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    Clinical Trial Results:
    A Phase IIIB, 6-Month, Double-blind, Double-dummy, Randomized, Parallel-group, Multicenter Exacerbation Study of Symbicort® pMDI 160/4.5 μg x 2 Actuations Twice-daily Compared to Formoterol Turbuhaler 4.5 μg x 2 Inhalations Twice-daily in COPD Patients The RISE study – Revealing the Impact of Symbicort in reducing Exacerbations in COPD

    Summary
    EudraCT number
    2014-000593-19
    Trial protocol
    DE   CZ   ES   BG  
    Global end of trial date
    10 Feb 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Feb 2017
    First version publication date
    24 Feb 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D589UC00001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Pepparedsleden 1, Mölndal, Sweden,
    Public contact
    Tor Skärby, AstraZeneca, +46 x, tor.skarby@astrazeneca.com
    Scientific contact
    Tor Skärby, AstraZeneca, +46 x, tor.skarby@astrazeneca.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
    03 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy in reducing exacerbations with Symbicort pMDI 160/4.5 μg x 2 actuations BID versus formoterol Turbuhaler 4.5 μg x 2 inhalations BID in COPD subjects
    Protection of trial subjects
    Albuterol or salbutamol was provided as rescue medication at every study visit as needed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Jun 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 States: 500
    Country: Number of subjects enrolled
    Bulgaria: 159
    Country: Number of subjects enrolled
    Poland: 159
    Country: Number of subjects enrolled
    Argentina: 87
    Country: Number of subjects enrolled
    Germany: 84
    Country: Number of subjects enrolled
    Czech Republic: 77
    Country: Number of subjects enrolled
    South Africa: 57
    Country: Number of subjects enrolled
    Chile: 47
    Country: Number of subjects enrolled
    Mexico: 37
    Country: Number of subjects enrolled
    Spain: 12
    Worldwide total number of subjects
    1219
    EEA total number of subjects
    491
    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)
    674
    From 65 to 84 years
    535
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    After the enrollment visit the entry criteria were confirmed and the subject entered a 4- week run-in period with Symbicort pMDI. Patients who still met the eligibility criteria were thereafter randomized to a 26-week treatment period.

    Period 1
    Period 1 title
    Randomization
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Carer, Data analyst, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Symbicort pMDI
    Arm description
    Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation
    Arm type
    Experimental

    Investigational medicinal product name
    Symbicort pMDI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    160/4.5 ug x2 bid

    Arm title
    Formoterol Turbuhaler
    Arm description
    Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation
    Arm type
    Active comparator

    Investigational medicinal product name
    Formoterol Turbuhaler
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    4.5 μg

    Number of subjects in period 1
    Symbicort pMDI Formoterol Turbuhaler
    Started
    606
    613
    Completed
    606
    613
    Period 2
    Period 2 title
    Overall Study
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Symbicort pMDI
    Arm description
    Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation
    Arm type
    Experimental

    Investigational medicinal product name
    Symbicort pMDI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    160/4.5 ug x2 bid

    Arm title
    Formoterol Turbuhaler
    Arm description
    Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation
    Arm type
    Active comparator

    Investigational medicinal product name
    Formoterol Turbuhaler
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    4.5 μg

    Number of subjects in period 2
    Symbicort pMDI Formoterol Turbuhaler
    Started
    606
    613
    Completed
    567
    548
    Not completed
    39
    65
         Progressive disease
    -
    2
         Protocol deviation
    1
    -
         Other
    5
    12
         Lack of efficacy
    -
    1
         Adverse event, serious fatal
    4
    4
         Adverse event, non-fatal
    3
    5
         Screen failure
    1
    2
         Consent withdrawn by subject
    25
    39

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Symbicort pMDI
    Reporting group description
    Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation

    Reporting group title
    Formoterol Turbuhaler
    Reporting group description
    Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation

    Reporting group values
    Symbicort pMDI Formoterol Turbuhaler Total
    Number of subjects
    606 613 1219
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    345 329 674
        From 65-84 years
    256 279 535
        85 years and over
    5 5 10
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    63.1 ± 8.65 63.9 ± 8.67 -
    Gender, Male/Female
    Units: Participants
        Female
    251 270 521
        Male
    355 343 698
    FEV1 post-bronchodilator
    FEV1 post-bronchodilator categories
    Units: Subjects
        <30%
    59 54 113
        >=30% to <50%
    234 247 481
        >=50% to <=70%
    307 308 615
        >70%
    4 3 7
        missing value
    2 1 3
    Number of prior exacerbations
    Number of exacerbations during 2 - 52 weeks prior to enrollment
    Units: Subjects
        1 exacerbation
    430 448 878
        2 exacerbations
    136 117 253
        3 exacerbations
    29 28 57
        4 exacerbations
    7 13 20
        5 exacerbations
    2 6 8
        6 exacerbations
    0 1 1
        7 exacerbations
    2 0 2

    End points

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    End points reporting groups
    Reporting group title
    Symbicort pMDI
    Reporting group description
    Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation

    Reporting group title
    Formoterol Turbuhaler
    Reporting group description
    Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation
    Reporting group title
    Symbicort pMDI
    Reporting group description
    Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation

    Reporting group title
    Formoterol Turbuhaler
    Reporting group description
    Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation

    Primary: The rate of moderate and severe COPD exacerbations defined as: Worsening of ≥2 major symptoms or worsening of 1 major symptom together with ≥1 minor symptom for ≥2 consecutive days

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    End point title
    The rate of moderate and severe COPD exacerbations defined as: Worsening of ≥2 major symptoms or worsening of 1 major symptom together with ≥1 minor symptom for ≥2 consecutive days
    End point description
    Moderate exacerbation: treatment of symptoms with systemic corticosteroids (≥3 days) and/or antibiotics. Severe exacerbation: symptoms that require hospitalization (including >24 hours in ED/urgent care setting). Major symptom: -Increased dyspnea -Increase in sputum volume -Increase in sputum color/purulence Minor symptoms: -Sore throat -Colds (nasal discharge and/or nasal congestion) -Fever without other cause -Increased cough -Increased wheeze
    End point type
    Primary
    End point timeframe
    Randomization W 0 to End of Treatment (EoT) W 26
    End point values
    Symbicort pMDI Formoterol Turbuhaler
    Number of subjects analysed
    606
    613
    Units: annual rate
        least squares mean (confidence interval 95%)
    0.85 (0.7 to 1.03)
    1.12 (0.93 to 1.35)
    Statistical analysis title
    Comparison the COPD exacerbation rate
    Comparison groups
    Symbicort pMDI v Formoterol Turbuhaler
    Number of subjects included in analysis
    1219
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0059
    Method
    Negative binomial model
    Parameter type
    Rate ratio
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.62
         upper limit
    0.92

    Secondary: Time to first moderate or severe COPD exacerbation - event count

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    End point title
    Time to first moderate or severe COPD exacerbation - event count
    End point description
    Time to first COPD exacerbation in the different treatment arms
    End point type
    Secondary
    End point timeframe
    From randomzation to EoT W 26
    End point values
    Symbicort pMDI Formoterol Turbuhaler
    Number of subjects analysed
    606
    613
    Units: Patients
    171
    204
    Statistical analysis title
    Comparison of time to first COPD exacerbation
    Comparison groups
    Symbicort pMDI v Formoterol Turbuhaler
    Number of subjects included in analysis
    1219
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0164
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    0.96

    Secondary: St. George’s Respiratory Questionnaire (SGRQ)

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    End point title
    St. George’s Respiratory Questionnaire (SGRQ)
    End point description
    St. George's Respiratory Questionnaire for measurement of quality of life in patients with diseases of airways obstruction. Change from baseline over the entire randomized treatment period was summarized and analyzed.
    End point type
    Secondary
    End point timeframe
    From Run-in W -4 to EoT W 26
    End point values
    Symbicort pMDI Formoterol Turbuhaler
    Number of subjects analysed
    589
    593
    Units: Total score
        arithmetic mean (standard deviation)
    -0.855 ± 8.941
    0.442 ± 9.457
    Statistical analysis title
    Comparison on SGRQ total score
    Comparison groups
    Symbicort pMDI v Formoterol Turbuhaler
    Number of subjects included in analysis
    1182
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.007
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.343
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.318
         upper limit
    -0.368

    Secondary: Pre-dose/pre-bronchodilator FEV1 at the study site

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    End point title
    Pre-dose/pre-bronchodilator FEV1 at the study site
    End point description
    Measurement of lung function. Change from baseline over the entire randomized treatment period was summarized and analyzed.
    End point type
    Secondary
    End point timeframe
    From Run-in W -4 to EoT W 26
    End point values
    Symbicort pMDI Formoterol Turbuhaler
    Number of subjects analysed
    588
    589
    Units: Liter
        arithmetic mean (standard deviation)
    0.008 ± 0.21
    -0.025 ± 0.198
    Statistical analysis title
    Comparison of FEV1 between two arms
    Comparison groups
    Symbicort pMDI v Formoterol Turbuhaler
    Number of subjects included in analysis
    1177
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0091
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.008
         upper limit
    0.053

    Secondary: Total rescue medication use (average puffs/day)

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    End point title
    Total rescue medication use (average puffs/day)
    End point description
    Use of rescue medication is a measure of symptoms that need to be treated with a short-acting bronchodilator. Change from baseline over the entire randomized treatment period was summarized and analyzed.
    End point type
    Secondary
    End point timeframe
    From Run-in W -4 to EoT W 26
    End point values
    Symbicort pMDI Formoterol Turbuhaler
    Number of subjects analysed
    602
    607
    Units: puffs/day
        arithmetic mean (standard deviation)
    0.135 ± 1.248
    0.343 ± 1.456
    Statistical analysis title
    Comparison of average usage of rescue medicaiton
    Comparison groups
    Symbicort pMDI v Formoterol Turbuhaler
    Number of subjects included in analysis
    1209
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0082
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.203
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.353
         upper limit
    -0.053

    Secondary: Nights with awakening due to COPD

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    End point title
    Nights with awakening due to COPD
    End point description
    Number of nights awakened due to COPD symptoms correspond to the severity of nocturnal symptoms from COPD. Change from baseline over the entire randomized treatment period was summarized and analyzed.
    End point type
    Secondary
    End point timeframe
    From Run-in W -4 to EoT W 26
    End point values
    Symbicort pMDI Formoterol Turbuhaler
    Number of subjects analysed
    603
    610
    Units: average awakenings/night
        arithmetic mean (standard deviation)
    -0.007 ± 0.173
    0.021 ± 0.195
    Statistical analysis title
    Comparsion average night awakening
    Comparison groups
    Symbicort pMDI v Formoterol Turbuhaler
    Number of subjects included in analysis
    1213
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0048
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.028
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.048
         upper limit
    -0.009

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the randomized treatment period, ie from first treatment to one day after the last treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Symbicort 160/4.5 ug x2 bid
    Reporting group description
    -

    Reporting group title
    Formoterol 4.5 ug x2 bid
    Reporting group description
    -

    Serious adverse events
    Symbicort 160/4.5 ug x2 bid Formoterol 4.5 ug x2 bid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 605 (8.10%)
    63 / 613 (10.28%)
         number of deaths (all causes)
    4
    4
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer female
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device malfunction
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Extradural haematoma
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Face injury
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 605 (0.33%)
    2 / 613 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 605 (0.00%)
    2 / 613 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 605 (0.33%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinoatrial block
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    2 / 605 (0.33%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (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
    20 / 605 (3.31%)
    28 / 613 (4.57%)
         occurrences causally related to treatment / all
    2 / 22
    2 / 29
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic respiratory failure
         subjects affected / exposed
    2 / 605 (0.33%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 605 (0.33%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal lymphadenopathy
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular insufficiency
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 605 (0.17%)
    2 / 613 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         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
    Back pain
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 605 (0.00%)
    2 / 613 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 605 (0.00%)
    2 / 613 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 605 (0.17%)
    2 / 613 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 605 (0.00%)
    5 / 613 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonella bacteraemia
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 613 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis syndrome
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 613 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 605 (0.17%)
    2 / 613 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    Symbicort 160/4.5 ug x2 bid Formoterol 4.5 ug x2 bid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 605 (6.28%)
    56 / 613 (9.14%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    8 / 605 (1.32%)
    27 / 613 (4.40%)
         occurrences all number
    8
    31
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    30 / 605 (4.96%)
    32 / 613 (5.22%)
         occurrences all number
    34
    35

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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