 44 (15.91%)
    6 / 42 (14.29%)
    12 / 42 (28.57%)
         occurrences all number
    12
    17
    18
    Pneumonia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    1 / 42 (2.38%)
         occurrences all number
    12
    17
    18
    Sepsis
         subjects affected / exposed
    1 / 44 (2.27%)
    5 / 42 (11.90%)
    1 / 42 (2.38%)
         occurrences all number
    12
    17
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Jun 2014
    The recruitment was prematurely stopped for safety reasons
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Mainly white population and of low immunological risk, make the results not representative of other transplant populations. Donor-specific antibody data were not planned in the study designed and thus were not collected for patients with BPAR.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30450457
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