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    Clinical Trial Results:
    A Phase 2 Double-blind, Placebo-controlled Study to Evaluate the Efficacy of MEDI8968 in Chronic Obstructive Pulmonary Disease

    Summary
    EudraCT number
    		 2011-002563-23
    Trial protocol
    		 GB   HU   LV   CZ   LT   PL  
    Global end of trial date
    18 Feb 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    12 Feb 2017
    First version publication date
    31 Jan 2016
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CD-RI-MEDI8968-1103
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01448850
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    MedImmune, LLC.
    Sponsor organisation address
    Milstein Building, Granta Park, Cambridge, United Kingdom, CB21 6GH
    Public contact
    Senior Director, Clinical Development, MedImmune, LLC., vandermerwer@medimmune.com
    Scientific contact
    Senior Director, Clinical Development, MedImmune, LLC., 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
    18 Feb 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Feb 2014
    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 MEDI8968 on the rate of moderate or severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in adult participants with symptomatic, moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease - GOLD stage II-IV) receiving standard maintenance therapy for their disease.
    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
    		 All participants received double or triple background maintenance therapy (tiotropium vs budesonide/formoterol 160/4.5 microgram (mcg) versus budesonide/formoterol 160/4.5 mcg + tiotropium).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Nov 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Safety, Safety, Safety, Safety, Safety, Safety, Safety, Safety
    Long term follow-up duration
    		 4 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 44
    Country: Number of subjects enrolled
    Bulgaria: 41
    Country: Number of subjects enrolled
    Czech Republic: 30
    Country: Number of subjects enrolled
    Hungary: 47
    Country: Number of subjects enrolled
    Latvia: 7
    Country: Number of subjects enrolled
    Lithuania: 24
    Country: Number of subjects enrolled
    Philippines: 17
    Country: Number of subjects enrolled
    Ukraine: 46
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 62
    Worldwide total number of subjects
    324
    EEA total number of subjects
    199
    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)
    189
    From 65 to 84 years
    135
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 464 participants were screened and 324 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, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo matched to MEDI8968 as intravenous (IV) infusion on Day 1 followed by subcutaneous (SC) injection every 4 weeks up to Week 53.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Placebo matched to MEDI8968 as intravenous (IV) infusion on Day 1 followed by subcutaneous (SC) injection every 4 weeks up to Week 53.

    Arm title
    		 MEDI8968 600 mg IV on day 1, followed by 300 mg SC
    Arm description
    		 MEDI8968 600 milligram (mg) as IV infusion on Day 1 followed by 300 mg injection SC every 4 weeks up to Week 53.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MEDI8968
    Investigational medicinal product code
    MEDI8968
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    MEDI8968 600 milligram (mg) as IV infusion on Day 1 followed by 300 mg injection SC every 4 weeks up to Week 53.

    Number of subjects in period 1
    		Placebo MEDI8968 600 mg IV on day 1, followed by 300 mg SC
    Started
    164
    160
    Completed
    130
    120
    Not completed
    34
    40
         Adverse event, serious fatal
    3
    6
         Consent withdrawn by subject
    13
    21
         Unspecified
    15
    12
         Lost to follow-up
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to MEDI8968 as intravenous (IV) infusion on Day 1 followed by subcutaneous (SC) injection every 4 weeks up to Week 53.

    Reporting group title
    MEDI8968 600 mg IV on day 1, followed by 300 mg SC
    Reporting group description
    		 MEDI8968 600 milligram (mg) as IV infusion on Day 1 followed by 300 mg injection SC every 4 weeks up to Week 53.

    Reporting group values
    		 Placebo MEDI8968 600 mg IV on day 1, followed by 300 mg SC Total
    Number of subjects
    		 164 160 324
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 98 91 189
        From 65-74 years
    		 64 68 132
        >= 75 years
    		 2 1 3
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    		 63 ( 6.8 ) 62.8 ( 6.7 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 54 50 104
        Male
    		 110 110 220

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to MEDI8968 as intravenous (IV) infusion on Day 1 followed by subcutaneous (SC) injection every 4 weeks up to Week 53.

    Reporting group title
    MEDI8968 600 mg IV on day 1, followed by 300 mg SC
    Reporting group description
    		 MEDI8968 600 milligram (mg) as IV infusion on Day 1 followed by 300 mg injection SC every 4 weeks up to Week 53.

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

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    End point title
    		 Mean 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. The severity of an AECOPD is defined as: Moderate exacerbations require treatment with systemic corticosteroids, and or antibiotics. Severe exacerbations require hospitalization.
    End point type
    Primary
    End point timeframe
    Day 1 up to 393
    End point values
    		 Placebo MEDI8968 600 mg IV on day 1, followed by 300 mg SC
    Number of subjects analysed
    164
    160
    Units: AECOPD events/person-year
        least squares mean (confidence interval 90%)
    0.78 (0.63 to 0.96)
    0.71 (0.57 to 0.9)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v MEDI8968 600 mg IV on day 1, followed by 300 mg SC
    Number of subjects included in analysis
    324
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.645 [1]
    Method
    		 Poisson regression
    Parameter type
    		 Rate ratio
    Point estimate
    0.92
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.25
    Notes
    [1] - Data was analyzed using Poisson regression with Pearson correction, adjusting for treatment, background therapy and history of previous exacerbations.

    Secondary: Mean Rate of Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD)

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    End point title
    		 Mean Rate of 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. Severe exacerbations require hospitalization.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 393
    End point values
    		 Placebo MEDI8968 600 mg IV on day 1, followed by 300 mg SC
    Number of subjects analysed
    164
    160
    Units: AECOPD events/person-year
        least squares mean (confidence interval 90%)
    0.14 (0.09 to 0.21)
    0.1 (0.06 to 0.16)
    No statistical analyses for this end point

    Secondary: Time to First Moderate or Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD)

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    End point title
    		 Time to First Moderate or Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD)
    End point description
    Time to first worsening of two or more major symptoms or one major and one minor symptom for two or more consecutive days. The severity of an AECOPD is defined as: Mild exacerbations require treatment with an increase in usual therapy, e.g., increase use of short acting bronchodilators. Moderate exacerbations require treatment with systemic corticosteroids, and or antibiotics. Severe exacerbations require hospitalization. '99999’ in the below table indicates median and upper limit of 95% confidence interval (CI). Median and upper limit of 95% CI were not evaluable as less than 50% of the participants had moderate or severe AECOPD, thus not applicable (NA) = '99999'.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 393
    End point values
    		 Placebo MEDI8968 600 mg IV on day 1, followed by 300 mg SC
    Number of subjects analysed
    164
    160
    Units: days
        median (inter-quartile range (Q1-Q3))
    99999 (173 to 99999)
    99999 (134 to 99999)
    No statistical analyses for this end point

    Secondary: Change from Baseline in COPD-Specific Saint George’s Respiratory Questionnaire (SGRQ-C) Total and Subscales Scores at Week 53

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    End point title
    		 Change from Baseline in COPD-Specific Saint George’s Respiratory Questionnaire (SGRQ-C) Total and Subscales Scores at Week 53
    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.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 53
    End point values
    		 Placebo MEDI8968 600 mg IV on day 1, followed by 300 mg SC
    Number of subjects analysed
    164
    160
    Units: units on scale
    least squares mean (standard error)
        Change at Week 53: Total Score (n=134, 123)
    -2.76 ( 1.069 )
    -2.22 ( 1.101 )
        Change at Week 53: Activity Score (n=134, 123)
    -1.15 ( 1.306 )
    -1.38 ( 1.348 )
        Change at Week 53: Impacts Score (n=134, 123)
    -2.91 ( 1.326 )
    -1.08 ( 1.366 )
        Change at Week 53: Symptoms Score (n=134, 123)
    -5.6 ( 1.279 )
    -6.81 ( 1.325 )
    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
    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. A 4-point change in total score demonstrates a clinically meaningful change, while an 8-point change and a 12-point change are interpreted as a moderate and large change in health status, respectively.
    End point type
    Secondary
    End point timeframe
    Week 53
    End point values
    		 Placebo MEDI8968 600 mg IV on day 1, followed by 300 mg SC
    Number of subjects analysed
    164
    160
    Units: percentage of participants
    number (not applicable)
        Week 53: 4-point improvement (n=134,123)
    45.5
    43.1
        Week 53: 12-point improvement (n=134,123)
    17.9
    17.1
    No statistical analyses for this end point

    Secondary:  Change from Baseline in Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) Score at Week 53

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    End point title
    		  Change from Baseline in Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) Score at Week 53
    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).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 53
    End point values
    		 Placebo MEDI8968 600 mg IV on day 1, followed by 300 mg SC
    Number of subjects analysed
    123
    116
    Units: units on a scale
        least squares mean (standard error)
    -0.27 ( 0.107 )
    -0.08 ( 0.11 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Improvement in Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) Score

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    End point title
    		 Percentage of Participants With Improvement in Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) Score
    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). Negative change score signifies improvement compared to baseline. Number of participants with improvement in BODE score compared to baseline were reported.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 53
    End point values
    		 Placebo MEDI8968 600 mg IV on day 1, followed by 300 mg SC
    Number of subjects analysed
    123
    116
    Units: percentage of participants
        number (not applicable)
    39
    33.6
    No statistical analyses for this end point

    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 Week 69 that were absent before treatment or that worsened relative to pre-treatment state. TEAEs reported below included both SAEs and non-serious AEs.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Week 69
    End point values
    		 Placebo MEDI8968 600 mg IV on day 1, followed by 300 mg SC
    Number of subjects analysed
    164
    160
    Units: participants
        TEAEs
    130
    130
        TESAEs
    35
    41
    No statistical analyses for this end point

    Secondary: Observed Serum Concentrations of MEDI8968

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    End point title
    		 Observed Serum Concentrations of MEDI8968 [2]
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-dose (Baseline), Post-dose on Week 53
    Notes
    [2] - 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: No formal statistical analyses performed for this End Point
    End point values
    		 MEDI8968 600 mg IV on day 1, followed by 300 mg SC
    Number of subjects analysed
    158
    Units: nanogram per milliliters (ng/mL)
    arithmetic mean (standard deviation)
        Baseline (n=145)
    1.7 ( 14.6 )
        Week 53 (n=120)
    28555.7 ( 27545.6 )
    No statistical analyses for this end point

    Secondary: Number of Participants Exhibiting Anti-Drug Antibodies for MEDI8968 at any Visit

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    End point title
    		 Number of Participants Exhibiting Anti-Drug Antibodies for MEDI8968 at any Visit
    End point description
    Anti-drug antibodies for MEDI8968 were analyzed for participants who received placebo or MEDI8968 as per planned analysis.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Week 69
    End point values
    		 Placebo MEDI8968 600 mg IV on day 1, followed by 300 mg SC
    Number of subjects analysed
    163
    157
    Units: participants
    10
    19
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Week 69
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    PLACEBO
    Reporting group description
    		 Placebo matched to MEDI8968 as intravenous (IV) infusion on Day 1 followed by subcutaneous (SC) injection every 4 weeks up to Week 53.

    Reporting group title
    MEDI8968 300 mg
    Reporting group description
    		 MEDI8968 600 milligram (mg) as IV infusion on Day 1 followed by 300 mg injection SC every 4 weeks up to Week 53.

    Serious adverse events
    		 PLACEBO MEDI8968 300 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 164 (21.34%)
    41 / 160 (25.63%)
         number of deaths (all causes)
    3
    6
         number of deaths resulting from adverse events
    3
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung cancer metastatic
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm of unknown primary site
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         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
    Chest pain
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         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
    4 / 164 (2.44%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    17 / 164 (10.37%)
    18 / 160 (11.25%)
         occurrences causally related to treatment / all
    1 / 29
    0 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Comminuted fracture
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Ebstein's anomaly
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    3 / 3
    6 / 6
    Adams-stokes syndrome
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 164 (1.22%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 164 (0.61%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 164 (0.61%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (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
    Cerebral artery occlusion
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Impaired gastric emptying
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis necrotising
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (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
    Atypical mycobacterial pneumonia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal oesophagitis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis bacterial
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 164 (2.44%)
    7 / 160 (4.38%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 PLACEBO MEDI8968 300 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    127 / 164 (77.44%)
    122 / 160 (76.25%)
    Investigations
    Weight decreased
         subjects affected / exposed
    3 / 164 (1.83%)
    4 / 160 (2.50%)
         occurrences all number
    3
    5
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 164 (4.27%)
    5 / 160 (3.13%)
         occurrences all number
    10
    6
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 164 (1.83%)
    4 / 160 (2.50%)
         occurrences all number
    3
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 164 (2.44%)
    4 / 160 (2.50%)
         occurrences all number
    4
    4
    Headache
         subjects affected / exposed
    7 / 164 (4.27%)
    10 / 160 (6.25%)
         occurrences all number
    27
    10
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 164 (3.66%)
    8 / 160 (5.00%)
         occurrences all number
    6
    13
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 164 (2.44%)
    3 / 160 (1.88%)
         occurrences all number
    4
    3
    Nausea
         subjects affected / exposed
    3 / 164 (1.83%)
    5 / 160 (3.13%)
         occurrences all number
    3
    5
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    71 / 164 (43.29%)
    64 / 160 (40.00%)
         occurrences all number
    138
    112
    Dyspnoea
         subjects affected / exposed
    6 / 164 (3.66%)
    4 / 160 (2.50%)
         occurrences all number
    8
    5
    Oropharyngeal pain
         subjects affected / exposed
    5 / 164 (3.05%)
    2 / 160 (1.25%)
         occurrences all number
    5
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 164 (3.05%)
    2 / 160 (1.25%)
         occurrences all number
    5
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 164 (1.22%)
    5 / 160 (3.13%)
         occurrences all number
    2
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 164 (2.44%)
    5 / 160 (3.13%)
         occurrences all number
    4
    7
    Nasopharyngitis
         subjects affected / exposed
    11 / 164 (6.71%)
    11 / 160 (6.88%)
         occurrences all number
    13
    12
    Pneumonia
         subjects affected / exposed
    4 / 164 (2.44%)
    3 / 160 (1.88%)
         occurrences all number
    4
    3
    Sinusitis
         subjects affected / exposed
    5 / 164 (3.05%)
    3 / 160 (1.88%)
         occurrences all number
    6
    5
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 164 (4.27%)
    5 / 160 (3.13%)
         occurrences all number
    7
    5
    Urinary tract infection
         subjects affected / exposed
    5 / 164 (3.05%)
    5 / 160 (3.13%)
         occurrences all number
    7
    8
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    4 / 164 (2.44%)
    3 / 160 (1.88%)
         occurrences all number
    5
    3
    Hypercholesterolaemia
         subjects affected / exposed
    3 / 164 (1.83%)
    4 / 160 (2.50%)
         occurrences all number
    3
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Aug 2011
    The blood collection plan for this analysis was modified due to difficulties in the logistics of collecting and processing samples. Including a smaller number of subjects was considered adequate for this as this was an exploratory analysis.
    03 Oct 2011
    Added exclusion criterion 27 that subjects with “uncontrolled, clinically significant history of liver disease or elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than or equal to (>) 1.5 * upper limit of normal (ULN) at screening” were to be excluded. Added that “Subjects who have AST or ALT > 3 * ULN and evidence of hepatic impairment (total bilirubin > 2 × the ULN or INR > 1.5) confirmed by repeat test within 48 hours” were to be withdrawn. Added text around the administration of an inactivated influenza vaccine, including that subjects may have received an egg-free inactivated influenza vaccination. Added Clinical Global Impression of Exacerbation Severity to assessment of AECOPD.

    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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