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    Clinical Trial Results:
    Envarsus® tablets administered once daily in combination with everolimus in elderly de-novo kidney transplant recipients: open-label, multicentre, single-arm, pharmacokinetic and clinical study

    Summary
    EudraCT number
    		 2015-005640-34
    Trial protocol
    		 IT  
    Global end of trial date
    22 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Feb 2019
    First version publication date
    28 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DFIDM-1501
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02970630
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 NA: NA
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A.
    Sponsor organisation address
    Via Palermo 26/A, Parma, Italy, 43122
    Public contact
    Clinical Trial Trasparency, Clinical Trial Trasparency, clinicaltrials_info@chiesi.com
    Scientific contact
    Clinical Trial Trasparency, Clinical Trial Trasparency, 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
    22 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To estimate tacrolimus (Envarsus®) pharmacokinetic parameters (AUC24, Cmin, Cmin/daily dose and AUC24/daily dose) in elderly de-novo kidney transplant recipients of ECD kidney grafts treated with Envarsus® prolonged release tablets in combination with everolimus tablets (Certican®).
    Protection of trial subjects
    The protocol, together with all required clinical trial documentation, was submitted to the appropriate independent ethics committee (IEC) in all participating sites. A copy of the favourable opinion from the IEC had to be received before the trial could be initiated at an investigational site. The membership of each IEC was also obtained. The study was performed in compliance with the ‘Declaration of Helsinki’, International Conference of Harmonization Tripartite Guidelines Guideline for Good Clinical Practice (ICH GCP), current international and national regulations, the study protocol and current Standard Operating Procedures (SOPs) of Chiesi Farmaceutici S.p.A. The consent document met all applicable local laws and provided the patient with information regarding the purpose, procedures, requirements and restrictions of the study, along with any known risks and potential benefits associated with the investigational product and the established provisions for maintaining the confidentiality of personal information. Subject’s written informed consent obtained prior to transplant intervention and prior to any study-related procedures.
    Background therapy
    		 Envarsus® is a new tacrolimus tablet formulation approved by the European Medicines Agency (EMA). Envarsus®, designed for once-daily administration, was developed utilising the MeltDoseTM drug delivery technology, which increases the bioavailability of poorly water-soluble compounds via solid formulation at molecular state. For this reason, the daily dose should be reduced by 30% in comparison with standard tacrolimus (with the exclusion of black patients), in order to reach the therapeutic exposure to tacrolimus.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Feb 2017
    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
    Italy: 28
    Worldwide total number of subjects
    28
    EEA total number of subjects
    28
    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)
    9
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Twenty-eight (28) patients were enrolled in the study in four (4) Italian sites. There were no screening failures. Of the 28 enrolled patients, 22 (78.6%) completed the study and 6 (21.4%) were discontinued (all due to adverse events).

    Pre-assignment
    Screening details
    		 The screening visit (V1) embraced a period of 24 hours before and after kidney transplantation (Tx). In case of unsuccessful transplantation, transplant failure or if the patient was withdrawn from study before the first dose of study treatments, the subject was to be classified as screening failure and replaced.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Study Treatment
    Arm description
    		 all the subjects receiving the study drugs (Envarsus® and everolimus)
    Arm type
    		 Experimental

    Investigational medicinal product name
    1_Envarsus®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Reference product: Envarsus® prolonged-release tablets, oral formulation. Active ingredient: tacrolimus monohydrate. Dose: IMP dosage form: 0.75 mg, 1.0 mg and 4.0 mg dosage strengths. Oral administration once daily Starting dose: 0.07 mg/kg/day The dose of Envarsus® was maintained constant until Day 3. Starting from Day 4, the initial tacrolimus dose was adjusted in order to maintain tacrolimus Ctrough within the following target: 4-7 ng/ml until end of Month 3, then 3-6 ng/ml.

    Investigational medicinal product name
    2_Certican®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Reference product: Certican® tablets, oral formulation. Active ingredient: everolimus Dose: IMP dosage form: 0.25 mg and 0.75 mg dosage strengths. Oral administration twice daily Starting dose: 2 mg/day The dose of everolimus was maintained constant until Day 3. Starting from Day 4, the initial dose was adjusted in order to maintain everolimus Ctrough within the following target: 3-8 ng/ml (5-8 ng/ml if determined with immunoassay).

    Number of subjects in period 1
    		Study Treatment
    Started
    28
    Completed
    22
    Not completed
    6
         Adverse event, non-fatal
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment period
    Reporting group description
    		 Active Treatment Arm with Envarsus tablets administred once daily in combination with Everolimus (Certican®). Envarsus® Active ingredient: tacrolimus monohydrate Oral administration once daily Starting dose: 0.07 mg/kg/day The dose of Envarsus® was maintained constant until Day 3. Starting from Day 4, the initial tacrolimus dose was adjusted in order to maintain tacrolimus Ctrough within the following target: 4-7 ng/ml until end of Month 3, then 3-6 ng/ml. Certican® Active ingredient: everolimus Oral administration twice daily Starting dose: 2 mg/day The dose of everolimus was maintained constant until Day 3. Starting from Day 4, the initial dose was adjusted in order to maintain everolimus Ctrough within the following target: 3-8 ng/ml (5-8 ng/ml if determined with immunoassay).

    Reporting group values
    		 Treatment period Total
    Number of subjects
    		 28 28
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 9 9
        From 65-84 years
    		 19 19
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.2 ± 3.3 -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 21 21
    Race
    Units: Subjects
        white
    		 28 28

    End points

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    End points reporting groups
    Reporting group title
    Study Treatment
    Reporting group description
    		 all the subjects receiving the study drugs (Envarsus® and everolimus)

    Primary: 1_Tacrolimus AUC24

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    End point title
    		 1_Tacrolimus AUC24 [1]
    End point description
    A 24-hour multiple blood sampling for PK assessment was performed on Visit 6 (study Day 10 to 12). Thirteen (13) samples for the determination of tacrolimus concentrations in whole blood in the 0-24 h interval were taken at the following times: 0.00 (within 5 minutes before the morning 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 h post-dose. Area under the whole blood drug concentration curve observed from time 0 to 24 hours post dose was computed using the linear trapezoidal rule. Overall results have been reported.
    End point type
    Primary
    End point timeframe
    Visit 6 (Day 10 to Day 12)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the study design (only one arm, without any comparator), primary endpoint's statistical analysis is a descriptive analysis.
    End point values
    		 Study Treatment
    Number of subjects analysed
    23 [2]
    Units: ng.h/ml
        arithmetic mean (standard deviation)
    160.20 ± 53.96
    Notes
    [2] - PK population
    No statistical analyses for this end point

    Primary: 2_Tacrolimus Cmin

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    End point title
    		 2_Tacrolimus Cmin [3]
    End point description
    A 24-hour multiple blood sampling for PK assessment was performed on Visit 6 (study Day 10 to 12). Thirteen (13) samples for the determination of tacrolimus concentrations in whole blood in the 0-24 h interval were taken at the following times: 0.00 (within 5 minutes before the morning 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 h post-dose. Minimum observed blood concentration following a single dose, obtained directly from the blood concentration versus time curves. It was obtained directly from the experimental data without interpolation. Overall results have been reported.
    End point type
    Primary
    End point timeframe
    Visit 6 (Day 10 to Day 12)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the study design (only one arm, without any comparator), primary endpoint's statistical analysis is a descriptive analysis.
    End point values
    		 Study Treatment
    Number of subjects analysed
    23 [4]
    Units: ng/ml
        arithmetic mean (standard deviation)
    4.26 ± 1.54
    Notes
    [4] - PK population
    No statistical analyses for this end point

    Secondary: 3_Tacrolimus Cmax

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    End point title
    		 3_Tacrolimus Cmax
    End point description
    A 24-hour multiple blood sampling for PK assessment was performed on Visit 6 (study Day 10 to 12). Thirteen (13) samples for the determination of tacrolimus concentrations in whole blood in the 0-24 h interval were taken at the following times: 0.00 (within 5 minutes before the morning 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 h post-dose. Maximum observed blood concentration (Cmax) following a single dose, obtained directly from the blood concentration versus time curves. It was obtained directly from the experimental data without interpolation. Overall results have been reported.
    End point type
    Secondary
    End point timeframe
    Visit 6 (Day 10 to Day 12)
    End point values
    		 Study Treatment
    Number of subjects analysed
    23 [5]
    Units: ng/ml
        arithmetic mean (standard deviation)
    10.50 ± 4.33
    Notes
    [5] - PK population
    No statistical analyses for this end point

    Secondary: 4_Tacrolimus tmax

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    End point title
    		 4_Tacrolimus tmax
    End point description
    A 24-hour multiple blood sampling for PK assessment was performed on Visit 6 (study Day 10 to 12). Thirteen (13) samples for the determination of tacrolimus concentrations in whole blood in the 0-24 h interval were taken at the following times: 0.00 (within 5 minutes before the morning 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 h post-dose. Time from dosing to Cmax (tmax), reported using actual times. Overall results have been reported.
    End point type
    Secondary
    End point timeframe
    Visit 6 (Day 10 to Day 12)
    End point values
    		 Study Treatment
    Number of subjects analysed
    23 [6]
    Units: hour
        arithmetic mean (standard deviation)
    6.62 ± 3.36
    Notes
    [6] - PK population
    No statistical analyses for this end point

    Secondary: 5_Tacrolimus linear correlation coefficient between AUC24 and Cmin

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    End point title
    		 5_Tacrolimus linear correlation coefficient between AUC24 and Cmin
    End point description
    A 24-hour multiple blood sampling for PK assessment was performed on Visit 6 (study Day 10 to 12). Thirteen (13) samples for the determination of tacrolimus concentrations in whole blood in the 0-24 h interval were taken at the following times: 0.00 (within 5 minutes before the morning 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 h post-dose. Time from dosing to Cmax, reported using actual times. Linear correlation refers to linear correlation coefficient (R2) between AUC24 and Cmin. Overall results have been reported expressed as a pure number to be multiplied by 10(-4).
    End point type
    Secondary
    End point timeframe
    Visit 6 (Day 10 to Day 12)
    End point values
    		 Study Treatment
    Number of subjects analysed
    23 [7]
    Units: pure number by 10(-4) [0 - 1]
    7309
    Notes
    [7] - PK population
    No statistical analyses for this end point

    Secondary: 6_Everolimus day time AUC12

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    End point title
    		 6_Everolimus day time AUC12
    End point description
    A 24-hour multiple blood sampling for PK assessment was performed on Visit 6 (study Day 10 to 12). Thirteen (13) samples for the determination of tacrolimus concentrations in whole blood in the 0-24 h interval were taken at the following times: 0.00 (within 5 minutes before the morning 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 h post-dose. Area under the whole blood drug concentration curve observed from time 0 to 12 hours post dose (AUC12, day time) was computed using the linear trapezoidal rule. Overall results have been reported.
    End point type
    Secondary
    End point timeframe
    Visit 6 (Day 10 to Day 12) - day time
    End point values
    		 Study Treatment
    Number of subjects analysed
    23 [8]
    Units: ng.h/ml
        arithmetic mean (standard deviation)
    58.84 ± 16.47
    Notes
    [8] - PK population
    No statistical analyses for this end point

    Secondary: 7_Everolimus day time Cmin and Cmax

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    End point title
    		 7_Everolimus day time Cmin and Cmax
    End point description
    A 24-hour multiple blood sampling for PK assessment was performed on Visit 6 (study Day 10 to 12). Thirteen (13) samples for the determination of tacrolimus concentrations in whole blood in the 0-24 h interval were taken at the following times: 0.00 (within 5 minutes before the morning 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 h post-dose. Minimum (Cmin) and maximum (Cmax) observed blood concentration following a single dose, obtained directly from the blood concentration versus time curves. It was obtained directly from the experimental data without interpolation. Overall results have been reported.
    End point type
    Secondary
    End point timeframe
    Visit 6 (Day 10 to Day 12) - day time
    End point values
    		 Study Treatment
    Number of subjects analysed
    23 [9]
    Units: ng/ml
    arithmetic mean (standard deviation)
        everolimus_Cmin_day time
    2.81 ± 0.91
        everolimus_Cmax_day time
    10.65 ± 3.55
    Notes
    [9] - PK population
    No statistical analyses for this end point

    Secondary: 8_Everolimus day time tmax

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    End point title
    		 8_Everolimus day time tmax
    End point description
    A 24-hour multiple blood sampling for PK assessment was performed on Visit 6 (study Day 10 to 12). Thirteen (13) samples for the determination of tacrolimus concentrations in whole blood in the 0-24 h interval were taken at the following times: 0.00 (within 5 minutes before the morning 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 h post-dose. Time from dosing to Cmax (tmax), reported using actual times. Overall results have been reported.
    End point type
    Secondary
    End point timeframe
    Visit 6 (Day 10 to Day 12) - day time
    End point values
    		 Study Treatment
    Number of subjects analysed
    23 [10]
    Units: hour
        arithmetic mean (standard deviation)
    1.34 ± 0.91
    Notes
    [10] - PK population
    No statistical analyses for this end point

    Secondary: 9_Everolimus day time linear correlation coefficient between AUC12 and Cmin

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    End point title
    		 9_Everolimus day time linear correlation coefficient between AUC12 and Cmin
    End point description
    A 24-hour multiple blood sampling for PK assessment was performed on Visit 6 (study Day 10 to 12). Thirteen (13) samples for the determination of tacrolimus concentrations in whole blood in the 0-24 h interval were taken at the following times: 0.00 (within 5 minutes before the morning 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 h post-dose. Linear correlation refers to linear correlation coefficent (R2) between Cmin and AUC12. Overall results have been reported expressed as a pure number to be multiplied by 10(-4).
    End point type
    Secondary
    End point timeframe
    Visit 6 (Day 10 to Day 12) - day time
    End point values
    		 Study Treatment
    Number of subjects analysed
    23 [11]
    Units: pure number by 10(-4) [0-1]
    7706
    Notes
    [11] - PK population
    No statistical analyses for this end point

    Secondary: 10_Serum creatinine

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    End point title
    		 10_Serum creatinine
    End point description
    For serum creatinine, baseline was defined as Visit 1 (screening) evaluation. Change from baseline for serum creatinine results have been reported from day 1 to month 6.
    End point type
    Secondary
    End point timeframe
    Renal function was evaluated measuring serum creatinine on blood samples taken at each visit (before transplant and on Day 1, 3, 5, 7, 10 and Month 1, 2, 3, 4, 5 and 6).
    End point values
    		 Study Treatment
    Number of subjects analysed
    28 [12]
    Units: micromole(s)/litre
    arithmetic mean (standard deviation)
        change from baseline_day 1
    -135.6 ± 298.2
        change from baseline_day 3
    -290.7 ± 378.6
        change from baseline_day 5
    -378.0 ± 402.5
        change from baseline_day 7
    -427.4 ± 374.2
        change from baseline_day 10
    -485.0 ± 349.3
        change from baseline_month 1
    -508.4 ± 308.8
        change from baseline_month 2
    -459.3 ± 277.7
        change from baseline_month 3
    -501.4 ± 313.9
        change from baseline_month 4
    -496.1 ± 312.5
        change from baseline_month 5
    -505.6 ± 327.1
        change from baseline_month 6
    -507.7 ± 333.8
    Notes
    [12] - ITT population
    No statistical analyses for this end point

    Secondary: 11_Estimated glomerular filtration rate (eGFR)

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    End point title
    		 11_Estimated glomerular filtration rate (eGFR)
    End point description
    The eGFR was calculated with different methods for each site, therefore at the DRM it was decided to derive the eGFR. It was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. For eGFR, baseline was defined as Visit 1 (screening) evaluation. Actual valueas and Change from baseline for eGFR results have been reported from day 1 to month 6.
    End point type
    Secondary
    End point timeframe
    Analised before transplant (screening) and on Day 1, 3, 5, 7, 10 and Month 1, 2, 3, 4, 5 and 6.
    End point values
    		 Study Treatment
    Number of subjects analysed
    28 [13]
    Units: ml/min per 1.73 m2
    arithmetic mean (standard deviation)
        change from baseline_day 1
    3.0 ± 7.9
        change from baseline_day 3
    13.7 ± 22.0
        change from baseline_day 5
    20.6 ± 23.3
        change from baseline_day 7
    24.8 ± 22.5
        change from baseline_day 10
    29.5 ± 26.0
        change from baseline_month 1
    32.4 ± 19.8
        change from baseline_month 2
    29.8 ± 15.6
        change from baseline_month 3
    29.5 ± 16.9
        change from baseline_month 4
    29.0 ± 18.8
        change from baseline_month 5
    30.4 ± 16.9
        change from baseline_month 6
    31.3 ± 17.8
        actual value_day 1
    10.5 ± 7.5
        actual value_day 3
    21.4 ± 21.2
        actual value_day 5
    28.5 ± 22.5
        actual value_day 7
    32.6 ± 21.7
        actual value_day 10
    37.3 ± 25.4
        actual value_month 1
    40.0 ± 18.0
        actual value_month 2
    37.6 ± 13.8
        actual value_month 3
    37.2 ± 15.3
        actual value_month 4
    36.9 ± 17.4
        actual value_month 5
    38.2 ± 15.0
        actual value_month 6
    39.2 ± 15.8
    Notes
    [13] - ITT Population
    No statistical analyses for this end point

    Secondary: 12_Treatment failure rate

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    End point title
    		 12_Treatment failure rate
    End point description
    Efficacy endpoint. Treatment failure rate, a composite endpoint,including biopsy proven acute rejection (BPAR), graft failure, death and lost to follow up, and the rate of each component of composite endpoint. Overall results have been reported. Note: BPAR= biopsy proven acute rejection.
    End point type
    Secondary
    End point timeframe
    Within 6 months.
    End point values
    		 Study Treatment
    Number of subjects analysed
    28 [14]
    Units: percentage of subject (0-100%)
        overall_BPAR
    0
        overall_graft failure
    0
        overall_death
    0
        overall_treatment failure
    0
        overall_lost to follow up
    0
    Notes
    [14] - ITT population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE, SAE and ADR were collected throughout the study. From Visit 1 (screening) to Visit 12 (month 6).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Study Treatment
    Reporting group description
    		 all the subjects receiving the study drugs (Envarsus® and everolimus)

    Serious adverse events
    		 Study Treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 28 (50.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Blood creatine increased
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Perirenal haematoma
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural urine leak
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Lymphocele
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pelvic fluid collection
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary oedema
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Study Treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 28 (96.43%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    3
    Hypertension
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Haematoma
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Hypotension
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Lymphocele
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Lymphorrhoea
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    General disorders and administration site conditions
    Oedema
         subjects affected / exposed
    6 / 28 (21.43%)
         occurrences all number
    6
    Chest pain
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Pyrexia
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Catheter site pain
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Pelvic fluid collection
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Dyspnoea
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 28 (14.29%)
         occurrences all number
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Sputum culture positive
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    White blood cell count decreased
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Procedural pain
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Sinus tachycardia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Tachycardia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 28 (50.00%)
         occurrences all number
    14
    Leukopenia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    4 / 28 (14.29%)
         occurrences all number
    4
    Diarrhoea
         subjects affected / exposed
    4 / 28 (14.29%)
         occurrences all number
    5
    Abdominal pain
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Dyspepsia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Inguinal hernia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    3
    Proteinuria
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    3
    Anuria
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Bladder spasm
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Oliguria
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Strangury
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    6 / 28 (21.43%)
         occurrences all number
    7
    Cytomegalovirus infection
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    3
    Urinary tract infection enterococcal
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    11 / 28 (39.29%)
         occurrences all number
    14
    Hypomagnesaemia
         subjects affected / exposed
    5 / 28 (17.86%)
         occurrences all number
    5
    Hyperuricaemia
         subjects affected / exposed
    4 / 28 (14.29%)
         occurrences all number
    4
    Hypocalcaemia
         subjects affected / exposed
    4 / 28 (14.29%)
         occurrences all number
    5
    Hypercholesterolaemia
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    3
    Hyperkalaemia
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    4
    Hypertriglyceridaemia
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    3
    Metabolic acidosis
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    4
    Hyperglycaemia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Hypernatraemia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Hyposideraemia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Vitamin D deficiency
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2

    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? 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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