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    Clinical Trial Results:
    An open-label, single-arm, non-randomized phase 3 study to evaluate clinical efficacy, safety, and pharmacokinetics of subcutaneous administration of human plasma-derived C1-esterase inhibitor in the prophylactic treatment of hereditary angioedema in Japanese subjects

    Summary
    EudraCT number
    		 2019-003921-99
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    22 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Sep 2021
    First version publication date
    01 Sep 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSL830_3003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CSL Behring K.K.
    Sponsor organisation address
    1-2-3-Kita Aoyama, Minato-ku, Tokyo, Japan, 107-0061
    Public contact
    Trial Registration Coordinator, CSL Behring K.K., +1 610878-4000, clinicaltrials@cslbehring.com
    Scientific contact
    Trial Registration Coordinator, CSL Behring K.K., +1 610878-4000, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Jun 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study are to evaluate the clinical efficacy and pharmacokinetics of subcutaneous (SC) CSL830 in the prophylactic treatment of hereditary angioedema (HAE) in Japanese subjects.
    Protection of trial subjects
    This study was carried out in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and standard operating procedures for clinical research and development at CSL Behring.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Jun 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 9
    Worldwide total number of subjects
    9
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    8
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects will enter into a Run-in Period to evaluate their underlying HAE disease status and their HAE attack rate. Subjects must experience ≥ 4 HAE attacks within any 2 consecutive months within the 3-months prior to Screening to be eligible to proceed to Screening.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 CSL830
    Arm description
    		 Powder and solvent for solution for injection for Subcutaneous use
    Arm type
    		 Experimental

    Investigational medicinal product name
    C1-esterase inhibitor (C1-INH)
    Investigational medicinal product code
    Other name
    CSL830, Berinert
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single SC injection of 60 IU/kg CSL830 twice per week for up to 16 weeks.

    Number of subjects in period 1
    		CSL830
    Started
    9
    Completed
    9

    Baseline characteristics

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

    Reporting group values
    		 Overall Total
    Number of subjects
    		 9 9
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 1 1
        Adults (18-64 years)
    		 8 8
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.9 ( 11.43 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 3 3

    End points

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    End points reporting groups
    Reporting group title
    CSL830
    Reporting group description
    		 Powder and solvent for solution for injection for Subcutaneous use

    Primary: Time-normalized number of HAE attacks during treatment with CSL830

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    End point title
    		 Time-normalized number of HAE attacks during treatment with CSL830 [1]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 14 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were used as this is a single-arm study.
    End point values
    		 CSL830
    Number of subjects analysed
    9
    Units: Number of HAE attacks per month
    arithmetic mean (standard deviation)
        Baseline (run-in period)
    3.691 ( 1.0909 )
        CSL830 Treatment Period
    0.295 ( 0.4815 )
    No statistical analyses for this end point

    Primary: Trough concentration of C1-INH functional activity

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    End point title
    		 Trough concentration of C1-INH functional activity [2]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 10-14 days after the last dose at Week 16
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were used as this is a single-arm study.
    End point values
    		 CSL830
    Number of subjects analysed
    9
    Units: percent
        arithmetic mean (standard deviation)
    59.77 ( 19.527 )
    No statistical analyses for this end point

    Primary: Area under the concentration curve (AUC) for C1-INH functional activity

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    End point title
    		 Area under the concentration curve (AUC) for C1-INH functional activity [3]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 10-14 days after the last dose on Week 16
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were used as this is a single-arm study.
    End point values
    		 CSL830
    Number of subjects analysed
    9
    Units: h*%
    arithmetic mean (standard deviation)
        AUC (0-tau)
    5317.1164 ( 1347.7965 )
        AUC (0-last)
    13091.4870 ( 3835.3917 )
    No statistical analyses for this end point

    Secondary: The percentage of subjects who achieved ≥ 90%, ≥ 70%, and ≥ 50% relative reduction in time-normalized monthly HAE attack rate

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    End point title
    		 The percentage of subjects who achieved ≥ 90%, ≥ 70%, and ≥ 50% relative reduction in time-normalized monthly HAE attack rate
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 14 weeks
    End point values
    		 CSL830
    Number of subjects analysed
    9
    Units: percent reduction in monthly HAE attacks
    number (confidence interval 95%)
        Reduction of >= 50%
    100.0 (70.1 to 100.0)
        Reduction of >= 70%
    77.8 (45.3 to 93.7)
        Reduction of >= 90%
    66.7 (35.4 to 87.9)
    No statistical analyses for this end point

    Secondary: The relative reduction in the time-normalized number of rescue medication uses per month for treatment of HAE attacks

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    End point title
    		 The relative reduction in the time-normalized number of rescue medication uses per month for treatment of HAE attacks
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 14 weeks
    End point values
    		 CSL830
    Number of subjects analysed
    9
    Units: percent
        arithmetic mean (standard deviation)
    84.980 ( 25.3320 )
    No statistical analyses for this end point

    Secondary: The number of reported adverse events (AEs)

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    End point title
    		 The number of reported adverse events (AEs)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 18 weeks
    End point values
    		 CSL830
    Number of subjects analysed
    9
    Units: number of AEs
    number (not applicable)
        Number of subjects reporting AEs
    7
        Number of AEs
    109
    No statistical analyses for this end point

    Secondary: Percentage of subjects reporting AEs and injection site reactions that began within 24 hours of CSL830 administration

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    End point title
    		 Percentage of subjects reporting AEs and injection site reactions that began within 24 hours of CSL830 administration
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 24 hours after dose of CSL830
    End point values
    		 CSL830
    Number of subjects analysed
    9
    Units: percent of subjects
    number (not applicable)
        AEs
    66.7
        Injection site reactions
    33.3
    No statistical analyses for this end point

    Secondary: Mean trough C1-INH functional activity during treatment with CSL830

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    End point title
    		 Mean trough C1-INH functional activity during treatment with CSL830
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 16 weeks
    End point values
    		 CSL830
    Number of subjects analysed
    9
    Units: percent functional activity
    arithmetic mean (standard deviation)
        week 3
    74.37 ( 12.719 )
        week 7
    66.32 ( 21.647 )
        week 11
    67.04 ( 18.471 )
        week 16
    59.77 ( 19.527 )
    No statistical analyses for this end point

    Secondary: Mean C1-INH antigen levels during treatment with CSL830

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    End point title
    		 Mean C1-INH antigen levels during treatment with CSL830
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 16 weeks
    End point values
    		 CSL830
    Number of subjects analysed
    9
    Units: mg/mL
    arithmetic mean (standard deviation)
        week 3
    0.2076 ( 0.1431 )
        week 7
    0.1957 ( 0.1639 )
        week 11
    0.2102 ( 0.1909 )
        week 16
    0.1857 ( 0.1503 )
    No statistical analyses for this end point

    Secondary: Mean C4 antigen levels during treatment with CSL830

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    End point title
    		 Mean C4 antigen levels during treatment with CSL830
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 16 weeks
    End point values
    		 CSL830
    Number of subjects analysed
    9
    Units: mg/dL
    arithmetic mean (standard deviation)
        week 3
    17.721 ( 6.2850 )
        week 7
    16.259 ( 6.8515 )
        week 11
    17.992 ( 6.3218 )
        week 16
    15.716 ( 7.6020 )
    No statistical analyses for this end point

    Secondary: Change from week 1 in Subject-reported Angioedema Quality of Life (AEQoL) total score at week 16

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    End point title
    		 Change from week 1 in Subject-reported Angioedema Quality of Life (AEQoL) total score at week 16
    End point description
    End point type
    Secondary
    End point timeframe
    Week 1 and Week 16
    End point values
    		 CSL830
    Number of subjects analysed
    9
    Units: percent
        arithmetic mean (standard deviation)
    -24.020 ( 22.9006 )
    No statistical analyses for this end point

    Secondary: Subject-reported Global Assessments of Reponse to Therapy outcomes (SGART)

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    End point title
    		 Subject-reported Global Assessments of Reponse to Therapy outcomes (SGART)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 16 weeks
    End point values
    		 CSL830
    Number of subjects analysed
    9
    Units: percent of subjects
    number (not applicable)
        Good
    33.3
        Excellent
    66.7
    No statistical analyses for this end point

    Secondary: Investigator-reported Global Assessments of Reponse to Therapy outcomes (IGART)

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    End point title
    		 Investigator-reported Global Assessments of Reponse to Therapy outcomes (IGART)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 16 weeks
    End point values
    		 CSL830
    Number of subjects analysed
    9
    Units: percent of subjects
    number (not applicable)
        Good
    11.1
        Excellent
    88.9
    No statistical analyses for this end point

    Secondary: Mean Absolute Reduction in Time-normalized Number of HAE Attacks per Month

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    End point title
    		 Mean Absolute Reduction in Time-normalized Number of HAE Attacks per Month
    End point description
    End point type
    Secondary
    End point timeframe
    up to 14 weeks
    End point values
    		 CSL830
    Number of subjects analysed
    9
    Units: Number of HAE attacks
        arithmetic mean (standard deviation)
    -3.396 ( 1.3788 )
    No statistical analyses for this end point

    Secondary: Median Absolute Reduction in Time-normalized Number of HAE Attacks per Month

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    End point title
    		 Median Absolute Reduction in Time-normalized Number of HAE Attacks per Month
    End point description
    End point type
    Secondary
    End point timeframe
    up to 14 weeks
    End point values
    		 CSL830
    Number of subjects analysed
    9
    Units: Number of HAE attacks
        median (inter-quartile range (Q1-Q3))
    -3.581 (-4.348 to -2.899)
    No statistical analyses for this end point

    Secondary: Mean Relative Reduction in Time-normalized Number of HAE Attacks per Month

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    End point title
    		 Mean Relative Reduction in Time-normalized Number of HAE Attacks per Month
    End point description
    End point type
    Secondary
    End point timeframe
    up to 14 weeks
    End point values
    		 CSL830
    Number of subjects analysed
    9
    Units: percent
        arithmetic mean (standard deviation)
    89.310 ( 18.0156 )
    No statistical analyses for this end point

    Secondary: Median Relative Reduction in Time-normalized Number of HAE Attacks per Month

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    End point title
    		 Median Relative Reduction in Time-normalized Number of HAE Attacks per Month
    End point description
    End point type
    Secondary
    End point timeframe
    up to 14 weeks
    End point values
    		 CSL830
    Number of subjects analysed
    9
    Units: percent
        median (inter-quartile range (Q1-Q3))
    100.0 (84.946 to 100.000)
    No statistical analyses for this end point

    Secondary: Mean Relative Reduction in Time-normalized Number of Moderate or Severe HAE Attacks per Month

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    End point title
    		 Mean Relative Reduction in Time-normalized Number of Moderate or Severe HAE Attacks per Month
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 14 weeks
    End point values
    		 CSL830
    Number of subjects analysed
    8
    Units: percent
        arithmetic mean (standard deviation)
    88.841 ( 16.0551 )
    No statistical analyses for this end point

    Secondary: Median Relative Reduction in Time-normalized Number of Moderate or Severe HAE Attacks per Month

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    End point title
    		 Median Relative Reduction in Time-normalized Number of Moderate or Severe HAE Attacks per Month
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 14 weeks
    End point values
    		 CSL830
    Number of subjects analysed
    8
    Units: percent
        median (inter-quartile range (Q1-Q3))
    100.0 (73.297 to 100.000)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 18 weeks per subject
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    CSL830
    Reporting group description
    		 Powder and solvent for solution for injection for Subcutaneous use

    Serious adverse events
    		 CSL830
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CSL830
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 9 (77.78%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    3
    Injection site erythema
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    25
    Injection site reaction
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    16
    Malaise
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    19
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    30
    Urticaria
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    4
    Blister
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Acute sinusitis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Otitis media
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Dec 2019
    -Modified rescue therapy to include only therapies approved in Japan. - Adjustments to clarify women of childbearing potential and contraception in Japan. - Added Appendix 2 for reporting of HAE attacks.

    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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