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    Clinical Trial Results:
    A Phase II Study to Evaluate the Efficacy of IdeS (IgG endopeptidase) to Desensitize Transplant Patients with a Positive Crossmatch Test

    Summary
    EudraCT number
    		 2016-002064-13
    Trial protocol
    		 SE   FR  
    Global end of trial date
    03 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jul 2019
    First version publication date
    25 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    15-HMedIdeS-06
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02790437
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hansa Biopharma AB
    Sponsor organisation address
    Scheelevägen 22, Lund, Sweden, 223 63
    Public contact
    Clinical Trials Information, Hansa Biopharma AB, Hansa Biopharma AB, clinicalstudyinfo@hansabiopharma.com
    Scientific contact
    Clinical Trials Information, Hansa Biopharma AB, Hansa Biopharma AB, clinicalstudyinfo@hansabiopharma.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
    27 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To asses the efficacy of imlifidase in creating a negative crossmatch test
    Protection of trial subjects
    Patients who were not eligible for transplantation after imlifidase treatment were not transplanted and thus did not receive any induction therapy or immunosuppression. All patients who received imlifidase were asked to remain in the study and followed up according to the study protocol even if they were not transplanted. Patients who lost their graft during the study remained in the study and were followed up according to the study protocol and/or clinical practice at the study site. After study completion, all patients were followed up regularly and interdisciplinary (by nephrologist and transplant surgeons) according to each centre’s follow-up routines for transplanted patients. The frequencies of outpatient visits were adjusted individually to the state of patient Health and transplant function. Patients whose ADA levels had not returned to normal range at study completion were asked to return for a follow-up ADA sample at 12 months.
    Background therapy
    		 Premedication: Glucocorticoids (methylprednisolone, 250 mg IV) and antihistamines (loratadine 10 mg orally or an equipotent antihistamine) before each imlifidase infusion. Prophylactic antibiotics or sulphonamides: According to clinical practice at each site from the start of imlifidase treatment until the serum IgG level was back within normal range. IVig and rituximab: High dose IVIg 10% solution 2 g/kg (maximum 140 g for >70 kg) 7 days after imlifidase treatment and 1 g rituximab (anti-CD20 antibody) 9 days after imlifidase treatment. If deemed necessary by the investigator, the IVIg dose could be split into two doses administered over days 6-8. Immunosuppressing agents: According to clinical practice at each study site. Induction therapy: If indicated, sites could use either ATGAM or alemtuzumab. Rabbit ATG could not be used since it is efficiently cleaved by imlifidase. Alemtuzumab could be administered 4 days after imlifidase at the earliest, based on limited experience. If alemtuzumab was used as induction therapy on day 4, pulse steroid treatment could be used up to day 4 to prevent T-cell mediated rejection.
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    30 Sep 2016
    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
    Sweden: 2
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    19
    EEA total number of subjects
    5
    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)
    19
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited between 30-Sep-2016 and 28-Nov-2017 in US. Patients were recruited between 21-Mar-2017 and 27-Nov-2017 in EEA.

    Pre-assignment
    Screening details
    		 A total of 21 patients were screened world-wide and 19 were enrolled in the study. One screening failure was reported from US and one from EEA.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 0.25 mg/kg
    Arm description
    		 One IV infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Imlifidase
    Investigational medicinal product code
    Other name
    IdeS, IgG endopeptidase
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    After dilution imfilidase was administered as an IV infusion over at least 15 minutes using a syringe or an infusion bag, an infusion pump and a particle filter.

    Arm title
    		 2 x 0.25 mg/kg
    Arm description
    		 Two IV infusions. The first dose on day 0 and as the desired effect was not achieved (i.e. a negative CXM test was not obtained) an additional imlifidase infusion was given within 2 days of the first infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Imlifidase
    Investigational medicinal product code
    Other name
    IdeS, IgG endopeptidase
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    After dilution imfilidase was administered as an IV infusion over at least 15 minutes using a syringe or an infusion bag, an infusion pump and a particle filter.

    Number of subjects in period 1
    		0.25 mg/kg 2 x 0.25 mg/kg
    Started
    16
    3
    Completed
    13
    3
    Not completed
    3
    0
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    1
    -
         Patient graft failure-nephrectomy
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 19 19
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 19 19
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 39.10 ( 10.80 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 13 13

    End points

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    End points reporting groups
    Reporting group title
    0.25 mg/kg
    Reporting group description
    		 One IV infusion.

    Reporting group title
    2 x 0.25 mg/kg
    Reporting group description
    		 Two IV infusions. The first dose on day 0 and as the desired effect was not achieved (i.e. a negative CXM test was not obtained) an additional imlifidase infusion was given within 2 days of the first infusion.

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS comprises data from all patients in the safety analysis set (SAS) with available post-dose efficacy data. The FAS is used for presentation of efficacy endpoints

    Subject analysis set title
    SAS
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The SAS comprises data from all patients dosed with any amount of study medication.

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP analysis set consists of all patients in the safety set who had at least one efficacy endpoint value. Data from patients with one or more major protocol deviations were excluded. The PP analysis set is used for presentation of PK and PD endpoints.

    Primary: Conversion of a positive crossmatch to a negative within 24h

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    End point title
    		 Conversion of a positive crossmatch to a negative within 24h [1]
    End point description
    Crossmatch was assessed using both FACS CXM and CDC CXM tests. The FACS CXM is a multi-staining procedure where the recipient’s serum is used to stain donor cells to identify the presence of donor specific antibodies (DSAs) in recipient’s serum. T- and B-cells were identified using conjugated antibodies against CD3 and CD19, respectively. DSAs were identified using a conjugated anti-human antibody. The CDC CXM test evaluates the cytotoxic capacity of the DSAs. The recipient’s serum was mixed with donor cells prior to addition of complement. Fluorescent dyes were added to the mixture and the percentage of live/dead cells was scored using a fluorescent microscope. In case an anti-human globulin was used as an amplifier for the CDC CXM, the laboratory was also required to perform a non-amplified CDC CXM test. The primary endpoint was met if at least one assay was positive pre-dose and the last assay within 24 h post-dose was negative.
    End point type
    Primary
    End point timeframe
    Crossmatch (CXM) was assessed pre-dose and at up to 3 times within 24 h post dose (i.e. 2h, 6h and 24h post dose). If one or both the tests at 2 and 6 h were negative the patient proceeded to transplantation and no more CXM test was performed.
    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: Data for the primary endpoint was summarized for FAS. No statistical significance testing was performed due to few patients in the two treatment arms. All endpoints were presented using descriptive statistics, individual listings and graphs.
    End point values
    		 FAS
    Number of subjects analysed
    19
    Units: CXM conversion within 24 h
        Yes
    17
        No
    2
    No statistical analyses for this end point

    Secondary: Donor Specific Antibodies (DSAs)

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    End point title
    		 Donor Specific Antibodies (DSAs)
    End point description
    DSA levels were measured using the single antigen beads (SAB) anti-HLA assay. The levels were determined as mean fluorescence intensity (MFI). Positive DSA (i.e. HLA antibodies) were defined as a MFI value >3000.
    End point type
    Secondary
    End point timeframe
    Pre-dose , 2h, 6 h, 24 h, 48 h, 96 h, 7 dys, 14 days, 28 days, 90 days and 180 days.
    End point values
    		 PP
    Number of subjects analysed
    18 [2]
    Units: Number of patients with DSA (MFI>3000)
        Pre-dose
    17
        2 h
    7
        6 h
    3
        24 h
    3
        48 h
    3
        96 h
    6
        7 days
    9
        14 days
    13
        28 days
    10
        90 days
    8
        180 days
    7
    Notes
    [2] - Except for Day 180 when the number of subjects was 17
    No statistical analyses for this end point

    Secondary: Kidney function - eGFR

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    End point title
    		 Kidney function - eGFR
    End point description
    Estimated glomerular filtration rate (eGFR) calculated as described by the MDRD equation is a measure of kidney function. eGFR for a kidney with normal function is 90 mL/min/1.72m2. Kidney disease is characterised by a decreased eGFR value.
    End point type
    Secondary
    End point timeframe
    Day 28, Day 90 and Day 180
    End point values
    		 PP
    Number of subjects analysed
    18 [3]
    Units: Number of patients
        >60 mL/min/1.72m2 at Day 28
    4
        >60 mL/min/1.72m2 at Day 90
    6
        >60 mL/min/1.72m2 at Day 180
    4
        30-59 mL/min/1.72m2 at Day 28
    9
        30-59 mL/min/1.72m2 at Day 90
    7
        30-59 mL/min/1.72m2 at Day 180
    11
        <30 mL/min/1.72m2 at Day 28
    5
        <30 mL/min/1.72m2 at Day 90
    4
        <30 mL/min/1.72m2 at Day 180
    2
    Notes
    [3] - Except for Day 90 and 180 when the number of subjects was 17 as 1 subject lost the graft Day 77
    No statistical analyses for this end point

    Secondary: Serum IgG concentration - PD

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    End point title
    		 Serum IgG concentration - PD
    End point description
    IgG concentration refers to the sum of intact IgG and single-cleaved IgG. Please note that IvIg was administered Day 7.
    End point type
    Secondary
    End point timeframe
    Pre-dose to Day 180
    End point values
    		 0.25 mg/kg 2 x 0.25 mg/kg PP
    Number of subjects analysed
    15 [4]
    3 [5]
    18 [6]
    Units: IgG concentration
    geometric mean (geometric coefficient of variation)
        Pre-dose
    10.11 ( 85.92 )
    8.35 ( 55.37 )
    9.79 ( 79.73 )
        2 h
    1.19 ( 91.05 )
    0.68 ( 165.87 )
    1.08 ( 100.51 )
        6 h
    0.55 ( 83.44 )
    0.38 ( 109.18 )
    0.52 ( 85.49 )
        24 h
    0.37 ( 79.14 )
    0.15 ( 42.46 )
    0.32 ( 83.92 )
        48 h
    0.51 ( 129.17 )
    0.17 ( 45.57 )
    0.43 ( 132.55 )
        Day 7 pre-IVIg
    0.64 ( 107.44 )
    0.2 ( 96.88 )
    0.53 ( 122.3 )
        Day 7 post-IVIg
    16.52 ( 49.9 )
    18.47 ( 23.91 )
    16.89 ( 45.05 )
        Day 9
    15.34 ( 85.32 )
    26.94 ( 50.82 )
    16.85 ( 83 )
        Day 14
    13.48 ( 55.67 )
    10.85 ( 53.42 )
    13 ( 54.34 )
        Day 21
    10.57 ( 58.67 )
    5.88 ( 88.3 )
    9.58 ( 66.04 )
        Day 28
    10.25 ( 69.85 )
    11.53 ( 66.45 )
    10.45 ( 67.16 )
        Day 64
    11.91 ( 71.52 )
    7.77 ( 45.82 )
    11.09 ( 69.02 )
        Day 180
    9.33 ( 42.58 )
    8.99 ( 0 )
    9.28 ( 39.21 )
    Notes
    [4] - Data for 7 patients at Day 180
    [5] - Data for 1 patient only at Day 180
    [6] - Data for 8 patients at Day 180
    No statistical analyses for this end point

    Secondary: PK - Cmax

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    End point title
    		 PK - Cmax
    End point description
    Cmax = Maximum observed plasma concentration of imlifidase following dosing (Non-compartmental PK analysis)
    End point type
    Secondary
    End point timeframe
    Pre-dose to Day 14
    End point values
    		 PP
    Number of subjects analysed
    18 [7]
    Units: microgram(s)/millilitre
    geometric mean (geometric coefficient of variation)
        Cmax (first dose)
    3.95 ( 25.2 )
        Cmax (second dose)
    4.13 ( 29.4 )
    Notes
    [7] - Cmax (second dose) calculated for 3 subjects only who received a 2nd dose 11-13h after the first.
    No statistical analyses for this end point

    Secondary: PK - Tmax

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    End point title
    		 PK - Tmax
    End point description
    Tmax = time point for maximum observed plasma concentration of imlifidase following dosing (Non-compartmental PK analysis)
    End point type
    Secondary
    End point timeframe
    Pre-dose to Day 14
    End point values
    		 PP
    Number of subjects analysed
    18 [8]
    Units: hour
    arithmetic mean (standard deviation)
        Tmax (first dose)
    2.21 ( 0.31 )
        Tmax (second dose)
    15.98 ( 5.50 )
    Notes
    [8] - Tmax (second dose) - 3 subjects only who received a second dose 11-13h after the first dose
    No statistical analyses for this end point

    Secondary: PK - AUC

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    End point title
    		 PK - AUC
    End point description
    AUC = area under the plasma concentration vs time curve (Non-compartmental PK analysis)
    End point type
    Secondary
    End point timeframe
    Pre-dose to Day 14
    End point values
    		 PP
    Number of subjects analysed
    9
    Units: h x microgram(s)/millilitre
        geometric mean (geometric coefficient of variation)
    156.09 ( 45.4 )
    No statistical analyses for this end point

    Secondary: PK - Alpha t1/2 and Beta t1/2

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    End point title
    		 PK - Alpha t1/2 and Beta t1/2
    End point description
    Alpha t1/2 = half-life during distribution phase, Beta t1/2 = half-life during elimination phase (Non-compartmental PK analysis)
    End point type
    Secondary
    End point timeframe
    Pre-dose to Day 14
    End point values
    		 PP
    Number of subjects analysed
    9 [9]
    Units: hour
    arithmetic mean (standard deviation)
        Alpha t1/2
    4.58 ( 3.85 )
        Beta t1/2
    76.30 ( 42.76 )
    Notes
    [9] - Please note - Harmonic mean (SD) was used rather than arithmetic mean (SD)
    No statistical analyses for this end point

    Secondary: PK - CL

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    End point title
    		 PK - CL
    End point description
    CL = clearance (Non-compartmental PK analysis)
    End point type
    Secondary
    End point timeframe
    Pre-dose to Day 14
    End point values
    		 PP
    Number of subjects analysed
    9
    Units: millilitre(s)/hour/kilogram
        geometric mean (geometric coefficient of variation)
    1.60 ( 45.4 )
    No statistical analyses for this end point

    Secondary: PK - Vss

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    End point title
    		 PK - Vss
    End point description
    Vss = Volume of distribution at steady state (Non-compartmental PK analysis)
    End point type
    Secondary
    End point timeframe
    Pre-dose to Day 14
    End point values
    		 PP
    Number of subjects analysed
    9
    Units: litre(s)/kilogram
        geometric mean (geometric coefficient of variation)
    0.14 ( 26.9 )
    No statistical analyses for this end point

    Secondary: PK - Vz

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    End point title
    		 PK - Vz
    End point description
    Vz = Volume of distribution during the elimination phase (Non-compartmental PK analysis)
    End point type
    Secondary
    End point timeframe
    Pre-dose to Day 14
    End point values
    		 PP
    Number of subjects analysed
    9
    Units: litre(s)/kilogram
        geometric mean (geometric coefficient of variation)
    0.19 ( 27.0 )
    No statistical analyses for this end point

    Secondary: Safety - AEs

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    End point title
    		 Safety - AEs
    End point description
    End point type
    Secondary
    End point timeframe
    AEs were collected from the time of signing of the ICF until end of study, incl the follow-up period (=day 180) Presented AEs include TEAEs and post-treatment AEs, i.e. all AEs occurring after first dose of IdeS until day 180
    End point values
    		 0.25 mg/kg 2 x 0.25 mg/kg SAS
    Number of subjects analysed
    16
    3
    19
    Units: Number of AEs
        Adverse Events
    332
    63
    395
        Serious Adverse Events
    33
    8
    41
        AEs leading to study discontinuation
    1
    0
    1
        AEs leading to death
    0
    0
    0
        Severe AEs (Grade 3 and 4)
    62
    19
    81
        Related AEs
    6
    1
    7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from the time of signing of the ICF until end of study, incl the follow-up period AEs reported in EudraCT include TEAEs and post-treatment AEs, i.e. all AEs occurring after admin of the IMP until end of study, incl the follow-up period
    Adverse event reporting additional description
    Data on AEs were obtained if spontaneously reported by the patient, if reported in response to an open question from the study personnel or if revealed by observation. A TEAE was defined as any AE occurring after the administration of the IMP and within the time of the residual drug effect period (i.e. 30 days after IMP administration).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    0.25 mg/kg
    Reporting group description
    		 -

    Reporting group title
    2 x 0.25 mg/kg
    Reporting group description
    		 -

    Reporting group title
    Total
    Reporting group description
    		 -

    Serious adverse events
    		 0.25 mg/kg 2 x 0.25 mg/kg Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 16 (75.00%)
    3 / 3 (100.00%)
    15 / 19 (78.95%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Blood creatine increased
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 3 (33.33%)
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Donor specific antibody present
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transplant failure
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weaning failure
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Axillary vein thrombosis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombotic microangiopathy
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Thrombosis in device
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Transplant rejection
         subjects affected / exposed
    7 / 16 (43.75%)
    2 / 3 (66.67%)
    9 / 19 (47.37%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 2
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Glomerulonephritis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 3 (33.33%)
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Perinephric abscess
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 0.25 mg/kg 2 x 0.25 mg/kg Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 16 (93.75%)
    3 / 3 (100.00%)
    18 / 19 (94.74%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Flushing
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Haematoma
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Hypertension
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 3 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    3
    0
    3
    Hypotension
         subjects affected / exposed
    4 / 16 (25.00%)
    0 / 3 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    5
    0
    5
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    General disorders and administration site conditions
    Administration site pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Application site pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Application site pruritus
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Breakthrough pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Catheter site haemorrhage
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Catheter site pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    2
    Chest discomfort
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Chest pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Generalised oedema
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Haemorrhagic cyst
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Oedema
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Oedema peripheral
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 3 (33.33%)
    3 / 19 (15.79%)
         occurrences all number
    5
    2
    7
    Pain
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    5
    0
    5
    Peripheral swelling
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Pyrexia
         subjects affected / exposed
    4 / 16 (25.00%)
    0 / 3 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    4
    0
    4
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    2
    0
    2
    Hypogammaglobulinaemia
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 3 (66.67%)
    4 / 19 (21.05%)
         occurrences all number
    2
    2
    4
    Transplant rejection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 3 (33.33%)
    3 / 19 (15.79%)
         occurrences all number
    2
    1
    3
    Dyspnoea
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    3
    0
    3
    Hiccups
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    2
    0
    2
    Laryngeal oedema
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Lung disorder
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Pulmonary oedema
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Throat irritation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Throat lesion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Agitation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Anxiety
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 3 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    3
    0
    3
    Depression
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    2
    0
    2
    Hallucination
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Insomnia
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 3 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    3
    0
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 3 (33.33%)
    3 / 19 (15.79%)
         occurrences all number
    2
    1
    3
    Blood potassium decreased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Clostridium test positive
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Donor specific antibody present
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 3 (33.33%)
    3 / 19 (15.79%)
         occurrences all number
    2
    1
    3
    Hepatitis B core antibody positive
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Respiratory rate decreased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Sapovirus test positive
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Transaminases increased
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 3 (33.33%)
    4 / 19 (21.05%)
         occurrences all number
    4
    1
    5
    Urine output decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    2
    Complications of transplant surgery
         subjects affected / exposed
    4 / 16 (25.00%)
    0 / 3 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    4
    0
    4
    Delayed graft function
         subjects affected / exposed
    7 / 16 (43.75%)
    1 / 3 (33.33%)
    8 / 19 (42.11%)
         occurrences all number
    7
    1
    8
    Incision site pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Infusion related reaction
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    3
    0
    3
    Procedural pain
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 3 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    4
    0
    4
    Renal lymphocele
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Seroma
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    2
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Pericardial effusion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Tachycardia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 3 (33.33%)
    3 / 19 (15.79%)
         occurrences all number
    2
    1
    3
    Hypoaesthesia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Tongue paralysis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Tremor
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 16 (56.25%)
    2 / 3 (66.67%)
    11 / 19 (57.89%)
         occurrences all number
    11
    4
    15
    Anaemia of chronic disease
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Leukopenia
         subjects affected / exposed
    4 / 16 (25.00%)
    0 / 3 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    5
    0
    5
    Neutropenia
         subjects affected / exposed
    4 / 16 (25.00%)
    2 / 3 (66.67%)
    6 / 19 (31.58%)
         occurrences all number
    4
    3
    7
    Thrombocytopenia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Thrombocytosis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 3 (33.33%)
    2 / 19 (10.53%)
         occurrences all number
    1
    1
    2
    Abdominal pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Abdominal pain lower
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Constipation
         subjects affected / exposed
    7 / 16 (43.75%)
    2 / 3 (66.67%)
    9 / 19 (47.37%)
         occurrences all number
    12
    3
    15
    Diarrhoea
         subjects affected / exposed
    7 / 16 (43.75%)
    0 / 3 (0.00%)
    7 / 19 (36.84%)
         occurrences all number
    9
    0
    9
    Dyspepsia
         subjects affected / exposed
    5 / 16 (31.25%)
    0 / 3 (0.00%)
    5 / 19 (26.32%)
         occurrences all number
    7
    0
    7
    Flatulence
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    3
    0
    3
    Gastritis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 3 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    3
    0
    3
    Impaired gastric emptying
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Intra-abdominal haemorrhage
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Nausea
         subjects affected / exposed
    7 / 16 (43.75%)
    1 / 3 (33.33%)
    8 / 19 (42.11%)
         occurrences all number
    7
    1
    8
    Paraesthesia oral
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Perianal erythema
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Vomiting
         subjects affected / exposed
    7 / 16 (43.75%)
    0 / 3 (0.00%)
    7 / 19 (36.84%)
         occurrences all number
    9
    0
    9
    Hepatobiliary disorders
    Hepatocellular injury
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Pruritus
         subjects affected / exposed
    6 / 16 (37.50%)
    0 / 3 (0.00%)
    6 / 19 (31.58%)
         occurrences all number
    8
    0
    8
    Rash
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 3 (33.33%)
    2 / 19 (10.53%)
         occurrences all number
    1
    2
    3
    Swelling face
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 16 (25.00%)
    0 / 3 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    5
    0
    5
    Bladder spasm
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Hypertonic bladder
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Micturition urgency
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Polyuria
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Proteinuria
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Renal cyst haemorrhage
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Endocrine disorders
    Hyperparathyroidism secondary
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Back pain
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    2
    0
    2
    Flank pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Muscle spasms
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 3 (33.33%)
    4 / 19 (21.05%)
         occurrences all number
    3
    1
    4
    Osteoporosis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Pain in extremity
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Bronchitis viral
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Cytomegalovirus viraemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Ear infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 3 (33.33%)
    2 / 19 (10.53%)
         occurrences all number
    1
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences all number
    0
    2
    2
    Perinephric abscess
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Pseudomonas infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Pyuria
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Rhinitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 3 (33.33%)
    2 / 19 (10.53%)
         occurrences all number
    1
    1
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    4
    0
    4
    Viraemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Dehydration
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Diabetes mellitus
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 3 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    3
    0
    3
    Fluid overload
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Fluid retention
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Gout
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    4 / 16 (25.00%)
    0 / 3 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    5
    0
    5
    Hyperkalaemia
         subjects affected / exposed
    5 / 16 (31.25%)
    2 / 3 (66.67%)
    7 / 19 (36.84%)
         occurrences all number
    6
    4
    10
    Hyperphosphataemia
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    2
    0
    2
    Hypertriglyceridaemia
         subjects affected / exposed
    4 / 16 (25.00%)
    3 / 3 (100.00%)
    7 / 19 (36.84%)
         occurrences all number
    5
    3
    8
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    4 / 16 (25.00%)
    0 / 3 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    5
    0
    5
    Hypoglycaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Hypokalaemia
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 3 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    3
    0
    3
    Hypomagnesaemia
         subjects affected / exposed
    6 / 16 (37.50%)
    3 / 3 (100.00%)
    9 / 19 (47.37%)
         occurrences all number
    8
    5
    13
    Hyponatraemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 3 (33.33%)
    4 / 19 (21.05%)
         occurrences all number
    3
    1
    4
    Iron deficiency
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Magnesium deficiency
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Metabolic acidosis
         subjects affected / exposed
    5 / 16 (31.25%)
    2 / 3 (66.67%)
    7 / 19 (36.84%)
         occurrences all number
    5
    2
    7
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Mar 2017
    - Information was added to the Risk/Benefit section. 2 patients had shown signs of serum sickness in an IdeS study in patients diagnosed with asymptomatic antibodymediated thrombotic thrombocytopenic purpura with low ADAMTS 13 activity. The 2 patients completed the study which was thereafter closed. 27 patients without concomitant immunosuppressive therapy have previously been given IdeS without signs of serum sickness why the sponsor cannot rule out that the underlying decease was a factor in the development of the signs. Based on all available safety information from non-clinical and clinical studies it was concluded that the overall benefit/risk profile of IdeS still appeared favorable. - Physical examination was added to the last visit (visit 12) - Biopsies were added at visit 2 (deceased donor and patient) and visit 12 (patient). Reason: Follow up on suspected rejections and other renal tissue damages are important information in the evaluation of kidney status. - The rescreening procedure was clarified - Exlusion criteria regarding HBV, HCV, CMV or EBV infections were updated to allow test results within 6 months. It was not determined feasible to await screening results given the turnaround time of the information for patients transplaned with a deceased donor kidney. - The exclusion criterion regarding thrombotic episodes was updated to include also patients with a history of a diagnosed hypercoagulable condition whithout a history of thrombotic episodes. - The protocol was updated to allow splitting the IVIg dose into 2 doses if deemed necessary by the investigator as the recommended dose may be too large to administer at one time for most patients. - The doses of methylprednisolone and loratadin were added. This information was inadvertently omitted in the previous version. In addition some clarifications to procedures (incl. updating of time windows) and editorial changes were done. This amendment was done to the US protocol
    09 May 2017
    This amendment was done to the French protocol. Please refer to the amendment dated 20-Mar-2017 for information on updates.
    14 Jun 2017
    This amendment was done to the Swedish protocol. Please refer to the amendment dated 20-Mar-2017 for information on updates.

    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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