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    Clinical Trial Results:
    A multicenter, randomized, placebo-controlled, parallel-arm study to investigate the efficacy, pharmacokinetics, and safety of CSL312 in subjects with hereditary angioedema

    Summary
    EudraCT number
    		 2018-000605-24
    Trial protocol
    		 DE  
    Global end of trial date
    15 Oct 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Oct 2022
    First version publication date
    29 Oct 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CSL312_2001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03712228
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CSL Behring LLC
    Sponsor organisation address
    1020 First Avenue, King of Prussia, United States, 19406
    Public contact
    Trial Registration Coordinator, CSL Behring LLC, +1 610 878 4000, clinicaltrials@cslbehring.com
    Scientific contact
    Trial Registration Coordinator, CSL Behring LLC, +1 610 878 4000, clinicaltrials@cslbehring.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
    06 Dec 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective is to evaluate the efficacy of CSL312 in the prevention of HAE attacks in subjects with C1-INH HAE.
    Protection of trial subjects
    Standard of care
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Oct 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    44
    EEA total number of subjects
    17
    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)
    43
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Treatment Period 1 participants were assigned to 1 of 5 treatment arms. Treatment period 2 participants that completed Treatment Period 1 were assigned to either CSL312 (medium) or CSL312 (high) and could be up-titrated from CSL312 (medium) to CSL312 (med/high), if necessary. They were down-titrated from CSL312 (high) to CSL312 (medium). Only 2 sub

    Period 1
    Period 1 title
    Treatment Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects with C1-INH HAE receiving buffer only. Placebo: Buffer without active ingredient.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Subjects with C1-INH HAE receiving buffer only. Placebo: Buffer without active ingredient.

    Arm title
    		 CSL312 (low)
    Arm description
    		 Subjects with C1-INH HAE receiving low dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSL312
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Subjects with C1-INH HAE receiving low dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Arm title
    		 CSL312 (med)
    Arm description
    		 Subjects with C1-INH HAE receiving medium dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSL312
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Subjects with C1-INH HAE receiving medium dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Arm title
    		 CSL312 (high)
    Arm description
    		 Subjects with C1-INH HAE receiving high dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSL312
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Subjects with C1-INH HAE receiving high dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Arm title
    		 CSL312 (med/high)
    Arm description
    		 Subjects with C1-INH HAE receiving medium/high dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSL312
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects with C1-INH HAE receiving medium/high dose CSL312 Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use

    Arm title
    		 CSL312 (FXII/PLG HAE)
    Arm description
    		 Subjects with FXII/PLG HAE (Hereditary Angioedema with Normal C1-esterase Inhibitor and Factor XII or Plasminogen Gene Mutation) receiving high dose CSL312
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSL312
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Subjects with FXII/PLG HAE (Hereditary Angioedema with Normal C1-esterase Inhibitor and Factor XII or Plasminogen Gene Mutation) receiving high dose CSL312

    Number of subjects in period 1
    		Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high) CSL312 (FXII/PLG HAE)
    Started
    8
    9
    8
    7
    6
    6
    Completed
    8
    9
    8
    7
    6
    5
    Not completed
    0
    0
    0
    0
    0
    1
         Lack of efficacy
    -
    -
    -
    -
    -
    1
    Period 2
    Period 2 title
    Treatment Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CSL312 (med)
    Arm description
    		 Subjects with C1-INH HAE receiving medium dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSL312
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects with C1-INH HAE receiving medium dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Arm title
    		 CSL312 (high)
    Arm description
    		 Subjects with C1-INH HAE receiving high dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSL312
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects with C1-INH HAE receiving high dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Arm title
    		 CSL312 (FXII/PLG HAE)
    Arm description
    		 Subjects with FXII/PLG HAE (Hereditary Angioedema with Normal C1-esterase Inhibitor and Factor XII or Plasminogen Gene Mutation) receiving high dose CSL312
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSL312
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects with FXII/PLG HAE (Hereditary Angioedema with Normal C1-esterase Inhibitor and Factor XII or Plasminogen Gene Mutation) receiving high dose CSL312.

    Number of subjects in period 2 [1]
    		CSL312 (med) CSL312 (high) CSL312 (FXII/PLG HAE)
    Started
    20
    18
    2
    Completed
    20
    16
    2
    Not completed
    0
    2
    0
         Consent withdrawn by subject
    -
    1
    -
         Pregnancy
    -
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only 2 subjects from the CSL312 (FXII/PLG HAE) arm were treated with CSL312 in Treatment Period 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with C1-INH HAE receiving buffer only. Placebo: Buffer without active ingredient.

    Reporting group title
    CSL312 (low)
    Reporting group description
    		 Subjects with C1-INH HAE receiving low dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Reporting group title
    CSL312 (med)
    Reporting group description
    		 Subjects with C1-INH HAE receiving medium dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Reporting group title
    CSL312 (high)
    Reporting group description
    		 Subjects with C1-INH HAE receiving high dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Reporting group title
    CSL312 (med/high)
    Reporting group description
    		 Subjects with C1-INH HAE receiving medium/high dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Reporting group title
    CSL312 (FXII/PLG HAE)
    Reporting group description
    		 Subjects with FXII/PLG HAE (Hereditary Angioedema with Normal C1-esterase Inhibitor and Factor XII or Plasminogen Gene Mutation) receiving high dose CSL312

    Reporting group values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high) CSL312 (FXII/PLG HAE) Total
    Number of subjects
    		 8 9 8 7 6 6 44
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 8 9 8 6 6 6 43
        From 65-84 years
    		 0 0 0 1 0 0 1
        85 years and over
    		 0 0 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 4 7 2 5 3 6 27
        Male
    		 4 2 6 2 3 0 17

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with C1-INH HAE receiving buffer only. Placebo: Buffer without active ingredient.

    Reporting group title
    CSL312 (low)
    Reporting group description
    		 Subjects with C1-INH HAE receiving low dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Reporting group title
    CSL312 (med)
    Reporting group description
    		 Subjects with C1-INH HAE receiving medium dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Reporting group title
    CSL312 (high)
    Reporting group description
    		 Subjects with C1-INH HAE receiving high dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Reporting group title
    CSL312 (med/high)
    Reporting group description
    		 Subjects with C1-INH HAE receiving medium/high dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Reporting group title
    CSL312 (FXII/PLG HAE)
    Reporting group description
    		 Subjects with FXII/PLG HAE (Hereditary Angioedema with Normal C1-esterase Inhibitor and Factor XII or Plasminogen Gene Mutation) receiving high dose CSL312
    Reporting group title
    CSL312 (med)
    Reporting group description
    		 Subjects with C1-INH HAE receiving medium dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Reporting group title
    CSL312 (high)
    Reporting group description
    		 Subjects with C1-INH HAE receiving high dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Reporting group title
    CSL312 (FXII/PLG HAE)
    Reporting group description
    		 Subjects with FXII/PLG HAE (Hereditary Angioedema with Normal C1-esterase Inhibitor and Factor XII or Plasminogen Gene Mutation) receiving high dose CSL312

    Primary: The mean Time normalized number of HAE attacks per month in Subjects With C1-INH HAE during Treatment Period 1

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    End point title
    		 The mean Time normalized number of HAE attacks per month in Subjects With C1-INH HAE during Treatment Period 1 [1]
    End point description
    The time-normalized number of HAE attacks per month during Treatment Period 1 for a subject was calculated as the (number of HAE attacks / length of subject’s evaluation period in days) * 30.4375
    End point type
    Primary
    End point timeframe
    13 weeks
    Notes
    [1] - 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: CSL312 (FXII/PLG HAE) arm used for exploratory endpoints.
    End point values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high)
    Number of subjects analysed
    8
    9
    8
    7
    6
    Units: Number of HAE attacks per month
        arithmetic mean (standard deviation)
    4.24 ( 1.801 )
    0.48 ( 1.057 )
    0.05 ( 0.127 )
    0.35 ( 0.407 )
    0.14 ( 0.222 )
    Statistical analysis title
    		 Dose comparisons
    Comparison groups
    CSL312 (med) v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Dose comparisons
    Comparison groups
    CSL312 (high) v Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Dose comparisons
    Comparison groups
    CSL312 (med) v CSL312 (high)
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.082
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: The number of responder subjects with C1-INH HAE during Treatment Period 1

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    End point title
    		 The number of responder subjects with C1-INH HAE during Treatment Period 1 [2]
    End point description
    Response is defined as a ≥ 50% relative reduction in the time-normalized number of HAE attacks (per month) during Treatment Period 1 compared to each subject’s time-normalized number of HAE attacks (per month) during the Run-in Period
    End point type
    Secondary
    End point timeframe
    13 weeks
    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: CSL312 (FXII/PLG HAE) arm used for exploratory endpoints.
    End point values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high)
    Number of subjects analysed
    8
    9
    8
    7
    6
    Units: Number of participants
        number (not applicable)
    0
    9
    8
    6
    6
    No statistical analyses for this end point

    Secondary: The percentage of responder subjects with C1-INH HAE during Treatment Period 1

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    End point title
    		 The percentage of responder subjects with C1-INH HAE during Treatment Period 1 [3]
    End point description
    Response is defined as a ≥ 50% relative reduction in the time-normalized number of HAE attacks (per month) during Treatment Period 1 compared to each subject’s time-normalized number of HAE attacks (per month) during the Run-in Period.
    End point type
    Secondary
    End point timeframe
    13 weeks
    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: CSL312 (FXII/PLG HAE) arm used for exploratory endpoints.
    End point values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high)
    Number of subjects analysed
    8
    9
    8
    7
    6
    Units: Percentage of participants
        number (not applicable)
    0
    100
    100
    85.7
    100
    No statistical analyses for this end point

    Secondary: The Number of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1

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    End point title
    		 The Number of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1 [4]
    End point description
    End point type
    Secondary
    End point timeframe
    13 weeks
    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: CSL312 (FXII/PLG HAE) arm used for exploratory endpoints.
    End point values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high)
    Number of subjects analysed
    8
    9
    8
    7
    6
    Units: Number of participants
        number (not applicable)
    0
    5
    7
    3
    4
    No statistical analyses for this end point

    Secondary: The percentage of HAE attack-free subjects with C1-INH HAE during Treatment Period 1

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    End point title
    		 The percentage of HAE attack-free subjects with C1-INH HAE during Treatment Period 1 [5]
    End point description
    End point type
    Secondary
    End point timeframe
    13 weeks
    Notes
    [5] - 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: CSL312 (FXII/PLG HAE) arm used for exploratory endpoints.
    End point values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high)
    Number of subjects analysed
    8
    9
    8
    7
    6
    Units: Percentage of participants
        number (not applicable)
    0
    55.6
    87.5
    42.9
    66.7
    No statistical analyses for this end point

    Secondary: The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1

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    End point title
    		 The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 [6]
    End point description
    End point type
    Secondary
    End point timeframe
    13 weeks
    Notes
    [6] - 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: CSL312 (FXII/PLG HAE) arm used for exploratory endpoints.
    End point values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high)
    Number of subjects analysed
    8
    9
    8
    7
    6
    Units: Number of HAE attacks
    number (not applicable)
        Mild
    32
    3
    0
    2
    2
        Moderate
    43
    9
    1
    4
    0
        Severe
    20
    0
    0
    1
    0
    No statistical analyses for this end point

    Secondary: The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1

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    End point title
    		 The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 [7]
    End point description
    End point type
    Secondary
    End point timeframe
    13 weeks
    Notes
    [7] - 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: CSL312 (FXII/PLG HAE) arm used for exploratory endpoints.
    End point values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high)
    Number of subjects analysed
    8
    9
    8
    7
    6
    Units: Percentage of HAE attacks
    number (not applicable)
        Mild
    33.7
    25.0
    0
    28.6
    100
        Moderate
    45.3
    75.0
    100
    57.1
    0
        Severe
    21.1
    0
    0
    14.3
    0
    No statistical analyses for this end point

    Secondary: The mean time-normalized number of mild, moderate or severe HAE attacks per month in subjects with C1-INH HAE during Treatment Period 1

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    End point title
    		 The mean time-normalized number of mild, moderate or severe HAE attacks per month in subjects with C1-INH HAE during Treatment Period 1 [8]
    End point description
    The time-normalized number of HAE attacks per month during Treatment Period 1 for a subject was calculated as the (number of HAE attacks / length of subject’s evaluation period in days) * 30.4375
    End point type
    Secondary
    End point timeframe
    13 weeks
    Notes
    [8] - 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: CSL312 (FXII/PLG HAE) arm used for exploratory endpoints.
    End point values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high)
    Number of subjects analysed
    8
    9
    8
    7
    6
    Units: Number of HAE attacks per month
    arithmetic mean (standard deviation)
        Mild
    1.42 ( 1.395 )
    0.12 ( 0.177 )
    0 ( 0 )
    0.10 ( 0.168 )
    0.14 ( 0.222 )
        Moderate
    1.93 ( 1.403 )
    0.36 ( 1.087 )
    0.05 ( 0.127 )
    0.20 ( 0.347 )
    0 ( 0 )
        Severe
    0.89 ( 1.365 )
    0 ( 0 )
    0 ( 0 )
    0.05 ( 0.136 )
    0 ( 0 )
    No statistical analyses for this end point

    Secondary: The Number of Subjects with at least one (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1

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    End point title
    		 The Number of Subjects with at least one (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1 [9]
    End point description
    End point type
    Secondary
    End point timeframe
    13 weeks
    Notes
    [9] - 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: CSL312 (FXII/PLG HAE) arm used for exploratory endpoints.
    End point values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high)
    Number of subjects analysed
    8
    9
    8
    7
    6
    Units: Number of participants
        number (not applicable)
    8
    3
    1
    2
    0
    No statistical analyses for this end point

    Secondary: The Percentage of Subjects with at least one (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1

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    End point title
    		 The Percentage of Subjects with at least one (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1 [10]
    End point description
    End point type
    Secondary
    End point timeframe
    13 weeks
    Notes
    [10] - 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: CSL312 (FXII/PLG HAE) arm used for exploratory endpoints.
    End point values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high)
    Number of subjects analysed
    8
    9
    8
    7
    6
    Units: Percentage of participants
        number (not applicable)
    100
    33.3
    12.5
    28.6
    0
    No statistical analyses for this end point

    Secondary: Maximum concentration (Cmax) of CSL312 in subjects with C1-INH HAE during Treatment Period 1

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    End point title
    		 Maximum concentration (Cmax) of CSL312 in subjects with C1-INH HAE during Treatment Period 1 [11]
    End point description
    End point type
    Secondary
    End point timeframe
    13 weeks
    Notes
    [11] - 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: CSL312 (FXII/PLG HAE) arm used for exploratory endpoints.
    End point values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high)
    Number of subjects analysed
    0 [12]
    9
    8
    7
    0 [13]
    Units: ug/mL
        arithmetic mean (standard deviation)
    ( )
    10.6 ( 6.09 )
    15.9 ( 5.22 )
    56.4 ( 15.9 )
    ( )
    Notes
    [12] - The PK population consisted of all subjects with at least 1 measurable concentration of CSL312
    [13] - The PK population consisted of all subjects with at least 1 measurable concentration of CSL312
    No statistical analyses for this end point

    Secondary: Area under the concentration-time curve in 1 dosing interval (AUC0-tau) of CSL312 in subjects with C1-INH HAE during Treatment Period 1

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    End point title
    		 Area under the concentration-time curve in 1 dosing interval (AUC0-tau) of CSL312 in subjects with C1-INH HAE during Treatment Period 1 [14]
    End point description
    End point type
    Secondary
    End point timeframe
    13 weeks
    Notes
    [14] - 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: CSL312 (FXII/PLG HAE) arm used for exploratory endpoints.
    End point values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high)
    Number of subjects analysed
    0 [15]
    9
    8
    7
    0 [16]
    Units: h*μg/mL
        arithmetic mean (standard deviation)
    ( )
    4507 ( 2424 )
    7166 ( 2410 )
    26514 ( 8151 )
    ( )
    Notes
    [15] - The PK population consisted of all subjects with at least 1 measurable concentration of CSL312
    [16] - The PK population consisted of all subjects with at least 1 measurable concentration of CSL312
    No statistical analyses for this end point

    Secondary: Time of maximum concentration (Tmax) of CSL312 in subjects with C1-INH HAE during Treatment Period 1

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    End point title
    		 Time of maximum concentration (Tmax) of CSL312 in subjects with C1-INH HAE during Treatment Period 1 [17]
    End point description
    End point type
    Secondary
    End point timeframe
    13 weeks
    Notes
    [17] - 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: CSL312 (FXII/PLG HAE) arm used for exploratory endpoints.
    End point values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high)
    Number of subjects analysed
    0 [18]
    9
    8
    7
    0 [19]
    Units: hours
        median (full range (min-max))
    ( to )
    143.38 (45.4 to 196)
    165.51 (116 to 218)
    165.63 (72.4 to 188)
    ( to )
    Notes
    [18] - The PK population consisted of all subjects with at least 1 measurable concentration of CSL312
    [19] - The PK population consisted of all subjects with at least 1 measurable concentration of CSL312
    No statistical analyses for this end point

    Secondary: Terminal elimination half-life (T1/2) of CSL312 in subjects with C1-INH HAE during Treatment Period 1

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    End point title
    		 Terminal elimination half-life (T1/2) of CSL312 in subjects with C1-INH HAE during Treatment Period 1 [20]
    End point description
    End point type
    Secondary
    End point timeframe
    13 weeks
    Notes
    [20] - 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: CSL312 (FXII/PLG HAE) arm used for exploratory endpoints.
    End point values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high)
    Number of subjects analysed
    0 [21]
    7
    7
    5
    0 [22]
    Units: hours
        arithmetic mean (standard deviation)
    ( )
    411.7 ( 96.97 )
    394.0 ( 85.64 )
    443.5 ( 44.00 )
    ( )
    Notes
    [21] - The PK population consisted of all subjects with at least 1 measurable concentration of CSL312
    [22] - The PK population consisted of all subjects with at least 1 measurable concentration of CSL312
    No statistical analyses for this end point

    Secondary: Clearance (CL/F) of CSL312 in subjects with C1-INH HAE during Treatment Period 1

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    End point title
    		 Clearance (CL/F) of CSL312 in subjects with C1-INH HAE during Treatment Period 1 [23]
    End point description
    End point type
    Secondary
    End point timeframe
    13 weeks
    Notes
    [23] - 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: CSL312 (FXII/PLG HAE) arm used for exploratory endpoints.
    End point values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high)
    Number of subjects analysed
    0 [24]
    9
    8
    7
    0 [25]
    Units: L/hour
        arithmetic mean (standard deviation)
    ( )
    0.0198 ( 0.0079 )
    0.0303 ( 0.0084 )
    0.0246 ( 0.0079 )
    ( )
    Notes
    [24] - The PK population consisted of all subjects with at least 1 measurable concentration of CSL312
    [25] - The PK population consisted of all subjects with at least 1 measurable concentration of CSL312
    No statistical analyses for this end point

    Secondary: Volume of distribution during the elimination phase (Vz/F) of CSL312 in subjects with C1-INH HAE during Treatment Period 1

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    End point title
    		 Volume of distribution during the elimination phase (Vz/F) of CSL312 in subjects with C1-INH HAE during Treatment Period 1 [26]
    End point description
    End point type
    Secondary
    End point timeframe
    13 weeks
    Notes
    [26] - 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: CSL312 (FXII/PLG HAE) arm used for exploratory endpoints.
    End point values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high)
    Number of subjects analysed
    0 [27]
    7
    7
    5
    0 [28]
    Units: Liters
        arithmetic mean (standard deviation)
    ( )
    10.6 ( 5.10 )
    17.0 ( 4.78 )
    17.1 ( 6.67 )
    ( )
    Notes
    [27] - The PK population consisted of all subjects with at least 1 measurable concentration of CSL312
    [28] - The PK population consisted of all subjects with at least 1 measurable concentration of CSL312
    No statistical analyses for this end point

    Secondary: The number of subjects with C1-INH HAE with adverse events (AEs), serious adverse events (SAEs), adverse events of special interest (AESI), injection site reactions (ISRs), binding antibodies to CSL312 during Treatment Period 1

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    End point title
    		 The number of subjects with C1-INH HAE with adverse events (AEs), serious adverse events (SAEs), adverse events of special interest (AESI), injection site reactions (ISRs), binding antibodies to CSL312 during Treatment Period 1 [29]
    End point description
    Adverse events of special interest is defined as anaphylaxis, thromboembolic events, and bleeding events.
    End point type
    Secondary
    End point timeframe
    13 weeks
    Notes
    [29] - 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: CSL312 (FXII/PLG HAE) arm used for exploratory endpoints.
    End point values
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high)
    Number of subjects analysed
    8
    9
    8
    7
    6
    Units: Number of participans
    number (not applicable)
        AEs
    7
    7
    7
    7
    4
        SAEs
    0
    0
    0
    0
    0
        AESI
    1
    0
    0
    0
    0
        ISRs
    2
    1
    1
    4
    2
        Binding Antibodies to CSL312
    1
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately 129 weeks per participant
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with C1-INH HAE receiving buffer only. Placebo: Buffer without active ingredient.

    Reporting group title
    CSL312 (low)
    Reporting group description
    		 Subjects with C1-INH HAE receiving low dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Reporting group title
    CSL312 (med)
    Reporting group description
    		 Subjects with C1-INH HAE receiving medium dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Reporting group title
    CSL312 (high)
    Reporting group description
    		 Subjects with C1-INH HAE receiving high dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Reporting group title
    CSL312 (med/high)
    Reporting group description
    		 Subjects with C1-INH HAE receiving medium/high dose CSL312. Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use.

    Reporting group title
    CSL312 (med-Period 2)
    Reporting group description
    		 Subjects with C1-INH HAE receiving medium dose CSL312

    Reporting group title
    CSL312 (med/high-Period 2)
    Reporting group description
    		 Subjects with C1-INH HAE receiving medium/high dose CSL312

    Reporting group title
    CSL312 (high-Period 2)
    Reporting group description
    		 Subjects with C1-INH HAE receiving high dose CSL312

    Reporting group title
    CSL312 (FXII/PLG HAE-Period 1)
    Reporting group description
    		 Subjects with FXII/PLG HAE (Hereditary Angioedema with Normal C1-esterase Inhibitor and Factor XII or Plasminogen Gene Mutation) receiving high dose CSL312

    Reporting group title
    CSL312 (FXII/PLG HAE-Period 2)
    Reporting group description
    		 Subjects with FXII/PLG HAE (Hereditary Angioedema with Normal C1-esterase Inhibitor and Factor XII or Plasminogen Gene Mutation) receiving high dose CSL312

    Serious adverse events
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high) CSL312 (med-Period 2) CSL312 (med/high-Period 2) CSL312 (high-Period 2) CSL312 (FXII/PLG HAE-Period 1) CSL312 (FXII/PLG HAE-Period 2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         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
    Congenital, familial and genetic disorders
    Hereditary angioedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticular perforation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         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
    Asthma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         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
    		 Placebo CSL312 (low) CSL312 (med) CSL312 (high) CSL312 (med/high) CSL312 (med-Period 2) CSL312 (med/high-Period 2) CSL312 (high-Period 2) CSL312 (FXII/PLG HAE-Period 1) CSL312 (FXII/PLG HAE-Period 2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 8 (87.50%)
    7 / 9 (77.78%)
    7 / 8 (87.50%)
    7 / 7 (100.00%)
    4 / 6 (66.67%)
    25 / 36 (69.44%)
    2 / 3 (66.67%)
    17 / 18 (94.44%)
    1 / 6 (16.67%)
    2 / 2 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
    0 / 3 (0.00%)
    3 / 18 (16.67%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    1
    2
    0
    1
    0
    6
    0
    0
    Injection site pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 7 (42.86%)
    1 / 6 (16.67%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    3
    4
    0
    0
    2
    0
    0
    Chest discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    2
    0
    0
    Injection site pruritus
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    4
    0
    0
    Injection site reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    1
    0
    Injection site swelling
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Injection site urticaria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Chills
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Facial pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Immune system disorders
    Food allergy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Social circumstances
    Pregnancy of partner
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    0
    0
    0
    0
    0
    Throat tightness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Cough
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    2 / 36 (5.56%)
    0 / 3 (0.00%)
    3 / 18 (16.67%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    3
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Dyspnoea at rest
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Hyperventilation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Pulmonary congestion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Psychiatric disorders
    Initial insomnia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    4
    0
    0
    Investigations
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Glycosylated haemoglobin increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    3
    0
    1
    0
    0
    Muscle strain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Vascular access site bruising
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    1
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Skin laceration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    2 / 7 (28.57%)
    2 / 6 (33.33%)
    6 / 36 (16.67%)
    0 / 3 (0.00%)
    4 / 18 (22.22%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    0
    1
    3
    5
    12
    0
    4
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    1
    0
    1
    Nerve compression
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    3
    0
    0
    Anosmia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Ear and labyrinth disorders
    Vestibular disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Eye disorders
    Photopsia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    3
    0
    3
    1
    0
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    5 / 36 (13.89%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    7
    1
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    2
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    1
    Inguinal hernia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    0
    0
    1
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    0
    0
    0
    0
    0
    Dermatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Ingrowing nail
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Polymorphic light eruption
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Psoriasis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Eczema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Renal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Nephrolithiasis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Ureterolithiasis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Dysuria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    3
    0
    2
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Patellofemoral pain syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Plantar fascial fibromatosis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Arthralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    3 / 36 (8.33%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    0
    1
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
    0 / 3 (0.00%)
    4 / 18 (22.22%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    4
    0
    0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    0
    0
    0
    0
    Torticollis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Bone swelling
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Limb discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 9 (22.22%)
    3 / 8 (37.50%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    4 / 36 (11.11%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    2
    3
    0
    0
    4
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
    0 / 3 (0.00%)
    3 / 18 (16.67%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    6
    0
    4
    0
    0
    Abscess limb
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    Gingivitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Nasal herpes
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    4
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    0
    0
    0
    0
    4
    0
    1
    0
    2
    Sinusitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    2
    0
    0
    Cystitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Hordeolum
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 2 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    5
    Herpes zoster
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 36 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    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
    18 Dec 2018
    - Frequency of pregnancy testing was increased in Treatment Period 2. - Urine testing for pregnancy was added as an alternative to serum testing. - Acceptable methods of contraception were updated. - The requirement that pregnancy test results obtained outside of the study site would be documented and tracked was added. - The duration of the Follow-up Period was extended to 95 days. - Activities related to the accessibility and accountability of CSL312 were clarified, in the case that Treatment Period 2 was extended. - Acceptable use of routine (long-term) HAE prophylaxis during the study was clarified. - Clarification to the laboratory values that were to be documented in the medical history page of the eCRF. - Clarifications were made to statistical methods.
    20 Mar 2020
    - For subjects with C1-esterase inhibitor deficiency (C1-INH HAE) receiving the 600 mg dose in Treatment Period 2, the dose was decreased to 200 mg. - Edits were made to the Statistical Analysis and Methods section.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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