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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of Brodalumab in Subjects With Inadequately Controlled Asthma and High Bronchodilator Reversibility

    Summary
    EudraCT number
    		 2012-003351-11
    Trial protocol
    		 DE   IE   IT   GR   PL  
    Global end of trial date
    15 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 May 2016
    First version publication date
    27 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20120141
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01902290
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen, Inc
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info - Clinical Trials, Amgen (EUROPE) GmbH, MedinfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info - Clinical Trials, Amgen (EUROPE) GmbH, MedinfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 May 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of brodalumab compared with placebo as measured by the change in asthma control (based on the Asthma Control Questionnaire [ACQ]) from baseline at week 24 in subjects with inadequately controlled asthma and high reversibility despite standard of care.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations and guidelines, and other applicable regulations/guidelines. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 May 2013
    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
    Poland: 64
    Country: Number of subjects enrolled
    Germany: 24
    Country: Number of subjects enrolled
    Greece: 14
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Canada: 27
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Russian Federation: 50
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 2
    Country: Number of subjects enrolled
    United States: 212
    Worldwide total number of subjects
    421
    EEA total number of subjects
    130
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    382
    From 65 to 84 years
    39
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 157 centers in Asia, Australia, Canada, Europe, and the United States.

    Pre-assignment
    Screening details
    		 Eligible subjects completed 3 run-in visits over 4 weeks after all eligibility criteria were met. After completion of the run-in visits, subjects returned to the clinic for randomization and the baseline visit. Randomization was stratified based on the current use of long-acting β-agonist (LABA) and number of prior exacerbations in the past year.

    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
    		 Participants received placebo subcutaneous injections on day 1 and weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection

    Arm title
    		 Brodalumab 210 mg
    Arm description
    		 Participants received brodalumab 210 mg administered by subcutaneous injection on day 1 and weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brodalumab
    Investigational medicinal product code
    AMG 827
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Brodalumab 210 mg administered by subcutaneous injection

    Number of subjects in period 1
    		Placebo Brodalumab 210 mg
    Started
    210
    211
    Received treatment
    207
    208
    Completed
    162
    158
    Not completed
    48
    53
         Consent withdrawn by subject
    19
    27
         Death
    1
    -
         Lost to follow-up
    2
    2
         Decision by sponsor
    26
    24

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneous injections on day 1 and weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22.

    Reporting group title
    Brodalumab 210 mg
    Reporting group description
    		 Participants received brodalumab 210 mg administered by subcutaneous injection on day 1 and weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22.

    Reporting group values
    		 Placebo Brodalumab 210 mg Total
    Number of subjects
    		 210 211 421
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.2 ( 13.3 ) 47.2 ( 13.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 122 124 246
        Male
    		 88 87 175
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 10 13 23
        Black or African American
    		 30 20 50
        Multiple
    		 1 1 2
        Native Hawaiian or Other Pacific Islander
    		 1 1 2
        White
    		 164 176 340
        Other
    		 3 0 3
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 8 13 21
        Not Hispanic or Latino
    		 202 198 400
    Randomized Strata
    Units: Subjects
        LABA -No; ≤ 2 asthma exacerbation prior year
    		 32 37 69
        LABA -No; > 2 asthma exacerbation prior year
    		 0 1 1
        LABA -Yes; ≤ 2 asthma exacerbation prior year
    		 161 156 317
        LABA -Yes; > 2 asthma exacerbation prior year
    		 17 17 34
    Duration of Asthma
    Data were available for 210 subjects in each treatment group.
    Units: years
        arithmetic mean (standard deviation)
    		 22.14 ( 14.8 ) 23.05 ( 14.45 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneous injections on day 1 and weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22.

    Reporting group title
    Brodalumab 210 mg
    Reporting group description
    		 Participants received brodalumab 210 mg administered by subcutaneous injection on day 1 and weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22.

    Primary: Change From Baseline in the Asthma Control Questionnaire (ACQ) Composite Score at Week 24

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    End point title
    		 Change From Baseline in the Asthma Control Questionnaire (ACQ) Composite Score at Week 24
    End point description
    The ACQ is an instrument to evaluate asthma control/impairment. It is a validated composite score that assesses disease control by evaluating 7 questions: night time awakenings, asthma symptoms upon wakening, activity limitation, shortness of breath, wheeze frequency, short-acting bronchodilator use, and forced expiratory volume in 1 second (FEV1). The total score is the mean of the responses to the 7 questions, and ranges between 0 (totally-controlled) and 6 (extremely poorly controlled). The full analysis set consists of all randomized subjects who received at least 1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo Brodalumab 210 mg
    Number of subjects analysed
    147 [1]
    137 [2]
    Units: units on a scale
        least squares mean (standard error)
    -0.815 ( 0.073 )
    -0.865 ( 0.074 )
    Notes
    [1] - Participants in the full analysis set with available data
    [2] - Participants in the full analysis set with available data
    Statistical analysis title
    		 Analysis of ACQ Change From Baseline at Week 24
    Statistical analysis description
    Change in the ACQ score from baseline at week 24 was tested for treatment effect (brodalumab versus placebo) using a mixed effects model with repeated measures at the significance level of 0.05 (2-sided).
    Comparison groups
    Placebo v Brodalumab 210 mg
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5219 [3]
    Method
    		 Mixed-effect model
    Parameter type
    		 Difference from placebo
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.203
         upper limit
    		 0.103
    Notes
    [3] - The model included treatment group, study week as a categorical variable, stratification factors, interaction of treatment group by week and baseline ACQ with random intercept, assuming first-order autoregressive covariance structure.

    Secondary: Asthma Exacerbation Rate From Baseline to Week 24

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    End point title
    		 Asthma Exacerbation Rate From Baseline to Week 24
    End point description
    The asthma exacerbation event rate is defined as the number of events per subject year during the 24 week treatment period. An asthma exacerbation was defined as an asthma worsening that requires systemic corticosteroids for at least 3 days during the study; distinct asthma exacerbations were defined as events with start dates more than 10 days apart from each other.
    End point type
    Secondary
    End point timeframe
    Baseline to week 24
    End point values
    		 Placebo Brodalumab 210 mg
    Number of subjects analysed
    204 [4]
    205 [5]
    Units: exacerbations per subject year
        number (not applicable)
    0.57
    0.81
    Notes
    [4] - Full analysis set
    [5] - Full analysis set
    Statistical analysis title
    		 Analysis of Asthma Exacerbation Rate
    Comparison groups
    Brodalumab 210 mg v Placebo
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.102 [6]
    Method
    		 Generalized Linear Model
    Parameter type
    		 Rate ratio
    Point estimate
    1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 2.12
    Notes
    [6] - P-value was from a generalized linear model under a negative binomial distribution assumption adjusting for stratification factors.

    Secondary: Change From Baseline in the ACQ Composite Score at Week 24 in the LABA Strata

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    End point title
    		 Change From Baseline in the ACQ Composite Score at Week 24 in the LABA Strata
    End point description
    The ACQ is an instrument to evaluate asthma control/impairment. It is a validated composite score that assesses disease control by evaluating 7 questions: night time awakenings, asthma symptoms upon wakening, activity limitation, shortness of breath, wheeze frequency, short-acting bronchodilator use, and FEV1. The total score is the mean of the responses to the 7 questions, and ranges between 0 (totally-controlled) and 6 (extremely poorly controlled).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo Brodalumab 210 mg
    Number of subjects analysed
    121 [7]
    108 [8]
    Units: units on a scale
        least squares mean (standard error)
    -0.793 ( 0.084 )
    -0.831 ( 0.088 )
    Notes
    [7] - Participants in the full analysis set in the LABA strata with available data
    [8] - Participants in the full analysis set in the LABA strata with available data
    Statistical analysis title
    		 Analysis of ACQ in LABA Strata
    Comparison groups
    Placebo v Brodalumab 210 mg
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6632 [9]
    Method
    		 Mixed effect model
    Parameter type
    		 Difference from placebo
    Point estimate
    -0.038
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 0.134
    Notes
    [9] - The model includes treatment group, study week as a categorical variable, stratification factors, interaction of treatment group by week and baseline ACQ with random intercept assuming first-order autoregressive covariance structure.

    Secondary: Asthma Exacerbation Rate From Baseline to Week 24 in LABA Strata

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    End point title
    		 Asthma Exacerbation Rate From Baseline to Week 24 in LABA Strata
    End point description
    The asthma exacerbation event rate is defined as the number of events per subject year during the 24 week treatment period. An asthma exacerbation was defined as an asthma worsening that requires systemic corticosteroids for at least 3 days during the study; distinct asthma exacerbations were defined as events with start dates more than 10 days apart from each other.
    End point type
    Secondary
    End point timeframe
    From baseline to week 24
    End point values
    		 Placebo Brodalumab 210 mg
    Number of subjects analysed
    174 [10]
    167 [11]
    Units: exacerbations per subject year
        number (not applicable)
    0.6
    0.89
    Notes
    [10] - Participants in the full analysis set in the LABA strata with available data
    [11] - Participants in the full analysis set in the LABA strata with available data
    Statistical analysis title
    		 Analysis of Exacerbation Rate in LABA Strata
    Comparison groups
    Placebo v Brodalumab 210 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.096 [12]
    Method
    		 Generalized Linear Model
    Parameter type
    		 Rate ratio
    Point estimate
    1.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 2.24
    Notes
    [12] - P-value was from a generalized linear model under a negative binomial distribution assumption adjusting for stratification factors.

    Secondary: Change From Baseline in Daily Asthma Symptoms Score at Week 24

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    End point title
    		 Change From Baseline in Daily Asthma Symptoms Score at Week 24
    End point description
    The Asthma Symptom Diary is comprised of 23 questions answered on a hand held device. There are 10 items completed in the Morning and 13 items completed in the evening. Subjects were asked to rate the severity of their symptoms, activity limitations and nighttime awakening due to symptoms and use of rescue medication and nebulizer each day. Five symptom related items in the morning and five symptom related items in the evening are used to compute a daily asthma symptom score that is aggregated over days to compute a 7 day average asthma symptom score. The range of the score is 0 to 4.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo Brodalumab 210 mg
    Number of subjects analysed
    121 [13]
    117 [14]
    Units: units on a scale
        least squares mean (standard error)
    -0.397 ( 0.042 )
    -0.443 ( 0.043 )
    Notes
    [13] - Full analysis set with available data
    [14] - Full analysis set with available data
    Statistical analysis title
    		 Analysis of Daily Asthma Symptom Score
    Comparison groups
    Placebo v Brodalumab 210 mg
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.329 [15]
    Method
    		 Mixed effect model
    Parameter type
    		 Difference from placebo
    Point estimate
    -0.046
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.137
         upper limit
    		 0.046
    Notes
    [15] - Includes treatment group, study week as a categorical variable, stratification factors, interaction of treatment group by week and baseline daily asthma symptom score with random intercept, assuming first-order autoregressive covariance structure.

    Secondary: Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 24

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    End point title
    		 Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo Brodalumab 210 mg
    Number of subjects analysed
    148 [16]
    137 [17]
    Units: L/sec
        least squares mean (standard error)
    0.207 ( 0.045 )
    0.237 ( 0.046 )
    Notes
    [16] - Full analysis set with available data
    [17] - Full analysis set with available data
    Statistical analysis title
    		 Analysis of Pre-bronchodilator FEV1
    Comparison groups
    Placebo v Brodalumab 210 mg
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4549 [18]
    Method
    		 Mixed effect model
    Parameter type
    		 Difference from placebo
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.049
         upper limit
    		 0.109
    Notes
    [18] - Includes treatment group, study week as categorical variable, stratification factors, interaction of treatment group by week and baseline age, gender, pooled race, height & pre-FEV1 with random intercept assuming first-order autoregressive structure.

    Secondary: Change From Baseline in Daily Rescue Short-acting Beta-agonist Use at Week 24

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    End point title
    		 Change From Baseline in Daily Rescue Short-acting Beta-agonist Use at Week 24
    End point description
    Participants recorded daily rescue short-acting beta-agonist (SABA) use in the asthma symptom diary. The daily rescue medication score was assigned based on daytime and night time rescue beta agonist use (rescue inhaler and nebulizer). Each use of the nebulizer was counted as 4 puffs.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo Brodalumab 210 mg
    Number of subjects analysed
    121 [19]
    117 [20]
    Units: units on a scale
        least squares mean (standard error)
    -1.359 ( 0.243 )
    -1.231 ( 0.246 )
    Notes
    [19] - Full analysis set with available data
    [20] - Full analysis set with available data
    Statistical analysis title
    		 Analysis of Rescue Short-acting β-agonist Use
    Comparison groups
    Placebo v Brodalumab 210 mg
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6317 [21]
    Method
    		 Mixed effect model
    Parameter type
    		 Difference from placebo
    Point estimate
    0.128
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.396
         upper limit
    		 0.653
    Notes
    [21] - Includes treatment group, study week as categorical variable, stratification factors, interaction of treatment group by week and baseline daily rescue SABA use with random intercept assuming first-order autoregressive covariance structure.

    Secondary: Time to First Asthma Exacerbation

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    End point title
    		 Time to First Asthma Exacerbation
    End point description
    An asthma exacerbation is defined as an asthma worsening that requires systemic corticosteroids for at least 3 days during the study. Median time to first asthma exacerbation could not be estimated, the percentage of participants with an asthma exacerbation is reported.
    End point type
    Secondary
    End point timeframe
    Baseline to week 24
    End point values
    		 Placebo Brodalumab 210 mg
    Number of subjects analysed
    204 [22]
    205 [23]
    Units: percentage of participants
        number (not applicable)
    20.1
    23.9
    Notes
    [22] - Full analysis set
    [23] - Full analysis set
    Statistical analysis title
    		 Analysis of Time to First Asthma Exacerbation
    Comparison groups
    Placebo v Brodalumab 210 mg
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.238 [24]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.277
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.843
         upper limit
    		 1.936
    Notes
    [24] - Log rank test stratified for baseline stratification factors.

    Secondary: Number of Participants with Asthma Exacerbations From Baseline to Week 24

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    End point title
    		 Number of Participants with Asthma Exacerbations From Baseline to Week 24
    End point description
    An asthma exacerbation is defined as an asthma worsening that requires systemic corticosteroids for at least 3 days during the study.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo Brodalumab 210 mg
    Number of subjects analysed
    204 [25]
    205 [26]
    Units: participants
    41
    49
    Notes
    [25] - Full analysis set
    [26] - Full analysis set
    Statistical analysis title
    		 Analysis of Asthma Exacerbations
    Comparison groups
    Placebo v Brodalumab 210 mg
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.351 [27]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 2.01
    Notes
    [27] - Testing of treatment effect in logistic regression and adjusted for stratification factors.

    Secondary: Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) Overall Score at Week 24

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    End point title
    		 Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) Overall Score at Week 24
    End point description
    The AQLQ is an asthma-specific instrument and includes evaluations of both symptom and quality of life measures. The 32-item instrument measures 4 domains affected by asthma including activity limitations, emotional function, exposure to environmental stimuli, and symptoms. Patients are asked to recall their experiences during the last 2 weeks and to respond to each question on a 7-point scale (7=no impairment, 1=severe impairment). The overall score was calculated as the mean of the responses to the 32 questions.
    End point type
    Secondary
    End point timeframe
    Baseline and week 24
    End point values
    		 Placebo Brodalumab 210 mg
    Number of subjects analysed
    147 [28]
    137 [29]
    Units: units on a scale
        least squares mean (standard error)
    0.804 ( 0.085 )
    0.803 ( 0.087 )
    Notes
    [28] - Full analysis set with available data
    [29] - Full analysis set with available data
    Statistical analysis title
    		 Analysis of AQLQ Overall Score
    Comparison groups
    Placebo v Brodalumab 210 mg
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.987 [30]
    Method
    		 Mixed effect model
    Parameter type
    		 Difference from placebo
    Point estimate
    -0.001
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.174
         upper limit
    		 0.171
    Notes
    [30] - The model includes treatment group, study week as a categorical variable, stratification factors, interaction of treatment group by week and baseline AQLQ with random intercept assuming first-order autoregressive covariance structure.

    Secondary: Change From Baseline in Peak Expiratory Flow Rate (PEFR) at Week 24

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    End point title
    		 Change From Baseline in Peak Expiratory Flow Rate (PEFR) at Week 24
    End point description
    PEFR was measured by the participant twice daily at approximately the same time each day, once in the morning and once in the evening.
    End point type
    Secondary
    End point timeframe
    Baseline and week 24
    End point values
    		 Placebo Brodalumab 210 mg
    Number of subjects analysed
    146 [31]
    129 [32]
    Units: L/min
    least squares mean (standard error)
        Morning peak flow
    0.072 ( 5.813 )
    0.706 ( 5.885 )
        Evening peak flow
    -10.008 ( 5.719 )
    -4.089 ( 5.771 )
    Notes
    [31] - Full analysis set with available data = 146 for morning and 135 for evening data
    [32] - Full analysis set with available data
    Statistical analysis title
    		 Analysis of Morning Peak Flow
    Comparison groups
    Placebo v Brodalumab 210 mg
    Number of subjects included in analysis
    275
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9053 [33]
    Method
    		 Mixed effect model
    Parameter type
    		 Difference from placebo
    Point estimate
    0.635
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.82
         upper limit
    		 11.089
    Notes
    [33] - Includes treatment group, study week, stratification factors, interaction of treatment group by week and baseline age, gender, pooled race, height, am peak flow with random intercept assuming first-order autoregressive covariance structure.
    Statistical analysis title
    		 Analysis of Evening Peak Flow
    Comparison groups
    Placebo v Brodalumab 210 mg
    Number of subjects included in analysis
    275
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2661 [34]
    Method
    		 Mixed effect model
    Parameter type
    		 Difference from placebo
    Point estimate
    5.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.515
         upper limit
    		 16.354
    Notes
    [34] - Includes treatment group, study week, stratification factors, interaction of treatment group by week and baseline age, gender, pooled race, height, am peak flow with random intercept assuming first-order autoregressive covariance structure.

    Secondary: Change From Baseline in PEFR Variation at Week 24

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    End point title
    		 Change From Baseline in PEFR Variation at Week 24
    End point description
    The variation of peak flow is defined as the absolute value of the difference between the A.M. and P.M. peak flow in one day for an individual patient.
    End point type
    Secondary
    End point timeframe
    Baseline and week 24
    End point values
    		 Placebo Brodalumab 210 mg
    Number of subjects analysed
    121 [35]
    115 [36]
    Units: L/min
        least squares mean (standard error)
    -0.872 ( 2.135 )
    -4.892 ( 2.169 )
    Notes
    [35] - Full analysis set with available data
    [36] - Full analysis set with available data
    Statistical analysis title
    		 Analysis of Variation of Peak Flow
    Comparison groups
    Placebo v Brodalumab 210 mg
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0871 [37]
    Method
    		 Mixed effect model
    Parameter type
    		 Difference from placebo
    Point estimate
    -4.021
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.627
         upper limit
    		 0.586
    Notes
    [37] - Includes treatment group, study week, stratification factors, interaction of treatment group by week and baseline age, gender, pooled race, height & variation of peak flow with random intercept assuming first-order autoregressive covariance structure

    Secondary: Proportion of Asthma Symptom-Free Days in 4-Weeks Intervals

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    End point title
    		 Proportion of Asthma Symptom-Free Days in 4-Weeks Intervals
    End point description
    The number of asthma symptom-free days was derived from the asthma symptom diary, and defined as days that a patient has a score of zero in their daily asthma symptom diary score. Proportion of asthma symptom-free days is calculated from the number of days the subject completed the diary in the corresponding 4-week interval during the treatment period.
    End point type
    Secondary
    End point timeframe
    4-week intervals from baseline to week 24
    End point values
    		 Placebo Brodalumab 210 mg
    Number of subjects analysed
    204 [38]
    205 [39]
    Units: proportion of days
    least squares mean (standard error)
        Week 4 (n = 204, 203)
    0.111 ( 0.021 )
    0.09 ( 0.021 )
        Week 8 (n = 193, 192)
    0.153 ( 0.029 )
    0.138 ( 0.029 )
        Week 12 (n = 185, 184)
    0.168 ( 0.032 )
    0.166 ( 0.032 )
        Week 16 (n = 176, 174)
    0.194 ( 0.036 )
    0.201 ( 0.036 )
        Week 20 (n = 167, 162)
    0.207 ( 0.038 )
    0.211 ( 0.039 )
        Week 24 (n = 160, 153)
    0.223 ( 0.04 )
    0.214 ( 0.04 )
    Notes
    [38] - Full analysis set
    [39] - Full analysis set
    Statistical analysis title
    		 Analysis of Asthma Symptom-free Days at Week 4
    Comparison groups
    Brodalumab 210 mg v Placebo
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2765 [40]
    Method
    		 ANCOVA
    Parameter type
    		 Difference from placebo
    Point estimate
    -0.021
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.059
         upper limit
    		 0.017
    Notes
    [40] - Testing of treatment effect in analysis of covariance test and adjusted for baseline daily asthma symptom score and stratification factors
    Statistical analysis title
    		 Analysis of Asthma Symptom-free Days at Week 8
    Comparison groups
    Placebo v Brodalumab 210 mg
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5805 [41]
    Method
    		 ANCOVA
    Parameter type
    		 Difference from placebo
    Point estimate
    -0.015
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.067
         upper limit
    		 0.037
    Notes
    [41] - Testing of treatment effect in analysis of covariance test and adjusted for baseline daily asthma symptom score and stratification factors
    Statistical analysis title
    		 Analysis of Asthma Symptom-free Days at Week 12
    Comparison groups
    Placebo v Brodalumab 210 mg
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9466 [42]
    Method
    		 ANCOVA
    Parameter type
    		 Difference from placebo
    Point estimate
    -0.002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.056
    Notes
    [42] - Testing of treatment effect in analysis of covariance test and adjusted for baseline daily asthma symptom score and stratification factors
    Statistical analysis title
    		 Analysis of Asthma Symptom-free Days at Week 16
    Comparison groups
    Placebo v Brodalumab 210 mg
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8179 [43]
    Method
    		 ANCOVA
    Parameter type
    		 Difference from placebo
    Point estimate
    0.008
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.057
         upper limit
    		 0.072
    Notes
    [43] - Testing of treatment effect in analysis of covariance test and adjusted for baseline daily asthma symptom score and stratification factors
    Statistical analysis title
    		 Analysis of Asthma Symptom-free Days at Week 20
    Comparison groups
    Placebo v Brodalumab 210 mg
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9139 [44]
    Method
    		 ANCOVA
    Parameter type
    		 Difference from placebo
    Point estimate
    0.004
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.066
         upper limit
    		 0.073
    Notes
    [44] - Testing of treatment effect in analysis of covariance test and adjusted for baseline daily asthma symptom score and stratification factors
    Statistical analysis title
    		 Analysis of Asthma Symptom-free Days at Week 24
    Comparison groups
    Placebo v Brodalumab 210 mg
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8316 [45]
    Method
    		 ANCOVA
    Parameter type
    		 Difference from placebo
    Point estimate
    -0.008
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.083
         upper limit
    		 0.067
    Notes
    [45] - Testing of treatment effect in analysis of covariance test and adjusted for baseline daily asthma symptom score and stratification factors

    Secondary: Serum Brodalumab Concentration

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    End point title
    		 Serum Brodalumab Concentration [46]
    End point description
    Serum brodalumab concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) = 0.0500 µg/mL; values below the LLOQ were set to zero.
    End point type
    Secondary
    End point timeframe
    Day 1 to week 22, day 14
    Notes
    [46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Brodalumab concentration was only measured in subjects in the Brodalumab treatment group.
    End point values
    		 Brodalumab 210 mg
    Number of subjects analysed
    196
    Units: µg/mL
    arithmetic mean (standard deviation)
        Day 1 predose (n = 196)
    0 ( 0 )
        Week 1 predose (n = 196)
    8.48 ( 5.55 )
        Week 2 predose (n = 178)
    16.8 ( 9.85 )
        Week 2 day 3 (n = 50)
    24.9 ( 15.8 )
        Week 4 predose (n = 174)
    14.5 ( 9.28 )
        Week 8 predose (n = 174)
    11.1 ( 9.03 )
        Week 12 predose (n = 161)
    10.6 ( 9.86 )
        Week 16 predose (n = 150)
    8.93 ( 9.06 )
        Wee 22 predose (n = 136)
    8.94 ( 9.32 )
        Week 22 day 3 (n = 46)
    18 ( 15.4 )
        Week 22 day 7 (n = 46)
    14.8 ( 13.3 )
        Week 22 day 10 (n = 43)
    12.5 ( 12.2 )
        Week 22 day 14 (n = 146)
    9.06 ( 9.78 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug until 30 days after last dose; median duration of treatment was 155 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneous injections on day 1 and weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22.

    Reporting group title
    Brodalumab 210 mg
    Reporting group description
    		 Participants received brodalumab 210 mg administered by subcutaneous injection on day 1 and weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22.

    Serious adverse events
    		 Placebo Brodalumab 210 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 207 (3.86%)
    7 / 208 (3.37%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bile duct adenocarcinoma
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Pneumothorax traumatic
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Microcytic anaemia
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status asthmaticus
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal behaviour
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo Brodalumab 210 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    132 / 207 (63.77%)
    156 / 208 (75.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm skin
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Flushing
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Hot flush
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 208 (0.48%)
         occurrences all number
    1
    1
    Haemorrhage
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    4 / 207 (1.93%)
    0 / 208 (0.00%)
         occurrences all number
    4
    0
    Pallor
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Thrombophlebitis
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Asthma prophylaxis
         subjects affected / exposed
    2 / 207 (0.97%)
    1 / 208 (0.48%)
         occurrences all number
    2
    1
    Endodontic procedure
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Mammoplasty
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 208 (0.96%)
         occurrences all number
    1
    2
    Application site pain
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    6
    0
    Chest discomfort
         subjects affected / exposed
    0 / 207 (0.00%)
    3 / 208 (1.44%)
         occurrences all number
    0
    3
    Fatigue
         subjects affected / exposed
    5 / 207 (2.42%)
    2 / 208 (0.96%)
         occurrences all number
    7
    2
    Induration
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Influenza like illness
         subjects affected / exposed
    2 / 207 (0.97%)
    3 / 208 (1.44%)
         occurrences all number
    2
    5
    Injection site bruising
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    3
    Injection site erythema
         subjects affected / exposed
    3 / 207 (1.45%)
    6 / 208 (2.88%)
         occurrences all number
    13
    16
    Injection site haemorrhage
         subjects affected / exposed
    2 / 207 (0.97%)
    1 / 208 (0.48%)
         occurrences all number
    3
    1
    Injection site induration
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    3
    Injection site nodule
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    2
    Injection site pain
         subjects affected / exposed
    1 / 207 (0.48%)
    4 / 208 (1.92%)
         occurrences all number
    12
    16
    Injection site paraesthesia
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    2
    Injection site pruritus
         subjects affected / exposed
    0 / 207 (0.00%)
    4 / 208 (1.92%)
         occurrences all number
    0
    5
    Injection site swelling
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    2
    Injection site urticaria
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 208 (0.96%)
         occurrences all number
    7
    5
    Malaise
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    2 / 207 (0.97%)
    1 / 208 (0.48%)
         occurrences all number
    2
    1
    Immune system disorders
    Food allergy
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Hypersensitivity
         subjects affected / exposed
    0 / 207 (0.00%)
    4 / 208 (1.92%)
         occurrences all number
    0
    5
    Seasonal allergy
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 208 (0.00%)
         occurrences all number
    2
    0
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Breast mass
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Menorrhagia
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Menstrual disorder
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Oedema genital
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    63 / 207 (30.43%)
    72 / 208 (34.62%)
         occurrences all number
    88
    108
    Bronchospasm
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    6 / 207 (2.90%)
    11 / 208 (5.29%)
         occurrences all number
    7
    11
    Dry throat
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Dyspnoea
         subjects affected / exposed
    3 / 207 (1.45%)
    7 / 208 (3.37%)
         occurrences all number
    3
    7
    Epistaxis
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Nasal congestion
         subjects affected / exposed
    3 / 207 (1.45%)
    3 / 208 (1.44%)
         occurrences all number
    4
    3
    Nasal polyps
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 207 (1.45%)
    1 / 208 (0.48%)
         occurrences all number
    3
    1
    Productive cough
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Respiratory tract congestion
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    2
    Rhinitis allergic
         subjects affected / exposed
    5 / 207 (2.42%)
    3 / 208 (1.44%)
         occurrences all number
    6
    3
    Rhinorrhoea
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Sinus congestion
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Throat irritation
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Wheezing
         subjects affected / exposed
    1 / 207 (0.48%)
    8 / 208 (3.85%)
         occurrences all number
    2
    9
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 207 (0.97%)
    1 / 208 (0.48%)
         occurrences all number
    2
    2
    Apathy
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Confusional state
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Depression
         subjects affected / exposed
    3 / 207 (1.45%)
    3 / 208 (1.44%)
         occurrences all number
    3
    3
    Insomnia
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 208 (0.96%)
         occurrences all number
    1
    2
    Mood swings
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Somnambulism
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Investigations
    Bilirubin conjugated increased
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Platelet count decreased
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 208 (0.48%)
         occurrences all number
    1
    1
    White blood cells urine positive
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Animal scratch
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Back injury
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Arthropod sting
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    2
    Chest injury
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Ear canal injury
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Face injury
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 208 (0.00%)
         occurrences all number
    2
    0
    Facial bones fracture
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Foot fracture
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 208 (0.48%)
         occurrences all number
    1
    1
    Hand fracture
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Laceration
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    2
    Joint dislocation
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    2
    Ligament sprain
         subjects affected / exposed
    3 / 207 (1.45%)
    1 / 208 (0.48%)
         occurrences all number
    3
    1
    Meniscus injury
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Muscle strain
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Procedural pain
         subjects affected / exposed
    3 / 207 (1.45%)
    0 / 208 (0.00%)
         occurrences all number
    4
    0
    Rib fracture
         subjects affected / exposed
    2 / 207 (0.97%)
    1 / 208 (0.48%)
         occurrences all number
    2
    1
    Skeletal injury
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Scratch
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Skin abrasion
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Upper limb fracture
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Aphonia
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Burning sensation
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    2
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Cervical radiculopathy
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 208 (0.96%)
         occurrences all number
    1
    3
    Dysgeusia
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    11 / 207 (5.31%)
    8 / 208 (3.85%)
         occurrences all number
    12
    13
    Hypersomnia
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Lethargy
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 208 (0.48%)
         occurrences all number
    1
    1
    Migraine
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 208 (0.00%)
         occurrences all number
    3
    0
    Nerve compression
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Peroneal nerve palsy
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Presyncope
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Radiculitis lumbosacral
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Sciatica
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 208 (0.48%)
         occurrences all number
    1
    1
    Sinus headache
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Lymphopenia
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Neutropenia
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    2
    Neutrophilia
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Middle ear effusion
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Vertigo
         subjects affected / exposed
    1 / 207 (0.48%)
    3 / 208 (1.44%)
         occurrences all number
    1
    4
    Tinnitus
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 208 (0.96%)
         occurrences all number
    1
    2
    Chalazion
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Macular oedema
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Vision blurred
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Abdominal discomfort
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Abdominal pain lower
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 208 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    8
    Dry mouth
         subjects affected / exposed
    3 / 207 (1.45%)
    0 / 208 (0.00%)
         occurrences all number
    4
    0
    Diarrhoea
         subjects affected / exposed
    4 / 207 (1.93%)
    4 / 208 (1.92%)
         occurrences all number
    4
    16
    Gastritis
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 208 (0.96%)
         occurrences all number
    1
    2
    Gingival pain
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Inguinal hernia
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    3 / 207 (1.45%)
    6 / 208 (2.88%)
         occurrences all number
    7
    7
    Loose tooth
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Oedema mouth
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Pancreatitis
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    3
    0
    Stomatitis
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Salivary gland enlargement
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    3 / 207 (1.45%)
    2 / 208 (0.96%)
         occurrences all number
    4
    2
    Toothache
         subjects affected / exposed
    3 / 207 (1.45%)
    0 / 208 (0.00%)
         occurrences all number
    3
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    2
    Acne
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Dermatitis contact
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Dermatitis atopic
         subjects affected / exposed
    1 / 207 (0.48%)
    3 / 208 (1.44%)
         occurrences all number
    1
    3
    Erythema
         subjects affected / exposed
    2 / 207 (0.97%)
    4 / 208 (1.92%)
         occurrences all number
    2
    6
    Eczema
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 208 (0.48%)
         occurrences all number
    1
    1
    Pruritus
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 208 (0.96%)
         occurrences all number
    2
    3
    Papule
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Pruritus generalised
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 208 (0.48%)
         occurrences all number
    1
    1
    Rash pruritic
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    0 / 207 (0.00%)
    4 / 208 (1.92%)
         occurrences all number
    0
    6
    Rash vesicular
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Swelling face
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 208 (0.48%)
         occurrences all number
    1
    1
    Urticaria
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 208 (0.48%)
         occurrences all number
    1
    1
    Transient acantholytic dermatosis
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Urticaria papular
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Nephrolithiasis
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 207 (0.97%)
    8 / 208 (3.85%)
         occurrences all number
    2
    10
    Back pain
         subjects affected / exposed
    5 / 207 (2.42%)
    6 / 208 (2.88%)
         occurrences all number
    5
    7
    Muscle spasms
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    2
    Muscular weakness
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 208 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal disorder
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 208 (0.96%)
         occurrences all number
    1
    2
    Myalgia
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    2
    Neck pain
         subjects affected / exposed
    3 / 207 (1.45%)
    0 / 208 (0.00%)
         occurrences all number
    4
    0
    Pain in extremity
         subjects affected / exposed
    0 / 207 (0.00%)
    4 / 208 (1.92%)
         occurrences all number
    0
    4
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    2
    Senile ankylosing vertebral hyperostosis
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Synovial cyst
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Tendonitis
         subjects affected / exposed
    2 / 207 (0.97%)
    1 / 208 (0.48%)
         occurrences all number
    2
    1
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    3 / 207 (1.45%)
    1 / 208 (0.48%)
         occurrences all number
    3
    1
    Bronchitis
         subjects affected / exposed
    14 / 207 (6.76%)
    13 / 208 (6.25%)
         occurrences all number
    16
    14
    Bronchitis bacterial
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    2
    Candida infection
         subjects affected / exposed
    0 / 207 (0.00%)
    3 / 208 (1.44%)
         occurrences all number
    0
    4
    Cellulitis
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 207 (0.48%)
    3 / 208 (1.44%)
         occurrences all number
    1
    3
    Diverticulitis
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Ear infection
         subjects affected / exposed
    2 / 207 (0.97%)
    1 / 208 (0.48%)
         occurrences all number
    2
    1
    Folliculitis
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    2
    Gastroenteritis viral
         subjects affected / exposed
    1 / 207 (0.48%)
    3 / 208 (1.44%)
         occurrences all number
    1
    3
    Genital herpes
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Genital infection fungal
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Gingivitis
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Hordeolum
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Incision site abscess
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    1 / 207 (0.48%)
    8 / 208 (3.85%)
         occurrences all number
    1
    8
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 207 (1.45%)
    1 / 208 (0.48%)
         occurrences all number
    3
    1
    Lung infection
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    19 / 207 (9.18%)
    24 / 208 (11.54%)
         occurrences all number
    22
    29
    Oral candidiasis
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Oral herpes
         subjects affected / exposed
    1 / 207 (0.48%)
    3 / 208 (1.44%)
         occurrences all number
    1
    3
    Otitis externa
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    4 / 207 (1.93%)
    3 / 208 (1.44%)
         occurrences all number
    4
    3
    Pharyngitis streptococcal
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 208 (0.00%)
         occurrences all number
    2
    0
    Pneumonia
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Post procedural infection
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    2
    Respiratory tract infection viral
         subjects affected / exposed
    2 / 207 (0.97%)
    1 / 208 (0.48%)
         occurrences all number
    2
    1
    Rhinitis
         subjects affected / exposed
    2 / 207 (0.97%)
    3 / 208 (1.44%)
         occurrences all number
    2
    3
    Sinusitis
         subjects affected / exposed
    10 / 207 (4.83%)
    5 / 208 (2.40%)
         occurrences all number
    11
    5
    Tonsillitis
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    2
    Tonsillitis bacterial
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Tooth abscess
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 208 (0.48%)
         occurrences all number
    1
    1
    Tooth infection
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 208 (0.96%)
         occurrences all number
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    19 / 207 (9.18%)
    24 / 208 (11.54%)
         occurrences all number
    21
    25
    Urinary tract infection
         subjects affected / exposed
    2 / 207 (0.97%)
    3 / 208 (1.44%)
         occurrences all number
    2
    4
    Viral infection
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 208 (0.00%)
         occurrences all number
    2
    0
    Viral pharyngitis
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    6 / 207 (2.90%)
    4 / 208 (1.92%)
         occurrences all number
    6
    4
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Gout
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    1
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 208 (0.48%)
         occurrences all number
    1
    1
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Oct 2012
    Major changes included: - Corrected an error in the list of proscribed medications in Section 6. - Section 8.1 was amended to remove reasons for removal of a subject from the study (investigator decision, withdrawal of partial consent, pregnancy, ineligibility, protocol deviations, noncompliance, and > 3 asthma exacerbations); 2 of these items (pregnancy and > 3 asthma exacerbations) were added to the reasons for a subject to stop investigational product (IP), but remain in the study.
    04 Dec 2013
    - Consistent with the intent of the protocol and rest of the brodalumab program, a follow-up assessment was added to collect safety information 4 weeks after the last dose of IP for those subjects who were terminated early from the study.
    26 Mar 2014
    - Based on the identification of suicidal behavior and suicidal ideation as a potential risk and after discussion with regulatory agencies, the Columbia Suicide Severity Rating Scale and the Patient Health Questionnaire depression scale were added as instruments to assess eligibility and monitor subject safety (ie, stopping rules). - Other minor editorial corrections and clarifications were made.
    03 Oct 2014
    - Included details about interim analysis

    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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