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    Clinical Trial Results:
    6 month, multi-center, open-label, prospective, randomized trial, investigating a standard regimen of an advagraf based immunosuppressive regimen in de-novo renal transplant patients versus a slower dose tapering and lower starting dose of Advagraf

    Summary
    EudraCT number
    		 2013-001770-19
    Trial protocol
    		 DE  
    Global end of trial date
    10 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jan 2026
    First version publication date
    30 Jan 2026
    Other versions
    Summary report(s)
    		 2013-001770-19_Report

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TUD-SplusL-061
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Technische Universität Dresden
    Sponsor organisation address
    Mommsenstraße 11, Dresden, Germany, 01069
    Public contact
    Koordinierungszentrum für Klinische Studien, Medizinische Fakultät C. G. Carus, 0049 351455160, kks@ukdd.de
    Scientific contact
    Koordinierungszentrum für Klinische Studien, Medizinische Fakultät C. G. Carus, 0049 351455160, kks@ukdd.de
    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
    21 Jan 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Nov 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate non-inferiority of biopsy-proven rejection of Banff class Ia or higher and/or graft loss and/or patient death in the study group with slower dose tapering and lower starting dose of Advagraf compared with an standard Advagraf based immunosuppressive regimen.
    Protection of trial subjects
    Regular IDMC meetings to monitor safety.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jul 2014
    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
    Germany: 398
    Worldwide total number of subjects
    398
    EEA total number of subjects
    398
    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)
    293
    From 65 to 84 years
    105
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Screening for patients planned for kidney transplantation in fourteen German transplantation centres.

    Pre-assignment
    Screening details
    		 see inclusion / exclusion criteria.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Slow and low
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    preoperative at day of transplantation: 1 x 5 mg; day 1 (first day after transplantation): 1 x 5 mg; day 2 to 6: 1 x 5 mg.

    Arm title
    		 Standard care
    Arm description
    		 -
    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
    preoperative at day of transplantation: 1x0,2 mg/kg BW; day 1 (first day after transplantation): 1x0,2 mg/kg BW; day 2 to 6: tacrolimus trough levels of 7-9 ng/ml.

    Number of subjects in period 1
    		Slow and low Standard care
    Started
    196
    202
    Completed
    196
    202
    Period 2
    Period 2 title
    Intervention
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Slow and low
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    preoperative at day of transplantation: 1 x 5 mg; day 1 (first day after transplantation): 1 x 5 mg; day 2 to 6: 1 x 5 mg.

    Arm title
    		 Standard care
    Arm description
    		 -
    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
    preoperative at day of transplantation: 1x0,2 mg/kg BW; day 1 (first day after transplantation): 1x0,2 mg/kg BW; day 2 to 6: tacrolimus trough levels of 7-9 ng/ml.

    Number of subjects in period 2
    		Slow and low Standard care
    Started
    196
    202
    Completed
    179
    187
    Not completed
    17
    15
         Insufficient compliance
    -
    1
         Consent withdrawn by subject
    5
    7
         Physician decision
    1
    -
         Graft loss
    8
    5
         Death
    2
    2
         Violation of I/E criteria
    1
    -
    Period 3
    Period 3 title
    Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Slow and low
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose adjustment according to standard of care.

    Arm title
    		 Standard care
    Arm description
    		 -
    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
    Dose adjustment according to standard of care.

    Number of subjects in period 3
    		Slow and low Standard care
    Started
    179
    187
    Completed
    130
    134
    Not completed
    49
    53
         Consent withdrawn by subject
    1
    -
         Graft loss
    13
    17
         Death
    17
    20
         Lost to follow-up
    18
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Slow and low
    Reporting group description
    		 -

    Reporting group title
    Standard care
    Reporting group description
    		 -

    Reporting group values
    		 Slow and low Standard care Total
    Number of subjects
    		 196 202 398
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 146 147 293
        From 65-84 years
    		 50 55 105
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55 ( 12 ) 54 ( 13 ) -
    Gender categorical
    Units: Subjects
        Female
    		 68 71 139
        Male
    		 128 131 259
    Type of donor
    Type of donor
    Units: Subjects
        Deceased
    		 163 167 330
        Living
    		 33 35 68
    Donor with expanded criteria
    Donor with expanded criteria
    Units: Subjects
        Yes
    		 107 105 212
        No
    		 89 97 186
    Subject analysis sets

    Subject analysis set title
    Intent to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intention-to-treat population consisted of all patients who received at least one dose of a study drug and underwent successful renal transplantation.

    Subject analysis set title
    Per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol population was defined, including only patients who received treatment without severe protocol violations (see Supplementary Methods of main paper; PubMed ID 38152417) throughout the study period.

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population consisted of all patients who received at least one dose of a study drug and underwent successful renal transplantation.

    Subject analysis sets values
    		 Intent to treat Per protocol Safety set
    Number of subjects
    398
    315
    398
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    293
    241
    293
        From 65-84 years
    105
    74
    105
        85 years and over
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55 ( 13 )
    54 ( 12 )
    55 ( 13 )
    Gender categorical
    Units: Subjects
        Female
    139
    117
    139
        Male
    259
    198
    259
    Type of donor
    Type of donor
    Units: Subjects
        Deceased
    330
    256
    330
        Living
    68
    59
    68
    Donor with expanded criteria
    Donor with expanded criteria
    Units: Subjects
        Yes
    212
    158
    212
        No
    186
    157
    186

    End points

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    End points reporting groups
    Reporting group title
    Slow and low
    Reporting group description
    		 -

    Reporting group title
    Standard care
    Reporting group description
    		 -
    Reporting group title
    Slow and low
    Reporting group description
    		 -

    Reporting group title
    Standard care
    Reporting group description
    		 -
    Reporting group title
    Slow and low
    Reporting group description
    		 -

    Reporting group title
    Standard care
    Reporting group description
    		 -

    Subject analysis set title
    Intent to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intention-to-treat population consisted of all patients who received at least one dose of a study drug and underwent successful renal transplantation.

    Subject analysis set title
    Per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol population was defined, including only patients who received treatment without severe protocol violations (see Supplementary Methods of main paper; PubMed ID 38152417) throughout the study period.

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population consisted of all patients who received at least one dose of a study drug and underwent successful renal transplantation.

    Primary: BPAR, Graft loss or death

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    End point title
    		 BPAR, Graft loss or death
    End point description
    The primary efficacy outcome was the combined end point of the incidence of BPAR including borderline rejection, graft failure, and death within the first 6 months after renal transplantation. All suspected episodes of acute rejection were confirmed by biopsy, with histologic characteristics described according to the Banff criteria of 2013.
    End point type
    Primary
    End point timeframe
    Day zero to day 180.
    End point values
    		 Slow and low Standard care Intent to treat
    Number of subjects analysed
    190
    193
    383
    Units: Patients
    42
    40
    82
    Statistical analysis title
    		 Primary end point
    Statistical analysis description
    Primary endpoint was tested by one-sided test of equivalence with a non-inferiority margin of 12.5% and a significance level of 5 percent. Accordingly, two-sided 90 percent confidence interval is presented for the absolute risk difference in primary endpoint.
    Comparison groups
    Standard care v Slow and low
    Number of subjects included in analysis
    383
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.004
    Method
    		 noninferiority for risk difference
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.4
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -5.5
         upper limit
    		 8.3

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day one to day 180.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Slow and low
    Reporting group description
    		 -

    Reporting group title
    Standard care
    Reporting group description
    		 -

    Serious adverse events
    		 Slow and low Standard care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    136 / 196 (69.39%)
    134 / 202 (66.34%)
         number of deaths (all causes)
    19
    22
         number of deaths resulting from adverse events
    1
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastrointestinal neoplasms malignant and unspecified
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphomas non-Hodgkin's unspecified histology
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (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 tract neoplasms malignant and unspecified
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive neoplasms male malignant and unspecified
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin neoplasms malignant and unspecified
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aneurysms and artery dissections
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis, stenosis, vascular insufficiency and necrosis
         subjects affected / exposed
    3 / 196 (1.53%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased and nonspecific blood pressure disorders and shock
         subjects affected / exposed
    0 / 196 (0.00%)
    3 / 202 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism and thrombosis
         subjects affected / exposed
    3 / 196 (1.53%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphatic vessel disorders
         subjects affected / exposed
    11 / 196 (5.61%)
    7 / 202 (3.47%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular haemorrhagic disorders
         subjects affected / exposed
    6 / 196 (3.06%)
    6 / 202 (2.97%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular inflammations
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Vascular therapeutic procedures
         subjects affected / exposed
    1 / 196 (0.51%)
    3 / 202 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal therapeutic procedures
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (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 tract therapeutic procedures
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Therapeutic procedures and supportive care NEC
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Administration site reactions
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Body temperature conditions
         subjects affected / exposed
    0 / 196 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tissue disorders NEC
         subjects affected / exposed
    2 / 196 (1.02%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General system disorders NEC
         subjects affected / exposed
    1 / 196 (0.51%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complications associated with device
         subjects affected / exposed
    2 / 196 (1.02%)
    3 / 202 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergic conditions
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune disorders NEC
         subjects affected / exposed
    37 / 196 (18.88%)
    34 / 202 (16.83%)
         occurrences causally related to treatment / all
    7 / 49
    7 / 41
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatic disorders (excl infections and inflammations)
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Thoracic disorders (excl lung and pleura)
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract disorders (excl obstruction and infection)
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural disorders
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary vascular disorders
         subjects affected / exposed
    4 / 196 (2.04%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorders NEC
         subjects affected / exposed
    3 / 196 (1.53%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract disorders (excl infections)
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Deliria (incl confusion)
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed mood disorders and disturbances
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disturbances in thinking and perception
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device issues
         subjects affected / exposed
    0 / 196 (0.00%)
    3 / 202 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Haematology investigations (incl blood groups)
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic, nutritional and blood gas investigations
         subjects affected / exposed
    1 / 196 (0.51%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Protein and chemistry analyses NEC
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary tract investigations and urinalyses
         subjects affected / exposed
    22 / 196 (11.22%)
    21 / 202 (10.40%)
         occurrences causally related to treatment / all
    8 / 28
    5 / 25
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory and pulmonary investigations (excl blood gases)
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Physical examination and organ system status topics
         subjects affected / exposed
    1 / 196 (0.51%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Bone and joint injuries
         subjects affected / exposed
    2 / 196 (1.02%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injuries NEC
         subjects affected / exposed
    0 / 196 (0.00%)
    3 / 202 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural related injuries and complications NEC
         subjects affected / exposed
    40 / 196 (20.41%)
    50 / 202 (24.75%)
         occurrences causally related to treatment / all
    8 / 50
    10 / 65
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exposures, chemical injuries and poisoning
         subjects affected / exposed
    1 / 196 (0.51%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrhythmias
         subjects affected / exposed
    2 / 196 (1.02%)
    4 / 202 (1.98%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disorders
         subjects affected / exposed
    3 / 196 (1.53%)
    4 / 202 (1.98%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart failures
         subjects affected / exposed
    1 / 196 (0.51%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Central nervous system vascular disorders
         subjects affected / exposed
    0 / 196 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Headaches
         subjects affected / exposed
    2 / 196 (1.02%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological disorders NEC
         subjects affected / exposed
    1 / 196 (0.51%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral neuropathies
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizures (incl subtypes)
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 202 (0.50%)
         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
    Anaemias nonhaemolytic and marrow depression
         subjects affected / exposed
    3 / 196 (1.53%)
    4 / 202 (1.98%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell disorders
         subjects affected / exposed
    4 / 196 (2.04%)
    4 / 202 (1.98%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulopathies and bleeding diatheses (excl thrombocytopenic)
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hearing disorders
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernias and other abdominal wall conditions
         subjects affected / exposed
    0 / 196 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhages NEC
         subjects affected / exposed
    0 / 196 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammatory conditions
         subjects affected / exposed
    2 / 196 (1.02%)
    3 / 202 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal motility and defaecation conditions
         subjects affected / exposed
    2 / 196 (1.02%)
    6 / 202 (2.97%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal signs and symptoms
         subjects affected / exposed
    4 / 196 (2.04%)
    5 / 202 (2.48%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal ulceration and perforation
         subjects affected / exposed
    2 / 196 (1.02%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal vascular conditions
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal and retroperitoneal conditions
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Gallbladder disorders
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic and hepatobiliary disorders
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 202 (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
    Genitourinary tract disorders NEC
         subjects affected / exposed
    1 / 196 (0.51%)
    7 / 202 (3.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathies
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal disorders (excl nephropathies)
         subjects affected / exposed
    3 / 196 (1.53%)
    4 / 202 (1.98%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric disorders
         subjects affected / exposed
    2 / 196 (1.02%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract signs and symptoms
         subjects affected / exposed
    2 / 196 (1.02%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Parathyroid gland disorders
         subjects affected / exposed
    2 / 196 (1.02%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders NEC
         subjects affected / exposed
    3 / 196 (1.53%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial infectious disorders
         subjects affected / exposed
    5 / 196 (2.55%)
    6 / 202 (2.97%)
         occurrences causally related to treatment / all
    2 / 6
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal infectious disorders
         subjects affected / exposed
    2 / 196 (1.02%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections - pathogen unspecified
         subjects affected / exposed
    41 / 196 (20.92%)
    44 / 202 (21.78%)
         occurrences causally related to treatment / all
    8 / 59
    12 / 80
         deaths causally related to treatment / all
    0 / 0
    1 / 3
    Viral infectious disorders
         subjects affected / exposed
    19 / 196 (9.69%)
    14 / 202 (6.93%)
         occurrences causally related to treatment / all
    8 / 21
    5 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Bone, calcium, magnesium and phosphorus metabolism disorders
         subjects affected / exposed
    1 / 196 (0.51%)
    4 / 202 (1.98%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte and fluid balance conditions
         subjects affected / exposed
    2 / 196 (1.02%)
    5 / 202 (2.48%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glucose metabolism disorders (incl diabetes mellitus)
         subjects affected / exposed
    2 / 196 (1.02%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Slow and low Standard care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    189 / 196 (96.43%)
    198 / 202 (98.02%)
    Investigations
    Blood calcium increased
         subjects affected / exposed
    11 / 196 (5.61%)
    7 / 202 (3.47%)
         occurrences all number
    11
    7
    Blood creatinine increased
         subjects affected / exposed
    35 / 196 (17.86%)
    39 / 202 (19.31%)
         occurrences all number
    45
    54
    Blood glucose increased
         subjects affected / exposed
    6 / 196 (3.06%)
    15 / 202 (7.43%)
         occurrences all number
    8
    18
    Blood potassium increased
         subjects affected / exposed
    32 / 196 (16.33%)
    27 / 202 (13.37%)
         occurrences all number
    38
    32
    C-reactive protein increased
         subjects affected / exposed
    11 / 196 (5.61%)
    9 / 202 (4.46%)
         occurrences all number
    11
    12
    Hepatic enzyme increased
         subjects affected / exposed
    12 / 196 (6.12%)
    8 / 202 (3.96%)
         occurrences all number
    12
    8
    Haemoglobin decreased
         subjects affected / exposed
    12 / 196 (6.12%)
    10 / 202 (4.95%)
         occurrences all number
    12
    11
    Injury, poisoning and procedural complications
    Complications of transplanted kidney
         subjects affected / exposed
    25 / 196 (12.76%)
    33 / 202 (16.34%)
         occurrences all number
    26
    35
    Wound complication
         subjects affected / exposed
    25 / 196 (12.76%)
    29 / 202 (14.36%)
         occurrences all number
    25
    32
    Vascular disorders
    Hypertension
         subjects affected / exposed
    20 / 196 (10.20%)
    22 / 202 (10.89%)
         occurrences all number
    21
    22
    Lymphocele
         subjects affected / exposed
    19 / 196 (9.69%)
    29 / 202 (14.36%)
         occurrences all number
    20
    29
    Hypertensive crisis
         subjects affected / exposed
    25 / 196 (12.76%)
    24 / 202 (11.88%)
         occurrences all number
    36
    32
    Hypotension
         subjects affected / exposed
    10 / 196 (5.10%)
    10 / 202 (4.95%)
         occurrences all number
    10
    10
    Nervous system disorders
    Tremor
         subjects affected / exposed
    16 / 196 (8.16%)
    23 / 202 (11.39%)
         occurrences all number
    16
    23
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    22 / 196 (11.22%)
    27 / 202 (13.37%)
         occurrences all number
    22
    28
    Leukocytosis
         subjects affected / exposed
    18 / 196 (9.18%)
    21 / 202 (10.40%)
         occurrences all number
    22
    27
    Leukopenia
         subjects affected / exposed
    46 / 196 (23.47%)
    42 / 202 (20.79%)
         occurrences all number
    47
    46
    Nephrogenic anaemia
         subjects affected / exposed
    24 / 196 (12.24%)
    18 / 202 (8.91%)
         occurrences all number
    24
    20
    General disorders and administration site conditions
    Oedema
         subjects affected / exposed
    13 / 196 (6.63%)
    23 / 202 (11.39%)
         occurrences all number
    13
    25
    Oedema peripheral
         subjects affected / exposed
    25 / 196 (12.76%)
    23 / 202 (11.39%)
         occurrences all number
    26
    24
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    3 / 196 (1.53%)
    11 / 202 (5.45%)
         occurrences all number
    3
    11
    Abdominal pain
         subjects affected / exposed
    8 / 196 (4.08%)
    12 / 202 (5.94%)
         occurrences all number
    9
    13
    Diarrhoea
         subjects affected / exposed
    26 / 196 (13.27%)
    41 / 202 (20.30%)
         occurrences all number
    27
    46
    Dyspepsia
         subjects affected / exposed
    4 / 196 (2.04%)
    13 / 202 (6.44%)
         occurrences all number
    5
    15
    Nausea
         subjects affected / exposed
    16 / 196 (8.16%)
    23 / 202 (11.39%)
         occurrences all number
    18
    24
    Vomiting
         subjects affected / exposed
    6 / 196 (3.06%)
    14 / 202 (6.93%)
         occurrences all number
    7
    18
    Constipation
         subjects affected / exposed
    15 / 196 (7.65%)
    21 / 202 (10.40%)
         occurrences all number
    20
    21
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 196 (6.12%)
    6 / 202 (2.97%)
         occurrences all number
    12
    6
    Dyspnoea
         subjects affected / exposed
    10 / 196 (5.10%)
    10 / 202 (4.95%)
         occurrences all number
    10
    14
    Dyspnoea exertional
         subjects affected / exposed
    11 / 196 (5.61%)
    2 / 202 (0.99%)
         occurrences all number
    11
    2
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    9 / 196 (4.59%)
    11 / 202 (5.45%)
         occurrences all number
    10
    11
    Proteinuria
         subjects affected / exposed
    15 / 196 (7.65%)
    12 / 202 (5.94%)
         occurrences all number
    15
    12
    Leukocyturia
         subjects affected / exposed
    7 / 196 (3.57%)
    13 / 202 (6.44%)
         occurrences all number
    7
    13
    Renal impairment
         subjects affected / exposed
    17 / 196 (8.67%)
    17 / 202 (8.42%)
         occurrences all number
    20
    23
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    7 / 196 (3.57%)
    11 / 202 (5.45%)
         occurrences all number
    7
    12
    Infections and infestations
    Cytomegalovirus infection
         subjects affected / exposed
    17 / 196 (8.67%)
    30 / 202 (14.85%)
         occurrences all number
    19
    33
    Nasopharyngitis
         subjects affected / exposed
    13 / 196 (6.63%)
    13 / 202 (6.44%)
         occurrences all number
    15
    13
    Urinary tract infection
         subjects affected / exposed
    46 / 196 (23.47%)
    53 / 202 (26.24%)
         occurrences all number
    65
    71
    Polyomavirus viraemia
         subjects affected / exposed
    27 / 196 (13.78%)
    34 / 202 (16.83%)
         occurrences all number
    28
    36
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    11 / 196 (5.61%)
    12 / 202 (5.94%)
         occurrences all number
    14
    12
    Glucose tolerance impaired
         subjects affected / exposed
    12 / 196 (6.12%)
    10 / 202 (4.95%)
         occurrences all number
    12
    10
    Hypercholesterolaemia
         subjects affected / exposed
    13 / 196 (6.63%)
    7 / 202 (3.47%)
         occurrences all number
    13
    7
    Hyperkalaemia
         subjects affected / exposed
    19 / 196 (9.69%)
    24 / 202 (11.88%)
         occurrences all number
    20
    28
    Hypophosphataemia
         subjects affected / exposed
    30 / 196 (15.31%)
    34 / 202 (16.83%)
         occurrences all number
    30
    34
    Metabolic acidosis
         subjects affected / exposed
    26 / 196 (13.27%)
    29 / 202 (14.36%)
         occurrences all number
    26
    34
    Hyperlipidaemia
         subjects affected / exposed
    10 / 196 (5.10%)
    17 / 202 (8.42%)
         occurrences all number
    10
    17
    New onset diabetes after transplantation
         subjects affected / exposed
    33 / 196 (16.84%)
    33 / 202 (16.34%)
         occurrences all number
    33
    33
    Folate deficiency
         subjects affected / exposed
    12 / 196 (6.12%)
    16 / 202 (7.92%)
         occurrences all number
    12
    17
    Hypokalaemia
         subjects affected / exposed
    11 / 196 (5.61%)
    8 / 202 (3.96%)
         occurrences all number
    12
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jul 2017
    Addition to the definition of screening failures and expansion of the sample collection for the substudy.
    11 Jan 2018
    Revision and correction of inaccuracies, as well as addition of secondary objectives and endpoints.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/38152417
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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