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    Clinical Trial Results:
    A Phase 2a, Double-blind, Placebo-controlled Study to Evaluate the Efficacy of MEDI-563 in Subjects with Moderate-to-severe Chronic Obstructive Pulmonary Disease and Sputum Eosinophilia

    Summary
    EudraCT number
    		 2010-020127-52
    Trial protocol
    		 GB   ES   DE   DK  
    Global end of trial date
    11 Jul 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Oct 2016
    First version publication date
    20 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MI-CP196
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01227278
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    MedImmune, LLC.
    Sponsor organisation address
    Milstein Building, Granta Park, Cambridge, CB21 6GH, United Kingdom,
    Public contact
    Rene van der Merwe, MBChB/Senior Director, Clinical Development, MedImmune, LLC., +1 3013980000, vandermerwer@medimmune.com
    Scientific contact
    Rene van der Merwe, MBChB/Senior Director, Clinical Development, MedImmune, LLC., +1 3013980000, vandermerwer@medimmune.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
    11 Jul 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the effect of multiple subcutaneous (SC) doses of benralizumab on the rate of moderate or severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in adult participants with moderate-to severe chronic obstructive pulmonary disease (COPD) who exhibited eosinophilia [greater than or equal to 9 (>=) 3.0 percent (%) sputum eosinophilia in the previous 12 months or at screening] in sputum compared to placebo.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Participating participant signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Nov 2010
    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
    United Kingdom: 13
    Country: Number of subjects enrolled
    Poland: 29
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Canada: 14
    Country: Number of subjects enrolled
    United States: 22
    Country: Number of subjects enrolled
    Denmark: 8
    Country: Number of subjects enrolled
    Spain: 7
    Worldwide total number of subjects
    101
    EEA total number of subjects
    65
    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)
    55
    From 65 to 84 years
    45
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 421 participants were screened and 101 participants were randomized into the study.

    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 reecieved placebo matched to benralizumab (MEDI-563) injection subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks for the next 5 doses (Day 1, 29, 57, 113, 169, 225, 281 and 337).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to benralizumab (MEDI-563) injection subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks for the next 5 doses (Day 1, 29, 57, 113, 169, 225, 281 and 337).

    Arm title
    		 Benralizumab 100 mg
    Arm description
    		 Particpants received Benralizumab (MEDI-563) 100 milligram (mg) injection subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks for the next 5 doses (Day 1, 29, 57, 113, 169, 225, 281 and 337).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Benralizumab
    Investigational medicinal product code
    MEDI-563
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Benralizumab (MEDI-563) 100 mg injection subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks for the next 5 doses (Day 1, 29, 57, 113, 169, 225, 281 and 337).

    Number of subjects in period 1
    		Placebo Benralizumab 100 mg
    Started
    50
    51
    Completed
    45
    43
    Not completed
    5
    8
         Adverse event, serious fatal
    -
    2
         Consent withdrawn by subject
    4
    4
         Unspecified
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants reecieved placebo matched to benralizumab (MEDI-563) injection subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks for the next 5 doses (Day 1, 29, 57, 113, 169, 225, 281 and 337).

    Reporting group title
    Benralizumab 100 mg
    Reporting group description
    		 Particpants received Benralizumab (MEDI-563) 100 milligram (mg) injection subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks for the next 5 doses (Day 1, 29, 57, 113, 169, 225, 281 and 337).

    Reporting group values
    		 Placebo Benralizumab 100 mg Total
    Number of subjects
    		 50 51 101
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 25 30 55
        Elderly (From 65-84 years)
    		 24 21 45
        Elderly 85 years and over
    		 1 0 1
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    		 64.6 ( 7.5 ) 62.9 ( 8.2 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 21 16 37
        Male
    		 29 35 64

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants reecieved placebo matched to benralizumab (MEDI-563) injection subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks for the next 5 doses (Day 1, 29, 57, 113, 169, 225, 281 and 337).

    Reporting group title
    Benralizumab 100 mg
    Reporting group description
    		 Particpants received Benralizumab (MEDI-563) 100 milligram (mg) injection subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks for the next 5 doses (Day 1, 29, 57, 113, 169, 225, 281 and 337).

    Primary: Annualized Incidence Rate of Moderate or Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD)

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    End point title
    		 Annualized Incidence Rate of Moderate or Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD)
    End point description
    An AECOPD is defined as worsening of two or more major symptoms or one major and one minor symptom for two or more consecutive days. Annualized Incidence Rate of Moderate or Severe AECOPD was assessed based on AECOPD data up to Day 393 (Rate = total number of moderate or severe AECOPD in each group/total person-year follow-up in each group). The severity of an exacerbation of COPD is defined as: a) Mild exacerbations, which require treatment with an increase in usual therapy, example, increase use of short acting bronchodilators, b) Moderate exacerbations which require treatment with systemic corticosteroids, and or antibiotics and c) Severe exacerbations which require hospitalization. The per protocol (PP) population included all participants who had no major protocol violations, received at least 6 of the 8 total doses of investigational product, and completed the study through Day 393.
    End point type
    Primary
    End point timeframe
    Day 1 up to 393
    End point values
    		 Placebo Benralizumab 100 mg
    Number of subjects analysed
    42
    40
    Units: AECOPD events/person-year
        number (confidence interval 95%)
    0.92 (0.67 to 1.25)
    0.95 (0.68 to 1.29)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Benralizumab 100 mg
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.941 [2]
    Method
    		 Van Elteren Test
    Parameter type
    		 Rate ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.58
    Notes
    [1] - 95 percent (%) confidence interval (CI) for rate ratio was based on normal approximation assuming rate with Poisson distribution.
    [2] - Day 1 to 393: Van Elteren test was used to compare the two arms.

    Secondary: Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
    End point description
    An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between administration of study drug and up to Day 561 that were absent before treatment or that worsened relative to pre-treatment state. TEAEs reported below included both SAEs and non-serious AEs. The safety population included all participants who received at least one dose of investigational drug.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 561
    End point values
    		 Placebo Benralizumab 100 mg
    Number of subjects analysed
    50
    51
    Units: participants
        TEAEs
    41
    45
        TESAEs
    9
    14
    No statistical analyses for this end point

    Secondary: Number of Participants Hospitalized due to Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD)

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    End point title
    		 Number of Participants Hospitalized due to Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD)
    End point description
    An AECOPD is defined as worsening of two or more major symptoms or one major and one minor symptom for two or more consecutive days. The PP population included all participants who had no major protocol violations, received at least 6 of the 8 total doses of investigational product and completed the study through Day 393.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 393
    End point values
    		 Placebo Benralizumab 100 mg
    Number of subjects analysed
    42
    40
    Units: participants
    5
    2
    No statistical analyses for this end point

    Secondary: Percentage of Participants Hospitalized due to Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD)

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    End point title
    		 Percentage of Participants Hospitalized due to Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD)
    End point description
    An AECOPD is defined as worsening of two or more major symptoms or one major and one minor symptom for two or more consecutive days. The PP population included all participants who had no major protocol violations, received at least 6 of the 8 total doses of investigational product, and completed the study through Day 393.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 393
    End point values
    		 Placebo Benralizumab 100 mg
    Number of subjects analysed
    42
    40
    Units: percentage of participants
        number (not applicable)
    11.9
    5
    No statistical analyses for this end point

    Secondary: Annual Incidence Rate of Hospitalization due to Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD)

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    End point title
    		 Annual Incidence Rate of Hospitalization due to Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD)
    End point description
    An AECOPD is defined as worsening of two or more major symptoms or one major and one minor symptom for two or more consecutive days. Annualized Incidence Rate of hospitalization due to AECOPD was calculated as Rate = total number of hospitalizations/ total person years. The PP population included all participants who had no major protocol violations, received at least 6 of the 8 total doses of investigational product, and completed the study through Day 393.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 393
    End point values
    		 Placebo Benralizumab 100 mg
    Number of subjects analysed
    42
    40
    Units: hospitalizations/person-year
        number (confidence interval 95%)
    0.11 (0.05 to 0.26)
    0.05 (0.01 to 0.18)
    No statistical analyses for this end point

    Secondary: Change from Baseline in COPD-Specific Saint George’s Respiratory Questionnaire (SGRQ-C) Total and Domain Scores at Day 393

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    End point title
    		 Change from Baseline in COPD-Specific Saint George’s Respiratory Questionnaire (SGRQ-C) Total and Domain Scores at Day 393
    End point description
    The SGRQ is a health related quality of life questionnaire consisting of 40 items in three domains: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). Each question’s response has a unique empirically derived weight where lowest possible weight is zero and the highest is 100. The total score and domain score are derived from the relevant items and converted to a score of 0 to 100 with a higher score indicating poorer health status. The PP population included all participants who had no major protocol violations, received at least 6 of the 8 total doses of investigational product, and completed the study through Day 393. Here, 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 393
    End point values
    		 Placebo Benralizumab 100 mg
    Number of subjects analysed
    42
    40
    Units: units on scale
    arithmetic mean (standard deviation)
        Baseline: Total Score (n=42, 40)
    48.04 ( 19.14 )
    51.75 ( 20.45 )
        Change at Day 393: Total Score (n=42, 37)
    -4.43 ( 11.71 )
    -5.51 ( 16.64 )
        Baseline: Symptoms (n=42, 40)
    64.59 ( 24.38 )
    67.18 ( 21.47 )
        Change at Day 393: Symptoms (n=42, 37)
    -3.19 ( 17.44 )
    -9.02 ( 21.27 )
        Baseline: Activity (n=42, 40)
    58.85 ( 23.22 )
    61.45 ( 25.53 )
        Change at Day 393: Activity (n=42, 37)
    -5.65 ( 14.85 )
    -4.37 ( 24.89 )
        Baseline: Impact (n=42, 40)
    35.94 ( 18.95 )
    40.69 ( 22.49 )
        Change at Day 393: Impact (n=42, 37)
    -4.16 ( 14.62 )
    -4.95 ( 16.97 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Improvement in COPD-Specific Saint George’s Respiratory Questionnaire (SGRQ-C) Total Score

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    End point title
    		 Percentage of Participants with Improvement in COPD-Specific Saint George’s Respiratory Questionnaire (SGRQ-C) Total Score
    End point description
    SGRQ is a health related quality of life questionnaire consisting of 40 items in three domains: symptoms (respiratory symptoms and severity) activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). Each question’s response has a unique empirically derived weight where lowest possible weight is zero and the highest is 100. The total score and domain score were derived from the relevant items and converted to a score of 0 to 100 with a higher score indicating poorer health status. Percentage of participants with 4-point, 8-point and 12-point change from baseline in COPD-Specific Saint George’s Respiratory Questionnaire (SGRQ-C) total score were observed. The PP population was analysed. Here, 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Day 393
    End point values
    		 Placebo Benralizumab 100 mg
    Number of subjects analysed
    42
    40
    Units: percentage of participants
    number (not applicable)
        Day 393: Total: 4-point change (n=42, 37)
    59.5
    54.1
        Day 393: 8-point change (n=42, 37)
    38.1
    40.5
        Day 393: Total: 12-point change (n=42, 37)
    21.4
    24.3
    No statistical analyses for this end point

    Secondary: Change from Baseline in Chronic Respiratory Questionnaire Self-Administered Standardized Format (CRQ-SAS) Domain scores at Day 393

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    End point title
    		 Change from Baseline in Chronic Respiratory Questionnaire Self-Administered Standardized Format (CRQ-SAS) Domain scores at Day 393
    End point description
    CRQ-SAS is a self-administered questionnaire which consist of 20 items across four domains: dyspnea (5 items), fatigue (4 items), emotional function (7 items), and mastery (4 items). Participants rated their experience on a 7-point scale in response to each item ranging from 1 (maximum impairment) to 7 (no impairment). Individual items were equally weighted, and domain scores were calculated as the mean of all items within each domain; domain score range: 1 (maximum impairment) to 7 (no impairment). The PP population included all participants who had no major protocol violations, received at least 6 of the 8 total doses of investigational product, and completed the study through Day 393. Here, 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 393
    End point values
    		 Placebo Benralizumab 100 mg
    Number of subjects analysed
    42
    40
    Units: units on scale
    arithmetic mean (standard deviation)
        Baseline: Dyspnea (n=42, 40)
    4.97 ( 1.45 )
    4.74 ( 1.32 )
        Change at Day 393: Dyspnea (n=42, 37)
    -0.08 ( 1.29 )
    0.09 ( 1 )
        Baseline: Fatigue (n=42, 40)
    4.38 ( 1.26 )
    3.96 ( 1.4 )
        Change at Day 393: Fatigue (n=42, 37)
    0.11 ( 0.94 )
    0.11 ( 1.15 )
        Baseline: Emotional function (n=42, 40)
    4.84 ( 1.24 )
    4.72 ( 1.17 )
        Change at Day 393: Emotional function (n=42, 37)
    0.18 ( 0.98 )
    0.08 ( 1.18 )
        Baseline: Mastery (n=42, 40)
    4.89 ( 1.5 )
    4.67 ( 1.4 )
        Change at Day 393: Mastery (n=42, 37)
    0.24 ( 1.12 )
    0.28 ( 1.24 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a 0.5-Point Improvement in Chronic Respiratory Questionnaire Self-administered Standardized Format (CRQ-SAS) Domain scores at Day 393

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    End point title
    		 Percentage of Participants With a 0.5-Point Improvement in Chronic Respiratory Questionnaire Self-administered Standardized Format (CRQ-SAS) Domain scores at Day 393
    End point description
    The CRQ-SAS is a self-administered questionnaire which consist of 20 items across four domains: dyspnea (5 items), fatigue (4 items), emotional function (7 items), and mastery (4 items). Participants rated their experience on a 7-point scale in response to each item ranging from 1 (maximum impairment) to 7 (no impairment). Individual items were equally weighted, and domain scores were calculated as the mean of all items within each domain; domain score range: 1 (maximum impairment) to 7 (no impairment). Participants with 0.5 point improvement from baseline in the domain scores were observed. The PP population included all participants who had no major protocol violations, received at least 6 of the 8 total doses of investigational product, and completed the study through Day 393. Here, 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Day 393
    End point values
    		 Placebo Benralizumab 100 mg
    Number of subjects analysed
    42
    40
    Units: percentage of participants
    number (not applicable)
        Day 393: Dyspnea (n=42, 37)
    28.6
    32.4
        Day 393: Fatigue (n=42, 37)
    35.7
    35.1
        Day 393: Emotional function (n=42, 37)
    35.7
    27
        Day 393: Mastery (n=42, 37)
    47.6
    37.8
    No statistical analyses for this end point

    Secondary: Change from Baseline in Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) Scores at Day 393

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    End point title
    		 Change from Baseline in Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) Scores at Day 393
    End point description
    The BODE index is a multi-dimension COPD grading system that incorporates body-mass index (B), degree of airflow obstruction (O), dyspnea (D), and exercise capacity (E) as measured by the modified medical research council (MMRC) dyspnea scale and the 6-minute walk test. The MMRC dyspnea scale is a 5-point scale that measures the level of dyspnea (trouble breathing) experienced by participants where score range is 0 (none) to 4 (very severe ). BODE score is derived into a score range of 0 (healthy) to 10 (severe COPD). The PP population included all participants who had no major protocol violations, received at least 6 of the 8 total doses of investigational product, and completed the study through Day 393. Here, 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 393
    End point values
    		 Placebo Benralizumab 100 mg
    Number of subjects analysed
    42
    40
    Units: units on scale
    arithmetic mean (standard deviation)
        Baseline (n=40, 39)
    2.8 ( 2 )
    2.9 ( 1.8 )
        Change at Day 393 (n=37, 32)
    -0.1 ( 1.4 )
    -0.5 ( 1.4 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to 561
    Adverse event reporting additional description
    The safety population included all participants who received at least one dose of investigational drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Benralizumab 100 mg
    Reporting group description
    		 Benralizumab (MEDI-563) 100 milligram (mg) injection subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks for the next 5 doses (Day 1, 29, 57, 113, 169, 225, 281 and 337).

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to benralizumab (MEDI-563) injection subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks for the next 5 doses (Day 1, 29, 57, 113, 169, 225, 281 and 337).

    Serious adverse events
    		 Benralizumab 100 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 51 (27.45%)
    9 / 50 (18.00%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Non-hodgkin's lymphoma
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (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
    Presyncope
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    6 / 51 (11.76%)
    6 / 50 (12.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal abscess
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis syndrome
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Benralizumab 100 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 51 (86.27%)
    41 / 50 (82.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 50 (2.00%)
         occurrences all number
    2
    1
    Hypertension
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 50 (4.00%)
         occurrences all number
    1
    2
    Aortic arteriosclerosis
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    Hypotension
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Injection site erythema
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 50 (0.00%)
         occurrences all number
    3
    0
    Injection site inflammation
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Injection site pain
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Injection site reaction
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 50 (0.00%)
         occurrences all number
    3
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Pyrexia
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 50 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    26 / 51 (50.98%)
    25 / 50 (50.00%)
         occurrences all number
    53
    62
    Cough
         subjects affected / exposed
    1 / 51 (1.96%)
    4 / 50 (8.00%)
         occurrences all number
    1
    4
    Dyspnoea
         subjects affected / exposed
    2 / 51 (3.92%)
    5 / 50 (10.00%)
         occurrences all number
    2
    5
    Dyspnoea exertional
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Epistaxis
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    Oropharyngeal pain
         subjects affected / exposed
    0 / 51 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    4
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 50 (2.00%)
         occurrences all number
    2
    1
    Breath sounds abnormal
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 50 (4.00%)
         occurrences all number
    2
    2
    Fall
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 50 (2.00%)
         occurrences all number
    3
    1
    Contusion
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 50 (0.00%)
         occurrences all number
    3
    0
    Post procedural complication
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 51 (7.84%)
    3 / 50 (6.00%)
         occurrences all number
    7
    3
    Dizziness
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Paraesthesia
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Sciatica
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Diarrhoea
         subjects affected / exposed
    0 / 51 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    4
    Constipation
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 51 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    4
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 50 (6.00%)
         occurrences all number
    2
    3
    Nausea
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 50 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Back pain
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 50 (2.00%)
         occurrences all number
    3
    1
    Joint swelling
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 50 (4.00%)
         occurrences all number
    1
    2
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    Musculoskeletal pain
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    Muscle spasms
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 50 (0.00%)
         occurrences all number
    3
    0
    Myalgia
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 50 (4.00%)
         occurrences all number
    1
    2
    Pain in extremity
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 50 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Gastroenteritis
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 50 (2.00%)
         occurrences all number
    3
    1
    Cystitis
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 50 (4.00%)
         occurrences all number
    1
    2
    Bronchitis
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 50 (6.00%)
         occurrences all number
    3
    3
    Nasopharyngitis
         subjects affected / exposed
    5 / 51 (9.80%)
    11 / 50 (22.00%)
         occurrences all number
    8
    13
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences all number
    1
    3
    Gastroenteritis viral
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    Pharyngitis
         subjects affected / exposed
    4 / 51 (7.84%)
    1 / 50 (2.00%)
         occurrences all number
    4
    1
    Pneumonia
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 50 (4.00%)
         occurrences all number
    2
    2
    Rhinitis
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences all number
    2
    1
    Sinusitis
         subjects affected / exposed
    3 / 51 (5.88%)
    4 / 50 (8.00%)
         occurrences all number
    3
    4
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 51 (9.80%)
    1 / 50 (2.00%)
         occurrences all number
    6
    1
    Urinary tract infection
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 50 (2.00%)
         occurrences all number
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2011
    - Study stopping criteria were amended.-Inclusion and exclusion criteria were revised.-Rescreening of participants was updated to 2 re-screenings for who had screen failed due to Hepatitis A and moderate-to-severe exacerbation prior to or after starting the 28-day run-in period.-Unblinding due to known effects of Benralizumab was revised.- Anticipated number of screened participants were removed from treatment regimens.- Treatment regimens and maintenance therapy were added.- Allowed concomitant medication during the study was revised.- Day28 was removed from Schedule of study procedures.- Text was updated in Schedule of study procedures and in Schedule of Participant Evaluations.-Office Spirometry Pre- and Post-bronchodilator was revised.- Wheeze was removed from visual analogue scales (VAS).- Patient-Reported Outcomes Questionnaire (PRO-Q) was added.- Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) Inpatient assessment was added.
    15 Feb 2011
    -Participants with a history of an untreated systemic helminth parasitic infestation were excluded. - Stool sampling added to Clinical Laboratory Tests. - Rescreening of participants was updated.

    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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