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    Clinical Trial Results:
    HELP Study®: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study to Evaluate DX-2930 For Long-Term Prophylaxis Against Acute Attacks of Hereditary Angioedema (HAE)

    Summary
    EudraCT number
    		 2015-003943-20
    Trial protocol
    		 DE   GB   IT  
    Global end of trial date
    13 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Oct 2017
    First version publication date
    28 Oct 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    DX-2930-03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02586805
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, MA, United States, 02421
    Public contact
    Study Physician, Shire, 1 866-842-5335,
    Scientific contact
    Study Physician, Shire, 1 866-842-5335,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Apr 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to evaluate the efficacy of DX-2930 in preventing hereditary angioedema (HAE) attacks.
    Protection of trial subjects
    This study was conducted in accordance with current applicable regulations, International Council for Harmonisation (ICH) of Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Mar 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    European Union: 29
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Jordan: 3
    Country: Number of subjects enrolled
    United States: 86
    Worldwide total number of subjects
    125
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    10
    Adults (18-64 years)
    110
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted at 41 sites in the United States, United Kingdom, Italy, Germany, Canada and Jordan between 03 March 2016 (first subject first visit) and 13 April 2017 (last subject last visit).

    Pre-assignment
    Screening details
    		 A total of 159 subjects were screened and 126 subjects were randomized in the ratio of 3:2:2:2 to the placebo versus DX-2930-03 arms. Of them, 125 subjects were assigned to study treatment and one subject determined to be screen failure after randomization.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo matched to DX-2930 subcutaneously (SC) once in every 2 weeks (q2wks)for 26 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received placebo matched to DX-2930 SC for 26 weeks.

    Arm title
    		 Lanadelumab (DX-2930) 150 mg every 4 weeks
    Arm description
    		 Subjects received 150 milligram (mg) dose of DX-2930 SC once in every 4 weeks (q4wks) and matched placebo SC q2wks between DX-2930 doses for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanadelumab
    Investigational medicinal product code
    DX-2930
    Other name
    SHP643
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received DX-2930 SC for 26 weeks

    Arm title
    		 Lanadelumab (DX-2930) 300 mg every 4 weeks
    Arm description
    		 Subjects received 300 mg dose of DX-2930 SC q4wks and matched placebo SC q2wks between DX-2930 doses for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanadelumab
    Investigational medicinal product code
    DX-2930
    Other name
    SHP643
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received DX-2930 SC for 26 weeks

    Arm title
    		 Lanadelumab (DX-2930) 300 mg every 2 weeks
    Arm description
    		 Subjects received 300 mg dose of DX-2930 SC q2wks for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanadelumab
    Investigational medicinal product code
    DX-2930
    Other name
    SHP643
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received DX-2930 SC for 26 weeks

    Number of subjects in period 1
    		Placebo Lanadelumab (DX-2930) 150 mg every 4 weeks Lanadelumab (DX-2930) 300 mg every 4 weeks Lanadelumab (DX-2930) 300 mg every 2 weeks
    Started
    41
    28
    29
    27
    Completed
    35
    27
    26
    25
    Not completed
    6
    1
    3
    2
         Consent withdrawn by subject
    3
    1
    1
    2
         Physician decision
    1
    -
    -
    -
         Adverse event, non-fatal
    2
    -
    1
    -
         Lost to follow-up
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to DX-2930 subcutaneously (SC) once in every 2 weeks (q2wks)for 26 weeks.

    Reporting group title
    Lanadelumab (DX-2930) 150 mg every 4 weeks
    Reporting group description
    		 Subjects received 150 milligram (mg) dose of DX-2930 SC once in every 4 weeks (q4wks) and matched placebo SC q2wks between DX-2930 doses for 26 weeks.

    Reporting group title
    Lanadelumab (DX-2930) 300 mg every 4 weeks
    Reporting group description
    		 Subjects received 300 mg dose of DX-2930 SC q4wks and matched placebo SC q2wks between DX-2930 doses for 26 weeks.

    Reporting group title
    Lanadelumab (DX-2930) 300 mg every 2 weeks
    Reporting group description
    		 Subjects received 300 mg dose of DX-2930 SC q2wks for 26 weeks.

    Reporting group values
    		 Placebo Lanadelumab (DX-2930) 150 mg every 4 weeks Lanadelumab (DX-2930) 300 mg every 4 weeks Lanadelumab (DX-2930) 300 mg every 2 weeks Total
    Number of subjects
    		 41 28 29 27
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.1 ± 16.75 43.4 ± 14.91 39.5 ± 12.85 40.3 ± 13.35 -
    Gender categorical
    Units: Subjects
        Female
    		 34 20 19 15 88
        Male
    		 7 8 10 12 37
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 1 2 3 9
        Not Hispanic or Latino
    		 38 27 27 23 115
        Unknown or Not Reported
    		 0 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to DX-2930 subcutaneously (SC) once in every 2 weeks (q2wks)for 26 weeks.

    Reporting group title
    Lanadelumab (DX-2930) 150 mg every 4 weeks
    Reporting group description
    		 Subjects received 150 milligram (mg) dose of DX-2930 SC once in every 4 weeks (q4wks) and matched placebo SC q2wks between DX-2930 doses for 26 weeks.

    Reporting group title
    Lanadelumab (DX-2930) 300 mg every 4 weeks
    Reporting group description
    		 Subjects received 300 mg dose of DX-2930 SC q4wks and matched placebo SC q2wks between DX-2930 doses for 26 weeks.

    Reporting group title
    Lanadelumab (DX-2930) 300 mg every 2 weeks
    Reporting group description
    		 Subjects received 300 mg dose of DX-2930 SC q2wks for 26 weeks.

    Primary: Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During Treatment Period

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    End point title
    		 Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During Treatment Period
    End point description
    HAE attack was defined as a discrete episode during which the subject progressed from no angioedema to symptoms of angioedema. Rate of investigator confirmed HAE attacks was analyzed using a generalized linear model (GLM) for count data assuming a poisson distribution with a log link function and Pearson chi-square scaling of standard errors to account for potential overdispersion. Intent-to-treat (ITT) population included all randomized subjects who received any exposure to the investigational product.
    End point type
    Primary
    End point timeframe
    From Day 0 to Day 182
    End point values
    		 Placebo Lanadelumab (DX-2930) 150 mg every 4 weeks Lanadelumab (DX-2930) 300 mg every 4 weeks Lanadelumab (DX-2930) 300 mg every 2 weeks
    Number of subjects analysed
    41
    28
    29
    27
    Units: Attacks per 4 weeks
    least squares mean (confidence interval 95%)
        Attacks per 4 weeks
    1.967 (1.640 to 2.358)
    0.480 (0.313 to 0.735)
    0.526 (0.358 to 0.771)
    0.257 (0.145 to 0.458)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Results from Poisson regression model with fixed effects for treatment group (categorical) and normalized baseline attack rate (continuous), and logarithm of time in days each subject was observed during treatment period as offset variable in model. Pearson chi-square scaling of standards errors was employed to account for potential overdispersion. Mean estimates are Least Squares (LS) means. Percent (%) change in mean rate corresponds to 100% * (estimated mean rate ratio - 1).
    Comparison groups
    Lanadelumab (DX-2930) 150 mg every 4 weeks v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [1]
    Method
    		 Chi-squared
    Parameter type
    		 % change in mean rate (vs placebo)
    Point estimate
    -75.609
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -84.65
         upper limit
    		 -61.243
    Notes
    [1] - p-values are adjusted for multiple testing.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Results from Poisson regression model with fixed effects for treatment group (categorical) and normalized baseline attack rate (continuous), and logarithm of time in days each subject was observed during treatment period as offset variable in model. Pearson chi-square scaling of standards errors was employed to account for potential overdispersion. Mean estimates are Least Squares (LS) means. Percent (%) change in mean rate corresponds to 100% * (estimated mean rate ratio - 1).
    Comparison groups
    Lanadelumab (DX-2930) 300 mg every 4 weeks v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [2]
    Method
    		 Chi-squared
    Parameter type
    		 % change in mean rate (vs placebo)
    Point estimate
    -73.271
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -82.379
         upper limit
    		 -59.456
    Notes
    [2] - p-values are adjusted for multiple testing.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Results from Poisson regression model with fixed effects for treatment group (categorical) and normalized baseline attack rate (continuous), and logarithm of time in days each subject was observed during treatment period as offset variable in model. Pearson chi-square scaling of standards errors was employed to account for potential overdispersion. Mean estimates are Least Squares (LS) means. Percent (%) change in mean rate corresponds to 100% * (estimated mean rate ratio - 1).
    Comparison groups
    Lanadelumab (DX-2930) 300 mg every 2 weeks v Placebo
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [3]
    Method
    		 Chi-squared
    Parameter type
    		 % change in mean rate (vs placebo)
    Point estimate
    -86.921
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -92.828
         upper limit
    		 -76.15
    Notes
    [3] - p-values are adjusted for multiple testing.

    Secondary: Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attack Requiring Acute Treatment

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    End point title
    		 Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attack Requiring Acute Treatment
    End point description
    HAE attack was defined as a discrete episode during which the subject progressed from no angioedema to symptoms of angioedema. Rate of investigator confirmed HAE attack were performed using the GLM for count data assuming a poisson distribution with a log link function and Pearson chi-square scaling of standard errors to account for potential overdispersion. ITT population included all randomized subjects who received any exposure to the investigational product.
    End point type
    Secondary
    End point timeframe
    From Day 0 to Day 182
    End point values
    		 Placebo Lanadelumab (DX-2930) 150 mg every 4 weeks Lanadelumab (DX-2930) 300 mg every 4 weeks Lanadelumab (DX-2930) 300 mg every 2 weeks
    Number of subjects analysed
    41
    28
    29
    27
    Units: Attacks per 4 weeks
    least squares mean (confidence interval 95%)
        Attacks per 4 weeks
    1.637 (1.337 to 2.005)
    0.314 (0.184 to 0.535)
    0.423 (0.276 to 0.648)
    0.208 (0.109 to 0.396)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Results from Poisson regression model with fixed effects for treatment group (categorical) and normalized baseline attack rate (continuous), and logarithm of time in days each subject was observed during treatment period as offset variable in model. Pearson chi-square scaling of standards errors was employed to account for potential overdispersion. Mean estimates are Least Squares (LS) means. Percent (%) change in mean rate corresponds to 100% * (estimated mean rate ratio - 1).
    Comparison groups
    Placebo v Lanadelumab (DX-2930) 150 mg every 4 weeks
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [4]
    Method
    		 Chi-squared
    Parameter type
    		 % change in mean rate (vs placebo)
    Point estimate
    -80.842
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -89.169
         upper limit
    		 -66.114
    Notes
    [4] - p-values are adjusted for multiple testing.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Results from Poisson regression model with fixed effects for treatment group (categorical) and normalized baseline attack rate (continuous), and logarithm of time in days each subject was observed during treatment period as offset variable in model. Pearson chi-square scaling of standards errors was employed to account for potential overdispersion. Mean estimates are Least Squares (LS) means. Percent (%) change in mean rate corresponds to 100% * (estimated mean rate ratio - 1).
    Comparison groups
    Placebo v Lanadelumab (DX-2930) 300 mg every 4 weeks
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [5]
    Method
    		 Chi-squared
    Parameter type
    		 % change in mean rate (vs placebo)
    Point estimate
    -74.169
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -83.733
         upper limit
    		 -58.983
    Notes
    [5] - p-values are adjusted for multiple testing.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Results from Poisson regression model with fixed effects for treatment group (categorical) and normalized baseline attack rate (continuous), and logarithm of time in days each subject was observed during treatment period as offset variable in model. Pearson chi-square scaling of standards errors was employed to account for potential overdispersion. Mean estimates are Least Squares (LS) means. Percent (%) change in mean rate corresponds to 100% * (estimated mean rate ratio - 1).
    Comparison groups
    Placebo v Lanadelumab (DX-2930) 300 mg every 2 weeks
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [6]
    Method
    		 Chi-squared
    Parameter type
    		 % change in mean rate (vs placebo)
    Point estimate
    -87.299
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -93.494
         upper limit
    		 -75.204
    Notes
    [6] - p-values are adjusted for multiple testing.

    Secondary: Rate of Moderate or Severe Investigator Confirmed Hereditary Angioedema (HAE) Attacks

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    End point title
    		 Rate of Moderate or Severe Investigator Confirmed Hereditary Angioedema (HAE) Attacks
    End point description
    HAE attack was defined as a discrete episode during which the subject progressed from no angioedema to symptoms of angioedema. Moderate and severe investigator-confirmed HAE attacks were the attacks that were moderate or severe as per the HAE attack assessment and reporting procedures (HAARP) defined severity. The overall severity of attack was determined by the investigator using following definitions: mild (transient or mild discomfort), moderate (mild to moderate limitation in activity), severe (marked limitation in activity). ITT population included all randomized subjects who received any exposure to the investigational product.
    End point type
    Secondary
    End point timeframe
    From Day 0 to Day 182
    End point values
    		 Placebo Lanadelumab (DX-2930) 150 mg every 4 weeks Lanadelumab (DX-2930) 300 mg every 4 weeks Lanadelumab (DX-2930) 300 mg every 2 weeks
    Number of subjects analysed
    41
    28
    29
    27
    Units: Attacks per 4 weeks
    least squares mean (confidence interval 95%)
        Attacks per 4 weeks
    1.216 (0.971 to 1.522)
    0.359 (0.221 to 0.581)
    0.325 (0.199 to 0.529)
    0.202 (0.106 to 0.386)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Results from Poisson regression model with fixed effects for treatment group (categorical) and normalized baseline attack rate (continuous), and logarithm of time in days each subject was observed during treatment period as offset variable in model. Pearson chi-square scaling of standards errors was employed to account for potential overdispersion. Mean estimates are Least Squares (LS) means. Percent (%) change in mean rate corresponds to 100% * (estimated mean rate ratio - 1).
    Comparison groups
    Placebo v Lanadelumab (DX-2930) 150 mg every 4 weeks
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [7]
    Method
    		 Chi-squared
    Parameter type
    		 % change in mean rate (vs placebo)
    Point estimate
    -70.497
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -82.696
         upper limit
    		 -49.699
    Notes
    [7] - p-values are adjusted for multiple testing.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Results from Poisson regression model with fixed effects for treatment group (categorical) and normalized baseline attack rate (continuous), and logarithm of time in days each subject was observed during treatment period as offset variable in model. Pearson chi-square scaling of standards errors was employed to account for potential overdispersion. Mean estimates are Least Squares (LS) means. Percent (%) change in mean rate corresponds to 100% * (estimated mean rate ratio - 1).
    Comparison groups
    Placebo v Lanadelumab (DX-2930) 300 mg every 4 weeks
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [8]
    Method
    		 Chi-squared
    Parameter type
    		 % change in mean rate (vs placebo)
    Point estimate
    -73.285
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -84.316
         upper limit
    		 -54.496
    Notes
    [8] - p-values are adjusted for multiple testing.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Results from Poisson regression model with fixed effects for treatment group (categorical) and normalized baseline attack rate (continuous), and logarithm of time in days each subject was observed during treatment period as offset variable in model. Pearson chi-square scaling of standards errors was employed to account for potential overdispersion. Mean estimates are Least Squares (LS) means. Percent (%) change in mean rate corresponds to 100% * (estimated mean rate ratio - 1).
    Comparison groups
    Placebo v Lanadelumab (DX-2930) 300 mg every 2 weeks
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [9]
    Method
    		 Chi-squared
    Parameter type
    		 % change in mean rate (vs placebo)
    Point estimate
    -83.394
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -91.618
         upper limit
    		 -67.099
    Notes
    [9] - p-values are adjusted for multiple testing.

    Secondary: Rate of Investigator confirmed Hereditary Angioedema (HAE) Attacks During Day 14 Through Day 182

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    End point title
    		 Rate of Investigator confirmed Hereditary Angioedema (HAE) Attacks During Day 14 Through Day 182
    End point description
    HAE attack was defined as a discrete episode during which the subject progressed from no angioedema to symptoms of angioedema. Rate of investigator confirmed HAE attacks were analyzed by poisson regression during day 14 after study drug administration through day 182. ITT population included all randomized subjects who received any exposure to the investigational product.
    End point type
    Secondary
    End point timeframe
    From Day 14 to Day 182
    End point values
    		 Placebo Lanadelumab (DX-2930) 150 mg every 4 weeks Lanadelumab (DX-2930) 300 mg every 4 weeks Lanadelumab (DX-2930) 300 mg every 2 weeks
    Number of subjects analysed
    41
    28
    29
    27
    Units: Attacks per 4 weeks
    least squares mean (confidence interval 95%)
        Attacks per 4 weeks
    1.988 (1.652 to 2.391)
    0.445 (0.283 to 0.698)
    0.489 (0.326 to 0.734)
    0.218 (0.115 to 0.414)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Results from Poisson regression model with fixed effects for treatment group (categorical) and normalized baseline attack rate (continuous), and logarithm of time in days each subject was observed during treatment period as offset variable in model. Pearson chi-square scaling of standards errors was employed to account for potential overdispersion. Mean estimates are Least Squares (LS) means. Percent (%) change in mean rate corresponds to 100% * (estimated mean rate ratio - 1).
    Comparison groups
    Placebo v Lanadelumab (DX-2930) 150 mg every 4 weeks
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [10]
    Method
    		 Chi-squared
    Parameter type
    		 % change in mean rate (vs placebo)
    Point estimate
    -77.622
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -86.253
         upper limit
    		 -63.572
    Notes
    [10] - p-values are adjusted for multiple testing.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Results from Poisson regression model with fixed effects for treatment group (categorical) and normalized baseline attack rate (continuous), and logarithm of time in days each subject was observed during treatment period as offset variable in model. Pearson chi-square scaling of standards errors was employed to account for potential overdispersion. Mean estimates are Least Squares (LS) means. Percent (%) change in mean rate corresponds to 100% * (estimated mean rate ratio - 1).
    Comparison groups
    Placebo v Lanadelumab (DX-2930) 300 mg every 4 weeks
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [11]
    Method
    		 Chi-squared
    Parameter type
    		 % change in mean rate (vs placebo)
    Point estimate
    -75.377
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -84.115
         upper limit
    		 -61.833
    Notes
    [11] - p-values are adjusted for multiple testing.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Results from Poisson regression model with fixed effects for treatment group (categorical) and normalized baseline attack rate (continuous), and logarithm of time in days each subject was observed during treatment period as offset variable in model. Pearson chi-square scaling of standards errors was employed to account for potential overdispersion. Mean estimates are Least Squares (LS) means. Percent (%) change in mean rate corresponds to 100% * (estimated mean rate ratio - 1).
    Comparison groups
    Placebo v Lanadelumab (DX-2930) 300 mg every 2 weeks
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [12]
    Method
    		 Chi-squared
    Parameter type
    		 % change in mean rate (vs placebo)
    Point estimate
    -89.008
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -94.325
         upper limit
    		 -78.707
    Notes
    [12] - p-values are adjusted for multiple testing.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration up to Day 238
    Adverse event reporting additional description
    Adverse events were collected over the entire treatment period and were assigned to the treatment group without regard to the type of injection (that is placebo or active drug in the 150 mg q4wk and 300 mg q4wk groups).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to DX-2930 SC q2wks for 26 weeks.

    Reporting group title
    Lanadelumab (DX-2930) 150 mg every 4 weeks
    Reporting group description
    		 Subjects received 150 mg dose of DX-2930 SC q4wks and matched placebo SC q2wks between DX-2930 doses for 26 weeks.

    Reporting group title
    Lanadelumab (DX-2930) 300 mg every 4 weeks
    Reporting group description
    		 Subjects received 300 mg dose of DX-2930 SC q4wks and matched placebo SC q2wks between DX-2930 doses for 26 weeks.

    Reporting group title
    Lanadelumab (DX-2930) 300 mg every 2 weeks
    Reporting group description
    		 Subjects received 300 mg dose of DX-2930 SC q2wks for 26 weeks.

    Serious adverse events
    		 Placebo Lanadelumab (DX-2930) 150 mg every 4 weeks Lanadelumab (DX-2930) 300 mg every 4 weeks Lanadelumab (DX-2930) 300 mg every 2 weeks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 28 (0.00%)
    3 / 29 (10.34%)
    2 / 27 (7.41%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Meniscus injury
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hereditary angioedema
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 28 (0.00%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar ii disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Catheter site infection
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 28 (0.00%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Lanadelumab (DX-2930) 150 mg every 4 weeks Lanadelumab (DX-2930) 300 mg every 4 weeks Lanadelumab (DX-2930) 300 mg every 2 weeks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 41 (97.56%)
    25 / 28 (89.29%)
    26 / 29 (89.66%)
    23 / 27 (85.19%)
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    4 / 41 (9.76%)
    0 / 28 (0.00%)
    1 / 29 (3.45%)
    1 / 27 (3.70%)
         occurrences all number
    4
    0
    1
    1
    Congenital, familial and genetic disorders
    Hereditary angioedema
         subjects affected / exposed
    40 / 41 (97.56%)
    17 / 28 (60.71%)
    20 / 29 (68.97%)
    15 / 27 (55.56%)
         occurrences all number
    577
    84
    108
    45
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 28 (3.57%)
    3 / 29 (10.34%)
    1 / 27 (3.70%)
         occurrences all number
    0
    2
    5
    1
    Headache
         subjects affected / exposed
    8 / 41 (19.51%)
    3 / 28 (10.71%)
    5 / 29 (17.24%)
    9 / 27 (33.33%)
         occurrences all number
    10
    10
    8
    18
    Migraine
         subjects affected / exposed
    4 / 41 (9.76%)
    2 / 28 (7.14%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    4
    5
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 28 (0.00%)
    0 / 29 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    0
    0
    2
    Injection site bruising
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 28 (10.71%)
    2 / 29 (6.90%)
    1 / 27 (3.70%)
         occurrences all number
    0
    5
    2
    1
    Injection site discomfort
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 28 (0.00%)
    2 / 29 (6.90%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    13
    10
    Injection site erythema
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 28 (14.29%)
    2 / 29 (6.90%)
    2 / 27 (7.41%)
         occurrences all number
    1
    23
    6
    7
    Injection site haematoma
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 28 (3.57%)
    1 / 29 (3.45%)
    1 / 27 (3.70%)
         occurrences all number
    3
    1
    2
    1
    Injection site haemorrhage
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    7
    2
    0
    11
    Injection site pain
         subjects affected / exposed
    12 / 41 (29.27%)
    13 / 28 (46.43%)
    9 / 29 (31.03%)
    14 / 27 (51.85%)
         occurrences all number
    71
    123
    68
    67
    Injection site paraesthesia
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 28 (7.14%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Injection site pruritus
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 28 (3.57%)
    2 / 29 (6.90%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 28 (7.14%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Abdominal pain
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 28 (3.57%)
    2 / 29 (6.90%)
    0 / 27 (0.00%)
         occurrences all number
    2
    1
    3
    0
    Abdominal pain upper
         subjects affected / exposed
    4 / 41 (9.76%)
    2 / 28 (7.14%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    4
    2
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 28 (10.71%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    2
    3
    0
    2
    Nausea
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    1
    0
    2
    Paraesthesia oral
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 28 (0.00%)
    0 / 29 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    0
    2
    Toothache
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 28 (7.14%)
    1 / 29 (3.45%)
    1 / 27 (3.70%)
         occurrences all number
    0
    4
    1
    1
    Vomiting
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 28 (7.14%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 28 (0.00%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    3
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 28 (3.57%)
    2 / 29 (6.90%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Pruritus
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 28 (0.00%)
    0 / 29 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    0
    2
    Rash
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 28 (3.57%)
    3 / 29 (10.34%)
    0 / 27 (0.00%)
         occurrences all number
    2
    2
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 28 (0.00%)
    2 / 29 (6.90%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Back pain
         subjects affected / exposed
    4 / 41 (9.76%)
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    7
    1
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 28 (7.14%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    0
    1
    0
    3
    Neck pain
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    1
    0
    3
    Pain in extremity
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 28 (7.14%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    2
    0
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Hordeolum
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 28 (0.00%)
    0 / 29 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    0
    2
    Otitis externa
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 28 (7.14%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Rhinitis
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 28 (0.00%)
    2 / 29 (6.90%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    3
    0
    Sinusitis
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 28 (3.57%)
    0 / 29 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    1
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 28 (0.00%)
    2 / 29 (6.90%)
    2 / 27 (7.41%)
         occurrences all number
    3
    0
    2
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 28 (7.14%)
    1 / 29 (3.45%)
    1 / 27 (3.70%)
         occurrences all number
    1
    2
    1
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    11 / 41 (26.83%)
    3 / 28 (10.71%)
    7 / 29 (24.14%)
    10 / 27 (37.04%)
         occurrences all number
    16
    5
    10
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Dec 2015
    Updated list of inactive ingredients and description of treatments and updates were made on components of both lanadelumab and placebo; Updated description of run-in period; Updated individual study subject stopping rules; Expected number of subjects aged 12 to 17 to be enrolled in the study was added; Updated blinding and unblinding text; Updated order of the sample collections when multiple sample types were collected at the same time point; Updated study day through which treatment emergent adverse events (AEs) were defined; Updated subject withdrawal text.
    21 Apr 2016
    Modified exclusion criteria to exclude subjects who may have participated in a prior study to eliminate non-naive from the study analysis; Modified inclusion criteria for contraception requirements; Four additional pregnancy tests were scheduled for monitoring of pregnancy during treatment; Correction was made in study activities footnote #7 on pregnancy test at final follow-up visit; Clarified that no interim analysis was planned; An independent Data Safety Monitoring Board (DSMB) replaced the internal study safety committee (SSC), and its procedures were clarified; Period for reporting HAE attacks after the final follow-up visit was clarified; Collection of HAE attack data was clarified; Tertiary objective was rephrased for clarity; Four additional quality of life (QoL) assessments using the Angioedema-Quality of Life (AE-QoL) Questionnaire were added; A safety assessment parameter, 12-lead electrocardiogram (ECG), was added at Visit 16/Day 238 in the tables for “study activities schedules”; Efficacy evaluation period was updated to begin at Day 0 instead of Day 14; Description of primary endpoint was modified for assessment during the efficacy evaluation period rather than per week for consistency with the statistical model; Secondary endpoint was modified and removed from the rank order and was to be considered an exploratory endpoint; Description of the secondary endpoints was modified for assessment during efficacy evaluation period rather than per week to for consistency with the statistical model; Statistical methods were updated; Sample size determination was updated to be consistent with the updated statistical methods; A new section, Premature Closure of the Study, was added to include conditions that may warrant termination of the study or site; A new section, Data Handling Considerations, was added to include specifics regarding handling of data to prevent potential unblinding.
    09 Jan 2017
    An efficacy measure was added to rank ordered secondary efficacy endpoints for inclusion in the multiple testing procedure.

    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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