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    Clinical Trial Results:
    A double-blind, randomized, placebo-controlled, cross-over study to evaluate the clinical efficacy and safety of subcutaneous administration of human plasma-derived C1-esterase inhibitor in the prophylactic treatment of hereditary angioedema

    Summary
    EudraCT number
    		 2013-000916-10
    Trial protocol
    		 GB   HU   IT   ES   CZ  
    Global end of trial date
    12 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Nov 2016
    First version publication date
    17 Nov 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSL830_3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01912456
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CSL Behring
    Sponsor organisation address
    Emil-von-Behring-Strasse 76, Marburg, Germany, 35041
    Public contact
    Trial Disclosure Manager, CSL Behring GmbH, clinicaltrials@cslbehring.com
    Scientific contact
    Trial Disclosure Manager, CSL Behring GmbH, 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
    04 Dec 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the clinical efficacy of subcutaneous (SC) CSL830 in the prophylactic treatment of hereditary angioedema (HAE). To compare the clinical efficacy of 2 doses of SC CSL830.
    Protection of trial subjects
    This study was carried out in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines, standard operating procedures for clinical research and development at CSL Behring and any other relevant procedures and applicable international and national regulatory requirements. The study protocol and all amendments were approved by the Independent Ethics Committee / Institutional Review Board of the participating centers. Before undergoing Screening procedures for possible enrollment into the study, the subjects’ legally acceptable representative was informed, in an understandable form, about the nature, scope, and possible consequences of the study. The investigator was responsible for obtaining a subject’s legally acceptable representative written informed consent to participate in the study. The investigator could cease study treatment and withdraw the subject, or the subject could withdraw himself from participation in the study at any time. If a subject was withdrawn from the study or further participation was declined, the subject would continue to have access to medical care and would be treated according to routine medical practice, but would no longer receive the investigational medicinal product.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Dec 2013
    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
    Australia: 1
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    United States: 54
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Italy: 5
    Worldwide total number of subjects
    90
    EEA total number of subjects
    18
    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)
    7
    Adults (18-64 years)
    76
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 115 subjects were screened and 90 were randomized/enrolled

    Period 1
    Period 1 title
    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 high/CSL830 (40)
    Arm description
    		 In Period 1, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks

    Arm title
    		 CSL830 (40)/placebo high
    Arm description
    		 In Period 1, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSL830
    Investigational medicinal product code
    CSL830
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A low-volume dose of C1-esterase inhibitor (40 IU/kg) will be administered subcutaneously twice a week for up to 16 weeks

    Arm title
    		 Placebo low/CSL830 (60)
    Arm description
    		 In Period 1, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks

    Arm title
    		 CSL830 (60)/placebo low
    Arm description
    		 In Period 1, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSL830
    Investigational medicinal product code
    CSL830
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A high-volume dose of C1-esterase inhibitor (60 IU/kg) will be administered subcutaneously twice a week for up to 16 weeks

    Number of subjects in period 1
    		Placebo high/CSL830 (40) CSL830 (40)/placebo high Placebo low/CSL830 (60) CSL830 (60)/placebo low
    Started
    22
    23
    23
    22
    Completed
    20
    22
    21
    19
    Not completed
    2
    1
    2
    3
         Consent withdrawn by subject
    -
    1
    1
    1
         Physician decision
    -
    -
    1
    -
         Adverse event, non-fatal
    1
    -
    -
    1
         Non-compliance
    1
    -
    -
    1
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo high/CSL830 (40)
    Arm description
    		 In Period 1, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSL830
    Investigational medicinal product code
    CSL830
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A low-volume dose of C1-esterase inhibitor (40 IU/kg) will be administered subcutaneously twice a week for up to 16 weeks

    Arm title
    		 CSL830 (40)/Placebo high
    Arm description
    		 In Period 1, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks

    Arm title
    		 Placebo low/CSL830 (60)
    Arm description
    		 In Period 1, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSL830
    Investigational medicinal product code
    CSL830
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A high-volume dose of C1-esterase inhibitor (60 IU/kg) will be administered subcutaneously twice a week for up to 16 weeks

    Arm title
    		 CSL830 (60)/Placebo low
    Arm description
    		 In Period 1, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks

    Number of subjects in period 2
    		Placebo high/CSL830 (40) CSL830 (40)/Placebo high Placebo low/CSL830 (60) CSL830 (60)/Placebo low
    Started
    20
    22
    21
    19
    Completed
    20
    20
    21
    18
    Not completed
    0
    2
    0
    1
         Adverse event, non-fatal
    -
    -
    -
    1
         Lack of efficacy
    -
    2
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo high/CSL830 (40)
    Reporting group description
    		 In Period 1, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks.

    Reporting group title
    CSL830 (40)/placebo high
    Reporting group description
    		 In Period 1, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks.

    Reporting group title
    Placebo low/CSL830 (60)
    Reporting group description
    		 In Period 1, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks.

    Reporting group title
    CSL830 (60)/placebo low
    Reporting group description
    		 In Period 1, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks.

    Reporting group values
    		 Placebo high/CSL830 (40) CSL830 (40)/placebo high Placebo low/CSL830 (60) CSL830 (60)/placebo low Total
    Number of subjects
    		 22 23 23 22 90
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 2 1 2 2 7
        Adults (18-64 years)
    		 17 21 19 19 76
        From 65-84 years
    		 3 1 2 1 7
        85 years and over
    		 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 14 14 17 15 60
        Male
    		 8 9 6 7 30

    End points

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    End points reporting groups
    Reporting group title
    Placebo high/CSL830 (40)
    Reporting group description
    		 In Period 1, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks.

    Reporting group title
    CSL830 (40)/placebo high
    Reporting group description
    		 In Period 1, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks.

    Reporting group title
    Placebo low/CSL830 (60)
    Reporting group description
    		 In Period 1, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks.

    Reporting group title
    CSL830 (60)/placebo low
    Reporting group description
    		 In Period 1, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks.
    Reporting group title
    Placebo high/CSL830 (40)
    Reporting group description
    		 In Period 1, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks.

    Reporting group title
    CSL830 (40)/Placebo high
    Reporting group description
    		 In Period 1, a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks.

    Reporting group title
    Placebo low/CSL830 (60)
    Reporting group description
    		 In Period 1, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks.

    Reporting group title
    CSL830 (60)/Placebo low
    Reporting group description
    		 In Period 1, a high-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then in Period 2, a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks.

    Subject analysis set title
    CSL830 (40) - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT Population consisted of all subjects who provided informed consent / assent and were randomized, regardless of whether they received investigational product.

    Subject analysis set title
    CSL830 (60) - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT Population consisted of all subjects who provided informed consent / assent and were randomized, regardless of whether they received investigational product.

    Subject analysis set title
    Placebo high - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT Population consisted of all subjects who provided informed consent / assent and were randomized, regardless of whether they received investigational product.

    Subject analysis set title
    Placebo Low - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT Population consisted of all subjects who provided informed consent / assent and were randomized, regardless of whether they received investigational product.

    Subject analysis set title
    CSL830 (40) - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population consisted of all subjects who provided informed consent / assent, were randomized, and received at least 1 dose (or partial dose) of investigational product.

    Subject analysis set title
    CSL830 (60) - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population consisted of all subjects who provided informed consent / assent, were randomized, and received at least 1 dose (or partial dose) of investigational product.

    Subject analysis set title
    Placebo high - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population consisted of all subjects who provided informed consent / assent, were randomized, and received at least 1 dose (or partial dose) of investigational product.

    Subject analysis set title
    Placebo low - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population consisted of all subjects who provided informed consent / assent, were randomized, and received at least 1 dose (or partial dose) of investigational product.

    Primary: Time-normalized number of hereditary angioedema attacks

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    End point title
    		 Time-normalized number of hereditary angioedema attacks
    End point description
    The time normalized number of HAE attacks as reported by the investigator per subject was calculated as: •The total number of HAE attacks per subject and per treatment period / length of stay of subject in treatment period (days), Where length of stay of subject in treatment period was calculated as: •Date of last day of subject in treatment period – date of first day of Week 3 of subject in treatment period + 1.
    End point type
    Primary
    End point timeframe
    During the treatment phase, up to 28 weeks
    End point values
    		 CSL830 (40) - ITT CSL830 (60) - ITT Placebo high - ITT Placebo Low - ITT
    Number of subjects analysed
    43
    43
    44
    42
    Units: Number/day
        least squares mean (standard error)
    0.04 ( 0.011 )
    0.02 ( 0.009 )
    0.12 ( 0.011 )
    0.13 ( 0.009 )
    Statistical analysis title
    		 Within-subject analysis - Placebo Low /CSL830 (60)
    Comparison groups
    Placebo Low - ITT v CSL830 (60) - ITT
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.14
         upper limit
    		 -0.09
    Notes
    [1] - Because of the crossover design, each subject was randomized to receive both the 60 IU/kg CSL830 and Placebo Low Volume treatments in consecutive treatment periods. Therefore, the subjects in each treatment period are the same subjects and data for all 45 subjects in the ITT population are included in this mixed model analysis.
    Statistical analysis title
    		 Within-subject analysis - CSL830 (40)/Placebo High
    Comparison groups
    CSL830 (40) - ITT v Placebo high - ITT
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 -0.05
    Notes
    [2] - Because of the crossover design, each subject was randomized to receive both the 40 IU/kg CSL830 and Placebo High Volume treatments in consecutive treatment periods. Therefore, the subjects in each treatment period are the same subjects and data for all 45 subjects in the ITT population are included in this mixed model analysis.
    Statistical analysis title
    		 Between-subject analysis - CSL830 (40)/CSL830 (60)
    Comparison groups
    CSL830 (40) - ITT v CSL830 (60) - ITT
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.114
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.01
    Notes
    [3] - Because of the crossover design, each subject was randomized to receive both CSL830 and Placebo treatments in consecutive treatment periods. Therefore, the subjects in each treatment period are the same subjects and data for all 90 subjects in the ITT population are included in this mixed model analysis.

    Secondary: Percentage of subjects with a ≥ 50% reduction in the number of hereditary angioedema attacks

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    End point title
    		 Percentage of subjects with a ≥ 50% reduction in the number of hereditary angioedema attacks
    End point description
    The percentage reduction (%) in the time normalized number of HAE attacks was calculated as: •100 x [1 – (the time normalized number of HAE attacks when treated with CSL830) / (the time normalized number of HAE attacks when treated with placebo)].
    End point type
    Secondary
    End point timeframe
    During the treatment phase, up to 28 weeks
    End point values
    		 CSL830 (40) - ITT CSL830 (60) - ITT
    Number of subjects analysed
    42
    40
    Units: Percent of subjects
        number (confidence interval 95%)
    76.2 (61.5 to 86.5)
    90 (76.9 to 96)
    Statistical analysis title
    		 Between-subject analysis - CSL830 (40)/CSL830 (60)
    Comparison groups
    CSL830 (60) - ITT v CSL830 (40) - ITT
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Wilson CI - calculation of percentages
    Parameter type
    		 difference in the percentages
    Point estimate
    13.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 29.7

    Secondary: Time-Normalized Number of Uses of Rescue Medication

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    End point title
    		 Time-Normalized Number of Uses of Rescue Medication
    End point description
    End point type
    Secondary
    End point timeframe
    During the treatment phase, up to 28 weeks
    End point values
    		 CSL830 (40) - ITT CSL830 (60) - ITT Placebo high - ITT Placebo Low - ITT
    Number of subjects analysed
    43
    43
    44
    42
    Units: Number/day
        least squares mean (standard error)
    0.04 ( 0.042 )
    0.01 ( 0.011 )
    0.18 ( 0.04 )
    0.13 ( 0.011 )
    Statistical analysis title
    		 Within-subject analysis - Placebo Low/CSL830 (60)
    Comparison groups
    CSL830 (60) - ITT v Placebo Low - ITT
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 -0.09
    Notes
    [4] - Because of the crossover design, each subject was randomized to receive both the 60 IU/kg CSL830 and Placebo Low Volume treatments in consecutive treatment periods. Therefore, the subjects in each treatment period are the same subjects and data for all 45 subjects in the ITT population are included in this mixed model analysis.
    Statistical analysis title
    		 Within-subject analysis - CSL830 (40)/Placebo High
    Comparison groups
    CSL830 (40) - ITT v Placebo high - ITT
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.018
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 -0.03
    Notes
    [5] - Because of the crossover design, each subject was randomized to receive both the 40 IU/kg CSL830 and Placebo High Volume treatments in consecutive treatment periods. Therefore, the subjects in each treatment period are the same subjects and data for all 45 subjects in the ITT population are included in this mixed model analysis.
    Statistical analysis title
    		 Between-subject analysis - CSL830 (40)/CSL830 (60)
    Comparison groups
    CSL830 (40) - ITT v CSL830 (60) - ITT
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.31
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.02
    Notes
    [6] - Because of the crossover design, each subject was randomized to receive both CSL830 and Placebo treatments in consecutive treatment periods. Therefore, the subjects in each treatment period are the same subjects and data for all 90 subjects in the ITT population are included in this mixed model analysis.

    Secondary: Percentage of subjects with adverse events (AEs) within 24 hours of C1-esterase inhibitor or placebo administration

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    End point title
    		 Percentage of subjects with adverse events (AEs) within 24 hours of C1-esterase inhibitor or placebo administration
    End point description
    End point type
    Secondary
    End point timeframe
    Within 24 hours of C1-esterase inhibitor or placebo administration
    End point values
    		 CSL830 (40) - Safety CSL830 (60) - Safety Placebo high - Safety Placebo low - Safety
    Number of subjects analysed
    43
    43
    44
    42
    Units: Percent of subjects
        number (not applicable)
    58.1
    60.5
    45.5
    54.8
    No statistical analyses for this end point

    Secondary: Percentage of subjects with AEs or other specified safety events

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    End point title
    		 Percentage of subjects with AEs or other specified safety events
    End point description
    The percentage of subjects experiencing the following during treatment with CSL830 and placebo: unsolicited AEs, serious AEs, suspected adverse drug reactions, increased risk scores for deep vein thrombosis and pulmonary embolism, thromboembolic events, inhibitory anti C1 INH antibodies, or clinically significant abnormalities in laboratory assessments.
    End point type
    Secondary
    End point timeframe
    During the treatment phase, up to 32 weeks
    End point values
    		 CSL830 (40) - Safety CSL830 (60) - Safety Placebo high - Safety Placebo low - Safety
    Number of subjects analysed
    43
    43
    44
    42
    Units: Percent of subjects
        number (not applicable)
    67.4
    69.8
    61.4
    71.4
    No statistical analyses for this end point

    Secondary: Percentage of subjects experiencing solicited local AEs (Injection site reactions)

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    End point title
    		 Percentage of subjects experiencing solicited local AEs (Injection site reactions)
    End point description
    The percentage of subjects experiencing solicited local AEs (discomfort [eg, pain, burning], swelling, bruising, or itching at the investigational product injection site) during treatment with CSL830 and placebo.
    End point type
    Secondary
    End point timeframe
    During the treatment phase, up to 32 weeks
    End point values
    		 CSL830 (40) - Safety CSL830 (60) - Safety Placebo high - Safety Placebo low - Safety
    Number of subjects analysed
    43
    43
    44
    42
    Units: Percent of subjects
        number (not applicable)
    27.9
    34.9
    22.7
    26.2
    No statistical analyses for this end point

    Secondary: Investigational product injections resulting in solicited local AEs (Injection site reactions)

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    End point title
    		 Investigational product injections resulting in solicited local AEs (Injection site reactions)
    End point description
    The rate/injection of injections of C1-esterase inhibitor or placebo that were followed by solicited local AEs (discomfort [eg, pain, burning], swelling, bruising, or itching at the investigational product injection site) during treatment with CSL830 and placebo. Rate/Injection = Number of events/number of injections.
    End point type
    Secondary
    End point timeframe
    During the treatment phase, up to 32 weeks
    End point values
    		 CSL830 (40) - Safety CSL830 (60) - Safety Placebo high - Safety Placebo low - Safety
    Number of subjects analysed
    43 [7]
    43 [8]
    44 [9]
    42 [10]
    Units: injection site reactions/injection
        number (not applicable)
    0.21
    0.08
    0.12
    0.05
    Notes
    [7] - 1307 total number of injections within treatment
    [8] - 1320 total number of injections within treatment
    [9] - 1290 total number of injections within treatment
    [10] - 1164 total number of injections within treatment
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the treatment phase, up to 32 weeks.
    Adverse event reporting additional description
    The Safety Population consisted of all subjects who provided informed consent / assent, were randomized, and received at least 1 dose (or partial dose) of investigational product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    CSL830 (40)
    Reporting group description
    		 -

    Reporting group title
    CSL830 (60)
    Reporting group description
    		 -

    Reporting group title
    Placebo high
    Reporting group description
    		 -

    Reporting group title
    Placebo low
    Reporting group description
    		 -

    Serious adverse events
    		 CSL830 (40) CSL830 (60) Placebo high Placebo low
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    1 / 42 (2.38%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Congenital, familial and genetic disorders
    Hereditary angioedema
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 43 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urosepsis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CSL830 (40) CSL830 (60) Placebo high Placebo low
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 43 (23.26%)
    17 / 43 (39.53%)
    12 / 44 (27.27%)
    12 / 42 (28.57%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 43 (9.30%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    5
    0
    0
    1
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    7 / 43 (16.28%)
    9 / 43 (20.93%)
    6 / 44 (13.64%)
    7 / 42 (16.67%)
         occurrences all number
    86
    20
    36
    28
    Injection site pain
         subjects affected / exposed
    7 / 43 (16.28%)
    7 / 43 (16.28%)
    5 / 44 (11.36%)
    4 / 42 (9.52%)
         occurrences all number
    90
    19
    34
    9
    Injection site bruising
         subjects affected / exposed
    2 / 43 (4.65%)
    4 / 43 (9.30%)
    2 / 44 (4.55%)
    3 / 42 (7.14%)
         occurrences all number
    5
    5
    2
    5
    Injection site swelling
         subjects affected / exposed
    1 / 43 (2.33%)
    4 / 43 (9.30%)
    2 / 44 (4.55%)
    2 / 42 (4.76%)
         occurrences all number
    1
    39
    6
    18
    Injection site induration
         subjects affected / exposed
    3 / 43 (6.98%)
    4 / 43 (9.30%)
    1 / 44 (2.27%)
    1 / 42 (2.38%)
         occurrences all number
    8
    6
    2
    2
    Fatigue
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 43 (2.33%)
    3 / 44 (6.82%)
    3 / 42 (7.14%)
         occurrences all number
    1
    1
    3
    3
    Injection site oedema
         subjects affected / exposed
    5 / 43 (11.63%)
    0 / 43 (0.00%)
    2 / 44 (4.55%)
    1 / 42 (2.38%)
         occurrences all number
    60
    0
    62
    1
    Injection site haemorrhage
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 43 (2.33%)
    4 / 44 (9.09%)
    0 / 42 (0.00%)
         occurrences all number
    8
    1
    4
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 43 (2.33%)
    3 / 44 (6.82%)
    2 / 42 (4.76%)
         occurrences all number
    1
    1
    4
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 43 (2.33%)
    8 / 43 (18.60%)
    3 / 44 (6.82%)
    3 / 42 (7.14%)
         occurrences all number
    1
    9
    3
    3
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 43 (6.98%)
    3 / 43 (6.98%)
    3 / 44 (6.82%)
    3 / 42 (7.14%)
         occurrences all number
    3
    3
    3
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Feb 2014
    The study design has been revised so that subjects are not required to discontinue use of their medication for hereditary angioedema (HAE) prophylaxis at entry into the Run-in Period. The inclusion criteria have been revised to permit the inclusion of subjects who have used a stable regimen of oral medication for prophylaxis against HAE attacks (ie, androgens, tranexamic acid, progestins) within 3 months of the Screening Visit and who do not plan to change that regimen during the study. The exclusion criteria have been revised to exclude: a. Subjects with body weight < 40 kilograms b. Subjects who have used intravenous C1-esterase inhibitor (C1-INH) for routine prophylaxis against HAE attacks (ie, administered every 3 or 4 days) within 3 months of the Screening Visit or who plan to use intravenous C1-INH for routine prophylaxis against HAE attacks during the study. c. Subjects who are unable to have their HAE adequately managed pharmacologically with on demand treatment, administered either independently or with assistance. Secondary safety and tolerability endpoints have been added. The planned statistical analyses have been revised: a. New sub-group analyses have been included. b. A description of missing data handling has been added. c. The lower bound of the 95% confidence interval for the responder rate of the combined active treatment group has been added. The lower bound is 33%. d. Additional details have been included to support statistical analyses. The list of permitted on-study medications has been revised to allow the use of medications (eg, intravenous C1-INH) for the pre-procedure prevention of acute HAE attacks during the study.
    11 Dec 2014
    The protocol has undergone administrative revisions to more clearly convey the joint intent of the Steering Committee, the Data Safety Monitoring Board, and CSL Behring regarding study conduct as pertains to the stopping, restarting, and termination rules.

    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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