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    Clinical Trial Results:
    An observer-blind study to evaluate the safety, reactogenicity and immunogenicity of GSK Biologicals’ investigational vaccine GSK2838504A when administered to COPD patients

    Summary
    EudraCT number
    		 2013-003062-13
    Trial protocol
    		 GB   SE  
    Global end of trial date
    19 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Apr 2018
    First version publication date
    06 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    200157
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02075541
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l’Institut 89, Rixensart, Belgium, B-1330
    Public contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.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
    20 Feb 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to describe the safety and reactogenicity of the investigational vaccine.
    Protection of trial subjects
    All subjects were observed closely for at least 60 minutes following the administration of the vaccine, with appropriate medical treatment readily available in case of anaphylaxis. Vaccines were administered by qualified and trained personnel. Vaccine was given only to eligible subjects that had no contraindications to any components of the vaccines. Subjects will be followed up till 13 months after last vaccine administration.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jul 2014
    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: 112
    Country: Number of subjects enrolled
    Sweden: 33
    Worldwide total number of subjects
    145
    EEA total number of subjects
    145
    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)
    45
    From 65 to 84 years
    100
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 145 subjects, aged 40 to 80 years were recruited from 4 sites in Sweden and 11 sites in the United Kingdom.

    Pre-assignment
    Screening details
    		 All enrolled subjects were included in 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, Monitor, Carer, Assessor
    Blinding implementation details
    Vaccine preparation & administration will be done by authorised medical personnel who will not participate in any of the study clinical evaluation assays.Laboratory in charge of testing will be blinded to treatment & codes will be used to link the subject & study to each sample.An analysis of immunogenicity & safety data up to Day 90 will be done on as cleaned as possible data.At this point,statistician of the project will be unblinded.Other study personnel will remain blinded until study end.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 10-AS01E Group
    Arm description
    		 Approximately 70 subjects who received 2 doses of the investigational NTHi vaccine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NTHi-10-AS01E
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and suspension for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL adminsitered in 2 doses.

    Arm title
    		 Control Group
    Arm description
    		 Approximately 70 subjects who received 2 doses of placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    NaCl Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL adminsitered in 2 doses.

    Number of subjects in period 1
    		10-AS01E Group Control Group
    Started
    73
    72
    Completed
    69
    64
    Not completed
    4
    8
         Consent withdrawn by subject
    1
    3
         Sponsor study termination
    -
    1
         Other- unable to perform study procedure
    1
    -
         Serious Adverse Event
    1
    4
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    10-AS01E Group
    Reporting group description
    		 Approximately 70 subjects who received 2 doses of the investigational NTHi vaccine.

    Reporting group title
    Control Group
    Reporting group description
    		 Approximately 70 subjects who received 2 doses of placebo.

    Reporting group values
    		 10-AS01E Group Control Group Total
    Number of subjects
    		 73 72 145
    Age categorical
    Units: Subjects
        40-59 years old
    		 12 11 23
        60-80 years-old
    		 61 60 121
        >80 years old
    		 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67 ( 8.41 ) 66.8 ( 7.21 ) -
    Gender categorical
    Units: Subjects
        Female
    		 34 36 70
        Male
    		 39 36 75
    Race/Ethnicity, Customized
    Units: Subjects
        White- Caucasian/ European Heritage
    		 73 72 145

    End points

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    End points reporting groups
    Reporting group title
    10-AS01E Group
    Reporting group description
    		 Approximately 70 subjects who received 2 doses of the investigational NTHi vaccine.

    Reporting group title
    Control Group
    Reporting group description
    		 Approximately 70 subjects who received 2 doses of placebo.

    Primary: Number of subjects with any solicited local adverse events (AEs).

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    End point title
    		 Number of subjects with any solicited local adverse events (AEs). [1]
    End point description
    Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade.
    End point type
    Primary
    End point timeframe
    During a 7-day follow-up period (from Day 0 to Day 6) after first dose.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    73
    72
    Units: Participants
        Any Pain
    49
    5
        Any Redness (mm)
    9
    0
        Any Swelling (mm)
    4
    0
    No statistical analyses for this end point

    Primary: Number of subjects with any solicited local AEs.

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    End point title
    		 Number of subjects with any solicited local AEs. [2]
    End point description
    Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade.
    End point type
    Primary
    End point timeframe
    During a 7-day follow-up period (from Day 60 to Day 66) after second dose.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    69
    68
    Units: Participants
        Any Pain
    49
    5
        Any Redness (mm)
    15
    2
        Any Swelling (mm)
    8
    0
    No statistical analyses for this end point

    Primary: Number of subjects with any solicited general AEs.

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    End point title
    		 Number of subjects with any solicited general AEs. [3]
    End point description
    Assessed solicited general symptoms are fatigue, gastrointestinal symptoms (included nausea, vomiting, diarrhoea and/or abdominal pain), headache, fever [defined as oral temperature equal to or above 37.5 degrees Celsius (°C)]. Any = occurrence of the symptom regardless of intensity grade.
    End point type
    Primary
    End point timeframe
    During a 7-day follow-up period (from Day 0 to Day 6) following the first dose.
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    73
    72
    Units: Participants
        Any Fatigue
    21
    19
        Any Gastrointestinal symptoms
    12
    10
        Any Headache
    19
    13
        Any Temperature/(Oral) (°C)
    2
    6
    No statistical analyses for this end point

    Primary: Number of subjects with any solicited general AEs

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    End point title
    		 Number of subjects with any solicited general AEs [4]
    End point description
    Assessed solicited general symptoms are fatigue, gastrointestinal symptoms (included nausea, vomiting, diarrhoea and/or abdominal pain), headache, fever (defined as oral temperature equal to or above 37.5 °C). Any = occurrence of the symptom regardless of intensity grade.
    End point type
    Primary
    End point timeframe
    During a 7-day follow-up period (from Day 60 to Day 66) following the second dose.
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    69
    68
    Units: Participants
        Any Fatigue
    28
    13
        Any Gastrointestinal symptoms
    15
    6
        Any Headache
    20
    13
        Any Temperature/(Oral) (°C)
    10
    1
    No statistical analyses for this end point

    Primary: Number of subjects with any unsolicited AEs.

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    End point title
    		 Number of subjects with any unsolicited AEs. [5]
    End point description
    Assessed unsolicited AEs covered any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.
    End point type
    Primary
    End point timeframe
    During the 30-day follow-up period (from Day 0 to Day 29) following the first dose.
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    73
    72
    Units: Participants
        Participants
    27
    26
    No statistical analyses for this end point

    Primary: Number of subjects with any unsolicited AEs

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    End point title
    		 Number of subjects with any unsolicited AEs [6]
    End point description
    Assessed unsolicited AEs covered any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.
    End point type
    Primary
    End point timeframe
    During the 30-day follow-up period (from Day 60 to Day 89) following the second dose.
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    73
    72
    Units: Participants
        Participants
    25
    22
    No statistical analyses for this end point

    Primary: Number of subjects with each haematological/ biochemical laboratory abnormality.

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    End point title
    		 Number of subjects with each haematological/ biochemical laboratory abnormality. [7]
    End point description
    Assessed haematological parameters are complete blood cell count: Leukocytes [white blood cells (WBC)], differential count (basophils, eosinophils, lymphocytes, monocytes, neutrophils), platelets count, and hemoglobin level below or above the normal laboratory ranges tabulated by time point. Assessed biochemical parameters are alanine aminotransferase (ALT), aspartate aminotransferase (AST) or creatinine below or above the normal laboratory ranges tabulated by time point.
    End point type
    Primary
    End point timeframe
    At Day 0.
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    73
    70
    Units: Participants
        WBC below (N=72,70)
    1
    1
        WBC above N=72,70)
    5
    1
        Basophils below (N=71,70)
    0
    0
        Basophils above N=71,70)
    0
    0
        Eosinophils below (N=71,70)
    0
    0
        Eosinophils above (N=71,70)
    3
    4
        Lymphocytes below (N=71,70)
    15
    9
        Lymphocytes above (N=71,70)
    7
    3
        Monocytes below (N=71,70)
    0
    1
        Monocytes above (N=71,70)
    6
    6
        Neutrophils below (N=71,70)
    1
    1
        Neutrophils above (N=71,70)
    6
    3
        Platelets below (N=72,70)
    2
    4
        Platelets above (N=72,70)
    12
    9
        Haemoglobin below (N=72,70)
    5
    6
        Haemoglobin above (N=72,70)
    12
    5
        ALT below (N=72,70)
    0
    0
        ALT above (N=72,70)
    4
    1
        AST below (N=72,70)
    0
    0
        AST above (N=72,70)
    2
    1
        Creatinine below (N=73,70)
    0
    0
        Creatinine above (N=73,70)
    10
    8
    No statistical analyses for this end point

    Primary: Number of subjects with each haematological/ biochemical laboratory abnormality.

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    End point title
    		 Number of subjects with each haematological/ biochemical laboratory abnormality. [8]
    End point description
    Assessed haematological parameters are complete blood cell count: Leukocytes [white blood cells (WBC)], differential count (basophils, eosinophils, lymphocytes, monocytes, neutrophils), platelets count, and hemoglobin level below or above the normal laboratory ranges tabulated by time point. Assessed biochemical parameters are alanine aminotransferase (ALT), aspartate aminotransferase (AST) or creatinine below or above the normal laboratory ranges tabulated by time point.
    End point type
    Primary
    End point timeframe
    At Day 7.
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    69
    67
    Units: Participants
        WBC below (N=69,67)
    0
    2
        WBC above (N=69,67)
    4
    0
        Basophils below (N=69,67)
    0
    0
        Basophils above (N=69,67)
    0
    0
        Eosinophils below (N=69,67)
    0
    0
        Eosinophils above (N=69,67)
    4
    2
        Lymphocytes below (N=69,67)
    9
    7
        Lymphocytes above (N=69,67)
    4
    2
        Monocytes below (N=69,67)
    1
    0
        Monocytes above (N=69,67)
    4
    5
        Neutrophils below (N=69,67)
    1
    1
        Neutrophils above (N=69,67)
    8
    1
        Platelets below (N=69,67)
    2
    3
        Platelets above (N=69,67)
    15
    12
        Haemoglobin below (N=69,67)
    5
    5
        Haemoglobin above (N=69,67)
    12
    4
        ALT below (N=69,67)
    0
    0
        ALT above (N=69,67)
    5
    1
        AST below (N=69,67)
    0
    0
        AST above (N=69,67)
    1
    2
        Creatinine below (N=69,67)
    0
    0
        Creatinine above (N=69,67)
    7
    10
    No statistical analyses for this end point

    Primary: Number of subjects with each haematological/ biochemical laboratory abnormality.

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    End point title
    		 Number of subjects with each haematological/ biochemical laboratory abnormality. [9]
    End point description
    Assessed haematological parameters are complete blood cell count: Leukocytes [white blood cells (WBC)], differential count (basophils, eosinophils, lymphocytes, monocytes, neutrophils), platelets count, and hemoglobin level below or above the normal laboratory ranges tabulated by time point. Assessed biochemical parameters are alanine aminotransferase (ALT), aspartate aminotransferase (AST) or creatinine below or above the normal laboratory ranges tabulated by time point.
    End point type
    Primary
    End point timeframe
    At Day 30.
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    68
    68
    Units: Participants
        WBC below (N=68,68)
    1
    1
        WBC above (N=68,68)
    8
    2
        Basophils below (N=68,68)
    0
    0
        Basophils above (N=68,68)
    0
    0
        Eosinophils below (N=68,68)
    0
    0
        Eosinophils above (N=68,68)
    3
    2
        Lymphocytes below (N=68,68)
    14
    6
        Lymphocytes above (N=68,68)
    7
    6
        Monocytes below (N=68,68)
    0
    0
        Monocytes above (N=68,68)
    8
    10
        Neutrophils below (N=68,68)
    1
    2
        Neutrophils above (N=68,68)
    9
    1
        Platelets below (N=68,68)
    3
    2
        Platelets above (N=68,68)
    14
    11
        Haemoglobin below (N=68,68)
    3
    8
        Haemoglobin above (N=68,68)
    10
    6
        ALT below (N=68,68)
    0
    0
        ALT above (N=68,68)
    5
    4
        AST below (N=68,68)
    0
    0
        AST above (N=68,68)
    1
    4
        Creatinine below (N=68,68)
    0
    0
        Creatinine above (N=68,68)
    6
    12
    No statistical analyses for this end point

    Primary: Number of subjects with each haematological/ biochemical laboratory abnormality.

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    End point title
    		 Number of subjects with each haematological/ biochemical laboratory abnormality. [10]
    End point description
    Assessed haematological parameters are complete blood cell count: Leukocytes [white blood cells (WBC)], differential count (basophils, eosinophils, lymphocytes, monocytes, neutrophils), platelets count, and hemoglobin level below or above the normal laboratory ranges tabulated by time point. Assessed biochemical parameters are alanine aminotransferase (ALT), aspartate aminotransferase (AST) or creatinine below or above the normal laboratory ranges tabulated by time point.
    End point type
    Primary
    End point timeframe
    At Day 60.
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    70
    69
    Units: Participants
        WBC below (N=70,69)
    1
    0
        WBC above (N=70,69)
    3
    8
        Basophils below (N=70,69)
    0
    0
        Basophils above (N=70,69)
    0
    0
        Eosinophils below (N=70,69)
    0
    0
        Eosinophils above (N=70,69)
    5
    2
        Lymphocytes below (N=70,69)
    12
    11
        Lymphocytes above (N=70,69)
    4
    5
        Monocytes below (N=70,69)
    0
    2
        Monocytes above (N=70,69)
    7
    12
        Neutrophils below (N=70,69)
    1
    2
        Neutrophils above (N=70,69)
    8
    7
        Platelets below (N=70,69)
    1
    3
        Platelets above (N=70,69)
    13
    9
        Haemoglobin below (N=70,69)
    4
    8
        Haemoglobin above (N=70,69)
    7
    5
        ALT below (N=70,68)
    0
    0
        ALT above (N=70,68)
    4
    1
        AST below (N=70,69)
    0
    0
        AST above (N=70,69)
    3
    2
        Creatinine below (N=70,69)
    0
    0
        Creatinine above (N=70,69)
    5
    8
    No statistical analyses for this end point

    Primary: Number of subjects with each haematological/ biochemical laboratory abnormality.

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    End point title
    		 Number of subjects with each haematological/ biochemical laboratory abnormality. [11]
    End point description
    Assessed haematological parameters are complete blood cell count: Leukocytes [white blood cells (WBC)], differential count (basophils, eosinophils, lymphocytes, monocytes, neutrophils), platelets count, and hemoglobin level below or above the normal laboratory ranges tabulated by time point. Assessed biochemical parameters are alanine aminotransferase (ALT), aspartate aminotransferase (AST) or creatinine below or above the normal laboratory ranges tabulated by time point.
    End point type
    Primary
    End point timeframe
    At Day 67.
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    65
    64
    Units: Participants
        WBC below (N=65,64)
    0
    0
        WBC above (N=65,64)
    4
    2
        Basophils below (N=65,64)
    0
    0
        Basophils above (N=65,64)
    0
    0
        Eosinophils below (N=65,64)
    0
    0
        Eosinophils above (N=65,64)
    5
    2
        Lymphocytes below (N=65,64)
    11
    8
        Lymphocytes above (N=65,64)
    6
    3
        Monocytes below (N=65,64)
    0
    0
        Monocytes above (N=65,64)
    4
    12
        Neutrophils below (N=65,64)
    2
    1
        Neutrophils above (N=65,64)
    5
    4
        Platelets below (N=65,64)
    0
    4
        Platelets above (N=65,64)
    16
    11
        Haemoglobin below (N=65,64)
    6
    11
        Haemoglobin above (N=65,64)
    8
    3
        ALT below (N=64,64)
    0
    0
        ALT above (N=64,64)
    5
    2
        AST below (N=64,64)
    0
    0
        AST above (N=64,64)
    3
    3
        Creatinine below (N=64,64)
    0
    0
        Creatinine above (N=64,64)
    5
    9
    No statistical analyses for this end point

    Primary: Number of subjects with each haematological/ biochemical laboratory abnormality.

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    End point title
    		 Number of subjects with each haematological/ biochemical laboratory abnormality. [12]
    End point description
    Assessed haematological parameters are complete blood cell count: Leukocytes [white blood cells (WBC)], differential count (basophils, eosinophils, lymphocytes, monocytes, neutrophils), platelets count, and hemoglobin level below or above the normal laboratory ranges tabulated by time point. Assessed biochemical parameters are alanine aminotransferase (ALT), aspartate aminotransferase (AST) or creatinine below or above the normal laboratory ranges tabulated by time point.
    End point type
    Primary
    End point timeframe
    At Day 90.
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    72
    69
    Units: Participants
        WBC below (N=72,69)
    0
    1
        WBC above (N=72,69)
    3
    2
        Basophils below (N=72,69)
    0
    0
        Basophils above (N=72,69)
    0
    0
        Eosinophils below (N=72,69)
    0
    0
        Eosinophils above (N=72,69)
    7
    5
        Lymphocytes below (N=72,69)
    11
    10
        Lymphocytes above (N=72,69)
    6
    4
        Monocytes below (N=72,69)
    0
    0
        Monocytes above (N=72,69)
    10
    6
        Neutrophils below (N=72,69)
    1
    0
        Neutrophils above (N=72,69)
    5
    5
        Platelets below (N=72,69)
    1
    3
        Platelets above (N=72,69)
    13
    13
        Haemoglobin below (N=72,69)
    4
    10
        Haemoglobin above (N=72,69)
    10
    6
        ALT below (N=72,69)
    0
    0
        ALT above (N=72,69)
    3
    4
        AST below (N=72,69)
    0
    0
        AST above (N=72,69)
    2
    2
        Creatinine below (N=72,69)
    0
    0
        Creatinine above (N=72,69)
    5
    8
    No statistical analyses for this end point

    Primary: Number of subjects with each haematological/ biochemical laboratory abnormality.

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    End point title
    		 Number of subjects with each haematological/ biochemical laboratory abnormality. [13]
    End point description
    Assessed haematological parameters are complete blood cell count: Leukocytes [white blood cells (WBC)], differential count (basophils, eosinophils, lymphocytes, monocytes, neutrophils), platelets count, and hemoglobin level below or above the normal laboratory ranges tabulated by time point. Assessed biochemical parameters are alanine aminotransferase (ALT), aspartate aminotransferase (AST) or creatinine below or above the normal laboratory ranges tabulated by time point.
    End point type
    Primary
    End point timeframe
    At Day 270.
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    67
    65
    Units: Participants
        WBC below (N=67,65)
    1
    0
        WBC above (N=67,65)
    7
    5
        Basophils below (N=67,65)
    0
    0
        Basophils above (N=67,65)
    0
    0
        Eosinophils below (N=67,65)
    0
    0
        Eosinophils above (N=67,65)
    4
    3
        Lymphocytes below (N=67,65)
    11
    5
        Lymphocytes above (N=67,65)
    7
    3
        Monocytes below (N=67,65)
    0
    0
        Monocytes above (N=67,65)
    10
    9
        Neutrophils below (N=67,65)
    1
    1
        Neutrophils above (N=67,65)
    10
    6
        Platelets below (N=67,65)
    1
    3
        Platelets above (N=67,65)
    9
    11
        Haemoglobin below (N=67,65)
    5
    10
        Haemoglobin above (N=67,65)
    13
    3
        ALT below (N=67,65)
    0
    0
        ALT above (N=67,65)
    5
    2
        AST below (N=67,65)
    0
    0
        AST above (N=67,65)
    5
    2
        Creatinine below (N=67,65)
    0
    0
        Creatinine above (N=67,65)
    9
    9
    No statistical analyses for this end point

    Primary: Number of subjects with each haematological/ biochemical laboratory abnormality.

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    End point title
    		 Number of subjects with each haematological/ biochemical laboratory abnormality. [14]
    End point description
    Assessed haematological parameters are complete blood cell count: Leukocytes [white blood cells (WBC)], differential count (basophils, eosinophils, lymphocytes, monocytes, neutrophils), platelets count, and hemoglobin level below or above the normal laboratory ranges tabulated by time point. Assessed biochemical parameters are alanine aminotransferase (ALT), aspartate aminotransferase (AST) or creatinine below or above the normal laboratory ranges tabulated by time point.
    End point type
    Primary
    End point timeframe
    At Day 450.
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    69
    61
    Units: Participants
        WBC below (N=68,61)
    1
    0
        WBC above (N=68,61)
    3
    1
        Basophils below (N=68,60)
    0
    0
        Basophils above (N=68,60)
    0
    0
        Eosinophils below (N=68,60)
    0
    0
        Eosinophils above (N=68,60)
    6
    3
        Lymphocytes below (N=68,60)
    17
    9
        Lymphocytes above (N=68,60)
    8
    3
        Monocytes below (N=68,60)
    0
    1
        Monocytes above (N=68,60)
    6
    5
        Neutrophils below (N=68,60)
    1
    1
        Neutrophils above (N=68,60)
    7
    4
        Platelets below (N=68,61)
    3
    3
        Platelets above (N=68,61)
    14
    13
        Haemoglobin below (N=68,61)
    6
    10
        Haemoglobin above (N=68,61)
    10
    6
        ALT below (N=69,61)
    0
    0
        ALT above (N=69,61)
    3
    3
        AST below (N=69,61)
    0
    0
        AST above (N=69,61)
    1
    3
        Creatinine below (N=69,61)
    0
    0
        Creatinine above (N=69,61)
    7
    9
    No statistical analyses for this end point

    Primary: Number of subjects reporting any potential immune-mediated diseases (pIMDs).

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    End point title
    		 Number of subjects reporting any potential immune-mediated diseases (pIMDs). [15]
    End point description
    pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology.
    End point type
    Primary
    End point timeframe
    From first vaccination (Day 0) up to study conclusion (Day 450).
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    73
    72
    Units: Participants
        Participants
    2
    0
    No statistical analyses for this end point

    Primary: Number of subjects with any serious adverse events (SAEs).

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    End point title
    		 Number of subjects with any serious adverse events (SAEs). [16]
    End point description
    SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity or are a congenital anomaly/ birth defect in the offspring of a study subject.
    End point type
    Primary
    End point timeframe
    From first vaccination (Day 0) up to study conclusion (Day 450).
    Notes
    [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this primary end point was descriptive, no statistical hypothesis test was performed.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    73
    72
    Units: Participants
        Participants
    15
    17
    No statistical analyses for this end point

    Secondary: Concentration of anti Protein D (anti-PD) total Immunoglobulin G (IgG) antibodies against the NTHi vaccine antigens.

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    End point title
    		 Concentration of anti Protein D (anti-PD) total Immunoglobulin G (IgG) antibodies against the NTHi vaccine antigens.
    End point description
    Antibody concentrations were measured by enzyme-linked immunosorbent assay (ELISA) and expressed as geometric mean concentrations (GMCs) in ELISA units per millilitre (EL.U/mL). The cut-off of the assay was 153 EL.U/mL for anti-PD.
    End point type
    Secondary
    End point timeframe
    At Day 0, Day 30, Day 60, Day 90, Day 270 and at Day 450.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    46
    45
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-PD antibody, Day 0 (N=44,45)
    107.3 (87.9 to 130.9)
    100.3 (85.3 to 118)
        Anti-PD antibody, Day 30 (N=43,44)
    840.1 (535.9 to 1317)
    102.6 (86.2 to 122.1)
        Anti-PD antibody, Day 60 (N=46,45)
    538 (358.6 to 807.1)
    104.1 (87.6 to 123.6)
        Anti-PD antibody, Day 90 (N=46,45)
    1692.1 (1242.6 to 2304)
    103 (87.3 to 121.7)
        Anti-PD antibody, Day 270 (N=44,42)
    598.3 (437 to 819.2)
    109.3 (90.9 to 131.4)
        Anti-PD antibody, Day 450 (N=46,41)
    463 (340.4 to 629.8)
    108.4 (90.1 to 130.4)
    No statistical analyses for this end point

    Secondary: Concentration of anti Protein E (anti-PE) total IgG antibodies against the NTHi vaccine antigens.

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    End point title
    		 Concentration of anti Protein E (anti-PE) total IgG antibodies against the NTHi vaccine antigens.
    End point description
    Antibody concentrations were measured by ELISA and expressed as GMCs in EL.U/mL. The cut-off of the assay was 8 EL.U/mL for anti-PE.
    End point type
    Secondary
    End point timeframe
    At Day 0, Day 30, Day 60, Day 90, Day 270 and at Day 450
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    46
    44
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-PE antibody, Day 0 (N=43,44)
    14.1 (9.5 to 21)
    14.8 (10.2 to 21.5)
        Anti-PE antibody, Day 30 (N=43,43)
    1007 (588.9 to 1722)
    13.6 (9.4 to 19.5)
        Anti-PE antibody, Day 60 (N=46,44)
    823.7 (503.3 to 1348.1)
    13.9 (9.7 to 19.9)
        Anti-PE antibody, Day 90 (N=44,44)
    10953.4 (8414.9 to 14257.9)
    15 (10.3 to 21.9)
        Anti-PE antibody, Day 270 (N=44,41)
    1743.3 (1226.9 to 2477)
    12.6 (8.7 to 18.1)
        Anti-PE antibody, Day 450 (N=46,40)
    1247.5 (866 to 1797)
    13.6 (9.3 to 20)
    No statistical analyses for this end point

    Secondary: Concentration of anti-PilA total IgG antibodies against the NTHi vaccine antigens.

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    End point title
    		 Concentration of anti-PilA total IgG antibodies against the NTHi vaccine antigens.
    End point description
    Antibody concentrations were measured by ELISA and expressed as GMCs in EL.U/mL. The cut-off of the assay was 7 EL.U/mL for anti-PilA.
    End point type
    Secondary
    End point timeframe
    At Day 0, Day 30, Day 60, Day 90, Day 270 and at Day 450.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    46
    43
    Units: El.U/mL
    geometric mean (confidence interval 95%)
        Anti-PilA antibody, Day 0 (N=39,43)
    12.3 (8.6 to 17.6)
    14.5 (10.2 to 20.5)
        Anti-PilA antibody, Day 30 (N=41,40)
    234.3 (133.5 to 411.5)
    15.6 (10.7 to 22.8)
        Anti-PilA antibody, Day 60 (N=43,43)
    207.5 (122.4 to 351.6)
    15.1 (10.7 to 21.3)
        Anti-PilA antibody, Day 90 (N=46,41)
    1353.7 (989.7 to 1851.7)
    16.5 (11.4 to 23.9)
        Anti-PilA antibody, Day 270 (N=43,39)
    333.5 (240.2 to 463.2)
    16.8 (11.6 to 24.3)
        Anti-PilA antibody, Day 450 (N=45,38)
    206.8 (147.7 to 289.5)
    16.2 (11.1 to 23.6)
    No statistical analyses for this end point

    Secondary: Frequency of specific Cluster of Differentiation 4 (CD4+) T-cells against NTHi antigens collected for evaluation of cell-mediated immune response.

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    End point title
    		 Frequency of specific Cluster of Differentiation 4 (CD4+) T-cells against NTHi antigens collected for evaluation of cell-mediated immune response.
    End point description
    Frequency of specific CD4+ T-cells were measured by flow cytometry intracellular cytokine staining (ICS) expressing two or more markers [such as Interleukin-2 (IL-2), IL-13, IL-17, Interferon-γ (IFN-γ), Tumor Necrosis Factor-α (TNF-α) and Cluster of Differentiation 40 Ligand (CD40L)]. The frequency of specific CD4+ T-cells are summarised [descriptive statistics: Mean and standard deviation (SD)] against each antigen (PD, PE and PilA), by group at each time point during which blood samples are collected for CMI.
    End point type
    Secondary
    End point timeframe
    At Day 0, Day 90, Day 270 and at Day 450.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    15
    9
    Units: CD4+ T-cells/ million cells
    arithmetic mean (standard deviation)
        CD4+ T-cells, PD, Day 0 (N=15,7)
    33.1 ( 49.97 )
    79.7 ( 91.48 )
        CD4+ T-cells, PD, Day 90 (N=15,8)
    521.6 ( 287.39 )
    38.4 ( 51.61 )
        CD4+ T-cells, PD, Day 270 (N=14,9)
    189.6 ( 146.87 )
    51.8 ( 59.4 )
        CD4+ T-cells, PD, Day 450 (N=14,5)
    148.6 ( 141.11 )
    97.8 ( 98.4 )
        CD4+ T-cells, PE, Day 0 (N=15,8)
    51.3 ( 68.72 )
    69.1 ( 82.87 )
        CD4+ T-cells, PE, Day 90 (N=15,8)
    857.9 ( 642.76 )
    65 ( 92.86 )
        CD4+ T-cells, PE, Day 270 (N=14,9)
    304.4 ( 292.46 )
    71.6 ( 90.51 )
        CD4+ T-cells, PE, Day 450 (N=14,5)
    337.2 ( 302.42 )
    117.8 ( 53.24 )
        CD4+ T-cells, PilA, Day 0 (N=15,7)
    29.7 ( 53.21 )
    98.3 ( 74.27 )
        CD4+ T-cells, PilA, Day 90 (N=15,8)
    474.4 ( 321.58 )
    37.4 ( 46.53 )
        CD4+ T-cells, PilA, Day 270 (N=14,9)
    145 ( 164.58 )
    80.3 ( 95.6 )
        CD4+ T-cells, PilA, Day 450 (N=14,5)
    157.7 ( 117.76 )
    102.8 ( 116.48 )
    No statistical analyses for this end point

    Secondary: Frequency of specific CD8+ T-cells against NTHi antigens collected for evaluation of cell-mediated immune response.

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    End point title
    		 Frequency of specific CD8+ T-cells against NTHi antigens collected for evaluation of cell-mediated immune response.
    End point description
    Frequency of specific CD8+ T-cells were measured by flow cytometry ICS expressing two or more markers (such as IL-2, IL-13, IL-17, IFN-γ, TNF-α and CD40L).The frequency of specific CD8+ T-cells are summarised [descriptive statistics: Mean and standard deviation (SD)] against each antigen (PD, PE and PilA), by group at each time point during which blood samples are collected for CMI.
    End point type
    Secondary
    End point timeframe
    At Day 0, Day 90, Day 270 and at Day 450.
    End point values
    		 10-AS01E Group Control Group
    Number of subjects analysed
    14
    9
    Units: CD8+ T-cells/ million cells
    arithmetic mean (standard deviation)
        CD8+ T-cells, PD, Day 0 (N=13,8)
    97.1 ( 186.24 )
    47.9 ( 72.9 )
        CD8+ T-cells, PD, Day 90 (N=12,8)
    39.6 ( 73.78 )
    45.8 ( 77.53 )
        CD8+ T-cells, PD, Day 270 (N=12,9)
    55.3 ( 59.18 )
    48.7 ( 56.33 )
        CD8+ T-cells, PD, Day 450 (N=13,5)
    51.5 ( 60.19 )
    16.2 ( 24.04 )
        CD8+ T-cells, PE, Day 0 (N=14,8)
    97.7 ( 204.06 )
    73.9 ( 131.71 )
        CD8+ T-cells, PE, Day 90 (N=14,8)
    44.9 ( 47.72 )
    30.6 ( 59.01 )
        CD8+ T-cells, PE, Day 270 (N=12,9)
    29.9 ( 57.16 )
    60.3 ( 83.47 )
        CD8+ T-cells, PE, Day 450 (N=13,5)
    41 ( 74.41 )
    31.6 ( 43.34 )
        CD8+ T-cells, PilA, Day 0 (N=13,8)
    63.1 ( 122.12 )
    23.1 ( 45.92 )
        CD8+ T-cells, PilA, Day 90 (N=13,8)
    39.7 ( 73.42 )
    80.3 ( 125.84 )
        CD8+ T-cells, PilA, Day 270 (N=12,9)
    27.4 ( 34.15 )
    13 ( 15.12 )
        CD8+ T-cells, PilA, Day 450 (N=13,5)
    63.7 ( 98.87 )
    31 ( 36.17 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicted AEs: during the 7-day interval post each vaccine dose, Unsolicited AEs: during the 30-day interval post each vaccine dose, SAEs: throughout the entire study, from Day 0 up to Day 450.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Control Group
    Reporting group description
    		 Approximately 70 subjects who received 2 doses of placebo.

    Reporting group title
    10-AS01E Group
    Reporting group description
    		 Approximately 70 subjects who received 2 doses of the investigational NTHi vaccine.

    Serious adverse events
    		 Control Group 10-AS01E Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 72 (23.61%)
    15 / 73 (20.55%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic bronchial carcinoma
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal squamous cell carcinoma
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 73 (1.37%)
         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
    Radius fracture
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 73 (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
    0 / 72 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 73 (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
    1 / 72 (1.39%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dressler's syndrome
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Dementia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 73 (1.37%)
         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
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Barrett's oesophagus
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 73 (1.37%)
         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 pulmonary oedema
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    10 / 72 (13.89%)
    4 / 73 (5.48%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung disorder
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 73 (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 viral
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    2 / 72 (2.78%)
    2 / 73 (2.74%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 72 (2.78%)
    2 / 73 (2.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 73 (1.37%)
         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: 5%
    Non-serious adverse events
    		 Control Group 10-AS01E Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 72 (58.33%)
    65 / 73 (89.04%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    22 / 72 (30.56%)
    30 / 73 (41.10%)
         occurrences all number
    34
    42
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    23 / 72 (31.94%)
    37 / 73 (50.68%)
         occurrences all number
    32
    51
    Injection site erythema
         subjects affected / exposed
    2 / 72 (2.78%)
    19 / 73 (26.03%)
         occurrences all number
    2
    26
    Injection site pain
         subjects affected / exposed
    9 / 72 (12.50%)
    59 / 73 (80.82%)
         occurrences all number
    10
    98
    Injection site swelling
         subjects affected / exposed
    0 / 72 (0.00%)
    9 / 73 (12.33%)
         occurrences all number
    0
    12
    Pyrexia
         subjects affected / exposed
    7 / 72 (9.72%)
    10 / 73 (13.70%)
         occurrences all number
    7
    12
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    15 / 72 (20.83%)
    22 / 73 (30.14%)
         occurrences all number
    16
    27
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 72 (1.39%)
    5 / 73 (6.85%)
         occurrences all number
    1
    5
    Oropharyngeal pain
         subjects affected / exposed
    5 / 72 (6.94%)
    5 / 73 (6.85%)
         occurrences all number
    6
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 72 (5.56%)
    7 / 73 (9.59%)
         occurrences all number
    4
    7
    Urinary tract infection
         subjects affected / exposed
    4 / 72 (5.56%)
    1 / 73 (1.37%)
         occurrences all number
    4
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Mar 2014
    • Because the volumes of the individual blood samples that will be collected were re-distributed after discussion with the central laboratory. The total volume of blood collected per subject across scheduled visits and at AECOPD visits remains similar. • Because information on processing and storage temperature until shipment was updated for some of the samples after discussion with the central laboratory. • To clarify that the plasma obtained during PBMC processing will be kept for potential future additional testing. • To clarify that white blood cell differential count will be done on blood samples for safety assessment. • In addition, some other, minor clarifications have been made and the list of contributing authors has been updated
    15 Dec 2014
    • To add clarification in the tertiary objectives: because acute exacerbations of COPD are complex events, triggered by multiple (interacting) pathogens, assessing the natural immunity to other pathogens might be important for interpretation of the data. • To add an additional blood sample for haematology assessment at each AECOPD visit. This blood sample will be collected to describe the systemic inflammation at time of exacerbation in terms of white blood cells and differential cell counts. • To clarify the list of concomitant medication that may lead to elimination of a subject from ATP analysis of immunogenicity (Section 7.6.2): because oral corticosteroids are commonly used in treatment of exacerbations, the administration of oral corticosteroids given for this indication will not fall under the definition of “chronic administration of immunosuppressants or other immune modifying drugs at any time during the study period”, used to determine elimination from the ATP analysis of immunogenicity. • To add a benefit: risk assessment section (Section 1.3). • In addition, a typo in the footnote of the table of intervals between visits (Table 9) has been corrected and the list of contributing authors has been updat-ed.
    15 Apr 2016
    • In compliance with ICH requirements, the protocol mentions that all results will be presented in an integrated report at the end of the study. • Following re-development and re-validation of the anti-PD ELISA, a new cut-off was defined. • Reference to the GSK Biologicals’ Laval laboratory was removed, as this laboratory will not be used in the study. In addition, this laboratory is no longer part of GSK Biologicals’ laboratories. • Internal assay qualification procedures were revised and it was decided that the level of characterisation of the ELISA assays can be minimal (set-up level) for this study as immunogenicity data are descriptive. In consequence, the assays will be standardized but not qualified as stated in the original version. This change will not impact the validity of the results. • A tertiary endpoint was added as the presence of viral pathogens in sputum will be examined as part of microbiome analysis. • In order to see early effects of the vaccine on the microbiome, analysis on fresh sputum samples (culture results) will be done on all available data up to the data lock point of the interim analysis. • In order to have a first look whether or not the inves-tigational vaccine has an impact on AECOPD, AECOPD analyses will be done up to the data lock point of the interim analysis. • Wording was added to clarify process for collection of sputum H. influenzae sweeps. • Wording was updated in order to be aligned with the Statistical Ananlysis Plan. • In addition, minor edits in other sections were made for clarification purposes.

    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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