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    Clinical Trial Results:
    A first-in-human, two-part (open label, and randomized/double blind/placebo controlled), single- and repeat-dose study of CSJ137 in erythropoietin-treated chronic hemodialysis patients with functional iron-deficiency anemia

    Summary
    EudraCT number
    		 2017-002926-19
    Trial protocol
    		 GB  
    Global end of trial date
    13 May 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    19 May 2022
    First version publication date
    12 Apr 2021
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Dose information updated

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CCSJ137X2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02570854
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    13 May 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 May 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of the study was to: - To assess safety and tolerability following a single dose of CSJ137 - To determine the minimum pharmacologically active dose (PAD) of CSJ137 Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 All prescription medications, over-the-counter drugs and significant non-drug therapies (including physical therapy and blood transfusions) administered or taken within the timeframe defined in the entry criteria prior to the start of the study and during the study, were recorded on the Concomitant medications/ Significant non-drug therapies section of the CRF.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Sep 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Israel: 19
    Country: Number of subjects enrolled
    United States: 21
    Worldwide total number of subjects
    40
    EEA total number of subjects
    0
    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)
    27
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a multicenteric study in which 40 participants were enrolled in 10 centers across 2 countries: Israel (6) and USA (4).

    Pre-assignment
    Screening details
    		 All the participants were assigned to one of the 8 open label dose cohorts.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding occurred in the Part 1 of this study as it was an open label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: 0.01mg/ kg
    Arm description
    		 participants received a single dose of CSJ137 having lower ferritin inclusion criteria than participants in subsequent cohorts
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSJ137
    Investigational medicinal product code
    CSJ137
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    participants received a single dose of CSJ137 having lower ferritin inclusion criteria than participants in subsequent cohorts

    Arm title
    		 Cohort 1: 1.62mg/ kg
    Arm description
    		 one participant had a dosing error and was thus reported in a separate group. The participant had lower ferritin inclusion criteria than participants in subsequent cohorts
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSJ137
    Investigational medicinal product code
    CSJ137
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    one participant had a dosing error and was thus reported in a separate group. Dose 1a was in the range between Dose 6 and Dose 7. The participant had lower ferritin inclusion criteria than participants in subsequent cohorts

    Arm title
    		 Cohort 2: 0.01mg/kg
    Arm description
    		 participants received the same dose level as participants in Cohort 1: 0.01mg/ kg:, but had higher ferritin inclusion criteria than participants from Cohort 1
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSJ137
    Investigational medicinal product code
    CSJ137
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    participants received the same dose level as participants in Cohort 1: Dose 1 group, but had higher ferritin inclusion criteria than participants from Cohort 1

    Arm title
    		 Cohort 3: 0.04mg/ kg
    Arm description
    		 single dose of CSJ137
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSJ137
    Investigational medicinal product code
    CSJ137
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    participants received a single dose of CSJ137

    Arm title
    		 Cohort 4: 0.10mg/ kg
    Arm description
    		 single dose of CSJ137
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSJ137
    Investigational medicinal product code
    CSJ137
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    participants received a single dose of CSJ137

    Arm title
    		 Cohort 5: 0.30mg/ kg
    Arm description
    		 single dose of CSJ137
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSJ137
    Investigational medicinal product code
    CSJ137
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    participants received a single dose of CSJ137

    Arm title
    		 Cohort 6: 1.00mg/ kg
    Arm description
    		 single dose of CSJ137
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSJ137
    Investigational medicinal product code
    CSJ137
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    participants received a single dose of CSJ137

    Arm title
    		 Cohort 7: 3.00mg/ kg
    Arm description
    		 single dose of CSJ137
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSJ137
    Investigational medicinal product code
    CSJ137
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    participants received a single dose of CSJ137

    Arm title
    		 Cohort 8: 10.00mg/ kg
    Arm description
    		 single dose of CSJ137
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSJ137
    Investigational medicinal product code
    CSJ137
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    participants received a single dose of CSJ137

    Number of subjects in period 1
    		Cohort 1: 0.01mg/ kg Cohort 1: 1.62mg/ kg Cohort 2: 0.01mg/kg Cohort 3: 0.04mg/ kg Cohort 4: 0.10mg/ kg Cohort 5: 0.30mg/ kg Cohort 6: 1.00mg/ kg Cohort 7: 3.00mg/ kg Cohort 8: 10.00mg/ kg
    Started
    5
    1
    5
    3
    6
    3
    6
    5
    6
    Pharmacodynamics (PD) analysis set
    5
    1
    5
    3
    6
    3
    6
    5
    6
    Completed
    4
    1
    5
    3
    6
    3
    6
    5
    6
    Not completed
    1
    0
    0
    0
    0
    0
    0
    0
    0
         Subject/guardian decision
    1
    -
    -
    -
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: 0.01mg/ kg
    Reporting group description
    		 participants received a single dose of CSJ137 having lower ferritin inclusion criteria than participants in subsequent cohorts

    Reporting group title
    Cohort 1: 1.62mg/ kg
    Reporting group description
    		 one participant had a dosing error and was thus reported in a separate group. The participant had lower ferritin inclusion criteria than participants in subsequent cohorts

    Reporting group title
    Cohort 2: 0.01mg/kg
    Reporting group description
    		 participants received the same dose level as participants in Cohort 1: 0.01mg/ kg:, but had higher ferritin inclusion criteria than participants from Cohort 1

    Reporting group title
    Cohort 3: 0.04mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 4: 0.10mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 5: 0.30mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 6: 1.00mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 7: 3.00mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 8: 10.00mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group values
    		 Cohort 1: 0.01mg/ kg Cohort 1: 1.62mg/ kg Cohort 2: 0.01mg/kg Cohort 3: 0.04mg/ kg Cohort 4: 0.10mg/ kg Cohort 5: 0.30mg/ kg Cohort 6: 1.00mg/ kg Cohort 7: 3.00mg/ kg Cohort 8: 10.00mg/ kg Total
    Number of subjects
    		 5 1 5 3 6 3 6 5 6 40
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 4 1 3 3 3 2 5 5 1 27
        From 65-84 years
    		 1 0 2 0 3 1 1 0 5 13
        85 years and over
    		 0 0 0 0 0 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 58.20 ( 8.319 ) 61.00 ( 999 ) 48.20 ( 22.231 ) 56.67 ( 9.452 ) 62.33 ( 11.742 ) 60.00 ( 6.557 ) 59.83 ( 13.212 ) 52.20 ( 10.663 ) 67.17 ( 16.654 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 4 0 2 0 2 1 5 3 1 18
        Male
    		 1 1 3 3 4 2 1 2 5 22
    Race/Ethnicity, Customized
    Units: Subjects
        Other
    		 5 1 5 3 6 3 5 5 6 39
        Hispanic/Latino
    		 0 0 0 0 0 0 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: 0.01mg/ kg
    Reporting group description
    		 participants received a single dose of CSJ137 having lower ferritin inclusion criteria than participants in subsequent cohorts

    Reporting group title
    Cohort 1: 1.62mg/ kg
    Reporting group description
    		 one participant had a dosing error and was thus reported in a separate group. The participant had lower ferritin inclusion criteria than participants in subsequent cohorts

    Reporting group title
    Cohort 2: 0.01mg/kg
    Reporting group description
    		 participants received the same dose level as participants in Cohort 1: 0.01mg/ kg:, but had higher ferritin inclusion criteria than participants from Cohort 1

    Reporting group title
    Cohort 3: 0.04mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 4: 0.10mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 5: 0.30mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 6: 1.00mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 7: 3.00mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 8: 10.00mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Primary: Number of participants with adverse events and serious adverse events

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    End point title
    		 Number of participants with adverse events and serious adverse events [1]
    End point description
    Adverse events were collected from first dose of study treatment until end of study treatment Day 85. Any sign or symptom that occurred during the study treatment were collected.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 85 (end of study)
    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: No statistical analysis was planned for this primary outcome
    End point values
    		 Cohort 1: 0.01mg/ kg Cohort 1: 1.62mg/ kg Cohort 2: 0.01mg/kg Cohort 3: 0.04mg/ kg Cohort 4: 0.10mg/ kg Cohort 5: 0.30mg/ kg Cohort 6: 1.00mg/ kg Cohort 7: 3.00mg/ kg Cohort 8: 10.00mg/ kg
    Number of subjects analysed
    5
    1
    5
    3
    6
    3
    6
    5
    6
    Units: Participants
        Patients with AEs
    5
    1
    4
    3
    5
    2
    3
    2
    3
        Serious AEs
    3
    0
    2
    3
    0
    0
    1
    0
    0
    No statistical analyses for this end point

    Primary: Number of participants with Hemoglobin (Hgb) response

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    End point title
    		 Number of participants with Hemoglobin (Hgb) response [2]
    End point description
    The Hgb response was determined by levels of hemoglobin in blood, without the subject showing evidence of liver dysfunction or other safety concerns.
    End point type
    Primary
    End point timeframe
    Day 29
    Notes
    [2] - 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: No statistical analysis was planned for this outcome
    End point values
    		 Cohort 1: 0.01mg/ kg Cohort 1: 1.62mg/ kg Cohort 2: 0.01mg/kg Cohort 3: 0.04mg/ kg Cohort 4: 0.10mg/ kg Cohort 5: 0.30mg/ kg Cohort 6: 1.00mg/ kg Cohort 7: 3.00mg/ kg Cohort 8: 10.00mg/ kg
    Number of subjects analysed
    4
    1
    5
    3
    6
    3
    6
    4
    6
    Units: Participants
        Hgb response
    0
    0
    2
    1
    2
    1
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Peak concentration (Cmax) of CSJ137 in serum

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    End point title
    		 Peak concentration (Cmax) of CSJ137 in serum
    End point description
    Cmax is the observed maximum plasma (or serum or blood) concentration following administration (ug/mL)
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5 hours and 6 hours post-dose on Day 1, 2, 3, 5, 12, 19, 28, and 84
    End point values
    		 Cohort 1: 0.01mg/ kg Cohort 1: 1.62mg/ kg Cohort 2: 0.01mg/kg Cohort 3: 0.04mg/ kg Cohort 4: 0.10mg/ kg Cohort 5: 0.30mg/ kg Cohort 6: 1.00mg/ kg Cohort 7: 3.00mg/ kg Cohort 8: 10.00mg/ kg
    Number of subjects analysed
    5
    1
    5
    3
    5
    3
    6
    5
    6
    Units: ug/mL
        arithmetic mean (standard deviation)
    0.232 ( 0.193 )
    40.7 ( 999 )
    0.235 ( 0.0585 )
    1.49 ( 1.20 )
    1.88 ( 2.09 )
    4.38 ( 4.02 )
    17.1 ( 3.06 )
    65.7 ( 15.7 )
    197 ( 37.7 )
    No statistical analyses for this end point

    Secondary: Measurement of CSJ137 serum concentration and calculation of AUClast

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    End point title
    		 Measurement of CSJ137 serum concentration and calculation of AUClast
    End point description
    AUClast is the area under the curve calculated to the last quantifiable concentration point (day*ug/mL)
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5 hours and 6 hours post-dose on Day 1, 2, 3, 5, 12, 19, 28, and 84
    End point values
    		 Cohort 1: 0.01mg/ kg Cohort 1: 1.62mg/ kg Cohort 2: 0.01mg/kg Cohort 3: 0.04mg/ kg Cohort 4: 0.10mg/ kg Cohort 5: 0.30mg/ kg Cohort 6: 1.00mg/ kg Cohort 7: 3.00mg/ kg Cohort 8: 10.00mg/ kg
    Number of subjects analysed
    5
    1
    5
    3
    5
    3
    6
    5
    6
    Units: day*ug/mL
        arithmetic mean (standard deviation)
    1.11 ( 1.14 )
    449 ( 999 )
    0.893 ( 0.254 )
    9.19 ( 9.87 )
    11.1 ( 15.0 )
    34.7 ( 37.3 )
    269 ( 72.8 )
    799 ( 145 )
    3030 ( 839 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment until end of study treatment Day 85 plus 30 days post treatment (Day 115).
    Adverse event reporting additional description
    Any sign or symptom collected from first dose of study treatment until end of study treatment Day 85 plus 30 days post treatment (Day 115).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Cohort 1: 0.01mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 1: 1.62mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 2: 0.01mg/kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 3: 0.04mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 4: 0.10mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 5: 0.30mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 6: 1.00mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 7: 3.00mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Cohort 8: 10.00mg/ kg
    Reporting group description
    		 single dose of CSJ137

    Reporting group title
    Total
    Reporting group description
    		 Total

    Serious adverse events
    		 Cohort 1: 0.01mg/ kg Cohort 1: 1.62mg/ kg Cohort 2: 0.01mg/kg Cohort 3: 0.04mg/ kg Cohort 4: 0.10mg/ kg Cohort 5: 0.30mg/ kg Cohort 6: 1.00mg/ kg Cohort 7: 3.00mg/ kg Cohort 8: 10.00mg/ kg Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 5 (60.00%)
    0 / 1 (0.00%)
    2 / 5 (40.00%)
    3 / 3 (100.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    10 / 40 (25.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to spine
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arteriovenous fistula site complication
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure acute
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Myoclonus
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Large intestinal obstruction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea exertional
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Subcapsular renal haematoma
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1: 0.01mg/ kg Cohort 1: 1.62mg/ kg Cohort 2: 0.01mg/kg Cohort 3: 0.04mg/ kg Cohort 4: 0.10mg/ kg Cohort 5: 0.30mg/ kg Cohort 6: 1.00mg/ kg Cohort 7: 3.00mg/ kg Cohort 8: 10.00mg/ kg Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 5 (80.00%)
    1 / 1 (100.00%)
    4 / 5 (80.00%)
    3 / 3 (100.00%)
    5 / 6 (83.33%)
    2 / 3 (66.67%)
    3 / 6 (50.00%)
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    27 / 40 (67.50%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign neoplasm of skin
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 1 (100.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    4 / 40 (10.00%)
         occurrences all number
    1
    0
    0
    2
    0
    1
    1
    0
    0
    5
    Chills
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Gait disturbance
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    2
    Sinus congestion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Arteriovenous fistula site complication
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Arteriovenous graft site stenosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    2
    Fall
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    1
    2
    Humerus fracture
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    1
    Joint injury
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Scapula fracture
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Thermal burn
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    Arteriovenous fistula site haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 1 (100.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Abdominal pain lower
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Constipation
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    0
    2
    Dental caries
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    2
    0
    0
    3
    Duodenitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    2 / 5 (40.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    6 / 40 (15.00%)
         occurrences all number
    1
    0
    2
    1
    0
    0
    2
    0
    0
    6
    Rectal haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    0
    0
    0
    3
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    2
    Skin ulcer
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Endocrine disorders
    Hyperparathyroidism secondary
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    1
    2
    Joint swelling
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Muscle twitching
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    2
    Polyarthritis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Synovial cyst
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Infections and infestations
    Fungal skin infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    1
    Pustule
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    0
    0
    3
    Vaginal infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    2
    Metabolism and nutrition disorders
    Calciphylaxis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Decreased appetite
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Folate deficiency
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Hypervolaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    1
    Iron deficiency
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    Vitamin B12 deficiency
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jul 2015
    This amendment was implemented to address changes requested by United states food and drug administration (USFDA)  Changes to Inclusion criteria - Ferritin: lowered inclusionary values. This criterion was applied in cohort 1 only.  Study stopping rule and Cohort stopping rule: 1 or more SAEs that were not clearly related to the patients underlying disease reported  Liver safety monitoring: AST/ALT > 3 x ULN or TBL >1.5 x ULN repeat LFT within 48 hours
    24 Jul 2015
    This amendment was implemented to address changes requested by USFDA  Study stopping rule: Two or more patients experience a severe AE (s) (common terminology criteria (CTC) AE grade 3 that does not qualify as an SAE) during the study. Two or more Hy’s law cases  Cohort stopping rule: One patient experiences a severe AE (CTC AE grade 3 that does not qualify as an SAE) during the study that is not clearly related to the patient’s underlying disease. One Hy’s law case
    10 Nov 2015
    This amendment was implemented to address changes requested by Medicines and Healthcare products Regulatory Agency (MHRA) during their review  Confirmatory language changes for better clarity in study design  to include PK data for confirmation and consistency along with removing the duplicate text  to clarify that a communication plan on dissemination of safety information to investigators for dose escalation meetings in Part 1 and clarify dose escalation stopping rules  Added a statement for better clarity on the management of renal bone disease at site
    04 Feb 2016
    The amendment was implemented to address operational issues based on investigator feedback and lower ferritin inclusion criterion  Study design: extending the screening period to 60 days and clarification on post-dialysis PK samples collection.  Updated the language for treatment assignment, patients domiciliation and emergency breaking of assigned treatment code  Changes to Part 1 and Part 2 assessment schedules  Updated the inclusion and exclusion criteria.
    12 Aug 2016
    The amendment was implemented to increase the ferritin inclusion criterion based on clinical data from the first dosed patients. This criterion was applied in cohorts 2-5. �� Updated study design figure and patients eligibility criteria.
    24 May 2017
    The amendment was implemented to conclude Cohort 2 and enable an interim analysis on five rather than six patients. Five patients in Cohort 2 received CSJ137 dose 1 (same dose as in Cohort 1).  Clarified prolonged iron response definition.  Updated to account for repeat dose design of part 2 for pregnancy and assessments of fertility
    25 Jul 2017
    The amendment was implemented in response to the MHRA deficiency letter as a part of an iCTA review.  Updated EudraCT number, assessment schedule and a reference  Clarified study completion and post-study treatment follow up time as 115 days following last CSJ137 dose  Updated exclusion criterion
    20 Mar 2018
    The amendment was implemented to summarize available safety data and allow for further dosing, to expand the upper limit of ferritin inclusion criteria and to redefine the mPAD.  Updated dose escalation scheme.  Updated inclusion criteria. These criteria were applied in cohorts 6-8.  Updated intravenous iron management rules
    29 Mar 2018
    The amendment was implemented to adapt the protocol design after 10 patients have received CSJ137, to reach a pharmacologically active dose more rapidly without compromising safety.  Implemented an adaptive dose escalation strategy in the remaining cohorts in Part 1.  Extended the dose escalation from Part 1 to one dose level higher than the minimum PAD  Changed the Part 2 design from a three arm single dose to a two arm repeat dose study with a maximum of 1 repeat dose (2 doses in total).
    16 Apr 2019
    The amendment was implemented to revise the mPAD based on the emerging data from Cohorts 5 and 6 in Part 1  Updated IV iron supplementation management conditions.  Updated blood sampling time-points  Revised mPAD definition  Minor changes to various sections

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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