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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Placebo-controlled, Double-blind Study to Evaluate the Efficacy and Safety of Lanadelumab for Prevention Against Acute Attacks of Non-histaminergic Angioedema with Normal C1-Inhibitor (C1-INH) and Acquired Angioedema (AAE) Due to C1-INH Deficiency

    Summary
    EudraCT number
    		 2019-001703-20
    Trial protocol
    		 GB   DE   HU   PL   IT   FR  
    Global end of trial date
    20 Oct 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Nov 2023
    First version publication date
    03 Nov 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SHP643-303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04206605
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 116647
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    95 Hayden Avenue, Lexington, United States, MA 02421
    Public contact
    Study Director, Takeda, ClinicalTransparency@takeda.com
    Scientific contact
    Study Director, Takeda, ClinicalTransparency@takeda.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
    20 Oct 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Oct 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main aim of this study is to check if repeated subcutaneous (SC) injections of lanadelumab can prevent angioedema attacks in teenagers and adults with non-histaminergic angioedema with normal C1-INH. Another aim is to check if they tolerate the repeated SC injections. Participants will receive a SC injection of lanadelumab every two weeks for 26 weeks. The first two doses of lanadelumab will be given at the study clinic. Once a participant (and/or parent/caregiver) has been appropriately trained, lanadelumab can be self-injected. Visits to the study clinic are planned for the first, third and fourth week and then every 4 weeks.
    Protection of trial subjects
    Each subject signed an informed consent form before participating in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 May 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
    Canada: 5
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Japan: 4
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United States: 40
    Worldwide total number of subjects
    77
    EEA total number of subjects
    28
    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)
    74
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 34 investigative sites in Canada, United States, Germany, Hungary, Italy, Spain, France, Japan, Netherlands, and Poland from 04 May 2020 to 20 October 2022.

    Pre-assignment
    Screening details
    		 Participants with a diagnosis of non-histaminergic angioedema were randomized in a 2:1 ratio to receive lanadelumab or placebo.

    Period 1
    Period 1 title
    Overall Period
    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
    		 Participants received placebo-matching lanadelumab subcutaneous (SC) injection once every 2 weeks (q2w) for up to 26 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo, SC injection, once Q2W.

    Arm title
    		 Lanadelumab 300 mg
    Arm description
    		 Participants received 300 mg of lanadelumab solution in a prefilled syringe (PFS) as SC injection once q2w for up to 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanadelumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lanadelumab 300 mg, SC injection, once Q2W.

    Number of subjects in period 1
    		Placebo Lanadelumab 300 mg
    Started
    27
    50
    Completed
    26
    49
    Not completed
    1
    1
         Adverse event, non-fatal
    -
    1
         Withdrawal by Subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo-matching lanadelumab subcutaneous (SC) injection once every 2 weeks (q2w) for up to 26 weeks.

    Reporting group title
    Lanadelumab 300 mg
    Reporting group description
    		 Participants received 300 mg of lanadelumab solution in a prefilled syringe (PFS) as SC injection once q2w for up to 26 weeks.

    Reporting group values
    		 Placebo Lanadelumab 300 mg Total
    Number of subjects
    		 27 50 77
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
        Age (2 to 6 years)
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43.8 ( 10.77 ) 42.3 ( 14.06 ) -
    Gender categorical
    Units: Subjects
        Male
    		 8 7 15
        Female
    		 19 43 62
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 7 9
        Not Hispanic or Latino
    		 24 43 67
        Unknown or Not Reported
    		 1 0 1
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 2 2 4
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 4 4
        White
    		 24 44 68
        More Than one Race
    		 0 0 0
        Unknown or Not Reported
    		 1 0 1
    Height
    Units: centimeter
        arithmetic mean (standard deviation)
    		 168.32 ( 9.779 ) 166.09 ( 8.232 ) -
    Weight
    Units: kilogram
        arithmetic mean (standard deviation)
    		 82.09 ( 22.701 ) 82.04 ( 25.217 ) -
    Body Mass Index (BMI)
    BMI is calculated as [weight(kg)/height(m^2)].
    Units: kilogram per squared meter
        arithmetic mean (standard deviation)
    		 28.88 ( 7.413 ) 29.75 ( 9.127 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo-matching lanadelumab subcutaneous (SC) injection once every 2 weeks (q2w) for up to 26 weeks.

    Reporting group title
    Lanadelumab 300 mg
    Reporting group description
    		 Participants received 300 mg of lanadelumab solution in a prefilled syringe (PFS) as SC injection once q2w for up to 26 weeks.

    Primary: Number of Investigator-Confirmed Angioedema Attacks During the Treatment Period of Day 0 Through Day 182

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    End point title
    		 Number of Investigator-Confirmed Angioedema Attacks During the Treatment Period of Day 0 Through Day 182
    End point description
    An angioedema attack was defined as symptoms or signs consistent with an attack in at least 1 of following locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with/without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Attack rate=number of attacks occurring during specified period divided by number of days participant contributed to specified period multiplied by 28 days. Number of investigator-confirmed angioedema attacks during treatment period of Day 0 through Day 182 were assessed. Full Analysis Set (FAS) included all randomized participants who received any exposure to the investigational product (IP) during the treatment period (Day 0 through Day 182).
    End point type
    Primary
    End point timeframe
    Day 0 through Day 182
    End point values
    		 Placebo Lanadelumab 300 mg
    Number of subjects analysed
    27
    50
    Units: attacks/month
        arithmetic mean (standard deviation)
    1.63 ( 1.357 )
    2.17 ( 2.062 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Lanadelumab 300 mg
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.899 [1]
    Method
    		 Chi-squared
    Parameter type
    		 Rate Ratio
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.47
    Notes
    [1] - P-value was from Wald-based chi-square test; unadjusted for multiple testing.

    Secondary: Number of Participants Achieving Attack-Free Status During the Treatment Period of Day 0 Through Day 182

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    End point title
    		 Number of Participants Achieving Attack-Free Status During the Treatment Period of Day 0 Through Day 182
    End point description
    An angioedema attack=symptoms/signs consistent with an attack in at least 1 of following: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with/without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of tongue, palate, uvula, or larynx). Participant was considered attack free if has no investigator-confirmed angioedema attacks during that time period. For participants who discontinued study prior to completion of analysis period, were classified as attack-free or not based on observed contribution to analysis period. Number of participants achieving attack-free status during treatment period of day 0 through day 182 was assessed. FAS included all randomized participants who receive any exposure to the IP during the treatment period (Day 0 through Day 182).
    End point type
    Secondary
    End point timeframe
    Day 0 through Day 182
    End point values
    		 Placebo Lanadelumab 300 mg
    Number of subjects analysed
    27
    50
    Units: participants
    1
    2
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Lanadelumab 300 mg
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk Difference (RD)
    Point estimate
    0.003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.153
         upper limit
    		 0.114
    Notes
    [2] - P-value was from the corresponding Mantel-Haenszel estimate for the common risk difference from Cochran-Mantel-Haenszel (CMH) test; unadjusted for multiple testing.

    Secondary: Number of Investigator-Confirmed Moderate or Severe Angioedema Attacks During the Treatment Period of Day 0 Through Day 182

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    End point title
    		 Number of Investigator-Confirmed Moderate or Severe Angioedema Attacks During the Treatment Period of Day 0 Through Day 182
    End point description
    An angioedema attack was defined as symptoms or signs consistent with an attack in at least 1 of the following locations: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of tongue, palate, uvula, or larynx). Attack rate=number of attacks occurring during the specified period divided by number of days the participant contributed to specified period multiplied by 28 days. Number of investigator-confirmed angioedema attacks during treatment period of Day 0 through Day 182 were assessed. FAS included all randomized participants who received any exposure to the IP during the treatment period (Day 0 through Day 182).
    End point type
    Secondary
    End point timeframe
    Day 0 Through Day 182
    End point values
    		 Placebo Lanadelumab 300 mg
    Number of subjects analysed
    27
    50
    Units: attacks/month
        arithmetic mean (standard deviation)
    1.10 ( 0.984 )
    1.45 ( 1.711 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Lanadelumab 300 mg
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.852 [3]
    Method
    		 Chi-squared
    Parameter type
    		 Rate Ratio
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.48
    Notes
    [3] - P-value was from Wald-based chi-square test; unadjusted for multiple testing.

    Secondary: Number of Investigator-Confirmed Angioedema Attacks During the Presumed Steady State Period of Day 70 Through Day 182

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    End point title
    		 Number of Investigator-Confirmed Angioedema Attacks During the Presumed Steady State Period of Day 70 Through Day 182
    End point description
    Angioedema attack=symptoms or signs consistent with an attack in at least 1 of following: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with/without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of tongue, palate, uvula, or larynx). Number of investigator-confirmed angioedema attacks during presumed steady state period of day 70 through day 182 were assessed. Attack rate =number of attacks occurring during the specified period divided by the number of days the participant contributed to the specified period multiplied by 28 days. Steady State (SS)-FAS included all randomized participants who received any exposure to the investigational product during the presumed steady state period (Day 70 through Day 182).
    End point type
    Secondary
    End point timeframe
    Day 70 through Day 182
    End point values
    		 Placebo Lanadelumab 300 mg
    Number of subjects analysed
    27
    49
    Units: attacks/month
        arithmetic mean (standard deviation)
    1.37 ( 1.231 )
    2.05 ( 2.211 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Lanadelumab 300 mg
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.66 [4]
    Method
    		 Chi-squared
    Parameter type
    		 Rate Ratio
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.7
    Notes
    [4] - P-value was from Wald-based chi-square test; unadjusted for multiple testing.

    Secondary: Number of Participants Achieving Attack-Free Status During the Presumed Steady State Period of Day 70

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    End point title
    		 Number of Participants Achieving Attack-Free Status During the Presumed Steady State Period of Day 70
    End point description
    Angioedema attack=symptoms/signs consistent with an attack in at least 1 of following: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with/without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of tongue, palate, uvula, or larynx). Participant was considered as attack free if participant has no investigator-confirmed angioedema attacks during that time period. Participants who discontinue study prior to completion of analysis period, were classified as attack-free. Number of participants achieving attack-free status during the presumed steady state period of day 70 through 182 was assessed. SS-FAS included all randomized participants who received any exposure to the investigational product during the presumed steady state period (Day 70 through Day 182).
    End point type
    Secondary
    End point timeframe
    Day 70 through Day 182
    End point values
    		 Placebo Lanadelumab 300 mg
    Number of subjects analysed
    27
    49
    Units: Participants
    4
    3
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Lanadelumab 300 mg
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk Difference (RD)
    Point estimate
    -0.087
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.28
         upper limit
    		 0.063
    Notes
    [5] - P-value was from the corresponding Mantel-Haenszel estimate for the common risk difference from CMH test; unadjusted for multiple testing.

    Secondary: Number of Participants With Maximum Attack Severity During Treatment Period of Day 0 Through Day 182

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    End point title
    		 Number of Participants With Maximum Attack Severity During Treatment Period of Day 0 Through Day 182
    End point description
    An angioedema attack was defined as the symptoms or signs consistent with an attack in at least 1 of the following locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Number of participants with maximum attack severity during treatment period of day 0 through day 182 was assessed. Angioedema attack severity was calculated per participant based on the severity categories as follows: No attack, Mild, Moderate, and Severe. FAS included all randomized participants who receive any exposure to the IP during the treatment period (Day 0 through Day 182).
    End point type
    Secondary
    End point timeframe
    Day 0 through Day 182
    End point values
    		 Placebo Lanadelumab 300 mg
    Number of subjects analysed
    27
    50
    Units: participants
        No Attack
    1
    2
        Mild
    2
    4
        Moderate
    17
    17
        Severe
    7
    27
    No statistical analyses for this end point

    Secondary: Number of Investigator-Confirmed Moderate or Severe Angioedema Attacks During the Presumed Steady State Period of Day 70 Through Day 182

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    End point title
    		 Number of Investigator-Confirmed Moderate or Severe Angioedema Attacks During the Presumed Steady State Period of Day 70 Through Day 182
    End point description
    Angioedema attack was defined as symptoms or signs consistent with an attack in at least 1 of following: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with/without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of tongue, palate, uvula, or larynx). Attack rate=number of attacks occurring during the specified period divided by number of days participant contributed to specified period multiplied by 28 days. Number of investigator-confirmed moderate or severe angioedema attacks during presumed steady state period of day 70 through day 182 were assessed. SS-FAS included all randomized participants who received any exposure to the investigational product during the presumed steady state period (Day 70 through Day 182).
    End point type
    Secondary
    End point timeframe
    Day 70 through Day 182
    End point values
    		 Placebo Lanadelumab 300 mg
    Number of subjects analysed
    27
    49
    Units: attacks/month
        arithmetic mean (standard deviation)
    0.97 ( 1.013 )
    1.35 ( 1.764 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Lanadelumab 300 mg
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.896 [6]
    Method
    		 Chi-squared
    Parameter type
    		 Rate Ratio
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 1.61
    Notes
    [6] - P-value was from Wald-based chi-square test; unadjusted for multiple testing.

    Secondary: Number of Participants With Maximum Attack Severity During Presumed Steady State Period of Day 70 Through Day 182

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    End point title
    		 Number of Participants With Maximum Attack Severity During Presumed Steady State Period of Day 70 Through Day 182
    End point description
    An angioedema attack was defined as the symptoms or signs consistent with an attack in at least 1 of the following locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Number of participants with maximum attack severity during the presumed steady state period of day 70 through day 182 was assessed. Angioedema attack severity was calculated per participant based on the severity categories as follows: No attack, Mild, Moderate, and Severe. SS-FAS included all randomized participants who received any exposure to the investigational product during the presumed steady state period (Day 70 through Day 182).
    End point type
    Secondary
    End point timeframe
    Day 70 through Day 182
    End point values
    		 Placebo Lanadelumab 300 mg
    Number of subjects analysed
    27
    49
    Units: participants
        No Attack
    4
    3
        Mild
    5
    5
        Moderate
    12
    23
        Severe
    6
    18
    No statistical analyses for this end point

    Secondary: Time to First Angioedema Attack After Day 0 Through Day 182

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    End point title
    		 Time to First Angioedema Attack After Day 0 Through Day 182
    End point description
    The time to the first angioedema attack (days) after Day 0 for the efficacy evaluation period of Day 0 through Day 182 was calculated from the date and time of the first dose of lanadelumab for the efficacy evaluation period (Day 0 through Day 182) to the date and time of the first in angioedema attack after the first dose for the efficacy evaluation period of Day 0 through Day 182. The data is reported for angioedema attack rate groups i.e. 1 to < 2 Attacks/Month and >=2 Attacks/Month. FAS included all randomized participants who receive any exposure to the IP during the treatment period (Day 0 through Day 182).
    End point type
    Secondary
    End point timeframe
    Day 0 Through Day 182
    End point values
    		 Placebo Lanadelumab 300 mg
    Number of subjects analysed
    27
    50
    Units: days
    median (confidence interval 95%)
        1 to <2 Attacks/Month
    10.5 (6.6 to 9999)
    81.0 (6.4 to 9999)
        >=2 Attacks/Month
    6.8 (1.4 to 11.6)
    5.9 (3.7 to 11.6)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Lanadelumab 300 mg
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.498 [7]
    Method
    		 Logrank
    Confidence interval
    Notes
    [7] - P-value comparing lanadelumab to placebo was from a log rank test stratified by baseline strata.

    Secondary: Time to First Angioedema Attack After Day 70 Through Day 182

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    End point title
    		 Time to First Angioedema Attack After Day 70 Through Day 182
    End point description
    The time to the first angioedema attack (days) after Day 0 for the efficacy evaluation period of Day 70 through Day 182 was calculated from the date and time of the first dose of lanadelumab for the efficacy evaluation period (Day 70 through Day 182) to the date and time of the first in angioedema attack after the first dose for the efficacy evaluation period of Day 70 through Day 182. The data is reported for angioedema attack rate groups i.e. 1 to < 2 Attacks/Month and >=2 Attacks/Month. SS-FAS included all randomized participants who received any exposure to the investigational product during the presumed steady state period (Day 70 through Day 182). '9999' indicates Upper limit of CI was not estimable due to censoring of participants who discontinued or completed the study before having an attack.
    End point type
    Secondary
    End point timeframe
    Day 70 through Day 182
    End point values
    		 Placebo Lanadelumab 300 mg
    Number of subjects analysed
    27
    49
    Units: days
    median (confidence interval 95%)
        1 to <2 Attacks/Month
    12.3 (10.3 to 9999)
    40.8 (3.4 to 9999)
        >=2 Attacks/Month
    16.9 (6.7 to 32.5)
    10.6 (5.0 to 15.9)
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving at Least 50 %, 70%, 90% and 100% Reduction in the Investigator-Confirmed Normalized Number of Attacks (NNA) Per 4 Weeks During Each of the Efficacy Evaluation Periods Relative to the Observation Period NNA

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    End point title
    		 Number of Participants Achieving at Least 50 %, 70%, 90% and 100% Reduction in the Investigator-Confirmed Normalized Number of Attacks (NNA) Per 4 Weeks During Each of the Efficacy Evaluation Periods Relative to the Observation Period NNA
    End point description
    Normalized number of investigator-confirmed angioedema attacks (NNA) during each efficacy evaluation period was expressed as a monthly (28 days) angioedema attack rate. Attack rate=number of attacks occurring during specified period divided by number of days participants contributed to specified period multiplied by 28 days. Number of participants achieving at least 50 %, 70%, 90% and 100% reduction in investigator-confirmed normalized number of attacks per 4 weeks during each of efficacy evaluation periods relative to the observation period NNA was assessed. Percentage reduction groups are not mutually exclusive, participants may appear in more than one group as applicable based on their percentage reduction. FAS included all randomized participants who receive any exposure to IP during treatment period (Day 0 through Day 182). Overall number of participants analyzed=number of participants achieving at Least 50 %, 70%, 90% and 100% reduction in investigator-confirmed normalized.
    End point type
    Secondary
    End point timeframe
    Day 0 Through Day 182
    End point values
    		 Placebo Lanadelumab 300 mg
    Number of subjects analysed
    26
    48
    Units: participants
        >=50% Reduction
    13
    28
        >=70% Reduction
    9
    12
        >=90% Reduction
    3
    6
        100% Reduction
    1
    2
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving Normalized Number of Attacks (NNA) Less Than (<)1.0 Per 4 Weeks During Each of the Efficacy Evaluation Periods

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    End point title
    		 Number of Participants Achieving Normalized Number of Attacks (NNA) Less Than (<)1.0 Per 4 Weeks During Each of the Efficacy Evaluation Periods
    End point description
    The normalized number of investigator-confirmed angioedema attacks (NNA) during each efficacy evaluation period was expressed as a monthly (28 days) angioedema attack rate. Attack rate was calculated for each participant as the number of attacks occurring during the specified period divided by the number of days the participant contributed to the specified period multiplied by 28 days. Number of participants achieving normalized number of attacks < 1.0 per 4 weeks during each of the efficacy evaluation periods was assessed. The percentage reduction groups are not mutually exclusive, participants may appear in more than one group as applicable based on their percentage reduction. SS-FAS included all randomized participants who received any exposure to the investigational product during the presumed steady state period (Day 70 through Day 182).
    End point type
    Secondary
    End point timeframe
    Day 0 through Day 182, Day 70 through Day 182
    End point values
    		 Placebo Lanadelumab 300 mg
    Number of subjects analysed
    27
    49
    Units: participants
        >=50% Reduction
    14
    31
        >=70% Reduction
    12
    18
        >=90% Reduction
    5
    5
        100% Reduction
    4
    3
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs)
    End point description
    TEAE=as any event emerging or manifesting at or after the initiation of treatment with an IP or medicinal product or any existing event that worsens in either intensity or frequency following exposure to the IP or medicinal product. SAE=untoward clinical manifestation of signs, symptoms or outcomes (whether considered related to investigational product or not and at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of hospitalization, results in persistent or significant disability/incapacity, congenital abnormality/birth defect, an important medical event. AESI included hypersensitivity reactions, events of disordered coagulation such as bleeding AESI, hypercoagulable AESI. Number of participants with TEAEs including AESI and SAE was assessed.
    End point type
    Secondary
    End point timeframe
    From the first study drug administration up to follow-up (Day 196)
    End point values
    		 Placebo Lanadelumab 300 mg
    Number of subjects analysed
    27
    50
    Units: participants
        Any TEAE
    23
    46
        AESI
    0
    1
        SAE
    1
    7
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Lanadelumab

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    End point title
    		 Plasma Concentrations of Lanadelumab
    End point description
    Pharmacokinetic Set (PK Set) included all participants in the SAS who had at least 1 evaluable postdose PK concentration value. Overall number of participants analyzed is the number of participants available with data for analyses. Number analyzed is the number of participants available for analyses at the given timepoint. 'n' indicates number of participants analysed are the participants available for analysis at the given timepoint. '9999' indicates the standard deviation (SD) was not estimable for a single participant.
    End point type
    Secondary
    End point timeframe
    Pre-dose and post-dose at Days 0, 4, 14, 28, 56, 84, 112, 140, 168 and 182
    End point values
    		 Placebo Lanadelumab 300 mg
    Number of subjects analysed
    27
    49
    Units: nanogram/milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Baseline (n=22,45)
    661.573 ( 2991.1363 )
    1.665 ( 7.8812 )
        Day 0 (n=0,1)
    0 ( 0 )
    0.000 ( 9999 )
        Day 4 (n=7,7)
    42.749 ( 113.1021 )
    16895.996 ( 8136.5164 )
        Day 14 (n=16,32)
    5.366 ( 21.4650 )
    11030.519 ( 4632.9383 )
        Day 28 (n=26,46)
    6.188 ( 17.9944 )
    15969.813 ( 7210.5963 )
        Day 56 (n=27,46)
    16.820 ( 61.3021 )
    20722.131 ( 8396.5980 )
        Day 84 (n=26,49)
    7.335 ( 30.0848 )
    22698.616 ( 8953.3488 )
        Day 112 (n=25,48)
    5.604 ( 22.1843 )
    22938.312 ( 10021.8340 )
        Day 140 (n=26,46)
    3.200 ( 16.3188 )
    22778.286 ( 9680.4686 )
        Day 168 (n=24,48)
    9.260 ( 23.0763 )
    21369.818 ( 11072.0806 )
        Day 182 (n=26,49)
    4.733 ( 18.7014 )
    20496.158 ( 10774.2169 )
    No statistical analyses for this end point

    Secondary: Plasma Kallikrein (pKal) Activity

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    End point title
    		 Plasma Kallikrein (pKal) Activity
    End point description
    Plasma Kallikrein activity was measured by biomarker cleaved high molecular weight kininogen (cHMWK ) level to assess pharmacodynamics of lanadelumab. The Pharmacodynamic Set (PD Set) included all participants in the SAS who had at least 1 evaluable PD concentration value. Overall number of participants analyzed are the number of participants with data available for analyses. Number analyzed is the number of participants available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose and post-dose at Days 4, 14, 28, 56, 84, 112, 140, 168 and 182
    End point values
    		 Placebo Lanadelumab 300 mg
    Number of subjects analysed
    27
    50
    Units: % cHMWK
    arithmetic mean (standard deviation)
        Baseline (n=25,50)
    20.30 ( 14.927 )
    18.69 ( 11.854 )
        Day 4 (n=7,7)
    25.94 ( 33.285 )
    20.20 ( 20.333 )
        Day 14 (n=16,31)
    17.23 ( 9.801 )
    12.83 ( 13.136 )
        Day 28 (n=27,47)
    16.16 ( 12.458 )
    14.24 ( 13.472 )
        Day 56 (n=27,46)
    17.83 ( 12.169 )
    15.88 ( 15.618 )
        Day 84 (n=27, 46)
    17.00 ( 15.508 )
    16.76 ( 15.941 )
        Day 112 (n=25,48)
    15.88 ( 11.109 )
    16.12 ( 17.242 )
        Day 140 (n=27,47)
    17.40 ( 15.413 )
    14.91 ( 14.656 )
        Day 168 (n=25,47)
    20.90 ( 16.588 )
    15.07 ( 15.061 )
        Day 182 (n=27,50)
    18.08 ( 20.384 )
    15.39 ( 15.333 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Neutralizing or Non-neutralizing Antidrug Antibodies (ADA) in Plasma

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    End point title
    		 Number of Participants With Neutralizing or Non-neutralizing Antidrug Antibodies (ADA) in Plasma
    End point description
    Number of participants with neutralizing or non-neutralizing antidrug antibodies in plasma was assessed. FAS included all randomized participants who receive any exposure to the IP during the treatment period (Day 0 through Day 182). Number analyzed is the number of participants available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose and post-dose at Days 28, 56, 84, 112, 140, 168 and 182
    End point values
    		 Placebo Lanadelumab 300 mg
    Number of subjects analysed
    27
    50
    Units: participants
        Baseline (n=22,46)
    0
    0
        Day 28 (n=26,46)
    0
    0
        Day 56 (n=27,47)
    0
    0
        Day 84 (n=26,50)
    0
    0
        Day 112 (n=25,48)
    0
    1
        Day 140 (n=26,46)
    0
    1
        Day 168 (n=24,48)
    0
    0
        Day 182 (n=26,50)
    0
    2
    No statistical analyses for this end point

    Secondary: Number of Participants With Change in Total Angioedema Quality of Life (AE-QoL) Questionnaire Score During the Treatment Period of Day 0 Through Day 182

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    End point title
    		 Number of Participants With Change in Total Angioedema Quality of Life (AE-QoL) Questionnaire Score During the Treatment Period of Day 0 Through Day 182
    End point description
    The AE-QoL questionnaire was a self-administered validated instrument to assess health related (HR) QoL among participants with recurrent angioedema. The AE-QoL consisted of 17 disease-specific quality-of-life items, to produce a total AEQoL score and 4 domain scores (functioning, fatigue/mood, fear/shame, and nutrition) and each of the 17 items has a five point response scale ranging from 0 (Never) to 4 (Very Often). Taw total score (mean of all item scores) was rescaled using linear transformations into final percentage scores ranging 0 to 100. SAS:all participants who receive any exposure to the IP. Overall number of participants analyzed are number of participants with data available for analyses. 'n' indicates number analyzed is the number of participants available for analyses in the specific category. Occassionally (O); Very Often (VO); Food or Beverages (F/B); Swelling Episodes (SE); Negative effects (NE). basline (n) = 26, 49 and Day 189 (n) = 26, 50.
    End point type
    Secondary
    End point timeframe
    Baseline through Day 182
    End point values
    		 Placebo Lanadelumab 300 mg
    Number of subjects analysed
    26
    50
    Units: participants
        Baseline: Work - Never
    7
    6
        Baseline: Work - Rarely
    4
    8
        Baseline: Work - O
    6
    14
        Baseline: Work - Often
    7
    10
        Baseline: Work - VO
    2
    10
        Baseline: Physical activity - Never
    1
    4
        Baseline: Physical activity - Rarely
    1
    7
        Baseline: Physical activity - O
    16
    15
        Baseline: Physical activity - Often
    4
    12
        Baseline: Physical activity - VO
    4
    11
        Baseline: Leisure time - Never
    1
    4
        Baseline: Leisure time - Rarely
    5
    9
        Baseline: Leisure time - O
    12
    17
        Baseline: Leisure time - Often
    5
    15
        Baseline: Leisure time - VO
    3
    4
        Baseline: Social relations - Never
    2
    4
        Baseline: Social relations - Rarely
    4
    9
        Baseline: Social relations - O
    12
    16
        Baseline: Social relations - Often
    7
    16
        Baseline: Social relations - VO
    1
    4
        Baseline: Eating and drinking - Never
    3
    8
        Baseline: Eating and drinking - Rarely
    6
    10
        Baseline: Eating and drinking - O
    9
    16
        Baseline: Eating and drinking - Often
    6
    13
        Baseline: Eating and drinking - VO
    2
    2
        Baseline: Difficulty falling asleep - Never
    3
    7
        Baseline: Difficulty falling asleep - Rarely
    11
    17
        Baseline: Difficulty falling asleep - O
    5
    8
        Baseline: Difficulty falling asleep - Often
    4
    10
        Baseline: Difficulty falling asleep - VO
    2
    2
        Baseline: Wake up during the night - Never
    7
    11
        Baseline: Wake up during the night - Rarely
    5
    12
        Baseline: Wake up during the night - O
    6
    10
        Baseline: Wake up during the night - Often
    6
    10
        Baseline: Wake up during the night - VO
    6
    14
        Baseline: Tired during the day - Never
    1
    3
        Baseline: Tired during the day - Rarely
    7
    8
        Baseline: Tired during the day - O
    6
    16
        Baseline: Tired during the day - Often
    7
    9
        Baseline: Tired during the day - VO
    5
    13
        Baseline: Trouble concentrating - Never
    2
    3
        Baseline: Trouble concentrating - Rarely
    8
    14
        Baseline: Trouble concentrating - O
    10
    14
        Baseline: Trouble concentrating - Often
    4
    10
        Baseline: Trouble concentrating - VO
    2
    8
        Baseline: Feel depressed - Never
    9
    10
        Baseline: Feel depressed - Rarely
    5
    18
        Baseline: Feel depressed - O
    5
    11
        Baseline: Feel depressed - VO
    1
    3
        Baseline: Limit your choices of F/B: Never
    10
    17
        Baseline: Limit your choices of F/B: Rarely
    1
    4
        Baseline: Limit your choices of F/B: O
    2
    13
        Baseline: Limit your choices of F/B: Often
    8
    7
        Baseline: Limit your choices of F/B: VO
    5
    8
        Baseline: SE place a burden on you: Never
    1
    1
        Baseline: SE place a burden on you: Rarely
    1
    0
        Baseline: SE place a burden on you: O
    7
    8
        Baseline: SE place a burden on you: Often
    10
    24
        Baseline: SE place a burden on you: VO
    7
    16
        Baseline: SE could occur suddenly - Never
    1
    2
        Baseline: SE could occur suddenly - Rarely
    4
    1
        Baseline: SE could occur suddenly - O
    4
    12
        Baseline: SE could occur suddenly - Often
    6
    16
        Baseline: SE could occur suddenly - VO
    11
    18
        Baseline: Freq of SE might increase - Never
    2
    1
        Baseline: Freq of SE might increase - Rarely
    3
    3
        Baseline: Freq of SE might increase - O
    5
    7
        Baseline: Freq of SE might increase - Often
    8
    21
        Baseline: Freq of SE might increase - VO
    8
    17
        Baseline: Ashamed to go out due to SE - Never
    6
    10
        Baseline: Ashamed to go out due to SE - Rarely
    1
    7
        Baseline: Ashamed to go out due to SE - O
    8
    10
        Baseline: Ashamed to go out due to SE - Often
    4
    11
        Baseline: Ashamed to go out due to SE - VO
    7
    11
        Baseline: SE make you embarrassed - Never
    5
    9
        Baseline: SE make you embarrassed - Rarely
    4
    5
        Baseline: SE make you embarrassed - O
    6
    13
        Baseline: SE make you embarrassed - Often
    3
    8
        Baseline: SE make you embarrassed - VO
    8
    14
        Baseline: Afraid of long term NE - Never
    3
    9
        Baseline: Afraid of long term NE - Rarely
    6
    15
        Baseline: Afraid of long term NE - O
    6
    4
        Baseline: Afraid of long term NE - Often
    6
    12
        Baseline: Afraid of long term NE - VO
    5
    9
        Day 182: Work - Never
    3
    17
        Day 182: Work - Rarely
    10
    8
        Day 182: Work - O
    8
    12
        Day 182: Work - Often
    4
    10
        Day 182: Work - VO
    1
    3
        Day 182: Physical activity - Never
    3
    13
        Day 182: Physical activity - Rarely
    10
    12
        Day 182: Physical activity - O
    8
    13
        Day 182: Physical activity - Often
    4
    8
        Day 182: Physical activity - VO
    1
    4
        Day 182: Leisure time - Never
    3
    14
        Day 182: Leisure time - Rarely
    12
    15
        Day 182: Leisure time - O
    7
    10
        Day 182: Leisure time - Often
    3
    7
        Day 182: Leisure time - VO
    1
    4
        Day 182: Social relations - Never
    4
    15
        Day 182: Social relations - Rarely
    8
    11
        Day 182: Social relations - O
    9
    13
        Day 182: Social relations - Often
    2
    6
        Day 182: Social relations - VO
    3
    5
        Day 182: Eating and drinking - Never
    5
    18
        Day 182: Eating and drinking - Rarely
    8
    8
        Day 182: Eating and drinking - O
    8
    9
        Day 182: Eating and drinking - Often
    4
    14
        Day 182: Eating and drinking - VO
    1
    1
        Day 182: Difficulty falling asleep - Never
    4
    9
        Day 182: Difficulty falling asleep - Rarely
    7
    15
        Day 182: Difficulty falling asleep - O
    8
    12
        Day 182: Difficulty falling asleep - Often
    6
    9
        Day 182: Difficulty falling asleep - VO
    1
    5
        Day 182: Wake up during the night - Never
    1
    9
        Day 182: Wake up during the night - Rarely
    7
    10
        Day 182: Wake up during the night - O
    8
    15
        Day 182: Wake up during the night - Often
    7
    9
        Day 182: Wake up during the night - VO
    3
    7
        Day 182: Tired during the day - Never
    2
    9
        Day 182: Tired during the day - Rarely
    6
    15
        Day 182: Tired during the day - O
    11
    12
        Day 182: Tired during the day - Often
    6
    9
        Day 182: Tired during the day - VO
    1
    5
        Day 182: Trouble concentrating - Never
    2
    13
        Day 182: Trouble concentrating - Rarely
    17
    10
        Day 182: Trouble concentrating - O
    5
    14
        Day 182: Trouble concentrating - Often
    1
    10
        Day 182: Trouble concentrating - VO
    1
    3
        Day 182: Feel depressed - Never
    8
    8
        Day 182: Feel depressed - Rarely
    8
    18
        Day 182: Feel depressed - O
    5
    7
        Day 182: Feel depressed - Often
    4
    5
        Day 182: Feel depressed - VO
    1
    2
        Day 182: Limit your choices of F/B - Never
    7
    19
        Day 182: Limit your choices of F/B - Rarely
    6
    8
        Day 182: Limit your choices of F/B - O
    6
    10
        Day 182: Limit your choices of F/B - Often
    5
    8
        Day 182: Limit your choices of F/B - VO
    2
    5
        Day 182: SE place a burden on you - Never
    2
    6
        Day 182: SE place a burden on you - Rarely
    7
    9
        Day 182: SE place a burden on you - O
    8
    17
        Day 182: SE place a burden on you - Often
    7
    7
        Day 182: SE place a burden on you - VO
    2
    11
        Day 182: SE could occur suddenly - Never
    2
    7
        Day 182: SE could occur suddenly - Rarely
    6
    14
        Day 182: SE could occur suddenly - O
    9
    10
        Day 182: SE could occur suddenly - Often
    5
    7
        Day 182: SE could occur suddenly - VO
    4
    12
        Day 182: Freq of SE might increase - Never
    2
    7
        Day 182: Freq of SE might increase - Rarely
    7
    12
        Day 182: Freq of SE might increase - O
    9
    13
        Day 182: Freq of SE might increase - Often
    5
    6
        Day 182: Freq of SE might increase - VO
    3
    12
        Day 182: Ashamed to go out due to SE - Never
    5
    15
        Day 182: Ashamed to go out due to SE - Rarely
    8
    11
        Day 182: Ashamed to go out due to SE - O
    4
    10
        Day 182: Ashamed to go out due to SE - Often
    7
    8
        Day 182: Ashamed to go out due to SE - VO
    2
    6
        Day 182: SE make you embarrassed - Never
    7
    14
        Day 182: SE make you embarrassed - Rarely
    5
    10
        Day 182: SE make you embarrassed - O
    6
    10
        Day 182: SE make you embarrassed - Often
    6
    8
        Day 182: SE make you embarrassed - VO
    2
    8
        Day 182: Afraid of long term NE - Never
    4
    15
        Day 182: Afraid of long term NE - Rarely
    10
    13
        Day 182: Afraid of long term NE - O
    7
    11
        Day 182: Afraid of long term NE - Often
    1
    3
        Day 182: Afraid of long term NE - VO
    4
    8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of the study up to follow up (Day 196)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo-matching lanadelumab subcutaneous (SC) injection once every 2 weeks (q2w) for up to 26 weeks.

    Reporting group title
    Lanadelumab 300 mg
    Reporting group description
    		 Participants received 300 mg of lanadelumab solution in a prefilled syringe (PFS) as SC injection once q2w for up to 26 weeks.

    Serious adverse events
    		 Placebo Lanadelumab 300 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 27 (3.70%)
    7 / 50 (14.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 27 (3.70%)
    6 / 50 (12.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis staphylococcal
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Lanadelumab 300 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 27 (100.00%)
    49 / 50 (98.00%)
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 27 (22.22%)
    6 / 50 (12.00%)
         occurrences all number
    13
    13
    Migraine
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 50 (6.00%)
         occurrences all number
    1
    3
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 50 (2.00%)
         occurrences all number
    2
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 27 (7.41%)
    4 / 50 (8.00%)
         occurrences all number
    9
    13
    Injection site erythema
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 50 (6.00%)
         occurrences all number
    6
    22
    Injection site pain
         subjects affected / exposed
    7 / 27 (25.93%)
    15 / 50 (30.00%)
         occurrences all number
    9
    61
    Pyrexia
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 50 (6.00%)
         occurrences all number
    2
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 50 (2.00%)
         occurrences all number
    3
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    Nausea
         subjects affected / exposed
    3 / 27 (11.11%)
    4 / 50 (8.00%)
         occurrences all number
    8
    4
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    26 / 27 (96.30%)
    48 / 50 (96.00%)
         occurrences all number
    305
    740
    Urticaria
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 27 (11.11%)
    1 / 50 (2.00%)
         occurrences all number
    3
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 27 (7.41%)
    7 / 50 (14.00%)
         occurrences all number
    2
    8
    Back pain
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Myalgia
         subjects affected / exposed
    1 / 27 (3.70%)
    4 / 50 (8.00%)
         occurrences all number
    2
    4
    Infections and infestations
    COVID-19
         subjects affected / exposed
    4 / 27 (14.81%)
    3 / 50 (6.00%)
         occurrences all number
    4
    3
    Nasopharyngitis
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 50 (6.00%)
         occurrences all number
    2
    5
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 50 (6.00%)
         occurrences all number
    3
    5
    Urinary tract infection
         subjects affected / exposed
    1 / 27 (3.70%)
    4 / 50 (8.00%)
         occurrences all number
    1
    6

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Apr 2021
    Amendment 3 changes: • Sponsor was revised from Shire to Takeda Development Centers Americas, Inc. (TDCA)/Takeda. • Removed IQVIA medical monitor contact information and added reference to the study specific contact list. The contact list contains the most accurate and up-to-date contact information. • Revised to include appropriate Takeda forms for reporting AEs and pregnancy. • Revised footnote to clarify that participants <18 years of age were only enrolled if allowed based on local site and/or country regulations. • Revised inclusion criterion #3 to clarify that participants with C4 level not below the normal range should be enrolled. • Revised footnote f for Table 1 (Table 1 Schedule of Activities - Screening and Observation Period) to clarify that an additional confirmatory test may be performed during the observation period if C1-INH therapy washout was not completed during the screening period. • Revised footnote g for Table 1 (Table 1 Schedule of Activities - Screening and Observation Period) to clarify that the 2-week washout period was completed in the screening period only for participants where it was deemed safe to complete. • Timeframe for male contraception was revised to align with female contraception (for the duration of the study and 70 days after the last dose of investigational product [IP]). • Specific quantitative stopping criteria, particularly in regard to liver values were added. • Added language to clarify that sample collection for genotype testing during the screening period was required; an additional sample for exploratory genetic analyses was optional.
    18 Aug 2022
    Amendment 2 changes: • Shire Global Drug Safety was updated to Takeda Global Patient Safety Evaluation (GPSE) Group. • The study population was revised to remove participants with acquired angioedema due to C1-INH deficiency. • For study site regions, removed specific countries in Europe and added Japan. • The study number for the open-label extension study was added (Study TAK-743-3001). • An additional visit prior to the start of the observation period was added. This visit would allow for an eligibility review, angioedema attack and adverse event (AE) monitoring, and distribution of icatibant and antihistamine treatment. • Removed plasma pharmacokinetic (PK) and pharmacodynamic (PD) sample from Visit 2 to Visit 3. Visit 2 was now an off-site visit. Reference to collecting samples predose on Study Day 4 was removed. • Provided clarification that participants were to begin Visit 1 in the treatment period within 7 days of the observation period. Any delay to the start of the treatment period should be discussed with the sponsor. • Added angioedema attack monitoring. • Revised physical examinations to include body weight as part of all examinations. • Revised exploratory endpoints to exploratory efficacy endpoints and added text indicating that exploratory efficacy endpoints would be defined in the statistical analysis plan (SAP).

    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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