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    Clinical Trial Results:
    Control of moderate or severe asthma with 160, 320 and 640 mcg ciclesonide/day. A one-year randomised, double-blind, multicenter trial.

    Summary
    EudraCT number
    2011-000683-99
    Trial protocol
    DE  
    Global end of trial date
    15 Aug 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    11 Aug 2016
    First version publication date
    10 May 2016
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Harmonization

    Trial information

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    Trial identification
    Sponsor protocol code
    CL-9709-301-RD
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    U1111-1133-6333
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    61 Aldwych, London, United Kingdom, WC2B 4AE
    Public contact
    Program Manager, Takeda Development Centre Europe Ltd., +1 877-825-3327, clinicaltrialregistry@tpna.com
    Scientific contact
    Program Manager, Takeda Development Centre Europe Ltd., +1 877-825-3327, clinicaltrialregistry@tpna.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of the trial is to investigate asthma control with 160 to 640 mcg ciclesonide/day. Asthma control will be assessed by the Asthma Control Questionnaire (ACQ).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    10 Nov 2011
    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
    Brazil: 86
    Country: Number of subjects enrolled
    Argentina: 72
    Country: Number of subjects enrolled
    Germany: 60
    Country: Number of subjects enrolled
    Israel: 59
    Country: Number of subjects enrolled
    Russian Federation: 90
    Worldwide total number of subjects
    367
    EEA total number of subjects
    60
    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)
    16
    Adults (18-64 years)
    314
    From 65 to 84 years
    37
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects took part in the study at 5 investigative sites in Argentina, Brazil, Germany, Israel and Russia from 10 November 2011 to 15 August 2014.

    Pre-assignment
    Screening details
    Subjects with a historical diagnosis of persistent bronchial asthma for at least 6 months,treated with a stable inhaled corticosteroid (ICS)dose for at least 12 weeks were enrolled in a single-blind baseline period receiving 160 microgram(mcg)ciclesonide,then a double-blind treatment period in 1 of 3 treatment arms: ciclesonide 160,320,640 mcg.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment Period: Ciclesonide 160 mcg
    Arm description
    Ciclesonide 80 mcg, metered dose inhaler (MDI), inhalational, twice daily for up to 3 weeks in the baseline period. Ciclesonide 80 mcg, MDI, inhalational, twice daily for up to 52 weeks in the double blind treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Ciclesonide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Ciclesonide 80 mcg, metered dose inhaler (MDI), inhalational, twice daily for up to 3 weeks in the baseline period. Ciclesonide 80 mcg, MDI, inhalational, twice daily for up to 52 weeks in the double blind treatment period.

    Arm title
    Treatment Period: Ciclesonide 320 mcg
    Arm description
    Ciclesonide 160 mcg, MDI, inhalational, twice daily for up to 52 weeks in the double blind treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Ciclesonide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Ciclesonide 160 mcg, MDI, inhalational, twice daily for up to 52 weeks in the double blind treatment period.

    Arm title
    Treatment Period: Ciclesonide 640 mcg
    Arm description
    Ciclesonide 320 mcg, MDI, inhalational, twice daily for up to 52 weeks in the double blind treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Ciclesonide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Ciclesonide 320 mcg, MDI, inhalational, twice daily for up to 52 weeks in the double blind treatment period.

    Number of subjects in period 1
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Period: Ciclesonide 640 mcg
    Started
    120
    122
    125
    Completed
    89
    92
    97
    Not completed
    31
    30
    28
         Miscellaneous
    5
    1
    4
         Pregnancy
    1
    1
    -
         Adverse event, non-fatal
    1
    1
    3
         Consent withdrawn by subject
    16
    12
    9
         Deterioration in asthma
    6
    14
    9
         Lost to follow-up
    -
    1
    1
         Discontinuation criterion fulfilled
    2
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period: Ciclesonide 160 mcg
    Reporting group description
    Ciclesonide 80 mcg, metered dose inhaler (MDI), inhalational, twice daily for up to 3 weeks in the baseline period. Ciclesonide 80 mcg, MDI, inhalational, twice daily for up to 52 weeks in the double blind treatment period.

    Reporting group title
    Treatment Period: Ciclesonide 320 mcg
    Reporting group description
    Ciclesonide 160 mcg, MDI, inhalational, twice daily for up to 52 weeks in the double blind treatment period.

    Reporting group title
    Treatment Period: Ciclesonide 640 mcg
    Reporting group description
    Ciclesonide 320 mcg, MDI, inhalational, twice daily for up to 52 weeks in the double blind treatment period.

    Reporting group values
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Period: Ciclesonide 640 mcg Total
    Number of subjects
    120 122 125 367
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    43.2 ± 14.86 44.7 ± 15.6 45.3 ± 16.22 -
    Gender, Male/Female
    Units: subjects
        Female
    72 77 81 230
        Male
    48 45 44 137
    Race/Ethnicity, Customized
    Units: Subjects
        Black or African American
    6 5 4 15
        White
    113 115 114 342
        Unknown or Not Reported
    1 2 7 10
    History of exacerbations
    Asthma exacerbations were defined as a worsening of asthma requiring either treatment with oral (or other systemic) glucocorticosteroids for at least 3 days or hospitalisation or a visit to the emergency room because of asthma.
    Units: Subjects
        0x
    70 70 63 203
        1x
    17 19 21 57
        2-3
    4 3 4 11
        4+
    0 0 0 0
        Unknown
    29 30 37 96
    Smoking Status
    Units: Subjects
        Never
    109 102 109 320
        Current
    1 1 1 3
        Former
    10 19 15 44
    Prestudy ICS dose
    Units: Subjects
        <200(mcg/day) fluticasone propionate(FP)equivalent
    3 3 2 8
        Low: ≥200 mcg/day (≤) 250 mcg/day FP equivalent
    40 37 42 119
        Medium:>250 mcg/day to ≤500 mcg/day FP equivalent
    72 75 70 217
        High:>500 mcg/day to ≤1000 mcg/day FP equivalent
    5 7 11 23
    Height
    Units: meter (m)
        arithmetic mean (standard deviation)
    1.65 ± 0.093 1.66 ± 0.101 1.65 ± 0.104 -
    Weight
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    74.59 ± 16.371 77.98 ± 18.993 73.72 ± 14.66 -
    Body Mass Index
    Units: kilogram per meter square (kg/m2)
        arithmetic mean (standard deviation)
    27.34 ± 5.217 28.42 ± 6.346 27.12 ± 5.373 -
    Baseline asthma control questionnaire (ACQ)
    ACQ=5 questions about symptoms,1 question about beta 2-agonist use and 1 about lung function (FEV1% predicted).Subjects recall their experiences during the previous 7 days and respond to each question using a 7-point scale.The items are equally weighted and the ACQ score is the mean of 7 items and ranges between 0 (well controlled) and 6 (extremely poorly controlled). Mean scores of =<0.75 indicate well-controlled asthma, scores between 0.76 and < 1.5 indicate partly controlled asthma, and a score >= 1.5 indicates uncontrolled asthma.
    Units: units on scale
        arithmetic mean (standard deviation)
    2.24 ± 0.304 2.16 ± 0.384 2.2 ± 0.361 -
    Pre-forced expiratory volume in 1 second (FEV1)
    Pre-FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration prior to salbutamol administration.
    Units: liter (L)
        arithmetic mean (standard deviation)
    2.2 ± 0.792 2.35 ± 0.798 2.23 ± 0.801 -
    Post-FEV1
    Post-FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration after salbutamol administration.
    Units: Lx
        arithmetic mean (standard deviation)
    2.71 ± 0.915 2.84 ± 0.883 2.76 ± 0.906 -
    FEV1 reversibility
    Reversibility is assessed using FEV1 measurements. Percent reversibility is calculated as the difference between highest FEV1 after salbutamol and highest FEV 1 before salbutamol divided by highest FEV 1 before salbutamol. FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration.
    Units: Lx
        arithmetic mean (standard deviation)
    25.5 ± 17.02 23 ± 17.1 26.5 ± 20.78 -
    Pre FEV1 predicted
    Pre-FEV1 is the maximal predicted volume of air exhaled in the first second of a forced expiration from a position of full inspiration prior to salbutamol administration calculated according to the respective formula for different age groups of subjects.
    Units: Lx
        arithmetic mean (standard deviation)
    69.095 ± 18.4683 74.345 ± 16.7285 71.835 ± 18.4365 -
    Post FEV1 predicted
    Post-FEV1 is the maximal predicted volume of air exhaled in the first second of a forced expiration from a position of full inspiration after salbutamol administration calculated according to the respective formula for different age groups of subjects.
    Units: Lx
        arithmetic mean (standard deviation)
    84.893 ± 19.3038 90.168 ± 17.7365 88.505 ± 17.7105 -

    End points

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    End points reporting groups
    Reporting group title
    Treatment Period: Ciclesonide 160 mcg
    Reporting group description
    Ciclesonide 80 mcg, metered dose inhaler (MDI), inhalational, twice daily for up to 3 weeks in the baseline period. Ciclesonide 80 mcg, MDI, inhalational, twice daily for up to 52 weeks in the double blind treatment period.

    Reporting group title
    Treatment Period: Ciclesonide 320 mcg
    Reporting group description
    Ciclesonide 160 mcg, MDI, inhalational, twice daily for up to 52 weeks in the double blind treatment period.

    Reporting group title
    Treatment Period: Ciclesonide 640 mcg
    Reporting group description
    Ciclesonide 320 mcg, MDI, inhalational, twice daily for up to 52 weeks in the double blind treatment period.

    Subject analysis set title
    Treatment Periods: Ciclesonide 640 mcg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Ciclesonide 320 mcg, MDI, inhalational, twice daily for up to 52 weeks in the double blind treatment period.

    Primary: Asthma Control Questionnaire (ACQ) Score at Baseline

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    End point title
    Asthma Control Questionnaire (ACQ) Score at Baseline [1]
    End point description
    The ACQ was developed to measure the adequacy of asthma control in clinical research and in clinical practice. It includes 5 questions about symptoms, 1 question about beta 2 -agonist use and 1 about lung function (FEV1% predicted). Subjects recall their experiences during the previous 7 days and respond to each question using a 7-point scale. The items are equally weighted and the ACQ score is the mean of 7 items and ranges between 0 (well controlled) and 6 (extremely poorly controlled). Mean scores of =<0.75 indicate well-controlled asthma, scores between 0.76 and < 1.5 indicate partly controlled asthma, and a score >= 1.5 indicates uncontrolled asthma. The intent-to-treat (ITT) analysis set included subjects having at least 1 postrandomization efficacy assessment.
    End point type
    Primary
    End point timeframe
    Baseline
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Period: Ciclesonide 640 mcg
    Number of subjects analysed
    120
    119
    122
    Units: units on a scale
        arithmetic mean (standard error)
    2.24 ± 0.031
    2.15 ± 0.035
    2.19 ± 0.032
    No statistical analyses for this end point

    Primary: Change from Baseline in ACQ Score to Tlast

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    End point title
    Change from Baseline in ACQ Score to Tlast
    End point description
    The ACQ was developed to measure the adequacy of asthma control in clinical research and in clinical practice. It includes 5 questions about symptoms, 1 question about beta 2 -agonist use and 1 about lung function (FEV1% predicted). Subjects recall their experiences during the previous 7 days and respond to each question using a 7-point scale. The items are equally weighted and the ACQ score is the mean of 7 items and ranges between 0 (well controlled) and 6 (extremely poorly controlled). Mean scores of =<0.75 indicate well-controlled asthma, scores between 0.76 and < 1.5 indicate partly controlled asthma, and a score >= 1.5 indicates uncontrolled asthma. The ITT analysis set included subjects having at least 1 postrandomization efficacy assessment.
    End point type
    Primary
    End point timeframe
    Week 52
    End point values
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Period: Ciclesonide 640 mcg
    Number of subjects analysed
    120
    119
    122
    Units: units on a scale
        arithmetic mean (standard error)
    -0.833 ± 0.1028
    -0.799 ± 0.1019
    -0.955 ± 0.0969
    Statistical analysis title
    Ciclesonide 160 mcg vs Ciclesonide 640 mcg
    Statistical analysis description
    Least square (LS) mean difference were derived from an ANCOVA model with baseline ACQ and age as covariates, and treatment, centre pool, sex, and prestudy ICS dose as factors.
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2988
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.122
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.353
         upper limit
    0.109
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1175
    Statistical analysis title
    Ciclesonide 160 mcg vs Ciclesonide 320 mcg
    Statistical analysis description
    LS mean difference were derived from an ANCOVA model with baseline ACQ and age as covariates, and treatment, centre pool, sex, and prestudy ICS dose as factors.
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 320 mcg
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7741
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.034
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.198
         upper limit
    0.266
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.118
    Statistical analysis title
    Ciclesonide 320 mcg vs Ciclesonide 640 mcg
    Statistical analysis description
    LS mean difference were derived from an ANCOVA model with baseline ACQ and age as covariates, and treatment, centre pool, sex, and prestudy ICS dose as factors.
    Comparison groups
    Treatment Period: Ciclesonide 320 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    241
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1835
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.156
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.387
         upper limit
    0.074
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1172

    Secondary: Time Course of ACQ

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    End point title
    Time Course of ACQ
    End point description
    Time course of incidence of 0.5 points improvement of ACQ score was evaluated.Mean ACQ values over time by treatment group for on-treatment site measurements assessed. It was done on a weekly base using home-based and site-based ACQ measurements. ACQ=5 questions about symptoms,1 question about beta 2-agonist use and 1 about lung function (FEV1% predicted).Subjects recall their experiences during the previous 7 days and respond to each question using a 7-point scale.The items are equally weighted and the ACQ score is the mean of 7 items and ranges between 0 (well controlled) and 6 (extremely poorly controlled). Mean scores of =<0.75 indicate well-controlled asthma, scores between 0.76 and < 1.5 indicate partly controlled asthma, and a score >= 1.5 indicates uncontrolled asthma". The ITT analysis set included subjects having at least 1 postrandomization efficacy assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52 (Treatment period)
    End point values
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Period: Ciclesonide 640 mcg
    Number of subjects analysed
    105
    108
    115
    Units: Weeks
        median (full range (min-max))
    1.1 (0 to 4.4)
    1 (0 to 3.9)
    1 (0 to 4.6)
    No statistical analyses for this end point

    Secondary: Time to Well-Controlled Asthma Over the Course of the Study

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    End point title
    Time to Well-Controlled Asthma Over the Course of the Study
    End point description
    The time to well-controlled asthma was defined as the number of weeks from randomization to the first instance with an ACQ score of 0.75 or lower. The ACQ was developed to measure the adequacy of asthma control in clinical research and in clinical practice. It includes 5 questions about symptoms, 1 question about beta 2 -agonist use and 1 about lung function (FEV1% predicted). Subjects recall their experiences during the previous 7 days and respond to each question using a 7-point scale. The items are equally weighted and the ACQ score is the mean of 7 items and ranges between 0 (well controlled) and 6 (extremely poorly controlled). Mean scores of =<0.75 indicate well-controlled asthma, scores between 0.76 and < 1.5 indicate partly controlled asthma, and a score >= 1.5 indicates uncontrolled asthma. The intent-to-treat ITT analysis set included subjects having at least 1 postrandomization efficacy assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52 (treatment period)
    End point values
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Period: Ciclesonide 640 mcg
    Number of subjects analysed
    120
    119
    122
    Units: weeks
        number (not applicable)
    1211
    1514
    1447
    Statistical analysis title
    Ciclesonide 160 mcg vs Ciclesonide 640 mcg
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 320 mcg
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4175
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Hodges-Lehmann point estimate
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    5
    Statistical analysis title
    Ciclesonide 160 mcg vs Ciclesonide 320 mcg
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8465
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Hodges-Lehmann point estimate
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3
         upper limit
    4

    Secondary: Number of Subjects With Well-controlled Asthma and ACQ Improvement at the End of the Study

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    End point title
    Number of Subjects With Well-controlled Asthma and ACQ Improvement at the End of the Study
    End point description
    Well-controlled asthma at the end of the study was defined as a subjects with an ACQ score of 0.75 or lower. The ACQ was developed to measure the adequacy of asthma control in clinical research and in clinical practice. It includes 5 questions about symptoms, 1 question about beta 2 -agonist use and 1 about lung function (FEV1% predicted). Subjects recall their experiences during the previous 7 days and respond to each question using a 7-point scale. The items are equally weighted and the ACQ score is the mean of 7 items and ranges between 0 (well controlled) and 6 (extremely poorly controlled). Mean scores of =<0.75 indicate well-controlled asthma, scores between 0.76 and < 1.5 indicate partly controlled asthma, and a score >= 1.5 indicates uncontrolled asthma. The intent-to-treat ITT analysis set included subjects having at least 1 postrandomization efficacy assessment.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Period: Ciclesonide 640 mcg
    Number of subjects analysed
    120
    122
    125
    Units: subjects
    number (not applicable)
        Well-controlled Asthma
    38
    45
    51
        ACQ Improvement
    87
    81
    85
    Statistical analysis title
    Wellcontrolled Asthma Ciclesonide 160mcgvs320mcg
    Statistical analysis description
    Well-controlled Asthma
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 320 mcg
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4186
    Method
    Fisher exact
    Confidence interval
    Statistical analysis title
    Wellcontrolled Asthma Ciclesonide 160mcgvs640mcg
    Statistical analysis description
    Well-controlled Asthma
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.146
    Method
    Fisher exact
    Confidence interval
    Statistical analysis title
    Wellcontrolled Asthma Ciclesonide 320mcgvs640mcg
    Statistical analysis description
    Well-controlled Asthma
    Comparison groups
    Treatment Period: Ciclesonide 320 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.6017
    Method
    Fisher exact
    Confidence interval
    Statistical analysis title
    ACQ Improvement Ciclesonide 160 mcg vs 320 mcg
    Statistical analysis description
    ACQ Improvement
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 320 mcg
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3305
    Method
    Fisher exact
    Confidence interval
    Statistical analysis title
    ACQ Improvement Ciclesonide 160 mcg vs 640 mcg
    Statistical analysis description
    ACQ Improvement
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.486
    Method
    Fisher exact
    Confidence interval
    Statistical analysis title
    ACQ Improvement Ciclesonide 320 mcg vs 640 mcg
    Statistical analysis description
    ACQ Improvement
    Comparison groups
    Treatment Period: Ciclesonide 320 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8922
    Method
    Fisher exact
    Confidence interval

    Secondary: Number of Subjects Reporting Time to First Well-Controlled Asthma and ACQ Improvement

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    End point title
    Number of Subjects Reporting Time to First Well-Controlled Asthma and ACQ Improvement
    End point description
    Well-controlled asthma at the end of the study was defined as a subjects with an ACQ score of 0.75 or lower.The ACQ was developed to measure the adequacy of asthma control in clinical research and in clinical practice. It includes 5 questions about symptoms, 1 question about beta 2 -agonist use and 1 about lung function (FEV1% predicted). Subjects recall their experiences during the previous 7 days and respond to each question using a 7-point scale. The items are equally weighted and the ACQ score is the mean of 7 items and ranges between 0 (well controlled) and 6 (extremely poorly controlled). Mean scores of =<0.75 indicate well-controlled asthma, scores between 0.76 and < 1.5 indicate partly controlled asthma, and a score >= 1.5 indicates uncontrolled asthma. The ITT analysis set included subjects having at least 1 postrandomization efficacy assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52 (treatment period)
    End point values
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Period: Ciclesonide 640 mcg
    Number of subjects analysed
    120
    122
    125
    Units: subjects
    number (not applicable)
        Well-controlled Asthma
    73
    84
    81
        ACQ Improvement
    112
    107
    115
    Statistical analysis title
    Well-controlled Asthma Ciclesonide 160mcgvs640 mcg
    Statistical analysis description
    Well-controlled Asthma
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.6062
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.042
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    1.221
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0806
    Statistical analysis title
    ACQ Improvement Ciclesonide 160 mcg vs 640 mcg
    Statistical analysis description
    ACQ Improvement
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4674
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.921
         upper limit
    1.197
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0669
    Statistical analysis title
    Well-controlled Asthma Ciclesonide 160mcgvs320 mcg
    Statistical analysis description
    Well-controlled Asthma
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 320 mcg
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2523
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.201
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.878
         upper limit
    1.642
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1597
    Statistical analysis title
    ACQ Improvement Ciclesonide 160 mcg vs 320 mcg
    Statistical analysis description
    ACQ Improvement
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 320 mcg
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.5026
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.913
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.191
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1354
    Statistical analysis title
    Well-controlled Asthma Ciclesonide 320mcgvs640 mcg
    Statistical analysis description
    Well-controlled Asthma
    Comparison groups
    Treatment Period: Ciclesonide 320 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4893
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.898
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.661
         upper limit
    1.219
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.156
    Statistical analysis title
    ACQ Improvement Ciclesonide 320 mcg vs 640 mcg
    Statistical analysis description
    ACQ Improvement
    Comparison groups
    Treatment Period: Ciclesonide 320 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2193
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.181
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.906
         upper limit
    1.538
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1351

    Secondary: Number of Subjects Reporting Time to First Well-Controlled Asthma Measurement by ACQ Cut-Off Point

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    End point title
    Number of Subjects Reporting Time to First Well-Controlled Asthma Measurement by ACQ Cut-Off Point
    End point description
    Well-controlled asthma was defined as an ACQ score of equal to or lower than the ACQ cut-off point.The ACQ was developed to measure the adequacy of asthma control in clinical research and in clinical practice. It includes 5 questions about symptoms, 1 question about beta 2 -agonist use and 1 about lung function (FEV1% predicted). Subjects recall their experiences during the previous 7 days and respond to each question using a 7-point scale. The items are equally weighted and the ACQ score is the mean of 7 items and ranges between 0 (well controlled) and 6 (extremely poorly controlled). Mean scores of =<0.75 indicate well-controlled asthma, scores between 0.76 and < 1.5 indicate partly controlled asthma, and a score >= 1.5 indicates uncontrolled asthma. The ITT analysis set included subjects having at least 1 postrandomization efficacy assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52 (treatment period)
    End point values
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Period: Ciclesonide 640 mcg
    Number of subjects analysed
    120
    122
    125
    Units: subjects
    number (not applicable)
        ACQ cut-off at 0.5
    56
    69
    63
        ACQ cut-off at 1.0
    91
    95
    93
        ACQ cut-off at 1.25
    99
    101
    101
        ACQ cut-off at 1.5
    103
    105
    107
    Statistical analysis title
    ACQ cut-off at 0.5 Ciclesonide 160 mcg vs 640 mcg
    Statistical analysis description
    ACQ cut-off at 0.5
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.5397
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.058
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.884
         upper limit
    1.266
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0917
    Statistical analysis title
    ACQ cut-off at 1.0 Ciclesonide 160 mcg vs 640 mcg
    Statistical analysis description
    ACQ cut-off at 1.0
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.9458
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.005
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.87
         upper limit
    1.161
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0738
    Statistical analysis title
    ACQ cut-off at 1.25 Ciclesonide 160 mcg vs 640 mcg
    Statistical analysis description
    ACQ cut-off at 1.25
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7213
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.026
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.893
         upper limit
    1.178
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0708
    Statistical analysis title
    ACQ cut-off at 1.5 Ciclesonide 160 mcg vs 640 mcg
    Statistical analysis description
    ACQ cut-off at 1.5
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4807
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.917
         upper limit
    1.202
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0692
    Statistical analysis title
    ACQ cut-off at 0.5 Ciclesonide 160 mcg vs 320 mcg
    Statistical analysis description
    ACQ cut-off at 0.5
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 320 mcg
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.115
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.326
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.934
         upper limit
    1.884
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1791
    Statistical analysis title
    ACQ cut-off at 1.0 Ciclesonide 160 mcg vs 320 mcg
    Statistical analysis description
    ACQ cut-off at 1.0
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 320 mcg
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.6281
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.074
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.805
         upper limit
    1.431
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1467
    Statistical analysis title
    ACQ cut-off at 1.25 Ciclesonide 160 mcg vs 320 mcg
    Statistical analysis description
    ACQ cut-off at 1.25
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 320 mcg
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.6853
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.059
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.803
         upper limit
    1.397
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1415
    Statistical analysis title
    ACQ cut-off at 1.5 Ciclesonide 160 mcg vs 320 mcg
    Statistical analysis description
    ACQ cut-off at 1.5
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 320 mcg
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.6995
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.055
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.804
         upper limit
    1.385
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1388
    Statistical analysis title
    ACQ cut-off at 0.5 Ciclesonide 320 mcg vs 640 mcg
    Statistical analysis description
    ACQ cut-off at 0.5
    Comparison groups
    Treatment Period: Ciclesonide 320 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.308
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.837
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.595
         upper limit
    1.178
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1744
    Statistical analysis title
    ACQ cut-off at 1.0 Ciclesonide 160 mcg vs 640 mcg
    Statistical analysis description
    ACQ cut-off at 1.0
    Comparison groups
    Treatment Period: Ciclesonide 320 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.6645
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.939
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.705
         upper limit
    1.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1461
    Statistical analysis title
    ACQ cut-off at 1.25 Ciclesonide 160 mcg vs 640 mcg
    Statistical analysis description
    ACQ cut-off at 1.25
    Comparison groups
    Treatment Period: Ciclesonide 320 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.9564
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.992
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.753
         upper limit
    1.308
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1408
    Statistical analysis title
    ACQ cut-off at 1.5 Ciclesonide 160 mcg vs 640 mcg
    Statistical analysis description
    ACQ cut-off at 1.5
    Comparison groups
    Treatment Period: Ciclesonide 320 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7367
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.047
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    1.371
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1375

    Secondary: Number of Subjects Reporting Time to First Asthma Exacerbation

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    End point title
    Number of Subjects Reporting Time to First Asthma Exacerbation
    End point description
    Asthma exacerbations were defined as a worsening of asthma requiring either treatment with oral (or other systemic) glucocorticosteroids for at least 3 days or hospitalisation or a visit to the emergency room because of asthma. Baseline was defined as the average of the ACQ measurements of the last 2 weeks at site prior to first intake of double-blind study medication. The ITT analysis set included subjects having at least 1 postrandomization efficacy assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52 (treatment period)
    End point values
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Period: Ciclesonide 640 mcg
    Number of subjects analysed
    120
    122
    125
    Units: subjects
        number (not applicable)
    5
    11
    10
    Statistical analysis title
    Ciclesonide 160 mcg vs Ciclesonide 640 mcg
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2264
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.367
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.824
         upper limit
    2.267
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2583
    Statistical analysis title
    Ciclesonide 320 mcg vs Ciclesonide 640 mcg
    Comparison groups
    Treatment Period: Ciclesonide 320 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7732
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.882
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.375
         upper limit
    2.074
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4365
    Statistical analysis title
    Ciclesonide 160 mcg vs Ciclesonide 320 mcg
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 320 mcg
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1373
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    2.102
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.789
         upper limit
    5.602
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5001

    Secondary: Number of Subjects Reporting Asthma Exacerbations Rates

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    End point title
    Number of Subjects Reporting Asthma Exacerbations Rates
    End point description
    Subjects with at least 1 asthma exacerbation in the double-blind treatment period have been reported. As predefined in the protocol, the results for subjects with missing data for any category were not included. The ITT analysis set included subjects having at least 1 postrandomization efficacy assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52 (treatment period)
    End point values
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Period: Ciclesonide 640 mcg
    Number of subjects analysed
    120
    122
    122
    Units: subjects
        number (not applicable)
    5
    10
    10
    Statistical analysis title
    Ciclesonide 160 mcg vs Ciclesonide 320 mcg
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 640 mcg
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.288
    Method
    Fisher exact
    Confidence interval
    Statistical analysis title
    Ciclesonide 160 mcg vs Ciclesonide 640 mcg
    Comparison groups
    Treatment Period: Ciclesonide 160 mcg v Treatment Period: Ciclesonide 320 mcg
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2864
    Method
    Fisher exact
    Confidence interval

    Secondary: Number of Subjects With Markedly High Benefits.

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    End point title
    Number of Subjects With Markedly High Benefits. [2]
    End point description
    Analyses was intended to identify subject subsets that would benefit from dose escalation.Analysis tested the potential factors, including age,sex,pretrial inhaled corticosteroid(ICS) dose category,history of exacerbations,baseline ACQ score,baseline BMI category and smoking status.ACQ=5 questions about symptoms,1 question about beta 2-agonist use and 1 about lung function (FEV1% predicted).Subjects recall their experiences during the previous 7 days and respond to each question using a 7-point scale.The items are equally weighted and the ACQ score is the mean of 7 items and ranges between 0(well controlled) and 6(extremely poorly controlled). Mean scores of =<0.75 indicate well-controlled asthma, scores between 0.76 and <1.5 indicate partly controlled asthma, and a score >=1.5 indicates uncontrolled asthma. SAS included all subjects who took at least 1 dose of study medication.One subjects erroneously randomized into 160 mcg arm actually received 640 mcg dose.
    End point type
    Secondary
    End point timeframe
    Week 1 up to Week 52
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Ciclesonide 640 mcg arm has been reported as subject analysis set created additionally for this endpoint in order to report the 1 subject who was erroneously randomized into this treatment arm.
    End point values
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Periods: Ciclesonide 640 mcg
    Number of subjects analysed
    119
    122
    126
    Units: subjects
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting One or More Treatment-emergent Adverse Events (TEAE)

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    End point title
    Number of Subjects Reporting One or More Treatment-emergent Adverse Events (TEAE) [3]
    End point description
    An Adverse Event(AE) is defined as any untoward medical occurrence in a clinical investigation subject administered a drug; it does not necessarily have to have a causal relationship with this treatment. AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding),symptom,or disease temporally associated with the use of a drug,whether or not it is considered related to the drug. TEAE is defined as an adverse event with an onset that occurs after receiving study drug. AEs included both serious AEs and non-serious AEs. Baseline of double-blind treatment period was defined as the average of the measurements of the last 2 weeks at site prior to first intake of double-blind study medication. SAS included all subjects who took at least 1 dose of study medication. One subject erroneously randomized into 160 mcg arm, actually received 640 mcg dose. For safety analysis, subjects were analyzed based on the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Baseline period (Week -3 up to -1), treatment period (Baseline up to Week 56)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Ciclesonide 640 mcg arm has been reported as subject analysis set created additionally for this endpoint in order to report the 1 subject who was erroneously randomized into this treatment arm.
    End point values
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Periods: Ciclesonide 640 mcg
    Number of subjects analysed
    119
    122
    126
    Units: subjects
        number (not applicable)
    85
    86
    89
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Clinically Significant Change from Baseline in Vital Signs

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    End point title
    Number of Subjects Reporting Clinically Significant Change from Baseline in Vital Signs [4]
    End point description
    Vital signs included body temperature, blood pressure (BP) and pulse rate. Normal range for vital signs included: Systolic BP >170 millimeters of mercury (mm Hg) or <85 mm Hg, Diastolic BP >105 mm Hg, resting pulse rate: >120 bpm or <50 bpm, difference in systolic BP at Visit x (increase or decrease) compared with pretreatment >40 mm Hg and difference in pulse rate at Visit x (increase or decrease) compared with pretreatment >30 bpm. Baseline of double-blind treatment period was defined as the average of the measurements of the last 2 weeks at site prior to first intake of double-blind study medication. Safety analysis set included all subjects who took at least 1 dose of study medication. One subject erroneously randomized into 160 mcg arm, actually received 640 mcg dose. For safety analysis, subjects were analyzed based on the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Baseline period (Week -3 up to -1), treatment period (Baseline up to Week 56)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Ciclesonide 640 mcg arm has been reported as subject analysis set created additionally for this endpoint in order to report the 1 subject who was erroneously randomized into this treatment arm.
    End point values
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Periods: Ciclesonide 640 mcg
    Number of subjects analysed
    119
    122
    126
    Units: subjects
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Clinically Significant Change from Baseline in Physical Examination Findings

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    End point title
    Number of Subjects Reporting Clinically Significant Change from Baseline in Physical Examination Findings [5]
    End point description
    Physical examination consists of examinations of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) physical examinations other than body systems described in (1) to (10). Baseline of double-blind treatment period was defined as the average of the measurements of the last 2 weeks at site prior to first intake of double-blind study medication. Safety analysis set included all subject who took at least 1 dose of study medication. One subject erroneously randomized into 160 mcg arm, actually received 640 mcg dose. For safety analysis, subjects were analyzed based on the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Baseline period (Week -3 up to -1), treatment period (Baseline up to Week 56)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Ciclesonide 640 mcg arm has been reported as subject analysis set created additionally for this endpoint in order to report the 1 subject who was erroneously randomized into this treatment arm.
    End point values
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Periods: Ciclesonide 640 mcg
    Number of subjects analysed
    119
    122
    126
    Units: subjects
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Markedly Abnormal Laboratory Values

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    End point title
    Number of Subjects With Markedly Abnormal Laboratory Values [6]
    End point description
    The number of subjects with any markedly abnormal standard safety laboratory values collected throughout study. Baseline of double-blind treatment period was defined as the average of the measurements of the last 2 weeks at site prior to first intake of double-blind study medication. Safety analysis set included all subjects who took at least 1 dose of study medication. One subject erroneously randomized into 160 mcg arm, actually received 640 mcg dose. For safety analysis, subjects were analyzed based on the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Baseline period (Week -3 up to -1), treatment period (Baseline up to Week 56)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Ciclesonide 640 mcg arm has been reported as subject analysis set created additionally for this endpoint in order to report the 1 subject who was erroneously randomized into this treatment arm.
    End point values
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Periods: Ciclesonide 640 mcg
    Number of subjects analysed
    119
    122
    126
    Units: subjects
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 30 days for a serious adverse event after the last dose of double-blind study drug.
    Adverse event reporting additional description
    Investigator documented any AEs and abnormal laboratory findings.Any event spontaneously reported was recorded,irrespective of the relation to study treatment. 1 subject erroneously randomized into 160 mcg arm,actually received 640 mcg dose.For safety analysis,subjects were analyzed based on the treatment they actually received.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Treatment Period: Ciclesonide 160 mcg
    Reporting group description
    Ciclesonide 80 mcg, MDI, inhalational, twice daily for up to 52 weeks in the double blind treatment period.

    Reporting group title
    Treatment Period: Ciclesonide 320 mcg
    Reporting group description
    Ciclesonide 160 mcg, MDI, inhalational, twice daily for up to 52 weeks in the double blind treatment period.

    Reporting group title
    Treatment Period: Ciclesonide 640 mcg
    Reporting group description
    Ciclesonide 320 mcg, MDI, inhalational, twice daily for up to 52 weeks in the double blind treatment period.

    Serious adverse events
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Period: Ciclesonide 640 mcg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 119 (5.04%)
    9 / 122 (7.38%)
    0 / 126 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 122 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 122 (0.82%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 122 (0.82%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 122 (0.82%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 122 (0.82%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 122 (0.82%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 122 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebellar ischaemia
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 122 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autonomic nervous system imbalance
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 122 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 122 (0.82%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroesophageal reflux disease
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 122 (0.82%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Invertebral disc protrusion
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 122 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 119 (0.00%)
    2 / 122 (1.64%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 122 (0.82%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 122 (0.82%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 122 (0.82%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 122 (0.82%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Treatment Period: Ciclesonide 160 mcg Treatment Period: Ciclesonide 320 mcg Treatment Period: Ciclesonide 640 mcg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    65 / 119 (54.62%)
    65 / 122 (53.28%)
    70 / 126 (55.56%)
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    4 / 119 (3.36%)
    7 / 122 (5.74%)
    4 / 126 (3.17%)
         occurrences all number
    5
    9
    5
    Cough
         subjects affected / exposed
    6 / 119 (5.04%)
    7 / 122 (5.74%)
    3 / 126 (2.38%)
         occurrences all number
    6
    15
    3
    Rhinitis allergic
         subjects affected / exposed
    8 / 119 (6.72%)
    3 / 122 (2.46%)
    6 / 126 (4.76%)
         occurrences all number
    10
    4
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    22 / 119 (18.49%)
    23 / 122 (18.85%)
    16 / 126 (12.70%)
         occurrences all number
    67
    82
    58
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 119 (3.36%)
    2 / 122 (1.64%)
    8 / 126 (6.35%)
         occurrences all number
    7
    5
    14
    Infections and infestations
    Influenza
         subjects affected / exposed
    6 / 119 (5.04%)
    6 / 122 (4.92%)
    11 / 126 (8.73%)
         occurrences all number
    6
    7
    12
    Bronchitis
         subjects affected / exposed
    18 / 119 (15.13%)
    16 / 122 (13.11%)
    16 / 126 (12.70%)
         occurrences all number
    22
    21
    18
    Nasopharyngitis
         subjects affected / exposed
    23 / 119 (19.33%)
    25 / 122 (20.49%)
    22 / 126 (17.46%)
         occurrences all number
    31
    32
    37
    Pharyngitis
         subjects affected / exposed
    4 / 119 (3.36%)
    8 / 122 (6.56%)
    4 / 126 (3.17%)
         occurrences all number
    4
    11
    6
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 119 (5.88%)
    1 / 122 (0.82%)
    6 / 126 (4.76%)
         occurrences all number
    7
    1
    6
    Rhinitis
         subjects affected / exposed
    2 / 119 (1.68%)
    8 / 122 (6.56%)
    4 / 126 (3.17%)
         occurrences all number
    6
    13
    4
    Sinusitis
         subjects affected / exposed
    7 / 119 (5.88%)
    5 / 122 (4.10%)
    8 / 126 (6.35%)
         occurrences all number
    7
    5
    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.
    Refer ClinicalTrials.gov (CL-9709-301-RD,NCT01455194)results of Ciclesonide 160mcg arm baseline period because EUDRACT system does not allow the reporting of data available for the arm, which includes subjects that were not part of target population.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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