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    Clinical Trial Results:
    SPRING STUDY: An Open-Label, Multicenter, Phase 3 Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Lanadelumab for Prevention Against Acute Attacks of Hereditary Angioedema (HAE) in Pediatric Subjects 2 to <12 Years of Age

    Summary
    EudraCT number
    2018-002093-42
    Trial protocol
    DE   HU   ES   Outside EU/EEA  
    Global end of trial date
    30 Oct 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    15 May 2022
    First version publication date
    15 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SHP643-301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04070326
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IND Number: 116647
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, United States, MA 02421
    Public contact
    Study Director, Shire, ClinicalTransparenc@takeda.com
    Scientific contact
    Study Director, Shire, ClinicalTransparenc@takeda.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001864-PIP01-15
    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
    30 Oct 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Oct 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the safety and pharmacokinetics (PK) of lanadelumab in children (2 to <12 years of age) with HAE.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    19 Aug 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    United States: 13
    Country: Number of subjects enrolled
    Canada: 2
    Worldwide total number of subjects
    21
    EEA total number of subjects
    6
    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)
    21
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Total 24 participants were screened and 21 participants were enrolled in the study at 15 investigative sites in the US, Canada, Spain, Hungary, and Germany from 19 August 2019 to 30 October 2021.

    Pre-assignment
    Screening details
    Participants were observed in 12-week Baseline Observation Period. Participants experiencing ≥1.0 angioedema attacks/3 months during 12-week Baseline Observation Period,who remained eligible per inclusion criteria entered treatment period(TP).Participants aged 2 to <12 years received lanadelumab SC Injection over 52-week Treatment Period.

    Period 1
    Period 1 title
    Baseline Observation-12 Weeks Before TP
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Lanadelumab 150 mg: Age 2 to <6 Years
    Arm description
    Participants aged 2 to <6 years received lanadelumab subcutaneous (SC) injection at a dose of 150 milligrams (mg) for every 4 weeks (q4wks) over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B).
    Arm type
    Experimental

    Investigational medicinal product name
    Lanadelumab
    Investigational medicinal product code
    Other name
    TAK-743, DX-2930, SHP643
    Pharmaceutical forms
    Intravesical solution/solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received 150 mg dose of lanadelumab every 2 or 4 weeks, depending on the participants age, over the 52-week Treatment Period.

    Arm title
    Lanadelumab 150 mg: Age 6 to <12 Years
    Arm description
    Participants aged 6 to <12 years received lanadelumab SC injection at a dose of 150 mg for every 2 weeks (q2wks) 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B). Participants could switch to a dosing regimen of 150 mg q4wks in Treatment Period B at the investigator’s discretion and sponsor’s medical monitor approval, if they were well controlled (e.g., attack free) for 26 weeks with lanadelumab treatment in this study.Participants aged 6 to <12 years received lanadelumab SC injection at a dose of 150 mg for every 2 weeks (q2wks) over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B). Participants could switch to a dosing regimen of 150 mg q4wks in Treatment Period B at the investigator’s discretion and sponsor’s medical monitor approval, if they were well controlled (e.g., attack free) for 26 weeks with lanadelumab treatment in this study.
    Arm type
    Experimental

    Investigational medicinal product name
    Lanadelumab
    Investigational medicinal product code
    Other name
    TAK-743, DX-2930, SHP643
    Pharmaceutical forms
    Intravesical solution/solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received 150 mg dose of lanadelumab every 2 or 4 weeks, depending on the participants age, over the 52-week Treatment Period.

    Number of subjects in period 1
    Lanadelumab 150 mg: Age 2 to <6 Years Lanadelumab 150 mg: Age 6 to <12 Years
    Started
    4
    17
    Completed
    4
    17
    Period 2
    Period 2 title
    Treatment Period A (Weeks 1 to 26)
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Lanadelumab 150 mg: Age 2 to <6 Years
    Arm description
    Participants aged 2 to <6 years received lanadelumab SC injection at a dose of 150 mg for q4wks over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B).
    Arm type
    Experimental

    Investigational medicinal product name
    Lanadelumab
    Investigational medicinal product code
    Other name
    TAK-743, DX-2930, SHP643
    Pharmaceutical forms
    Intravesical solution/solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received 150 mg dose of lanadelumab every 2 or 4 weeks, depending on the participants age, over the 52-week Treatment Period.

    Arm title
    Lanadelumab 150 mg: Age 6 to <12 Years
    Arm description
    Participants aged 6 to <12 years received lanadelumab SC injection at a dose of 150 mg for q2wks over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B). Participants could switch to a dosing regimen of 150 mg q4wks in Treatment Period B at the investigator’s discretion and sponsor’s medical monitor approval, if they were well controlled (e.g., attack free) for 26 weeks with lanadelumab treatment in this study.
    Arm type
    Experimental

    Investigational medicinal product name
    Lanadelumab
    Investigational medicinal product code
    Other name
    TAK-743, DX-2930, SHP643
    Pharmaceutical forms
    Intravesical solution/solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received 150 mg dose of lanadelumab every 2 or 4 weeks, depending on the participants age, over the 52-week Treatment Period.

    Number of subjects in period 2
    Lanadelumab 150 mg: Age 2 to <6 Years Lanadelumab 150 mg: Age 6 to <12 Years
    Started
    4
    17
    Completed
    3
    17
    Not completed
    1
    0
         Withdrawal by Parent/Guardian
    1
    -
    Period 3
    Period 3 title
    Treatment Period B (Weeks 27 to 52)
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Lanadelumab 150 mg: Age 2 to <6 Years
    Arm description
    Participants aged 2 to <6 years received lanadelumab SC injection at a dose of 150 mg for q4wks over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B).
    Arm type
    Experimental

    Investigational medicinal product name
    Lanadelumab
    Investigational medicinal product code
    Other name
    TAK-743, DX-2930, SHP643
    Pharmaceutical forms
    Intravesical solution/solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received 150 mg dose of lanadelumab every 2 or 4 weeks, depending on the participants age, over the 52-week Treatment Period.

    Arm title
    Lanadelumab 150 mg: Age 6 to <12 Years
    Arm description
    Participants aged 6 to <12 years received lanadelumab SC injection at a dose of 150 mg for q2wks over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B). Participants could switch to a dosing regimen of 150 mg q4wks in Treatment Period B at the investigator’s discretion and sponsor’s medical monitor approval, if they were well controlled (e.g., attack free) for 26 weeks with lanadelumab treatment in this study.
    Arm type
    Experimental

    Investigational medicinal product name
    Lanadelumab
    Investigational medicinal product code
    Other name
    TAK-743, DX-2930, SHP643
    Pharmaceutical forms
    Intravesical solution/solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received 150 mg dose of lanadelumab every 2 or 4 weeks, depending on the participants age, over the 52-week Treatment Period.

    Number of subjects in period 3
    Lanadelumab 150 mg: Age 2 to <6 Years Lanadelumab 150 mg: Age 6 to <12 Years
    Started
    3
    17
    Completed
    3
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lanadelumab 150 mg: Age 2 to <6 Years
    Reporting group description
    Participants aged 2 to <6 years received lanadelumab subcutaneous (SC) injection at a dose of 150 milligrams (mg) for every 4 weeks (q4wks) over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B).

    Reporting group title
    Lanadelumab 150 mg: Age 6 to <12 Years
    Reporting group description
    Participants aged 6 to <12 years received lanadelumab SC injection at a dose of 150 mg for every 2 weeks (q2wks) 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B). Participants could switch to a dosing regimen of 150 mg q4wks in Treatment Period B at the investigator’s discretion and sponsor’s medical monitor approval, if they were well controlled (e.g., attack free) for 26 weeks with lanadelumab treatment in this study.Participants aged 6 to <12 years received lanadelumab SC injection at a dose of 150 mg for every 2 weeks (q2wks) over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B). Participants could switch to a dosing regimen of 150 mg q4wks in Treatment Period B at the investigator’s discretion and sponsor’s medical monitor approval, if they were well controlled (e.g., attack free) for 26 weeks with lanadelumab treatment in this study.

    Reporting group values
    Lanadelumab 150 mg: Age 2 to <6 Years Lanadelumab 150 mg: Age 6 to <12 Years Total
    Number of subjects
    4 17 21
    Age categorical
    Units: Subjects
        Children (2-11 years)
    4 17 21
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    4.45 ± 0.843 8.68 ± 1.391 -
    Gender categorical
    Units: Subjects
        Female
    2 10 12
        Male
    2 7 9
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    0 1 1
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    0 0 0
        White
    4 16 20
        More than one race
    0 0 0
        Unknown or Not Reported
    0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    0 2 2
        Not Hispanic or Latino
    4 15 19
        Unknown or Not Reported
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Lanadelumab 150 mg: Age 2 to <6 Years
    Reporting group description
    Participants aged 2 to <6 years received lanadelumab subcutaneous (SC) injection at a dose of 150 milligrams (mg) for every 4 weeks (q4wks) over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B).

    Reporting group title
    Lanadelumab 150 mg: Age 6 to <12 Years
    Reporting group description
    Participants aged 6 to <12 years received lanadelumab SC injection at a dose of 150 mg for every 2 weeks (q2wks) 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B). Participants could switch to a dosing regimen of 150 mg q4wks in Treatment Period B at the investigator’s discretion and sponsor’s medical monitor approval, if they were well controlled (e.g., attack free) for 26 weeks with lanadelumab treatment in this study.Participants aged 6 to <12 years received lanadelumab SC injection at a dose of 150 mg for every 2 weeks (q2wks) over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B). Participants could switch to a dosing regimen of 150 mg q4wks in Treatment Period B at the investigator’s discretion and sponsor’s medical monitor approval, if they were well controlled (e.g., attack free) for 26 weeks with lanadelumab treatment in this study.
    Reporting group title
    Lanadelumab 150 mg: Age 2 to <6 Years
    Reporting group description
    Participants aged 2 to <6 years received lanadelumab SC injection at a dose of 150 mg for q4wks over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B).

    Reporting group title
    Lanadelumab 150 mg: Age 6 to <12 Years
    Reporting group description
    Participants aged 6 to <12 years received lanadelumab SC injection at a dose of 150 mg for q2wks over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B). Participants could switch to a dosing regimen of 150 mg q4wks in Treatment Period B at the investigator’s discretion and sponsor’s medical monitor approval, if they were well controlled (e.g., attack free) for 26 weeks with lanadelumab treatment in this study.
    Reporting group title
    Lanadelumab 150 mg: Age 2 to <6 Years
    Reporting group description
    Participants aged 2 to <6 years received lanadelumab SC injection at a dose of 150 mg for q4wks over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B).

    Reporting group title
    Lanadelumab 150 mg: Age 6 to <12 Years
    Reporting group description
    Participants aged 6 to <12 years received lanadelumab SC injection at a dose of 150 mg for q2wks over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B). Participants could switch to a dosing regimen of 150 mg q4wks in Treatment Period B at the investigator’s discretion and sponsor’s medical monitor approval, if they were well controlled (e.g., attack free) for 26 weeks with lanadelumab treatment in this study.

    Subject analysis set title
    Lanadelumab 150 mg, q4wks
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants received lanadelumab SC injection at a dose of 150 mg for q4wks with over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B).

    Subject analysis set title
    Lanadelumab 150 mg, q2wks
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants received lanadelumab SC injection at a dose of 150 mg for q2wks over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B).

    Primary: Number of Participants with Adverse Events Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)

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    End point title
    Number of Participants with Adverse Events Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) [1]
    End point description
    Adverse event(AE):any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with investigational product or medicinal product.SAE:any untoward clinical manifestation of signs,symptoms or outcomes(whether considered related to investigational product or not and at any dose which results in death,is life-threatening,requires inpatient hospitalization or prolongation of hospitalization,results in persistent or significant disability/incapacity,results in congenital abnormality/birth defect,is important medical event.AEs of special interest(AESIs):are hypersensitivity reactions and disordered coagulation(hypercoagulability events and bleeding events).Safety Analysis Set:all participants who received study drug.'n'=participants presented by actual treatment regimen.Due to dose modifications,some participants treated with both dosing regimens were counted in both treatment groups.
    End point type
    Primary
    End point timeframe
    Up to approximately 115 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: Only descriptive summary statistics was planned for this outcome measure.
    End point values
    Lanadelumab 150 mg, q4wks Lanadelumab 150 mg, q2wks
    Number of subjects analysed
    11
    18
    Units: participants
        SAEs
    0
    0
        AESIs
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants With Clinically Significant Laboratory Assessment Abnormalities

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    End point title
    Number of Participants With Clinically Significant Laboratory Assessment Abnormalities [2]
    End point description
    Laboratory values (chemistry, hematology, and coagulation) were to be considered clinically significant based on investigator's discretion. The Safety Analysis Set consisted of all participants who received study drug.
    End point type
    Primary
    End point timeframe
    Up to approximately 115 weeks
    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: Only descriptive summary statistics was planned for this outcome measure.
    End point values
    Lanadelumab 150 mg: Age 2 to <6 Years Lanadelumab 150 mg: Age 6 to <12 Years
    Number of subjects analysed
    4
    17
    Units: participants
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants With Clinically Significant Vital Signs Measurements

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    End point title
    Number of Participants With Clinically Significant Vital Signs Measurements [3]
    End point description
    Vital signs included blood pressure, heart rate, body temperature, and respiratory rate. The Safety Analysis Set consisted of all participants who received study drug.
    End point type
    Primary
    End point timeframe
    Up to approximately 115 weeks
    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: Only descriptive summary statistics was planned for this outcome measure.
    End point values
    Lanadelumab 150 mg: Age 2 to <6 Years Lanadelumab 150 mg: Age 6 to <12 Years
    Number of subjects analysed
    4
    17
    Units: participants
    0
    0
    No statistical analyses for this end point

    Primary: Plasma Concentrations of Lanadelumab Over The Treatment Period

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    End point title
    Plasma Concentrations of Lanadelumab Over The Treatment Period [4]
    End point description
    The plasma concentration of lanadelumab over treatment period was assessed. The Pharmacokinetic (PK) Set included all participants in the Safety Analysis Set who have at least 1 evaluable post dose PK concentration value.
    End point type
    Primary
    End point timeframe
    Day 0 (Pre-dose), Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392
    Notes
    [4] - 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: Only descriptive summary statistics was planned for this outcome measure.
    End point values
    Lanadelumab 150 mg: Age 2 to <6 Years Lanadelumab 150 mg: Age 6 to <12 Years
    Number of subjects analysed
    4
    17
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Visit 1 Day 0 (n=4,17)
    0.000 ± 0.0000
    11.735 ± 39.2984
        Visit 2 Day 4 (n=3,14)
    32407.215 ± 9785.4332
    20349.609 ± 12587.7085
        Visit 3 Day 14 (n=4,17)
    20443.818 ± 7800.4019
    14589.883 ± 4734.4461
        Visit 4 Day 28 (n=4,14)
    10636.682 ± 6168.5347
    21198.858 ± 8378.3961
        Visit 8 Day 56 (n=3,14)
    10433.382 ± 3345.1718
    27751.659 ± 10048.7527
        Visit 12 Day 84 (n=3,14)
    14758.407 ± 8392.8620
    24895.121 ± 11852.7671
        Visit 16 Day 112 (n=3,10)
    15020.780 ± 5730.4397
    31053.260 ± 14012.6464
        Visit 20 Day 140 (n=3,12)
    13318.715 ± 4432.0728
    26534.885 ± 11234.6051
        Visit 24 Day 168 (3,12)
    12189.214 ± 11367.4241
    26166.340 ± 11070.0337
        Visit 26 Day 182 (n=3,11)
    25630.909 ± 11054.3701
    25372.349 ± 8242.4858
        Visit 28 Day 196 (n=3,14)
    14293.013 ± 6014.0384
    25238.600 ± 9921.4264
        Visit 36 Day 252 (n=3,16)
    23110.526 ± 18241.5743
    19058.886 ± 12079.1976
        Visit 44 Day 308 (n=3,16)
    22687.442 ± 20911.9442
    15774.463 ± 12043.0984
        Visit 52 Day 364 (n=3,15)
    27178.967 ± 24111.9243
    17239.653 ± 11975.4861
        Visit 56 Day 392 (End of Study Visit) (n=2,14)
    32400.148 ± 24303.4128
    15689.458 ± 11811.7412
    No statistical analyses for this end point

    Primary: Maximum Observed Concentration at Steady State (Cmax,ss) of Lanadelumab in Plasma

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    End point title
    Maximum Observed Concentration at Steady State (Cmax,ss) of Lanadelumab in Plasma [5]
    End point description
    The PK Set included all participants in the Safety Analysis Set who have at least 1 evaluable post dose PK concentration value.
    End point type
    Primary
    End point timeframe
    Day 0 (Pre-dose), at any time pre-dose on Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392
    Notes
    [5] - 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: Only descriptive summary statistics was planned for this outcome measure.
    End point values
    Lanadelumab 150 mg: Age 2 to <6 Years Lanadelumab 150 mg: Age 6 to <12 Years
    Number of subjects analysed
    4
    17
    Units: micrograms per mL (μg/mL)
        geometric mean (geometric coefficient of variation)
    37.7 ± 30.1
    39.0 ± 39.2
    No statistical analyses for this end point

    Primary: Average Concentration Over Dosing Interval at Steady State (Cavg,ss) of Lanadelumab in Plasma

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    End point title
    Average Concentration Over Dosing Interval at Steady State (Cavg,ss) of Lanadelumab in Plasma [6]
    End point description
    The PK Set included all participants in the Safety Analysis Set who have at least 1 evaluable post dose PK concentration value.
    End point type
    Primary
    End point timeframe
    Day 0 (Pre-dose), at any time pre-dose on Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392
    Notes
    [6] - 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: Only descriptive summary statistics was planned for this outcome measure.
    End point values
    Lanadelumab 150 mg: Age 2 to <6 Years Lanadelumab 150 mg: Age 6 to <12 Years
    Number of subjects analysed
    4
    17
    Units: μg/mL
        geometric mean (geometric coefficient of variation)
    24.6 ± 34.0
    33.2 ± 37.7
    No statistical analyses for this end point

    Primary: Minimum Concentration at Steady State (Cmin,ss) of Lanadelumab in Plasma

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    End point title
    Minimum Concentration at Steady State (Cmin,ss) of Lanadelumab in Plasma [7]
    End point description
    The PK Set included all participants in the Safety Analysis Set who have at least 1 evaluable post dose PK concentration value.
    End point type
    Primary
    End point timeframe
    Day 0 (Pre-dose), at any time pre-dose on Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392
    Notes
    [7] - 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: Only descriptive summary statistics was planned for this outcome measure.
    End point values
    Lanadelumab 150 mg: Age 2 to <6 Years Lanadelumab 150 mg: Age 6 to <12 Years
    Number of subjects analysed
    4
    17
    Units: µg/mL
        geometric mean (geometric coefficient of variation)
    11.1 ± 46.5
    24.8 ± 37.3
    No statistical analyses for this end point

    Primary: Time to Reach Maximum Observed Concentration (Cmax) [tmax] of Lanadelumab in Plasma

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    End point title
    Time to Reach Maximum Observed Concentration (Cmax) [tmax] of Lanadelumab in Plasma [8]
    End point description
    The PK Set included all participants in the Safety Analysis Set who have at least 1 evaluable post dose PK concentration value.
    End point type
    Primary
    End point timeframe
    Day 0 (Pre-dose), at any time pre-dose on Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392
    Notes
    [8] - 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: Only descriptive summary statistics was planned for this outcome measure.
    End point values
    Lanadelumab 150 mg: Age 2 to <6 Years Lanadelumab 150 mg: Age 6 to <12 Years
    Number of subjects analysed
    4
    17
    Units: hours (h)
        median (full range (min-max))
    122 (108 to 135)
    86.0 (66.0 to 137)
    No statistical analyses for this end point

    Primary: Area Under the Concentration-Time Curve Over the Dosing Interval at Steady State (AUCtau,ss) of Lanadelumab in Plasma

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    End point title
    Area Under the Concentration-Time Curve Over the Dosing Interval at Steady State (AUCtau,ss) of Lanadelumab in Plasma [9]
    End point description
    The PK Set included all participants in the Safety Analysis Set who have at least 1 evaluable post dose PK concentration value.
    End point type
    Primary
    End point timeframe
    Day 0 (Pre-dose), at any time pre-dose on Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392
    Notes
    [9] - 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: Only descriptive summary statistics was planned for this outcome measure.
    End point values
    Lanadelumab 150 mg: Age 2 to <6 Years Lanadelumab 150 mg: Age 6 to <12 Years
    Number of subjects analysed
    4
    17
    Units: μg.day/mL
        geometric mean (geometric coefficient of variation)
    690 ± 34.0
    464 ± 37.7
    No statistical analyses for this end point

    Primary: Terminal half-life (t1/2) of Lanadelumab in Plasma

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    End point title
    Terminal half-life (t1/2) of Lanadelumab in Plasma [10]
    End point description
    The PK Set included all participants in the Safety Analysis Set who have at least 1 evaluable post dose PK concentration value.
    End point type
    Primary
    End point timeframe
    Day 0 (Pre-dose), at any time pre-dose on Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392
    Notes
    [10] - 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: Only descriptive summary statistics was planned for this outcome measure.
    End point values
    Lanadelumab 150 mg: Age 2 to <6 Years Lanadelumab 150 mg: Age 6 to <12 Years
    Number of subjects analysed
    4
    17
    Units: days
        median (full range (min-max))
    11.7 (10.2 to 13.9)
    12.6 (9.59 to 27.3)
    No statistical analyses for this end point

    Primary: Apparent clearance (CL/F) of Lanadelumab

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    End point title
    Apparent clearance (CL/F) of Lanadelumab [11]
    End point description
    The PK Set included all participants in the Safety Analysis Set who have at least 1 evaluable post dose PK concentration value.
    End point type
    Primary
    End point timeframe
    Day 0 (Pre-dose), at any time pre-dose on Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392
    Notes
    [11] - 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: Only descriptive summary statistics was planned for this outcome measure.
    End point values
    Lanadelumab 150 mg: Age 2 to <6 Years Lanadelumab 150 mg: Age 6 to <12 Years
    Number of subjects analysed
    4
    17
    Units: L/h
        geometric mean (geometric coefficient of variation)
    0.00906 ± 34.0
    0.0135 ± 37.8
    No statistical analyses for this end point

    Primary: Apparent Volume of Distribution (V/F) of Lanadelumab

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    End point title
    Apparent Volume of Distribution (V/F) of Lanadelumab [12]
    End point description
    The PK Set included all participants in the Safety Analysis Set who have at least 1 evaluable post dose PK concentration value.
    End point type
    Primary
    End point timeframe
    Day 0 (Pre-dose), at any time pre-dose on Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392
    Notes
    [12] - 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: Only descriptive summary statistics was planned for this outcome measure.
    End point values
    Lanadelumab 150 mg: Age 2 to <6 Years Lanadelumab 150 mg: Age 6 to <12 Years
    Number of subjects analysed
    4
    17
    Units: Litres
        geometric mean (geometric coefficient of variation)
    3.63 ± 25.9
    5.59 ± 39.2
    No statistical analyses for this end point

    Secondary: Normalized Number of Investigator-Confirmed Hereditary Angioedema (HAE) Attacks During Overall Treatment Period

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    End point title
    Normalized Number of Investigator-Confirmed Hereditary Angioedema (HAE) Attacks During Overall Treatment Period
    End point description
    Normalized number of investigator-confirmed HAE attacks during overall period are expressed as monthly HAE attack rate.Investigator-confirmed HAE attack rate calculated for each participant as number of investigator-confirmed HAE attacks occurring during given study period divided by number of days participant contributed to period multiplied by 28days.HAE attack:symptoms/signs consistent with attack in>=1of following locations:peripheral angioedema(cutaneous swelling involving extremity,face,neck,torso,and/or genitourinary region),abdominal angioedema(abdominal pain,with/without abdominal distention,nausea,vomiting,/diarrhea),laryngeal angioedema(stridor,dyspnea,difficulty speaking,difficulty swallowing,throat tightening,/swelling of tongue,palate,uvula,/larynx).Safety Analysis Set: participants who received study drug.n=participants presented by actual treatment regimen;due to dose modifications,some them were treated with both dosing regimens,counted in both treatment groups.
    End point type
    Secondary
    End point timeframe
    Day 0 (after start of study drug administration) through Day 364 (Week 52)
    End point values
    Lanadelumab 150 mg, q4wks Lanadelumab 150 mg, q2wks
    Number of subjects analysed
    11
    18
    Units: HAE attacks per month
        arithmetic mean (standard deviation)
    0.07 ± 0.219
    0.08 ± 0.157
    No statistical analyses for this end point

    Secondary: Normalized Number of Investigator-Confirmed HAE Attacks For Each Efficacy Evaluation Period Other Than the Overall Treatment Period

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    End point title
    Normalized Number of Investigator-Confirmed HAE Attacks For Each Efficacy Evaluation Period Other Than the Overall Treatment Period
    End point description
    Normalized number of investigator-confirmed HAE attacks in each efficacy evaluation period except overall treatment period are expressed as monthly HAE attack rate and is calculated for each participant as number of investigator-confirmed HAE attacks occurring during given study period divided by number of days participant contributed to period multiplied by 28days.HAE attack:symptoms/signs consistent with attack in>=1of following locations:peripheral angioedema(cutaneous swelling involving extremity,face,neck,torso,and/or genitourinary region),abdominal angioedema(abdominal pain,with/without abdominal distention,nausea,vomiting,/diarrhea),laryngeal angioedema(stridor,dyspnea,difficulty speaking,difficulty swallowing,throat tightening,/swelling of tongue,palate,uvula,/larynx).Safety Analysis Set:participants who received study drug.n=participants presented by actual treatment;due to dose modifications,some of them were treated with both doses and counted in both treatment groups.
    End point type
    Secondary
    End point timeframe
    Day 0 through Day 182, Day 70 through Day 182, Day 183 through Day 364, Day 70 through Day 364
    End point values
    Lanadelumab 150 mg, q4wks Lanadelumab 150 mg, q2wks
    Number of subjects analysed
    11
    18
    Units: HAE attacks per month
    arithmetic mean (standard deviation)
        Overall Presumed Steady-state Period(n=10,18)
    0.09 ± 0.288
    0.07 ± 0.143
        Treatment Period A(n=4,17)
    0.15 ± 0.308
    0.08 ± 0.207
        Presumed Steady-state Period for TP-A(n=3,17)
    0.25 ± 0.433
    0.06 ± 0.192
        Treatment Period B(n=10,18)
    0.28 ± 0.878
    0.08 ± 0.142
    No statistical analyses for this end point

    Secondary: Time to the First Investigator-Confirmed HAE Attack for Each Evaluation Period

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    End point title
    Time to the First Investigator-Confirmed HAE Attack for Each Evaluation Period
    End point description
    Time to first investigator-confirmed HAE attack for each efficacy evaluation period,was calculated from date and time of first dose to date and time of first investigator-confirmed HAE attack after first open-label dose for that efficacy evaluation period.HAE attack:symptoms/signs consistent with an attack in>=1of following locations:peripheral angioedema(cutaneous swelling involving extremity,face,neck,torso,and/or genitourinary region),abdominal angioedema(abdominal pain,with/without abdominal distention,nausea,vomiting,/diarrhea),laryngeal angioedema(stridor,dyspnea,difficulty speaking,difficulty swallowing,throat tightening,/swelling of tongue,palate,uvula,/larynx).Kaplan-Meier Method used for analysis.Safety Analysis Set:participants who received study drug.n=participants presented by actual treatment;due to dose modifications,some of them treated with both doses,counted in both treatment groups.99999:Median,95%CI not evaluable due to low number of events.
    End point type
    Secondary
    End point timeframe
    Day 0 through Day 364, Day 0 through Day 182, Day 70 through Day 182, Day 183 through Day 364, Day 70 through Day 364
    End point values
    Lanadelumab 150 mg, q4wks Lanadelumab 150 mg, q2wks
    Number of subjects analysed
    11
    18
    Units: days
    median (full range (min-max))
        Treatment Period A(n=10,18)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Presumed Steady-state Period for TP-A(n=3,17)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Treatment Period B (n=10,18)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Overall Treatment Period (n=11,18)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Overall Presumed Steady-state Period(n=10,18)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Normalized Number of HAE Attacks Requiring Acute Treatment for Each Efficacy Evaluation Period

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    End point title
    Normalized Number of HAE Attacks Requiring Acute Treatment for Each Efficacy Evaluation Period
    End point description
    Normalized number of investigator-confirmed HAE attacks requiring acute treatment during each efficacy evaluation period are expressed as monthly HAE attack rate and is calculated for each participant as number of investigator-confirmed HAE attacks occurring during given study period divided by number of days participant contributed to period multiplied by 28days.HAE attack:symptoms/signs consistent with attack in>=1of following locations:peripheral angioedema(cutaneous swelling involving extremity,face,neck,torso,and/or genitourinary region),abdominal angioedema(abdominal pain,with/without abdominal distention,nausea,vomiting,/diarrhea),laryngeal angioedema(stridor,dyspnea,difficulty speaking,difficulty swallowing,throat tightening,/swelling of tongue,palate,uvula,/larynx).Safety Analysis Set:participants who received study drug.n=participants presented by actual treatment;due to dose modifications,some of them were treated with both doses and counted in both treatment groups.
    End point type
    Secondary
    End point timeframe
    Day 0 through Day 364, Day 0 through Day 182, Day 70 through Day 182, Day 183 through Day 364, Day 70 through Day 364
    End point values
    Lanadelumab 150 mg, q4wks Lanadelumab 150 mg, q2wks
    Number of subjects analysed
    11
    18
    Units: HAE attacks per month
    arithmetic mean (standard deviation)
        Overall Treatment Period(n=11,18)
    0.07 ± 0.219
    0.07 ± 0.140
        Overall Presumed Steady-state Period(n=10,18)
    0.09 ± 0.288
    0.06 ± 0.126
        Treatment Period A(n=4,17)
    0.15 ± 0.308
    0.07 ± 0.175
        Presumed Steady-state Period for TP-A(n=3,17)
    0.25 ± 0.433
    0.04 ± 0.135
        Treatment Period B(n=10,18)
    0.28 ± 0.878
    0.06 ± 0.132
    No statistical analyses for this end point

    Secondary: Normalized Number of Moderate or Severe Investigator-Confirmed HAE Attacks for Each Efficacy Evaluation Period

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    End point title
    Normalized Number of Moderate or Severe Investigator-Confirmed HAE Attacks for Each Efficacy Evaluation Period
    End point description
    Normalized number of moderate/severe investigator-confirmed HAE attacks requiring acute treatment during each efficacy evaluation period are expressed as monthly HAE attack rate,is calculated for each participant as number of investigator-confirmed HAE attacks occurring during given study period divided by number of days participant contributed to period multiplied by 28days.HAE attack:symptoms/signs consistent with attack in>=1of following locations:peripheral angioedema(cutaneous swelling involving extremity,face,neck,torso,and/or genitourinary region),abdominal angioedema(abdominal pain,with/without abdominal distention,nausea,vomiting,/diarrhea),laryngeal angioedema(stridor,dyspnea,difficulty speaking,difficulty swallowing,throat tightening,/swelling of tongue,palate,uvula,/larynx).Safety Analysis Set:participants received study drug.n=participants presented by actual treatment;due to dose modifications,some of them treated with both doses are counted in both treatment groups.
    End point type
    Secondary
    End point timeframe
    Day 0 through Day 364, Day 0 through Day 182, Day 70 through Day 182, Day 183 through Day 364, Day 70 through Day 364
    End point values
    Lanadelumab 150 mg, q4wks Lanadelumab 150 mg, q2wks
    Number of subjects analysed
    11
    18
    Units: HAE attacks per month
    arithmetic mean (standard deviation)
        Overall Treatment Period(n=11,18)
    0.07 ± 0.219
    0.07 ± 0.144
        Overall Presumed Steady-state Period(n=10,18)
    0.09 ± 0.288
    0.06 ± 0.125
        Treatment Period A(n=4,17)
    0.15 ± 0.308
    0.07 ± 0.175
        Steady-state Period for TP-A(n=3,17)
    0.25 ± 0.433
    0.04 ± 0.135
        Treatment Period B(n=10,18)
    0.3 ± 0.88
    0.1 ± 0.13
    No statistical analyses for this end point

    Secondary: Normalized Number of High Morbidity Investigator-Confirmed HAE Attacks for Each Efficacy Evaluation Period

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    End point title
    Normalized Number of High Morbidity Investigator-Confirmed HAE Attacks for Each Efficacy Evaluation Period
    End point description
    Normalized number of high morbidity investigator-confirmed HAE attacks requiring acute treatment during each efficacy evaluation period are expressed as monthly HAE attack rate,is calculated for each participant as number of investigator-confirmed HAE attacks occurring during given study period divided by number of days participant contributed to period multiplied by 28days.HAE attack:symptoms/signs consistent with attack in>=1of following locations:peripheral angioedema(cutaneous swelling involving extremity,face,neck,torso,and/or genitourinary region),abdominal angioedema(abdominal pain,with/without abdominal distention,nausea,vomiting,/diarrhea),laryngeal angioedema(stridor,dyspnea,difficulty speaking,difficulty swallowing,throat tightening,/swelling of tongue,palate,uvula,/larynx).Safety Analysis Set:participants received study drug.n=participants presented by actual treatment;due to dose modifications,some of them treated with both doses are counted in both treatment groups.
    End point type
    Secondary
    End point timeframe
    Day 0 through Day 364, Day 0 through Day 182, Day 70 through Day 182, Day 183 through Day 364, Day 70 through Day 364
    End point values
    Lanadelumab 150 mg, q4wks Lanadelumab 150 mg, q2wks
    Number of subjects analysed
    11
    18
    Units: HAE attacks per month
    arithmetic mean (standard deviation)
        Overall Treatment Period(n=11,18)
    0.01 ± 0.044
    0.01 ± 0.039
        Overall Presumed Steady-state Period(n=10,18)
    0.02 ± 0.072
    0.01 ± 0.039
        Treatment Period A(n=4,17)
    0.04 ± 0.077
    0.00 ± 0.000
        Presumed Steady-state Period for TP-A(n=3,17)
    0.08 ± 0.144
    0.00 ± 0.000
        Treatment Period B(n=10,18)
    0.00 ± 0.000
    0.01 ± 0.039
    No statistical analyses for this end point

    Secondary: Number of Participants with Characteristics of Investigator-Confirmed HAE Attacks for Each Efficacy Evaluation Period

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    End point title
    Number of Participants with Characteristics of Investigator-Confirmed HAE Attacks for Each Efficacy Evaluation Period
    End point description
    Characteristics of investigator-confirmed HAE attacks for each efficacy evaluation period included duration,severity,attack location,and rescue medication use.HAE attack:symptoms or signs consistent with an attack in >=1 of 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).Safety Analysis Set:all participants who received study drug.Overall number analyzed:participants presented by actual treatment regimen. Because of dose modifications,some participants were treated with both dosing regimens and were counted in both treatment groups.Only categories with data are reported.TP:Treatment Period;PSSP:presumed steady state period.
    End point type
    Secondary
    End point timeframe
    Day 0 through Day 364, Day 0 through Day 182, Day 70 through Day 182, Day 183 through Day 364, Day 70 through Day 364
    End point values
    Lanadelumab 150 mg, q4wks Lanadelumab 150 mg, q2wks
    Number of subjects analysed
    11
    18
    Units: participants
        TP-A:Mean attack duration:0 hour[h],n=4,17
    3
    14
        TP-A:Mean attack duration:<12h,n=4,17
    1
    2
        TP-A:Mean attack duration:>24-48h,n=4,17
    0
    1
        TP-A:Max. attack severity:No attack,n=4,17
    3
    14
        TP-A:Max. attack severity:Moderate,n=4,17
    0
    3
        TP-A:Max. attack severity:Severe,n=4,17
    1
    0
        PSSP(TP-A):Mean attack duration: 0 h,n=3,17
    2
    15
        PSSP(TP-A):Mean attack duration:<12h,n=3,17
    1
    1
        PSSP(TP-A):Mean attack duration:>24-48h,n=3,17
    0
    1
        PSSP(TP-A):Max. attack severity:No attack,n=3,17
    2
    15
        PSSP(TP-A):Max. attack severity:Moderate,n=3,17
    0
    2
        PSSP(TP-A):Max. attack severity: Severe,n=3,17
    1
    0
        TP-B:Mean attack duration: 0 h,n=10,18
    9
    13
        TP-B:Mean attack duration:>0-<12h,n=10,18
    1
    3
        TP-B:Mean attack duration:12-24h,n=10,18
    0
    1
        TP-B:Mean attack duration:>48h,n=10,18
    0
    1
        TP-B:Max. attack severity:No attack,n=10,18
    9
    13
        TP-B:Max. attack severity:Moderate,n=10,18
    1
    4
        TP-B:Max. attack severity:Severe,n=10,18
    0
    1
        Overall TP:Mean attack duration:0 h,n=11,18
    10
    13
        Overall TP:Mean attack duration:>0-<12h,n=11,18
    1
    4
        Overall TP:Mean attack duration:>24-48h,n=11,18
    0
    1
        Overall TP:Max. attack severity:No attack,n=11,18
    10
    13
        Overall TP:Max. attack severity:Moderate,n=11,18
    0
    4
        Overall TP:Max. attack severity:Severe,n=11,18
    1
    1
        Overall PSSP:Mean attack duration:0h,n=10,18
    9
    13
        Overall PSSP:Mean attack duration:>0-<12h,n=10,18
    1
    4
        Overall PSSP:Mean attack duration:>48h,n=10,18
    0
    1
        Overall PSSP:Max.attack severity:No attack,n=10,18
    9
    13
        Overall PSSP:Max.attack severity:Moderate,n=10,18
    0
    4
        Overall PSSP:Max. attack severity:Severe,n=10,18
    1
    1
        TP-A:Primary Attack Location:Peripheral,n=4,17
    1
    2
        TP-A:Primary Attack Location:Abdominal,n=4,17
    1
    1
        TP-A:Attack Derived Location:Peripheral,n=4,17
    1
    2
        TP-A:Attack Derived Location:Abdominal,n=4,17
    1
    1
        TP-A:Rescue Medication(RM):No Use,n=4,17
    0
    1
        TP-A:RM:Icatibant,n=4,17
    0
    1
        TP-A:RM:Nano-filtered C1-INH,n=4,17
    0
    1
        TP-A:RM:Plasma-derivedC1-INH,n=4,17
    1
    1
        PSSP,TPA:Primary Attack Location:Peripheral,n=3,17
    0
    2
        PSSP,TPA:Primary Attack Location:Abdominal,n=3,17
    1
    0
        PSSP,TPA:Attack Derived Location:Peripheral,n=3,17
    0
    2
        PSSP,TPA:Attack Derived Location:Abdominal,n=3,17
    1
    0
        PSSP,TPA:Rescue Medication(RM):No Use,n=3,17
    0
    1
        PSSP,TPA:RM:Icatibant,n=3,17
    0
    1
        PSSP,TPA:RM:Plasma-derivedC1-INH,n=3,17
    1
    1
        TP-B:Primary Attack Location:Peripheral,n=10,18
    0
    3
        TP-B:Primary Attack Location:Abdominal,n=10,18
    1
    4
        TP-B:Attack Derived Location:Peripheral,n=10,18
    0
    3
        TP-B:Attack Derived Location:Abdominal,n=10,18
    1
    4
        TP-B:RM:No Use,n=10,18
    0
    2
        TP-B:RM:Icatibant,n=10,18
    0
    2
        TP-B:RM:Plasma-derivedC1-INH,n=10,18
    1
    2
        Overall TP:Pri.Attack Location:Peripheral,n=11,18
    1
    3
        Overall TP:Pri.Attack Location:Abdominal,n=11,18
    1
    4
        Overall TP:Attack Der.Location:Peripheral,n=11,18
    1
    3
        Overall TP:Attack Der.Location:Abdominal,n=11,18
    1
    4
        Overall TP:RM:No Use,n=11,18
    0
    3
        Overall TP:RM:Icatibant,n=11,18
    0
    2
        Overall TP:RM:Nano-filteredC1-INH,n=11,18
    0
    1
        Overall TP:RM:Plasma-derivedC1-INH,n=11,18
    1
    2
        OverallPSSP:Pri.Attack Location:Peripheral,n=10,18
    0
    3
        OverallPSSP:Pri.Attack Location:Abdominal,n=10,18
    1
    4
        OverallPSSP:Der.Attack Location:Peripheral,n=10,18
    0
    3
        Overall PSSP:Der.Attack Location:Abdominal,n=10,18
    1
    4
        Overall PSSP:RM:No Use,n=10,18
    0
    3
        Overall PSSP:RM:Icatibant,n=10,18
    0
    2
        Overall PSSP:RM:Plasma-derivedC1-INH,n=10,18
    1
    2
    No statistical analyses for this end point

    Secondary: Number of Participants with HAE Attack-Free Status for Each Evaluation Period

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    End point title
    Number of Participants with HAE Attack-Free Status for Each Evaluation Period
    End point description
    A HAE attack is 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). The Safety Analysis Set consists of all participants who received study drug. Overall number analyzed are participants presented by the actual treatment regimen. Because of dose modifications, some participants were treated with both dosing regimens and were counted in both treatment groups.
    End point type
    Secondary
    End point timeframe
    Day 0 through Day 364, Day 0 through Day 182, Day 70 through Day 182, Day 183 through Day 364, Day 70 through Day 364
    End point values
    Lanadelumab 150 mg, q4wks Lanadelumab 150 mg, q2wks
    Number of subjects analysed
    11
    18
    Units: participants
        Treatment Period A(n=4,17)
    3
    14
        Presumed Steady-state Period for TP-A(n=10,18)
    2
    15
        Treatment Period B(n=10,18)
    9
    13
        Overall Treatment Period(n=11,18)
    10
    13
        Overall Presumed Steady-state Period(n=10,18)
    9
    13
    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
    pKal activity was measured by biomarker cleaved high molecular weight kininogen (cHMWK) level to assess pharmacodynamics of lanadelumab. The Pharmacodynamic (PD) Set included all participants in the Safety Analysis Set who have at least 1 evaluable post dose PD value. Number analyzed is the number of participants with data available for analysis at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Day 0 (Pre-dose), at any time on Days 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392
    End point values
    Lanadelumab 150 mg: Age 2 to <6 Years Lanadelumab 150 mg: Age 6 to <12 Years
    Number of subjects analysed
    4
    17
    Units: percentage of cHMWK
    arithmetic mean (standard deviation)
        Visit 1 Day 0 (n=4,16)
    30.2500 ± 13.61017
    45.6438 ± 25.79470
        Visit 2 Day 4(n=3,14)
    16.4000 ± 8.94036
    32.2857 ± 17.89606
        Visit 3 Day 14(n=4,17)
    9.5750 ± 4.05740
    25.7176 ± 11.75565
        Visit 4 Day 28(n=4.14)
    18.8500 ± 14.15968
    26.1571 ± 11.76616
        Visit 8 Day 56(n=3,15)
    15.1333 ± 12.95582
    24.6267 ± 14.28963
        Visit 12 Day 84(n=3,14)
    18.2333 ± 17.91768
    24.7214 ± 12.84339
        Visit 16 Day 112(n=3,12)
    10.7333 ± 5.48118
    18.0000 ± 11.05992
        Visit 20 Day 140(n=3,12)
    15.2000 ± 16.96202
    16.3417 ± 12.53841
        Visit 24 Day 168(n=3,12)
    21.9000 ± 20.71545
    19.6167 ± 16.61762
        Visit 26 Day 182(n=3,11)
    17.9000 ± 14.29021
    18.6818 ± 10.54332
        Visit 28 Day 196(n=3,14)
    9.2000 ± 2.52389
    14.6571 ± 7.29939
        Visit 36 Day 252(n=3,15)
    15.2000 ± 13.16397
    16.3067 ± 10.26008
        Visit 44 Day 308(n=3,16)
    13.5333 ± 7.24316
    23.2750 ± 15.23577
        Visit 52 Day 364(n=3,15)
    10.7333 ± 2.87112
    14.4733 ± 8.51448
        Visit 56 Day 392 EOS (n=3,14)
    10.9000 ± 3.15753
    19.4286 ± 14.57677
    No statistical analyses for this end point

    Secondary: Number of Participants with Immunogenicity Status as Positive or Negative

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    End point title
    Number of Participants with Immunogenicity Status as Positive or Negative
    End point description
    Immunogenicity was measured based on the presence or absence of neutralizing or non-neutralizing Anti-drug Antibody (ADA) in plasma. The Safety Analysis Set consisted of all participants who received study drug. Number analyzed are the number of participants with data available for given category.
    End point type
    Secondary
    End point timeframe
    Day 0 (Pre-dose), Days 28, 84, 140, 182, 196, 252, 308, 364 and 392
    End point values
    Lanadelumab 150 mg: Age 2 to <6 Years Lanadelumab 150 mg: Age 6 to <12 Years
    Number of subjects analysed
    4
    17
    Units: participants
        Baseline (Day 0): ADA Negative(-),n=4,17
    4
    17
        Baseline (Day 0): ADA Positive(+),n=4,17
    0
    0
        Baseline (Day 0): ADA+ (Neutralizing),n=4,17
    0
    0
        Baseline(Day0):ADA+ (Non-neutralizing),n=4,17
    0
    0
        Visit 4 Day 28:ADA-,n=4,14
    4
    13
        Visit 4 Day 28:ADA+,n=4,14
    0
    1
        Visit 4 Day 28:ADA+(Neutralizing),n=4,14
    0
    0
        Visit 4 Day 28:ADA+(Non-neutralizing),n=4,14
    0
    1
        Overall TP-A:ADA-,n=4,16
    4
    13
        Overall TP-A:ADA+,n=4,16
    0
    3
        Overall TP-A:ADA+(Neutralizing),n=4,16
    0
    1
        Overall TP-A:ADA+(Non-neutralizing),n=4,16
    0
    3
        Overall TP-B:ADA-,n=3,16
    3
    15
        Overall TP-B:ADA+,n=3,16
    0
    1
        Overall TP-B:ADA+(Neutralizing),n=3,16
    0
    0
        Overall TP-B:ADA+(Non-neutralizing),n=3,16
    0
    1
        Overall Study Period:ADA-,n=4,16Overall Study Peri
    4
    13
        Overall Study Period:ADA+,n=4,16
    0
    3
        Overall Study Period:ADA+(Neutralizing),n=4,16
    0
    1
        Overall Study Period:ADA+(Non-neutralizing),n=4,16
    0
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 115 weeks
    Adverse event reporting additional description
    The Safety Analysis Set consists of all participants who received study drug. Due to dose modification, some participants were counted in both arms, and thus the overall number of participants analyzed in arms Lanadelumab 150 mg, q4wks and Lanadelumab 150 mg, q2wks were 11 and 18, respectively.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Lanadelumab 150 mg, q4wks
    Reporting group description
    Participants received lanadelumab SC injection at a dose of 150 mg for q4wks with over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B).

    Reporting group title
    Lanadelumab 150 mg, q2wks
    Reporting group description
    Participants received lanadelumab SC injection at a dose of 150 mg for q2wks over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B).

    Serious adverse events
    Lanadelumab 150 mg, q4wks Lanadelumab 150 mg, q2wks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 18 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Lanadelumab 150 mg, q4wks Lanadelumab 150 mg, q2wks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 11 (54.55%)
    15 / 18 (83.33%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    0
    4
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    2 / 11 (18.18%)
    6 / 18 (33.33%)
         occurrences all number
    12
    76
    Injection site erythema
         subjects affected / exposed
    2 / 11 (18.18%)
    2 / 18 (11.11%)
         occurrences all number
    8
    21
    Injection site swelling
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    3
    Pyrexia
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Administration site pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Feeling cold
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Injection site injury
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Injection site reaction
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Affect lability
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Skin abrasion
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 18 (16.67%)
         occurrences all number
    3
    13
    Joint injury
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Arthropod bite
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Contusion
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Limb injury
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Skin laceration
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Eosinophil count increased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    Nasal congestion
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Oropharyngeal discomfort
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Epistaxis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 18 (11.11%)
         occurrences all number
    1
    3
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Eye inflammation
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 18 (11.11%)
         occurrences all number
    1
    3
    Tooth loss
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Toothache
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Dermatitis allergic
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Skin abrasion
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Growing pains
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Limb discomfort
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Rhinitis
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 18 (5.56%)
         occurrences all number
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Adenoiditis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Asymptomatic COVID-19
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    COVID-19
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Paronychia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Aug 2019
    The primary purpose of this amendment was to make following changes: The protocol requirements for reporting Serious Adverse Events (SAEs) have been updated. Revised self-administration instructions to allow participants aged 6 years or older to self-administer lanadelumab only after they have received appropriate training and assessed by the investigator as being capable of self-treatment. Participants less than 6 years of age must have a parent/caregiver self-administer lanadelumab. Removed the requirement for eligibility to include “a family history consistent with HAE I or II, or C1q within the normal range” since these elements are not necessary. Added the requirement to exclude participants with a known hypersensitivity to the investigational product or its components as a new exclusion criterion. The assay used for HIV testing at screening has been revised to a more robust testing procedure. The volume of blood to be collected from each participant has been decreased in consideration of the pediatric population. Removed non-applicable Adverse Event (AE) guidance on “Symptoms of the Disease under Study”, as all angioedema attacks are reported as AEs in this study.
    22 Jun 2021
    The primary purpose of this amendment was to make following changes: Sponsor approval and emergency contact information has been updated to reflect the current medical monitor. Individual participant participation duration was revised to clarify that maximum duration for study participation is 72 weeks. Participants receiving treatment q2wks may complete the study in 70 weeks. Revised follow-up period to 2-4 weeks as follow-up period depends on the treatment schedule. Participants receiving treatment q2wks will have a 2-week follow-up period (EOS Visit at Day 378); participants receiving treatment q4wks will have a 4-week follow-up period (EOS Visit at Day 392). The interim analysis summarizing data up to Treatment Period A has been removed as it is no longer planned. EOS/ET visit in footnote “a” was incorrectly written as Day 292. This has been corrected to Day 392. Text regarding Study DX-2930-04 as “ongoing” has been removed as this study has been completed. Severity categorization for AEs was revised to clarify a portion of the protocol template language that is incongruous with program data collection and analysis procedures in the previous HAE clinical studies.

    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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