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    Clinical Trial Results:
    A Phase 1b/2, multi-center, double-blind (principal investigators and study subjects blinded, sponsor unblinded), placebo-controlled, randomized, single-ascending dose study to assess the safety, pharmacokinetics, and pharmacodynamics of DS-1040B in subjects with acute ischemic stroke.

    Summary
    EudraCT number
    2015-001824-43
    Trial protocol
    DE   FR   GB   CZ   ES   SK   IT  
    Global end of trial date
    13 Aug 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    17 Aug 2020
    First version publication date
    17 Aug 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DS1040-A-U103
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02586233
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo
    Sponsor organisation address
    211 Mt. Airy Road, Basking Ridge, United States, 07920
    Public contact
    Contact for Clinical Trial Information, Daiichi Sankyo Development Ltd, +1 908-992-6400, CTRinfo@dsi.com
    Scientific contact
    Contact for Clinical Trial Information, Daiichi Sankyo Development Ltd, +1 908-992-6400, CTRinfo@dsi.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 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety and tolerability of DS-1040b (IV infusion over 6 hours) in subjects with AIS within 3 to 8 hours after stroke symptom onset
    Protection of trial subjects
    This study was conducted in compliance with the protocol, the ethical principles that have their origin in the Declaration of Helsinki, the International Council for Harmonisation consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/International Council for Harmonisation/135/95), the United States Food and Drug Administration GCP Regulations: Code of Federal Regulations Title 21, Parts 11, 50, 54, 56, and 312 as appropriate and other applicable local regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 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
    Spain: 24
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    United States: 46
    Country: Number of subjects enrolled
    Taiwan: 13
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Worldwide total number of subjects
    106
    EEA total number of subjects
    37
    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)
    55
    From 65 to 84 years
    49
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 106 participants who met all inclusion criteria and no exclusion criteria were randomized to treatment at a total of 78 clinic sites (46 in Europe, 19 in the United States, 7 in Asia, 5 in Australia, and 1 in Canada). Of the 106 participants randomized, 101 participants received treatment.

    Pre-assignment
    Screening details
    The study consisted of 6, sequential, ascending-dose cohorts. Participants were randomized to either DS-1040b or placebo in a 3:1 ratio.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1: DS-1040b 0.6 mg
    Arm description
    Subjects who received a single intravenous infusion of DS-1040b 0.6 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-1040b
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion of 0.6 mg to 9.6 mg over a 6-hour period

    Arm title
    Cohort 2: DS-1040b 1.2 mg
    Arm description
    Subjects who received a single intravenous infusion of DS-1040b 1.2 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-1040b
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion of 0.6 mg to 9.6 mg over a 6-hour period

    Arm title
    Cohort 3: DS-1040b 2.4 mg
    Arm description
    Subjects who received a single intravenous infusion of DS-1040b 2.4 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-1040b
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion of 0.6 mg to 9.6 mg over a 6-hour period

    Arm title
    Cohort 4: DS-1040 4.8 mg
    Arm description
    Subjects who received a single intravenous infusion of DS-1040b 4.8 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-1040b
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion of 0.6 mg to 9.6 mg over a 6-hour period

    Arm title
    Cohort 5: DS-1040b 7.2 mg
    Arm description
    Subjects who received a single intravenous infusion of DS-1040b 7.2 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-1040b
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion of 0.6 mg to 9.6 mg over a 6-hour period

    Arm title
    Cohort 6: DS-1040b 9.6 mg
    Arm description
    Subjects who received a single intravenous infusion of DS-1040b 9.6 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-1040b
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion of 0.6 mg to 9.6 mg over a 6-hour period

    Arm title
    Placebo
    Arm description
    Subjects who received a single intravenous infusion of placebo.
    Arm type
    Placebo

    Investigational medicinal product name
    0.9% sodium chloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion over 6-hour period

    Number of subjects in period 1
    Cohort 1: DS-1040b 0.6 mg Cohort 2: DS-1040b 1.2 mg Cohort 3: DS-1040b 2.4 mg Cohort 4: DS-1040 4.8 mg Cohort 5: DS-1040b 7.2 mg Cohort 6: DS-1040b 9.6 mg Placebo
    Started
    7
    7
    13
    17
    18
    18
    26
    Completed
    7
    5
    13
    17
    16
    16
    24
    Not completed
    0
    2
    0
    0
    2
    2
    2
         Death
    -
    1
    -
    -
    2
    -
    -
         Randomized, but did not receive treatment
    -
    1
    -
    -
    -
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: DS-1040b 0.6 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 0.6 mg.

    Reporting group title
    Cohort 2: DS-1040b 1.2 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 1.2 mg.

    Reporting group title
    Cohort 3: DS-1040b 2.4 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 2.4 mg.

    Reporting group title
    Cohort 4: DS-1040 4.8 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 4.8 mg.

    Reporting group title
    Cohort 5: DS-1040b 7.2 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 7.2 mg.

    Reporting group title
    Cohort 6: DS-1040b 9.6 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 9.6 mg.

    Reporting group title
    Placebo
    Reporting group description
    Subjects who received a single intravenous infusion of placebo.

    Reporting group values
    Cohort 1: DS-1040b 0.6 mg Cohort 2: DS-1040b 1.2 mg Cohort 3: DS-1040b 2.4 mg Cohort 4: DS-1040 4.8 mg Cohort 5: DS-1040b 7.2 mg Cohort 6: DS-1040b 9.6 mg Placebo Total
    Number of subjects
    7 7 13 17 18 18 26 106
    Age categorical
    Based on Randomized Analysis Set
    Units: Subjects
        In utero
    0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0 0 0
        Adults (18-64 years)
    2 4 8 8 9 10 14 55
        From 65-84 years
    5 2 5 9 9 7 12 49
        85 years and over
    0 1 0 0 0 1 0 2
    Age continuous
    Based on Safety Analysis Set (N=101); age data were missing for participants in some cohorts.
    Units: years
        arithmetic mean (standard deviation)
    68.2 ± 7.8 68.2 ± 10.2 62.7 ± 9.7 69.1 ± 11.1 65.8 ± 11.7 64.8 ± 12.8 62.2 ± 12.3 -
    Gender categorical
    Based on the Randomized Analysis Set
    Units: Subjects
        Female
    3 2 5 6 8 7 11 42
        Male
    4 5 8 11 10 11 15 64

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: DS-1040b 0.6 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 0.6 mg.

    Reporting group title
    Cohort 2: DS-1040b 1.2 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 1.2 mg.

    Reporting group title
    Cohort 3: DS-1040b 2.4 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 2.4 mg.

    Reporting group title
    Cohort 4: DS-1040 4.8 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 4.8 mg.

    Reporting group title
    Cohort 5: DS-1040b 7.2 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 7.2 mg.

    Reporting group title
    Cohort 6: DS-1040b 9.6 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 9.6 mg.

    Reporting group title
    Placebo
    Reporting group description
    Subjects who received a single intravenous infusion of placebo.

    Subject analysis set title
    All DS-1040b
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received a single intravenous infusion of DS-1040b.

    Primary: Treatment-emergent Adverse Event Reported by >10% of Participants Following Ascending Doses of DS-1040b and a Placebo in Subjects With Acute Ischemic Stroke

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    End point title
    Treatment-emergent Adverse Event Reported by >10% of Participants Following Ascending Doses of DS-1040b and a Placebo in Subjects With Acute Ischemic Stroke [1]
    End point description
    Treatment-emergent adverse event (TEAE) is defined as an adverse event that emerges during the treatment period (from first dose date until 30 days after the last dosing date), having been absent at predose; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-dose state, when the adverse event is continuous.
    End point type
    Primary
    End point timeframe
    Baseline up to 90 days post last dose, up to 3 years 11 months
    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: Descriptive analyses were performed based on the study groups and study drugs administered for this outcome.
    End point values
    Cohort 1: DS-1040b 0.6 mg Cohort 2: DS-1040b 1.2 mg Cohort 3: DS-1040b 2.4 mg Cohort 4: DS-1040 4.8 mg Cohort 5: DS-1040b 7.2 mg Cohort 6: DS-1040b 9.6 mg Placebo All DS-1040b
    Number of subjects analysed
    7
    6
    13
    17
    18
    16
    24
    77
    Units: Subjects
    number (not applicable)
        Any TEAE
    5
    5
    10
    15
    14
    14
    18
    63
        Hypokalaemia
    1
    2
    2
    0
    2
    2
    6
    9
        Constipation
    1
    2
    3
    1
    5
    2
    5
    14
        Insomnia
    0
    0
    1
    0
    1
    3
    5
    5
        Hypertension
    0
    0
    1
    3
    1
    0
    3
    5
        Anxiety
    0
    1
    0
    0
    0
    2
    3
    3
        Hyperglycaemia
    0
    0
    0
    1
    1
    0
    3
    2
        Dyslipidaemia
    0
    0
    0
    0
    1
    1
    3
    2
        Thrombocytopenia
    0
    1
    0
    0
    0
    0
    3
    1
        Vomiting
    0
    1
    0
    0
    0
    0
    3
    1
        Pyrexia
    0
    0
    0
    1
    0
    0
    3
    1
        Vitamin B12 deficiency
    0
    0
    0
    0
    0
    0
    3
    0
        Headache
    3
    1
    2
    2
    1
    4
    2
    13
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter Maximum (Peak) Observed Plasma Concentration (Cmax) of DS-1040b Following Ascending Doses in Subjects With Acute Ischemic Stroke

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    End point title
    Pharmacokinetic Parameter Maximum (Peak) Observed Plasma Concentration (Cmax) of DS-1040b Following Ascending Doses in Subjects With Acute Ischemic Stroke [2]
    End point description
    The PK parameter of Maximum (Peak) Observed Plasma Concentration (Cmax) of DS-1040b was calculated from the plasma concentrations of DS-1040b using non-compartmental analysis.
    End point type
    Secondary
    End point timeframe
    Predose, 0.5, 3, 6, 9, 12, 24, 48, 72, and 96 hours postdose
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive analyses were performed based on the study groups and study drugs administered for this outcome.
    End point values
    Cohort 1: DS-1040b 0.6 mg Cohort 2: DS-1040b 1.2 mg Cohort 3: DS-1040b 2.4 mg Cohort 4: DS-1040 4.8 mg Cohort 5: DS-1040b 7.2 mg Cohort 6: DS-1040b 9.6 mg
    Number of subjects analysed
    5
    6
    13
    16
    17
    10
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cmax
    10.09 ± 3.26
    26.95 ± 9.39
    61.28 ± 35.67
    729.76 ± 1661.06
    191.06 ± 59.60
    203.70 ± 41.49
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter Area Under the Concentration Versus Time Curve From Zero to Last Quantifiable Concentration Sampling Point (AUClast) of DS-1040b Following Ascending Doses in Subjects With Acute Ischemic Stroke

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    End point title
    Pharmacokinetic Parameter Area Under the Concentration Versus Time Curve From Zero to Last Quantifiable Concentration Sampling Point (AUClast) of DS-1040b Following Ascending Doses in Subjects With Acute Ischemic Stroke [3]
    End point description
    The PK parameter of Area Under the Concentration Versus Time Curve from Zero to Last Quantifiable Concentration Sampling Point of DS-1040b was calculated from the plasma concentrations of DS-1040b using non-compartmental analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 3, 6, 9, 12, 24, 48, 72, and 96 hours post-dose
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive analyses were performed based on the study groups and study drugs administered for this outcome.
    End point values
    Cohort 1: DS-1040b 0.6 mg Cohort 2: DS-1040b 1.2 mg Cohort 3: DS-1040b 2.4 mg Cohort 4: DS-1040 4.8 mg Cohort 5: DS-1040b 7.2 mg Cohort 6: DS-1040b 9.6 mg
    Number of subjects analysed
    5
    6
    13
    16
    17
    10
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        AUClast
    69.74 ± 16.19
    219.83 ± 95.16
    447.75 ± 199.97
    2611.87 ± 4471.65
    1489.21 ± 460.78
    1700.24 ± 346.43
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter Terminal Half-life (t1/2) of DS-1040b Following Ascending Doses in Subjects With Acute Ischemic Stroke

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    End point title
    Pharmacokinetic Parameter Terminal Half-life (t1/2) of DS-1040b Following Ascending Doses in Subjects With Acute Ischemic Stroke [4]
    End point description
    The PK parameter of Terminal Half-life of DS-1040b was calculated from the plasma concentrations of DS-1040b using non-compartmental analysis in patients with available sample for the analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 3, 6, 9, 12, 24, 48, 72, and 96 hours post-dose
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive analyses were performed based on the study groups and study drugs administered for this outcome.
    End point values
    Cohort 1: DS-1040b 0.6 mg Cohort 2: DS-1040b 1.2 mg Cohort 3: DS-1040b 2.4 mg Cohort 4: DS-1040 4.8 mg Cohort 5: DS-1040b 7.2 mg Cohort 6: DS-1040b 9.6 mg
    Number of subjects analysed
    4
    2
    7
    8
    14
    8
    Units: hours
    arithmetic mean (standard deviation)
        Terminal half-life
    2.59 ± 0.46
    4.14 ± 0.17
    10.50 ± 15.02
    36.68 ± 25.94
    33.37 ± 14.71
    35.86 ± 10.98
    No statistical analyses for this end point

    Secondary: Activated Form of Thrombin-activatable Fibrinolysis Inhibitor (TAFIa) Following Ascending Doses of DS-1040b and a Placebo in Subjects With Acute Ischemic Stroke

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    End point title
    Activated Form of Thrombin-activatable Fibrinolysis Inhibitor (TAFIa) Following Ascending Doses of DS-1040b and a Placebo in Subjects With Acute Ischemic Stroke
    End point description
    The enzymatic activity of thrombin-activatable fibrinolysis inhibitor was assessed using the Stago Coagulation Analyzer.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 hours postdose
    End point values
    Cohort 1: DS-1040b 0.6 mg Cohort 2: DS-1040b 1.2 mg Cohort 3: DS-1040b 2.4 mg Cohort 4: DS-1040 4.8 mg Cohort 5: DS-1040b 7.2 mg Cohort 6: DS-1040b 9.6 mg Placebo
    Number of subjects analysed
    7
    6
    13
    17
    18
    10
    24
    Units: Mean percentage of TAFIa activity
    arithmetic mean (standard deviation)
        Baseline
    96.7 ± 23.7
    97.8 ± 17.5
    100.4 ± 21.6
    105.1 ± 23.4
    108.1 ± 30.5
    112.6 ± 27.2
    100.9 ± 20.8
        6 hours postdose
    93.5 ± 26.6
    98.8 ± 27.2
    86.7 ± 16.7
    75.9 ± 20.9
    72.9 ± 22.6
    73.9 ± 14.4
    104.1 ± 24.7
    No statistical analyses for this end point

    Secondary: Change From Baseline at Day 30 in National Institute of Health Stroke Scale (NIHSS) Score Following Ascending Doses of DS-1040b and a Placebo in Subjects With Acute Ischemic Stroke

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    End point title
    Change From Baseline at Day 30 in National Institute of Health Stroke Scale (NIHSS) Score Following Ascending Doses of DS-1040b and a Placebo in Subjects With Acute Ischemic Stroke
    End point description
    The National Institute of Health Stroke Scale (NIHSS) quantifies stroke severity based on weighted evaluation findings. The score for each ability is a number between 0 and 4, with 0 being normal functioning and 4 being completely impaired. The patient's NIHSS score is calculated by adding the number for each element of the scale; 42 is the highest score possible. In the NIHSS, the higher the score indicates more impairment (worse outcome) in a stroke patient.
    End point type
    Secondary
    End point timeframe
    30 days postdose
    End point values
    Cohort 1: DS-1040b 0.6 mg Cohort 2: DS-1040b 1.2 mg Cohort 3: DS-1040b 2.4 mg Cohort 4: DS-1040 4.8 mg Cohort 5: DS-1040b 7.2 mg Cohort 6: DS-1040b 9.6 mg Placebo All DS-1040b
    Number of subjects analysed
    7
    6
    13
    17
    18
    16
    24
    77
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change from baseline in NIHSS score
    -3.7 ± 2.21
    -3.0 ± 2.00
    -3.5 ± 1.71
    -2.06 ± 1.06
    -3.4 ± 2.70
    -6.2 ± 3.08
    -3.6 ± 4.27
    -3.9 ± 2.56
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a Modified Rankin Scale (mRS) Score of 0 to 2 Following Ascending Doses of DS-1040b and a Placebo in Subjects With Acute Ischemic Stroke

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    End point title
    Percentage of Participants With a Modified Rankin Scale (mRS) Score of 0 to 2 Following Ascending Doses of DS-1040b and a Placebo in Subjects With Acute Ischemic Stroke
    End point description
    The modified Rankin scale (mRS) is a commonly used disability scale derived from the Rankin scale that is used to measure the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The level of disability following a stroke is assessed via a scale from 0 to 6, where 0 is no symptoms at all and 6 indicates death. Higher scores indicate worse outcome. The proportion (%) of participants with an mRS score of 0 to 2 at Day 5 (baseline) and Day 90 is being reported.
    End point type
    Secondary
    End point timeframe
    Day 5 (baseline) and Day 90 post dose
    End point values
    Cohort 1: DS-1040b 0.6 mg Cohort 2: DS-1040b 1.2 mg Cohort 3: DS-1040b 2.4 mg Cohort 4: DS-1040 4.8 mg Cohort 5: DS-1040b 7.2 mg Cohort 6: DS-1040b 9.6 mg Placebo All DS-1040b
    Number of subjects analysed
    7
    6
    13
    17
    18
    16
    24
    77
    Units: Percentage of subjects
    number (not applicable)
        Day 5 (baseline)
    66.7
    40.0
    76.9
    82.4
    72.2
    53.3
    54.2
    68.9
        Day 90 postdose
    85.7
    60.0
    76.9
    82.4
    93.8
    68.8
    75.0
    79.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (TEAEs) were collected from baseline up to 30 days post last dose, up to 3 years 11 months.
    Adverse event reporting additional description
    A TEAE is defined as an adverse event (AE) that emerges from first dose date until 30 days after the last dose, having been absent at predose; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-dose state, when the AE is continuous.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Cohort 1: DS-1040b 0.6 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 0.6 mg.

    Reporting group title
    Cohort 2: DS-1040b 1.2 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 1.2 mg.

    Reporting group title
    Cohort 3: DS-1040b 2.4 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 2.4 mg.

    Reporting group title
    Cohort 4: DS-1040 4.8 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 4.8 mg.

    Reporting group title
    Cohort 5: DS-1040b 7.2 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 7.2 mg.

    Reporting group title
    Cohort 6: DS-1040b 9.6 mg
    Reporting group description
    Subjects who received a single intravenous infusion of DS-1040b 9.6 mg.

    Reporting group title
    Placebo
    Reporting group description
    Subjects who received a single intravenous infusion of placebo.

    Reporting group title
    All DS-1040b
    Reporting group description
    All subjects who received a single intravenous infusion of DS-1040b.

    Serious adverse events
    Cohort 1: DS-1040b 0.6 mg Cohort 2: DS-1040b 1.2 mg Cohort 3: DS-1040b 2.4 mg Cohort 4: DS-1040 4.8 mg Cohort 5: DS-1040b 7.2 mg Cohort 6: DS-1040b 9.6 mg Placebo All DS-1040b
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 7 (14.29%)
    4 / 6 (66.67%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
    4 / 24 (16.67%)
    10 / 77 (12.99%)
         number of deaths (all causes)
    0
    1
    0
    0
    2
    0
    0
    3
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 24 (4.17%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid arteriosclerosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    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
    Carotid artery stenosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    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
    Cerebrovascular accident
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Simple partial seizures
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    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
    Spinal cord infarction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    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
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    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
    Hepatocellular injury
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    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
    Pneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    Urosepsis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cohort 1: DS-1040b 0.6 mg Cohort 2: DS-1040b 1.2 mg Cohort 3: DS-1040b 2.4 mg Cohort 4: DS-1040 4.8 mg Cohort 5: DS-1040b 7.2 mg Cohort 6: DS-1040b 9.6 mg Placebo All DS-1040b
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 7 (71.43%)
    5 / 6 (83.33%)
    10 / 13 (76.92%)
    15 / 17 (88.24%)
    14 / 18 (77.78%)
    14 / 16 (87.50%)
    18 / 24 (75.00%)
    63 / 77 (81.82%)
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Haematoma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    2
    Hypertension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    3 / 17 (17.65%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    3 / 24 (12.50%)
    5 / 77 (6.49%)
         occurrences all number
    0
    0
    1
    3
    1
    0
    3
    5
    Hypotension
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 24 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Chest discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    2
    Fatigue
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    4 / 77 (5.19%)
         occurrences all number
    1
    0
    0
    1
    1
    1
    0
    4
    Inflammation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Infusion site phlebitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    2
    Peripheral swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    3 / 24 (12.50%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    3
    1
    Vessel puncture site pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Agitation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    3 / 77 (3.90%)
         occurrences all number
    0
    1
    0
    0
    1
    1
    0
    3
    Anxiety
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    2 / 16 (12.50%)
    3 / 24 (12.50%)
    3 / 77 (3.90%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    3
    3
    Confusional state
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    2
    Delirium
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    2 / 24 (8.33%)
    0 / 77 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Depressed mood
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    2
    Depression
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    2 / 24 (8.33%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    2
    2
    Hallucination
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    3 / 16 (18.75%)
    5 / 24 (20.83%)
    5 / 77 (6.49%)
         occurrences all number
    0
    0
    1
    0
    1
    3
    5
    5
    Mood altered
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Sleep disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    1 / 24 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    1 / 24 (4.17%)
    4 / 77 (5.19%)
         occurrences all number
    1
    0
    1
    1
    0
    1
    1
    4
    Joint injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Post procedural haematuria
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Wound
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    2 / 24 (8.33%)
    0 / 77 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Biopsy bone
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Blood albumin decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    2 / 24 (8.33%)
    0 / 77 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Blood fibrinogen increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    2 / 24 (8.33%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    2
    1
    Blood glucose increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Body temperature increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Ejection fraction decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Red blood cell sedimentation rate increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Vitamin D decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
    1 / 24 (4.17%)
    4 / 77 (5.19%)
         occurrences all number
    1
    0
    1
    0
    1
    1
    1
    4
    Bradycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    2
    Cardiac arrest
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 24 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    1
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    2
    Sinus tachycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchiectasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Cough
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    2 / 18 (11.11%)
    0 / 16 (0.00%)
    1 / 24 (4.17%)
    3 / 77 (3.90%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    1
    3
    Dyspnoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 24 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    1
    Hypoxia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Nasal obstruction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Pulmonary mass
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Pulmonary oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Respiratory failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    2
    Rhinorrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    2 / 24 (8.33%)
    0 / 77 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    2 / 13 (15.38%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    2 / 24 (8.33%)
    4 / 77 (5.19%)
         occurrences all number
    0
    1
    2
    0
    1
    0
    2
    4
    Hyperfibrinogenaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Leukocytosis
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 13 (7.69%)
    1 / 17 (5.88%)
    2 / 18 (11.11%)
    0 / 16 (0.00%)
    2 / 24 (8.33%)
    6 / 77 (7.79%)
         occurrences all number
    1
    1
    1
    1
    2
    0
    2
    6
    Thrombocytopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    3 / 24 (12.50%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    3
    1
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Carotid arteriosclerosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Carotid artery stenosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Cerebrovascular accident
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 24 (4.17%)
    2 / 77 (2.60%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    1
    2
    Circadian rhythm sleep disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    1 / 24 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    Dysaesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    1 / 24 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Headache
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 6 (16.67%)
    2 / 13 (15.38%)
    2 / 17 (11.76%)
    1 / 18 (5.56%)
    4 / 16 (25.00%)
    2 / 24 (8.33%)
    13 / 77 (16.88%)
         occurrences all number
    3
    1
    2
    2
    1
    4
    2
    13
    Memory impairment
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    2
    Partial seizures
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    3 / 77 (3.90%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    0
    3
    Sedation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Simple partial seizures
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Somnolence
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Stroke in evolution
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Dry eye
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    1 / 24 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    1
    Constipation
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 6 (33.33%)
    3 / 13 (23.08%)
    1 / 17 (5.88%)
    5 / 18 (27.78%)
    2 / 16 (12.50%)
    5 / 24 (20.83%)
    14 / 77 (18.18%)
         occurrences all number
    1
    2
    3
    1
    5
    2
    5
    14
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    2 / 16 (12.50%)
    1 / 24 (4.17%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    2
    Dyspepsia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    1 / 24 (4.17%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    1
    2
    Nausea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
    2 / 17 (11.76%)
    0 / 18 (0.00%)
    2 / 16 (12.50%)
    2 / 24 (8.33%)
    6 / 77 (7.79%)
         occurrences all number
    0
    0
    2
    2
    0
    2
    2
    6
    Toothache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    3 / 24 (12.50%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    3
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Glycosuria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    2 / 24 (8.33%)
    2 / 77 (2.60%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    2
    2
    Neurogenic bladder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    1 / 24 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    1
    Renal failure acute
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    2 / 16 (12.50%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    2
    Urethral pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 24 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    1
    Urinary retention
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    2
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Hepatocellular injury
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Decubitis ulcer
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    2 / 24 (8.33%)
    0 / 77 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    2
    Petechiae
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    2
    Psoriasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Swelling face
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 13 (15.38%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    2 / 24 (8.33%)
    3 / 77 (3.90%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    2
    3
    Arthritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Back pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    1 / 24 (4.17%)
    2 / 77 (2.60%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    1
    2
    Muscle spasms
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Muscle spasticity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    2 / 17 (11.76%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 24 (4.17%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    1
    2
    Musculoskeletal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    2 / 24 (8.33%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    2
    1
    Neurological decompensation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Neurological symptom
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Osteoarthritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Tendonitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Tenosynovitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Dyslipidaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
    3 / 24 (12.50%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    3
    2
    Electrolyte imbalance
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Fluid imbalance
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Hyperchloraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    4 / 13 (30.77%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    2 / 24 (8.33%)
    5 / 77 (6.49%)
         occurrences all number
    0
    1
    4
    0
    0
    0
    2
    5
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    2 / 16 (12.50%)
    0 / 24 (0.00%)
    3 / 77 (3.90%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    0
    3
    Hyperglycaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    3 / 24 (12.50%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    3
    2
    Hyperlipidaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    1 / 24 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    2 / 24 (8.33%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    2 / 13 (15.38%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    2 / 24 (8.33%)
    4 / 77 (5.19%)
         occurrences all number
    1
    1
    2
    0
    0
    0
    2
    4
    Hypoglycaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 24 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 6 (33.33%)
    2 / 13 (15.38%)
    0 / 17 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
    6 / 24 (25.00%)
    9 / 77 (11.69%)
         occurrences all number
    1
    2
    2
    0
    2
    2
    6
    9
    Hypomagnesaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    2 / 24 (8.33%)
    3 / 77 (3.90%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    2
    3
    Malnutrition
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    3 / 77 (3.90%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    0
    3
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    3 / 24 (12.50%)
    0 / 77 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Infections and infestations
    Bacterial disease carrier
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Conjunctivitis bacterial
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Hepatitis B
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    1 / 17 (5.88%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    2
    Pneumonia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    2 / 18 (11.11%)
    1 / 16 (6.25%)
    1 / 24 (4.17%)
    4 / 77 (5.19%)
         occurrences all number
    1
    0
    0
    0
    2
    1
    1
    4
    Postoperative wound infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Pyuria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 13 (7.69%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    2 / 18 (11.11%)
    0 / 16 (0.00%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 13 (0.00%)
    2 / 17 (11.76%)
    3 / 18 (16.67%)
    1 / 16 (6.25%)
    1 / 24 (4.17%)
    6 / 77 (7.79%)
         occurrences all number
    0
    0
    0
    2
    3
    1
    1
    6
    Urosepsis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 13 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 24 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 May 2015
    Included an intermediate dose, updated number of sites, revised exclusion criteria, updated pharmacokinetics protocol, clarified dose escalation procedure, updated treatment details, and clarified purpose of assessments and details/timing of sample collection
    01 Oct 2015
    Updated secondary objectives, study duration, pharmacokinetic parameters, updated inclusion and exclusion criteria, and clarified rationale for assessments and details/timing of sample collection
    12 Jul 2016
    Revised inclusion and exclusion criteria, updated enrollment section and study duration, included exploratory assessments, updated primary objective, and clarified adverse event assessment
    04 May 2018
    Updated study rationale and number of subjects, revised cohort enrollment description, updated eligibility criteria, updated pharmacokinetic parameters, added exploratory assessments, extended study duration, clarified concomitant medications and procedures, and provided details of ECG assessment

    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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