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    Clinical Trial Results:
    Open-label, multicentre, randomized clinical trial to compare the pharmacokinetics of Envarsus® tablets and Advagraf® capsules administered once daily In adult de-novo kidney transplant patients

    Summary
    EudraCT number
    		 2014-005572-28
    Trial protocol
    		 FR  
    Global end of trial date
    24 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jul 2017
    First version publication date
    23 Jul 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-06235AA1-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A.
    Sponsor organisation address
    Via Palermo 26/A, Parma, Italy, 43122
    Public contact
    Clinical Trial Transparency, Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., ClinicalTrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency, Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., ClinicalTrials_info@chiesi.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
    29 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare pharmacokinetics of tacrolimus early after transplantation following administration of Envarsus® tablets or Advagraf® capsules in adult de-novo kidney transplant recipients.
    Protection of trial subjects
    The study was conducted according to the clinical study protocol, the current International Council for Harmonization (ICH) Good Clinical Practice (GCP) guidelines, any local guidelines, and the Declaration of Helsinki (1964 and amendments). At all visits, from screening onwards, concomitant medication, AEs, and vital signs were recorded.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jun 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 75
    Worldwide total number of subjects
    75
    EEA total number of subjects
    75
    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)
    50
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Overall, 76 patients were enrolled according to inclusion and exclusion criteria; of these, 75 patients were randomized to treatment.

    Pre-assignment
    Screening details
    		 Screening was performed from 0 to 14 days prior to kidney transplantation. At the screening visit, inclusion/exclusion criteria were assessed. Day 0, the day of transplantation, was defined as the day on which the transplanted organ was reperfused in vivo with the recipient's blood.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open-label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Envarsus
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tacrolimus (Envarsus)
    Investigational medicinal product code
    Other name
    Envarsus
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Envarsus (tacrolimus) prolonged-release tablets: 0.75 mg, 1.0 mg, and 4.0 mg dose strengths. Envarsus tablets (oral administration] once daily in the morning starting at the dose of 0.17 mg/kg). The dose of Envarsus was maintained constant until Day 3 and adjusted on Days 4, 8, 15, and 22 according to the trough levels, assessed at the local laboratory the day prior to the dose change. The dose of Envarsus was adjusted on the scheduled days to maintain whole blood tacrolimus trough levels within the target range. Target trough level range was within 5-15 ng/mL (average 10 ng/mL) from Day 2 to Day 15 and within 5-10 ng/mL (average 7.5 ng/mL) from Day 16 to Day 28. Day 0, the day of transplantation, was defined as the day on which the transplanted organ was reperfused in vivo with the recipient's blood. Treatment with the study drug was initiated within 24 hours of transplantation (graft reperfusion) and continued for 28 consecutive days.

    Arm title
    		 Advagraf
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tacrolimus (Advagraf)
    Investigational medicinal product code
    Other name
    Advagraf
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Advagraf (tacrolimus) prolonged-release hard capsules provided in 0.5 mg, 1.0 mg, 3.0 mg, and 5.0 mg dose strengths. Advagraf capsules (oral administratioin) once daily in the morning starting at the dose of 0.2 mg/kg. The dose of Advagraf was maintained constant until Day 3 and adjusted at Days 4, 8, 15, and 22 according to the trough levels, assessed at the local laboratory the day prior the dose change. The doses of Advagraf were adjusted on the scheduled days to maintain whole blood tacrolimus trough levels within the target range. Target trough level range was within 5-15 ng/mL (average 10 ng/mL) from Day 2 to Day 15 and within 5-10 ng/mL (average 7.5 ng/mL) from Day 16 to Day 28. Day 0, the day of transplantation, was defined as the day on which the transplanted organ was reperfused in vivo with the recipient's blood. Treatment with the study drug was initiated within 24 hours of transplantation (graft reperfusion) and continued for 28 consecutive days.

    Number of subjects in period 1
    		Envarsus Advagraf
    Started
    37
    38
    Completed
    31
    32
    Not completed
    6
    6
         Consent withdrawn by subject
    6
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Envarsus
    Reporting group description
    		 -

    Reporting group title
    Advagraf
    Reporting group description
    		 -

    Reporting group values
    		 Envarsus Advagraf Total
    Number of subjects
    		 37 38 75
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 21 29 50
        From 65-84 years
    		 16 9 25
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.9 ± 14 53.4 ± 15.9 -
    Gender categorical
    Units: Subjects
        Female
    		 12 8 20
        Male
    		 25 30 55
    Race
    Units: Subjects
        White
    		 37 38 75

    End points

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    End points reporting groups
    Reporting group title
    Envarsus
    Reporting group description
    		 -

    Reporting group title
    Advagraf
    Reporting group description
    		 -

    Primary: 1_Tacrolimus daily dose normalized area under the whole blood drug concentration-time curve; AUC 0-24h/Dose

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    End point title
    		 1_Tacrolimus daily dose normalized area under the whole blood drug concentration-time curve; AUC 0-24h/Dose
    End point description
    Tacrolimus AUC0-24h normalized to the daily dose (AUC0-24h/Dose) was evaluated on Day 1, Day 3, Day 7 and Day 14. The AUC0-24h (AUC0-24h/Dose can be considered an index of oral bioavailability. The following blood samples for the 0-24 hour PK profiles were drawn: 0.00 (pre-dose), 0.50, 1.00, 1.50, 2.00, 3.00, 4.00, 6.00, 8.00, 12.00, 16.00, 20.00, and 24.00 hours after the morning dose (a total of 13 samples). Pharmacokinetic (PK) variables were calculated based on individual blood concentration-time data using non-compartmental methods. Note: 1) The actual number of patients (N) contributing to the data on each evaluation day is shown under the results table. 2) For the geometric coefficient of variation, the sign ± was assigned automatically by the database system. 3) Data were summarized using descriptive statistics by treatment and visit.
    End point type
    Primary
    End point timeframe
    From time 0 (pre-dose) to 24 hours post dose on Day 1, Day 3, Day 7 and Day 14.
    End point values
    		 Envarsus Advagraf
    Number of subjects analysed
    33 [1]
    35 [2]
    Units: ng.h/mL/mg dose
    geometric mean (geometric coefficient of variation)
        Day 1
    19.02 ± 43.5
    20.09 ± 41
        Day 3
    45.63 ± 38.4
    34.6 ± 39.9
        Day 7
    45.21 ± 42.3
    36.25 ± 44.4
        Day 14
    50.4 ± 41.3
    35.35 ± 44.2
    Notes
    [1] - PK population Day 1 N=31 Day 3 N=33 Day 7 N=28 Day 14 N=28
    [2] - PK population Day 1 N=33 Day 3 N=33 Day 7 N=31 Day 14 N=30
    Statistical analysis title
    		 AUC0-24h (AUC0-24h/Dose); Day 3
    Statistical analysis description
    Day 3 Envarsus vs Advagraf Normalised AUC0-24h: Normalised AUC0-24h = AUC0-24h / dose on that day. The ratios of adjusted geometric means between the 2 groups were calculated with 90% (2-sided confidence intervals). N=66 patients were included in this analysis. The value N=68, shown below is due to innate error of the EudraCT database.
    Comparison groups
    Envarsus v Advagraf
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.007 [4]
    Method
    		 ANOVA
    Parameter type
    		 LSMean adjusted
    Point estimate
    131.89
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 111.82
         upper limit
    		 155.56
    Notes
    [3] - Descriptive characterisation of the PK parameters for the study drugs was performed. No formal hypothesis was predefined.
    [4] - ANOVA Analysis using logged values. LSMean adjusted for treatment, back-transformed to original scale.
    Statistical analysis title
    		 AUC0-24h (AUC0-24h/Dose); Day 7
    Statistical analysis description
    Day 7 Envarsus vs Advagraf Normalised AUC0-24h: Normalised AUC0-24h = AUC0-24h / dose on that day. The ratios of adjusted geometric means between the 2 groups were calculated with 90% (2-sided confidence intervals). N=59 patients were included in this analysis. The value N=68, shown below is due to innate error of the EudraCT database.
    Comparison groups
    Advagraf v Envarsus
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.051 [6]
    Method
    		 ANOVA
    Parameter type
    		 LSMean adjusted
    Point estimate
    124.73
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 103.67
         upper limit
    		 150.06
    Notes
    [5] - Descriptive characterisation of the PK parameters for the study drugs was performed. No formal hypothesis was predefined.
    [6] - ANOVA Analysis using logged values. LSMean adjusted for treatment, back-transformed to original scale.
    Statistical analysis title
    		 AUC0-24h (AUC0-24h/Dose); Day 14
    Statistical analysis description
    Day 14 Envarsus vs Advagraf Normalised AUC0-24h: Normalised AUC0-24h = AUC0-24h / dose on that day. The ratios of adjusted geometric means between the 2 groups were calculated with 90% (2-sided confidence intervals). N=58 patients were included in this analysis. The value N=68, shown below is due to innate error of the EudraCT database.
    Comparison groups
    Envarsus v Advagraf
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.002 [8]
    Method
    		 ANOVA
    Parameter type
    		 LSMean adjusted
    Point estimate
    142.57
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 118.63
         upper limit
    		 171.35
    Notes
    [7] - Descriptive characterisation of the PK parameters for the study drugs was performed. No formal hypothesis was predefined.
    [8] - ANOVA Analysis using logged values. LSMean adjusted for treatment, back-transformed to original scale.

    Primary: 2_Percent fluctuation [(Cmax-Cmin)*100/Cavg]

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    End point title
    		 2_Percent fluctuation [(Cmax-Cmin)*100/Cavg]
    End point description
    Tacrolimus maximum whole blood drug concentration (Cmax), average whole blood drug concentration (Cavg), minimum whole blood drug concentration (Cmin), % fluctuation [(Cmax-Cmin)*100/Cavg], following the morning dose of Day 1, Day 3, Day 7, and Day 14. Note: 1) The actual number of patients (N) contributing to the data on each evaluation day is shown under the results table. 2) For the geometric coefficient of variation, the sign ± was assigned automatically by the database system.
    End point type
    Primary
    End point timeframe
    From time 0 (pre-dose) to 24 hours post dose (AUC 0-24h) on Day 1, Day 3, Day 7 and Day 14.
    End point values
    		 Envarsus Advagraf
    Number of subjects analysed
    33 [9]
    35 [10]
    Units: percent
    geometric mean (geometric coefficient of variation)
        Day 1
    180.74 ± 30.4
    148.52 ± 25.6
        Day 3
    82.97 ± 43
    118.24 ± 30.2
        Day 7
    94.24 ± 46.1
    137.9 ± 29.1
        Day 14
    98.57 ± 43.8
    135.78 ± 35.2
    Notes
    [9] - Pharmacokinetic population Day 1 N=31 Day 3 N=33 Day 7 N=28 Day 14 N=28
    [10] - Pharmacokinetic population Day 1 N=33 Day 3 N=33 Day 7 N=31 Day 14 N=30
    Statistical analysis title
    		 Treatment effect ratio Envarsus/Advagraf; Day 3
    Statistical analysis description
    % Fluctuation normalized to the daily dose [AUC0-24h/Dose] on Day 3, Day 7 and Day 14 were log-transformed to the natural logarithmic scale and then analyzed (analysis of variance (ANOVA) model with treatment as a fixed effect). The ratios of adjusted geometric means between the 2 groups were calculated with 90% (2-sided confidence intervals). N=66 patients were included in this analysis. The value N=68, shown below is due to innate error of the EudraCT database.
    Comparison groups
    Envarsus v Advagraf
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 < 0.001 [12]
    Method
    		 ANOVA
    Parameter type
    		 Treatment effect ratio
    Point estimate
    70.17
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 60.09
         upper limit
    		 81.95
    Notes
    [11] - Descriptive characterisation of the PK parameters for the study drugs was performed. No formal hypothesis was predefined.
    [12] - ANOVA Analysis using logged values. LSMean adjusted for treatment, back-transformed to original scale.
    Statistical analysis title
    		 Treatment effect ratio Envarsus/Advagraf; Day 7
    Statistical analysis description
    % Fluctuation normalized to the daily dose [AUC0-24h/Dose] on Day 3, Day 7 and Day 14 were log-transformed to the natural logarithmic scale and then analyzed (analysis of variance (ANOVA) model with treatment as a fixed effect). The ratios of adjusted geometric means between the 2 groups were calculated with 90% (2-sided confidence intervals). N=59 patients were included in this analysis. The value N=68, shown below is due to innate error of the EudraCT database.
    Comparison groups
    Envarsus v Advagraf
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 < 0.001 [14]
    Method
    		 ANOVA
    Parameter type
    		 Treatment effect ratio
    Point estimate
    68.34
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 58.21
         upper limit
    		 80.23
    Notes
    [13] - Descriptive characterisation of the PK parameters for the study drugs was performed. No formal hypothesis was predefined.
    [14] - ANOVA Analysis using logged values. LSMean adjusted for treatment, back-transformed to original scale.
    Statistical analysis title
    		 Treatment effect ratio Envarsus/Advagraf; Day 14
    Statistical analysis description
    % Fluctuation normalized to the daily dose [AUC0-24h/Dose] on Day 3, Day 7 and Day 14 were log-transformed to the natural logarithmic scale and then analyzed (analysis of variance (ANOVA) model with treatment as a fixed effect). The ratios of adjusted geometric means between the 2 groups were calculated with 90% (2-sided confidence intervals). N=58 patients were included in this analysis. The value N=68, shown below is due to innate error of the EudraCT database.
    Comparison groups
    Envarsus v Advagraf
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 < 0.004 [16]
    Method
    		 ANOVA
    Parameter type
    		 Treatment effect ratio
    Point estimate
    72.6
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 60.87
         upper limit
    		 86.59
    Notes
    [15] - Descriptive characterisation of the PK parameters for the study drugs was performed. No formal hypothesis was predefined.
    [16] - ANOVA Analysis using logged values. LSMean adjusted for treatment, back-transformed to original scale.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from the time of patient informed consent signature to study completion (Day 28) or discontinuation.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Envarsus
    Reporting group description
    		 -

    Reporting group title
    Advagraf
    Reporting group description
    		 -

    Serious adverse events
    		 Envarsus Advagraf
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 33 (45.45%)
    11 / 36 (30.56%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon adenoma
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Kidney transplant rejection
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 36 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 36 (2.78%)
         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
    Lung disorder
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 36 (2.78%)
         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
    0 / 33 (0.00%)
    1 / 36 (2.78%)
         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
    Complications of transplanted kidney
         subjects affected / exposed
    3 / 33 (9.09%)
    4 / 36 (11.11%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft complication
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft thrombosis
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 36 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery thrombosis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Hemorrhagic disorder
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial prostatitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter sepsis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (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 / 33 (3.03%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonella bacteraemia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (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
    		 Envarsus Advagraf
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 33 (100.00%)
    36 / 36 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 33 (0.00%)
    5 / 36 (13.89%)
         occurrences all number
    0
    5
    Haematoma
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Hot flush
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Lymphocele
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Hypotension
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    7 / 33 (21.21%)
    9 / 36 (25.00%)
         occurrences all number
    8
    9
    Asthenia
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 36 (8.33%)
         occurrences all number
    2
    3
    Pyrexia
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    Pain
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    Catheter site pain
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Chest pain
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 36 (2.78%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 33 (18.18%)
    6 / 36 (16.67%)
         occurrences all number
    9
    7
    Anxiety
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 36 (8.33%)
         occurrences all number
    2
    3
    Confusional state
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 36 (8.33%)
         occurrences all number
    2
    3
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    7 / 33 (21.21%)
    8 / 36 (22.22%)
         occurrences all number
    7
    8
    Complications of transplanted kidney
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    3
    Overdose
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 33 (15.15%)
    7 / 36 (19.44%)
         occurrences all number
    5
    9
    Tremor
         subjects affected / exposed
    4 / 33 (12.12%)
    4 / 36 (11.11%)
         occurrences all number
    4
    4
    Neuralgia
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Paraesthesia
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    19 / 33 (57.58%)
    20 / 36 (55.56%)
         occurrences all number
    19
    20
    Lymphopenia
         subjects affected / exposed
    5 / 33 (15.15%)
    5 / 36 (13.89%)
         occurrences all number
    6
    7
    Leukocytosis
         subjects affected / exposed
    0 / 33 (0.00%)
    6 / 36 (16.67%)
         occurrences all number
    0
    6
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Thrombocytopenia
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    10 / 33 (30.30%)
    9 / 36 (25.00%)
         occurrences all number
    10
    11
    Abdominal pain
         subjects affected / exposed
    7 / 33 (21.21%)
    8 / 36 (22.22%)
         occurrences all number
    9
    8
    Diarrhoea
         subjects affected / exposed
    8 / 33 (24.24%)
    7 / 36 (19.44%)
         occurrences all number
    9
    7
    Nausea
         subjects affected / exposed
    5 / 33 (15.15%)
    2 / 36 (5.56%)
         occurrences all number
    7
    2
    Vomiting
         subjects affected / exposed
    0 / 33 (0.00%)
    5 / 36 (13.89%)
         occurrences all number
    0
    6
    Haemorrhoids
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 36 (8.33%)
         occurrences all number
    1
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    3
    Skin and subcutaneous tissue disorders
    Scar pain
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    10 / 33 (30.30%)
    14 / 36 (38.89%)
         occurrences all number
    10
    15
    Proteinuria
         subjects affected / exposed
    3 / 33 (9.09%)
    4 / 36 (11.11%)
         occurrences all number
    3
    4
    Renal impairment
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 36 (11.11%)
         occurrences all number
    2
    4
    Bladder spasm
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Dysuria
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Hypertonic bladder
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    Pain in extremity
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    Back pain
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    6 / 33 (18.18%)
    4 / 36 (11.11%)
         occurrences all number
    6
    4
    Bacterial prostatitis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    3
    Metabolism and nutrition disorders
    Metabolic acidosis
         subjects affected / exposed
    5 / 33 (15.15%)
    6 / 36 (16.67%)
         occurrences all number
    5
    6
    Diabetes mellitus
         subjects affected / exposed
    3 / 33 (9.09%)
    6 / 36 (16.67%)
         occurrences all number
    3
    6
    Hyperglycemia
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 36 (11.11%)
         occurrences all number
    3
    4
    Vitamin D deficiency
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 36 (8.33%)
         occurrences all number
    2
    3
    Hypocalcaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    4 / 36 (11.11%)
         occurrences all number
    0
    4
    Acidosis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Fluid retention
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Hypercalcaemia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Hyperglycaemia
         subjects affected / exposed
    3 / 33 (9.09%)
    2 / 36 (5.56%)
         occurrences all number
    3
    2
    Hyperkalaemia
         subjects affected / exposed
    4 / 33 (12.12%)
    6 / 36 (16.67%)
         occurrences all number
    4
    9
    Hyperphosphataemia
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    3
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Hypokalaemia
         subjects affected / exposed
    5 / 33 (15.15%)
    9 / 36 (25.00%)
         occurrences all number
    5
    9
    Hypophosphataemia
         subjects affected / exposed
    5 / 33 (15.15%)
    4 / 36 (11.11%)
         occurrences all number
    5
    4
    Hypovitaminosis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jun 2015
    The dose of the study drug was to be adjusted on the scheduled days to maintain whole blood tacrolimus trough levels within the target range. Target trough level range were within 5–15 ng/mL (average 10 ng/mL) from Day 2 to Day 14 and within 5-10 ng/mL (average 7.5 ng/mL) from Day 15 to Day 28. Update of the study inclusion criteria; patients with BMI outside the range 15-35 kg/m2 were excluded from the study.

    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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    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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