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    Clinical Trial Results:
    An open-label, non-controlled, multicenter, multinational study to evaluate the efficacy and safety of Zemaira® administration in chronic augmentation and maintenance therapy in subjects with emphysema due to alpha1-proteinase inhibitor deficiency who completed clinical study CE1226_4001

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2007-007129-38
    Trial protocol
    		 IE   CZ   DE   FI   SE   EE   DK  
    Global end of trial date
    09 Sep 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jul 2016
    First version publication date
    29 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CE1226_3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00670007
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CSL Behring GmbH
    Sponsor organisation address
    Emil-von-Behring-Strasse 76, Marburg, Germany, 35041
    Public contact
    Trial Registration Co-ordinator, CSL Behring GmbH, clinicaltrials@cslbehring.com
    Scientific contact
    Trial Registration Co-ordinator, CSL Behring GmbH, clinicaltrials@cslbehring.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Dec 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect of Zemaira® on the progression of emphysema, assessed by the decline of lung density, measured by yearly computed tomography (CT).
    Protection of trial subjects
    This study was carried out in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines, and local legal requirements. The study protocol and all amendments were approved by the Independent Ethics Committee(s)/ Institutional Review Board(s) of the participating centers. Before undergoing screening procedures for possible enrollment into the study, subjects were informed, in an understandable form, about the nature, scope, and possible consequences of the study. The investigator was responsible for obtaining a subject’s written informed consent to participate in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Apr 2008
    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
    Romania: 1
    Country: Number of subjects enrolled
    Sweden: 17
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Denmark: 35
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Ireland: 19
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    Canada: 25
    Worldwide total number of subjects
    140
    EEA total number of subjects
    98
    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)
    130
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This multicenter study was conducted at 22 centers in Europe, Canada, and Australia. Alpha1-proteinase inhibitor (A1-PI) deficient individuals with emphysema, who had completed the 2-year treatment and observation periods in study CE1226_4001, except those participating in the USA, were invited to participate in study CE1226_3001.

    Pre-assignment
    Screening details
    		 Subjects who had participated in the CE1226_4001 study, met the inclusion and exclusion criteria, and signed the informed consent were included in study CE1226_3001.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Zemaira®
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zemaira®
    Investigational medicinal product code
    CE1226
    Other name
    Alpha1-Proteinase Inhibitor (human)
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The Zemaira® dose was 60 mg/kg body weight, administered intravenously once per week.

    Number of subjects in period 1
    		Zemaira®
    Started
    140
    Completed
    131
    Not completed
    9
         Adverse event, serious fatal
    1
         Consent withdrawn by subject
    4
         Adverse event, non-fatal
    1
         Lung transplant
    1
         Travel/vacation
    1
         Drug abuse
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 140 140
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 130 130
        From 65-84 years
    		 10 10
    Gender categorical
    Units: Subjects
        Female
    		 61 61
        Male
    		 79 79

    End points

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    End points reporting groups
    Reporting group title
    Zemaira®
    Reporting group description
    		 -

    Subject analysis set title
    Zemaira® (Early Start)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Those subjects who had already been allocated to receive Zemaira® treatment during study CE1226_4001 represent the Early Start group. This group had received up to 4 years of continuous therapy at the end of study CE1226_3001. The subjects in this group were from the Intention-to-treat population. Subjects may not have been included in all efficacy analyses because of missing efficacy assessments.

    Subject analysis set title
    Zemaira® (Delayed Start)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who received placebo in study CE1226_4001 and only began to receive Zemaira® treatment upon entry into study CE1226_3001 represent the Delayed Start group. This group had a maximal exposure of 2 years at the end of study CE1226_3001. The subjects in this group were from the Intention-to-treat population. Subjects may not have been included in all efficacy analyses because of missing efficacy assessments.

    Primary: Rate of change of adjusted lung density

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    End point title
    		 Rate of change of adjusted lung density
    End point description
    As measured by centralized, standardized computer tomographic (CT) lung densitometry. CT scans were acquired at 2 inspiration states: TLC (Total Lung Capacity; ie, full inspiration) and FRC (Functional Residual Capacity; ie, full expiration). Results were adjusted for total lung volume and are presented as point estimates for the average rate of decline in the early start and delayed start subgroups from a linear random regression model with country, inspiration state (only for 'TLC and FRC state'), time (time elapsed since Day 1 [CE1226_4001]), treatment and treatment by time interaction as fixed effects and subject and subject by time interaction as random coefficients.
    End point type
    Primary
    End point timeframe
    Up to 2 years
    End point values
    		 Zemaira® (Early Start) Zemaira® (Delayed Start)
    Number of subjects analysed
    75
    64
    Units: g/L per year
    least squares mean (standard error)
        TLC + FRC combined
    -1.632 ± 0.2824
    -1.352 ± 0.2961
        TLC
    -1.627 ± 0.2743
    -1.256 ± 0.2891
        FRC
    -1.658 ± 0.3186
    -1.482 ± 0.3346
    Statistical analysis title
    		 TLC and FRC combined
    Statistical analysis description
    Analysis of the annual rate of change in lung density (for TLC + FRC combined) was a linear random regression model with country, inspiration state, time since Day 1 [CE1226_4001], and treatment-by-time interaction as fixed effects and subject and subject-by-time interaction as random coefficients at a 1-sided significance level of 0.025.
    Comparison groups
    Zemaira® (Early Start) v Zemaira® (Delayed Start)
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.752 [1]
    Method
    		 Regression, Linear
    Parameter type
    		 Difference in lung density(adjusted P15)
    Point estimate
    -0.279
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.089
         upper limit
    		 0.53
    Notes
    [1] - A 1-sided P-value < 0.025 and a positive estimate of the treatment difference Early Start minus Delayed Start (ie, the lower bound of the 95% confidence interval [CI] being > zero) will indicate superiority of Early Start compared with Delayed Start.
    Statistical analysis title
    		 TLC
    Statistical analysis description
    Analysis of the annual rate of change in lung density (for TLC) was a linear random regression model with country, time since Day 1 [CE1226_4001], and treatment-by-time interaction as fixed effects and subject and subject-by-time interaction as random coefficients at a 1-sided significance level of 0.025.
    Comparison groups
    Zemaira® (Early Start) v Zemaira® (Delayed Start)
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.823 [2]
    Method
    		 Regression, Linear
    Parameter type
    		 Difference in lung density(adjusted P15)
    Point estimate
    -0.371
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.159
         upper limit
    		 0.417
    Notes
    [2] - A 1-sided P-value < 0.025 and a positive estimate of the treatment difference Early Start minus Delayed Start (ie, the lower bound of the 95% CI being > zero) will indicate superiority of Early Start compared with Delayed Start.
    Statistical analysis title
    		 FRC
    Statistical analysis description
    Analysis of the annual rate of change in lung density (for FRC) was a linear random regression model with country, time since Day 1 [CE1226_4001], and treatment-by-time interaction as fixed effects and subject and subject-by-time interaction as random coefficients at a 1-sided significance level of 0.025.
    Comparison groups
    Zemaira® (Early Start) v Zemaira® (Delayed Start)
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.648 [3]
    Method
    		 Regression, Linear
    Parameter type
    		 Difference in lung density(adjusted P15)
    Point estimate
    -0.176
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.09
         upper limit
    		 0.738
    Notes
    [3] - A 1-sided P-value < 0.025 and a positive estimate of the treatment difference Early Start minus Delayed Start (ie, the lower bound of the 95% CI being > zero) will indicate superiority of Early Start compared with Delayed Start.

    Secondary: Absolute change in adjusted lung density

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    End point title
    		 Absolute change in adjusted lung density
    End point description
    Absolute change from baseline to 2 years as measured by centralized, standardized CT lung densitometry. CT scans were acquired at 2 inspiration states: TLC (ie, full inspiration) and FRC (ie, full expiration). Results were adjusted for total lung volume and are presented as point estimates for the average absolute change in the early start and delayed start subgroups from an analysis of covariance (ANCOVA) model with country, treatment, and baseline lung density as fixed effects and inspiration state as a repeated random effect. The baseline is the last assessment from the preceding study CE1226_4001.
    End point type
    Secondary
    End point timeframe
    From baseline to 2 years
    End point values
    		 Zemaira® (Early Start) Zemaira® (Delayed Start)
    Number of subjects analysed
    64
    60
    Units: g/L
    least squares mean (standard error)
        TLC and FRC combined, n = 64, 60
    -3.031 ± 0.5888
    -2.502 ± 0.6142
        TLC, n = 64, 59
    -2.971 ± 0.5826
    -2.485 ± 0.6142
        FRC, n = 64, 60
    -2.934 ± 0.6671
    -2.953 ± 0.6993
    Statistical analysis title
    		 TLC + FRC combined
    Statistical analysis description
    Analysis of the change in lung density (for TLC + FRC combined) from baseline to 2 years was analyzed using an ANCOVA model with country, treatment, and baseline lung density as fixed effects and inspiration state as a repeated random effect.
    Comparison groups
    Zemaira® (Early Start) v Zemaira® (Delayed Start)
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.526 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in lung density(adjusted P15)
    Point estimate
    -0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.179
         upper limit
    		 1.12
    Notes
    [4] - Two-sided P-value
    Statistical analysis title
    		 TLC
    Statistical analysis description
    Analysis of the change in lung density (for TLC) from baseline to 2 years was analyzed using an ANCOVA model with country, treatment, and baseline lung density as fixed effects.
    Comparison groups
    Zemaira® (Early Start) v Zemaira® (Delayed Start)
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.558 [5]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in lung density(adjusted P15)
    Point estimate
    -0.486
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.126
         upper limit
    		 1.154
    Notes
    [5] - Two-sided P-value
    Statistical analysis title
    		 FRC
    Statistical analysis description
    Analysis of the change in lung density (for FRC) from baseline to 2 years was analyzed using an ANCOVA model with country, treatment, and baseline lung density as fixed effects.
    Comparison groups
    Zemaira® (Early Start) v Zemaira® (Delayed Start)
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.984 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in lung density(adjusted P15)
    Point estimate
    0.019
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.858
         upper limit
    		 1.895
    Notes
    [6] - Two-sided P-value

    Secondary: Percent change in adjusted lung density

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    End point title
    		 Percent change in adjusted lung density
    End point description
    Percent change from baseline to 2 years as measured by centralized, standardized CT lung densitometry. CT scans were acquired at 2 inspiration states: TLC (ie, full inspiration) and FRC (ie, full expiration). Results were adjusted for total lung volume and are presented as point estimates for the average percent change in the early start and delayed start subgroups from an ANCOVA model with country, treatment, and baseline lung density as fixed effects and inspiration state as a repeated random effect. The baseline is the last assessment from the preceding study CE1226_4001.
    End point type
    Secondary
    End point timeframe
    From baseline to 2 years
    End point values
    		 Zemaira® (Early Start) Zemaira® (Delayed Start)
    Number of subjects analysed
    64
    60
    Units: Percent change from baseline
    least squares mean (standard error)
        TLC and FRC combined, n = 64, 60
    -6.741 ± 1.4031
    -7.035 ± 1.4671
        TLC, n = 64, 59
    -6.825 ± 1.4286
    -6.674 ± 1.5061
        FRC, n = 64, 60
    -6.494 ± 1.5027
    -8.281 ± 1.5752
    Statistical analysis title
    		 TLC and FRC combined
    Statistical analysis description
    Analysis of the percent change in lung density (for TLC + FRC combined) from baseline to 2 years was analyzed using an ANCOVA model with country, treatment, and baseline lung density as fixed effects and inspiration state as a repeated random effect.
    Comparison groups
    Zemaira® (Early Start) v Zemaira® (Delayed Start)
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.883 [7]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in lung density(adjusted P15)
    Point estimate
    0.294
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.645
         upper limit
    		 4.233
    Notes
    [7] - Two-sided P-value
    Statistical analysis title
    		 TLC
    Statistical analysis description
    Analysis of the percent change in lung density (for TLC) from baseline to 2 years was analyzed using an ANCOVA model with country, treatment, and baseline lung density as fixed effects.
    Comparison groups
    Zemaira® (Early Start) v Zemaira® (Delayed Start)
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.941 [8]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in lung density(adjusted P15)
    Point estimate
    -0.151
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.172
         upper limit
    		 3.87
    Notes
    [8] - Two-sided P-value
    Statistical analysis title
    		 FRC
    Statistical analysis description
    Analysis of the percent change in lung density (for FRC) from baseline to 2 years was analyzed using an ANCOVA model with country, treatment, and baseline lung density as fixed effects.
    Comparison groups
    Zemaira® (Early Start) v Zemaira® (Delayed Start)
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.404 [9]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in lung density(adjusted P15)
    Point estimate
    1.787
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.44
         upper limit
    		 6.014
    Notes
    [9] - Two-sided P-value

    Secondary: Change in subject-reported symptoms

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    End point title
    		 Change in subject-reported symptoms
    End point description
    Patient-reported symptoms were measured using the St George's Respiratory Questionnaire (SGRQ). SGRQ total, symptoms, activity and impact scores range from 0 to 100, with higher scores indicating more limitations, and change from baseline below zero (0) is favorable, indicating improvement.
    End point type
    Secondary
    End point timeframe
    From baseline to 2 years
    End point values
    		 Zemaira® (Early Start) Zemaira® (Delayed Start)
    Number of subjects analysed
    67
    58
    Units: Units on a scale (change from baseline)
    arithmetic mean (standard deviation)
        Total score, n = 62, 56
    1.185 ± 13.624
    1.499 ± 12.0507
        Symptoms score, n = 67, 58
    6.601 ± 22.29
    0.728 ± 19.2189
        Activity score, n = 67, 57
    0.55 ± 14.1429
    2.831 ± 14.0013
        Impact score, n = 65, 57
    -0.22 ± 15.8999
    1.626 ± 13.5699
    No statistical analyses for this end point

    Secondary: Percent change in lung function as measured by forced expiratory volume in 1 second (FEV1)

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    End point title
    		 Percent change in lung function as measured by forced expiratory volume in 1 second (FEV1)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline up to 2 years
    End point values
    		 Zemaira® (Early Start) Zemaira® (Delayed Start)
    Number of subjects analysed
    69
    56
    Units: Percent change from baseline
        arithmetic mean (standard deviation)
    -8.61 ± 12.9541
    -8.666 ± 10.9057
    No statistical analyses for this end point

    Secondary: Percent change in lung function as measured by ratio of FEV1/FVC (forced vital capacity)

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    End point title
    		 Percent change in lung function as measured by ratio of FEV1/FVC (forced vital capacity)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline up to 2 years
    End point values
    		 Zemaira® (Early Start) Zemaira® (Delayed Start)
    Number of subjects analysed
    69
    56
    Units: Percent change from baseline
        arithmetic mean (standard deviation)
    0.56 ± 12.9685
    -5.441 ± 10.8993
    No statistical analyses for this end point

    Secondary: Percent change in lung function as measured by percent predicted FEV1

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    End point title
    		 Percent change in lung function as measured by percent predicted FEV1
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline up to 2 years
    End point values
    		 Zemaira® (Early Start) Zemaira® (Delayed Start)
    Number of subjects analysed
    68
    54
    Units: Percent change from baseline
        arithmetic mean (standard deviation)
    -7.165 ± 13.2053
    -6.958 ± 11.0846
    No statistical analyses for this end point

    Secondary: Number of subjects with pulmonary exacerbations

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    End point title
    		 Number of subjects with pulmonary exacerbations
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    		 Zemaira® (Early Start) Zemaira® (Delayed Start)
    Number of subjects analysed
    76
    64
    Units: Subjects
        No exacerbation
    13
    16
        Overall (at least 1 exacerbation)
    63
    48
        Moderate exacerbation
    60
    46
        Severe exacerbation
    17
    11
        Neither moderate or severe exacerbation
    21
    17
    No statistical analyses for this end point

    Secondary: Annual rate in subject years of pulmonary exacerbations

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    End point title
    		 Annual rate in subject years of pulmonary exacerbations
    End point description
    Annual exposure‑adjusted incidence rate of pulmonary exacerbations.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    		 Zemaira® (Early Start) Zemaira® (Delayed Start)
    Number of subjects analysed
    76
    64
    Units: Exacerbations/subject year
        number (confidence interval 95%)
    1.71 (1.49 to 1.92)
    1.39 (1.18 to 1.59)
    No statistical analyses for this end point

    Secondary: Time to first pulmonary exacerbation

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    End point title
    		 Time to first pulmonary exacerbation
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    		 Zemaira® (Early Start) Zemaira® (Delayed Start)
    Number of subjects analysed
    76
    64
    Units: years
        median (confidence interval 95%)
    0.405 (0.315 to 0.687)
    0.602 (0.287 to 0.843)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Treatment Emergent Adverse Events

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    End point title
    		 Percentage of Subjects With Treatment Emergent Adverse Events
    End point description
    Percentage of subjects with treatment-emergent adverse events (TEAEs): overall, by severity, by relatedness, by seriousness, and which occurred within 24 hours of Zemaira® administration.
    End point type
    Secondary
    End point timeframe
    From baseline up to 2.5 years
    End point values
    		 Zemaira® (Early Start) Zemaira® (Delayed Start)
    Number of subjects analysed
    76
    64
    Units: Percentage of subjects
    number (not applicable)
        Any TEAE
    100
    96.9
        Mild TEAE
    19.7
    15.6
        Moderate TEAE
    50
    51.6
        Severe TEAE
    30.3
    29.7
        Any related TEAE
    14.5
    10.9
        Any serious TEAE
    36.8
    35.9
        Any TEAE within 24 hrs
    86.8
    79.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 2.5 years
    Adverse event reporting additional description
    Treatment-emergent adverse events are presented.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Zemaira®
    Reporting group description
    		 The safety population comprised all subjects enrolled in study CE1226_3001 and who received at least 1 administration of Zemaira® during study CE1226_3001.

    Serious adverse events
    		 Zemaira®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    51 / 140 (36.43%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    2 / 140 (1.43%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Hysterectomy
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung transplant
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Strangulated hernia repair
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    2 / 140 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cerebral thrombosis
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypotonia
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    3 / 140 (2.14%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    17 / 140 (12.14%)
         occurrences causally related to treatment / all
    0 / 43
         deaths causally related to treatment / all
    0 / 1
    Pneumothorax
         subjects affected / exposed
    2 / 140 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nocturnal dyspnoea
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 140 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    6 / 140 (4.29%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 140 (2.86%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    2 / 140 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Zemaira®
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    137 / 140 (97.86%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    28 / 140 (20.00%)
         occurrences all number
    58
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    27 / 140 (19.29%)
         occurrences all number
    71
    Oedema peripheral
         subjects affected / exposed
    12 / 140 (8.57%)
         occurrences all number
    13
    Pyrexia
         subjects affected / exposed
    10 / 140 (7.14%)
         occurrences all number
    15
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    11 / 140 (7.86%)
         occurrences all number
    11
    Nausea
         subjects affected / exposed
    10 / 140 (7.14%)
         occurrences all number
    11
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    50 / 140 (35.71%)
         occurrences all number
    137
    Oropharyngeal pain
         subjects affected / exposed
    19 / 140 (13.57%)
         occurrences all number
    21
    Dyspnoea
         subjects affected / exposed
    17 / 140 (12.14%)
         occurrences all number
    40
    Cough
         subjects affected / exposed
    15 / 140 (10.71%)
         occurrences all number
    27
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    15 / 140 (10.71%)
         occurrences all number
    19
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    40 / 140 (28.57%)
         occurrences all number
    72
    Lower respiratory tract infection
         subjects affected / exposed
    20 / 140 (14.29%)
         occurrences all number
    106
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 140 (11.43%)
         occurrences all number
    37
    Influenza
         subjects affected / exposed
    15 / 140 (10.71%)
         occurrences all number
    17
    Oral candidiasis
         subjects affected / exposed
    13 / 140 (9.29%)
         occurrences all number
    37
    Bronchitis
         subjects affected / exposed
    12 / 140 (8.57%)
         occurrences all number
    22
    Pneumonia
         subjects affected / exposed
    10 / 140 (7.14%)
         occurrences all number
    17
    Sinusitis
         subjects affected / exposed
    8 / 140 (5.71%)
         occurrences all number
    15
    Urinary tract infection
         subjects affected / exposed
    8 / 140 (5.71%)
         occurrences all number
    14

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jul 2008
    Protocol version 2 harmonized the statistical analysis methods to match those foreseen for study CE1226_4001 and introduced a more detailed efficacy analysis.
    15 May 2013
    Protocol version 4 reflects changes to the statistical analysis plan for study CE1226_3001 following the corroboration of study CE1226_4001 data with the EXACTLE results (Dirksen et al 2009). An interim analysis was added to study CE1226_3001 to occur 2 years prior to study completion, to assess the disease-modifying potential over 4 years.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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