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    Clinical Trial Results:
    A Comparison of Symbicort SMART (Symbicort Turbuhaler 160/4,5 mcg, 1 inhalation b.i.d. plus as needed) and conventional best practice for the treatment of persistent asthma in adolescents and adults – a 26-week, open-labelled, parallel-group, multicentre study

    Summary
    EudraCT number
    		 2005-000532-25
    Trial protocol
    		 IS   LT   LV   CZ   SK  
    Global end of trial date
    06 Jun 2008

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Apr 2016
    First version publication date
    28 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D5890L00014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    AstraZeneca R&D, Lund, Sweden,
    Public contact
    Tomas LG Andersson, AstraZeneca, clinicaltrialtranparency@astrazeneca.com
    Scientific contact
    Tomas LG Andersson, AstraZeneca, clinicaltrialtranparency@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 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jun 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jun 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to compare the efficacy of Symbicort SMART with treatment according to conventional best practice in adolescent and adult patients with persistent asthma.
    Protection of trial subjects
    The final study protocol, including the final version of the Informed Consent Form, was approved or given a favourable opinion in writing by an IRB or IEC as appropriate. The investigator submitted written approval to AstraZeneca before he or she enrolled any patient into the study. The principal investigator(s) at each centre ensured that the patient/patient’s legally acceptable representative was given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study. Patients were also notified that they were free to discontinue from the study at any time. The patient was given the opportunity to ask questions and allowed time to consider the information provided. The patient’s signed and dated informed consent was obtained before conducting any procedure specifically for the study,
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Jul 2005
    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
    Chile: 60
    Country: Number of subjects enrolled
    Croatia: 100
    Country: Number of subjects enrolled
    Czech Republic: 72
    Country: Number of subjects enrolled
    Greece: 134
    Country: Number of subjects enrolled
    Iceland: 100
    Country: Number of subjects enrolled
    Latvia: 110
    Country: Number of subjects enrolled
    Lithuania: 110
    Country: Number of subjects enrolled
    Portugal: 108
    Country: Number of subjects enrolled
    Slovakia: 121
    Country: Number of subjects enrolled
    Slovenia: 80
    Worldwide total number of subjects
    995
    EEA total number of subjects
    935
    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)
    52
    Adults (18-64 years)
    943
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a 26-week, randomised, open-label, parallel group study, recruiting patients from 10 countries.

    Pre-assignment
    Screening details
    		 The study consisted of an enrolment/randomization visit, and 3 further visits (Visits 2, 3 and 4) at 4, 13 and 26 weeks, with a telephone contact at weeks 2, 11 and 24. Subjects received 1 of 2 open label treatments allocated in a random order.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Symbicort 160/4.5μg
    Arm description
    		 Symbicort 160/4.5μg, 1 inhalation b.i.d. + as needed
    Arm type
    		 Experimental

    Investigational medicinal product name
    Symbicort 160/4.5μg, 1 inhalation b.i.d. + as needed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Symbicort 160/4.5μg, 1 inhalation b.i.d. + as needed

    Arm title
    		 Conventional Best Practice (CBP)
    Arm description
    		 Conventional Best Practice
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Symbicort 160/4.5μg Conventional Best Practice (CBP)
    Started
    497
    498
    Completed
    470
    467
    Not completed
    27
    31
         Consent withdrawn by subject
    5
    2
         Adverse event, non-fatal
    6
    3
         Other
    5
    5
         Lost to follow-up
    8
    18
         Protocol deviation
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Symbicort 160/4.5μg
    Reporting group description
    		 Symbicort 160/4.5μg, 1 inhalation b.i.d. + as needed

    Reporting group title
    Conventional Best Practice (CBP)
    Reporting group description
    		 Conventional Best Practice

    Reporting group values
    		 Symbicort 160/4.5μg Conventional Best Practice (CBP) Total
    Number of subjects
    		 497 498 995
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 24 28 52
        Adults (18-64 years)
    		 473 470 943
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.1 ( 15.7 ) 45.2 ( 16.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 323 315 638
        Male
    		 174 183 357
    Time since diagnosis
    Units: years
        median (full range (min-max))
    		 10.2 (0.7 to 62.7) 9.2 (0.3 to 70.9) -

    End points

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    End points reporting groups
    Reporting group title
    Symbicort 160/4.5μg
    Reporting group description
    		 Symbicort 160/4.5μg, 1 inhalation b.i.d. + as needed

    Reporting group title
    Conventional Best Practice (CBP)
    Reporting group description
    		 Conventional Best Practice

    Primary: Patients with severe exacerbations

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    End point title
    		 Patients with severe exacerbations
    End point description
    End point type
    Primary
    End point timeframe
    26 weeks
    End point values
    		 Symbicort 160/4.5μg Conventional Best Practice (CBP)
    Number of subjects analysed
    497
    498
    Units: Patients
    46
    61
    Statistical analysis title
    		 Time to first severe exacerbation
    Comparison groups
    Conventional Best Practice (CBP) v Symbicort 160/4.5μg
    Number of subjects included in analysis
    995
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.107
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.728
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.495
         upper limit
    		 1.071

    Secondary: Number of severe exacerbations

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    End point title
    		 Number of severe exacerbations
    End point description
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    		 Symbicort 160/4.5μg Conventional Best Practice (CBP)
    Number of subjects analysed
    497
    498
    Units: patients
        No. with 1 event
    32
    47
        No. with 2 events
    12
    12
        No. with 3 events
    1
    2
        No. with > 3 events
    1
    0
    Statistical analysis title
    		 Mean number of severe exacerbations
    Comparison groups
    Symbicort 160/4.5μg v Conventional Best Practice (CBP)
    Number of subjects included in analysis
    995
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.246
    Method
    		 Poisson regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.821
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.589
         upper limit
    		 1.146

    Secondary: Mean no of inhalations per day

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    End point title
    		 Mean no of inhalations per day
    End point description
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    		 Symbicort 160/4.5μg Conventional Best Practice (CBP)
    Number of subjects analysed
    463
    462
    Units: average no per day
        arithmetic mean (full range (min-max))
    0.95 (0 to 7.357)
    1.078 (0 to 8.96)
    Statistical analysis title
    		 Mean no of inhalations per day
    Comparison groups
    Symbicort 160/4.5μg v Conventional Best Practice (CBP)
    Number of subjects included in analysis
    925
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.14
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.129
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.043

    Secondary: As needed free days (%)

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    End point title
    		 As needed free days (%)
    End point description
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    		 Symbicort 160/4.5μg Conventional Best Practice (CBP)
    Number of subjects analysed
    460
    459
    Units: Percentage
        arithmetic mean (full range (min-max))
    59.037 (0 to 100)
    59.425 (0 to 100)
    Statistical analysis title
    		 As needed free days (%)
    Statistical analysis description
    Percentage of as needed rescue medication free days
    Comparison groups
    Symbicort 160/4.5μg v Conventional Best Practice (CBP)
    Number of subjects included in analysis
    919
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.874
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.388
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.184
         upper limit
    		 4.408

    Secondary: Mean daily dose of inhaled steroids

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    End point title
    		 Mean daily dose of inhaled steroids
    End point description
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    		 Symbicort 160/4.5μg Conventional Best Practice (CBP)
    Number of subjects analysed
    463
    442
    Units: μg
        arithmetic mean (full range (min-max))
    471.9 (320 to 1497.1)
    515.5 (125 to 1333.3)
    Statistical analysis title
    		 Mean daily dose of inhaled steroids
    Comparison groups
    Symbicort 160/4.5μg v Conventional Best Practice (CBP)
    Number of subjects included in analysis
    905
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.002
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -43.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -71.4
         upper limit
    		 -15.6

    Secondary: Mean daily dose (μg BDP or equivalent)

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    End point title
    		 Mean daily dose (μg BDP or equivalent)
    End point description
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    		 Symbicort 160/4.5μg Conventional Best Practice (CBP)
    Number of subjects analysed
    463
    442
    Units: μg BDP or equivalent
        arithmetic mean (full range (min-max))
    737.4 (500 to 2339.3)
    852 (250 to 2666.7)
    Statistical analysis title
    		 Mean daily dose (μg BDP or equivalent)
    Comparison groups
    Symbicort 160/4.5μg v Conventional Best Practice (CBP)
    Number of subjects included in analysis
    905
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -114.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -160.3
         upper limit
    		 69

    Secondary: Average overall Asthma Control Questionnaire (ACQ) score in the treatment period

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    End point title
    		 Average overall Asthma Control Questionnaire (ACQ) score in the treatment period
    End point description
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    		 Symbicort 160/4.5μg Conventional Best Practice (CBP)
    Number of subjects analysed
    213
    212
    Units: average score
        arithmetic mean (full range (min-max))
    1.11 (0 to 4.2)
    1.215 (0 to 4.267)
    Statistical analysis title
    		 Change in average overall ACQ score
    Statistical analysis description
    Change in average overall ACQ score during the treatment period
    Comparison groups
    Symbicort 160/4.5μg v Conventional Best Practice (CBP)
    Number of subjects included in analysis
    425
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.092
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.116
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.252
         upper limit
    		 0.019

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the enrolment visit until viist 4 (26 weeks after randomisation). Only AEs occuring on or after the first dose of study medication are presented in the summaries below.
    Adverse event reporting additional description
    A total of 260 patients reported non-serious adverse events; 125 on Symbicort Symbicort 160/4.5μg, 135 on CBP. Numbers for non-serious AEs in the reporting group table are based on the 5% threshold frequency.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    9.1
    Reporting groups
    Reporting group title
    Conventional Best Practice (CBP)
    Reporting group description
    		 Conventional Best Practice

    Reporting group title
    Symbicort 160/4.5μg
    Reporting group description
    		 Symbicort 160/4.5μg, 1 inhalation b.i.d. + as needed

    Serious adverse events
    		 Conventional Best Practice (CBP) Symbicort 160/4.5μg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 493 (2.23%)
    6 / 493 (1.22%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Multiple Myeloma
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 493 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 493 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic Stroke
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 493 (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
    Sudden Cardiac Death
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 493 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    Angioedema
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 493 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulitis
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 493 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 493 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchitis
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 493 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    3 / 493 (0.61%)
    0 / 493 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 493 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis viral
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 493 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 493 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 493 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus lesion
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 493 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial Infection
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 493 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 493 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Conventional Best Practice (CBP) Symbicort 160/4.5μg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 493 (4.67%)
    20 / 493 (4.06%)
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory infection
         subjects affected / exposed
    9 / 493 (1.83%)
    11 / 493 (2.23%)
         occurrences all number
    13
    11
    Infections and infestations
    Common cold
         subjects affected / exposed
    14 / 493 (2.84%)
    9 / 493 (1.83%)
         occurrences all number
    15
    10

    More information

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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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    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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