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    Clinical Trial Results:
    A single (assessor) - blind, randomised, three-period, cross-over study to compare the safety of flutiform® pMDI, fluticasone pMDI and beclometasone Autohaler® in paediatric subjects aged 5 to less than 12 years with mild persistent asthma by means of knemometry.

    Summary
    EudraCT number
    2013-004719-32
    Trial protocol
    DK  
    Global end of trial date
    13 Jun 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Feb 2016
    First version publication date
    03 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    FLT2504
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02063139
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Mundipharma Research Ltd.
    Sponsor organisation address
    Cambridge Science Park, Milton Road, Cambridge, United Kingdom, CB4 0GW
    Public contact
    European Medical Operations, Mundipharma Research Ltd, 0044 1223 424900, info@contact-clinical-trails.com
    Scientific contact
    European Medical Operations, Mundipharma Research Ltd, 0044 1223 424900, info@contact-clinical-trails.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
    13 Jun 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Jun 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    •To show non-inferiority of flutiform pMDI 50/5 µg (2 puffs bid) versus fluticasone pMDI 50 µg (2 puffs bid) based on the mean lower leg growth rates.
    Protection of trial subjects
    Over the course of the study there were 3 periods of 2 weeks each (the run-in and 2 washout periods) during which subjects were not treated with inhaled corticosteroids (but were able to use salbutamol rescue medication). To minimise the risk to subjects during these periods, only children with mild asthma treated with a short acting beta agonist (SABA) alone or non-ICS controller were enrolled such that the risk of not administering inhaled corticosteroids during the run-in / washout periods was low. Regarding the ethics of conducting a growth suppressive study, the total treatment-related growth inhibition during this short-term trial would have been expected to be less than 1 millimetre. Furthermore this inhibition would cease on discontinuation of the study treatment and no long-term residual impacts on growth would be expected.
    Background therapy
    Salbutamol Airomir® Autohaler® rescue medication (breath actuated inhaler) was used in the run in, wash-out and treatment periods, as required, up to four occasions per day (2 puffs on each occasion). If a subject required rescue medication on more than 4 occasions on any day they were to contact the Investigator.
    Evidence for comparator
    Flixotide Evohaler was chosen as the primary comparator as it contains the same ICS component as Flutiform and represents the same pharmaceutical form (a pressurised metered dose inhaler). The benefit:risk of Flixotide in paediatric asthma is long established hence this product is an appropriate comparator against which to gauge the safety of the ICS component of Flutiform. Both products were used in conjunction with a spacer device, which is consistent with the GINA recommendation to use a pMDI in conjunction with a spacer as a first line device option in paediatric asthma. A third treatment arm, Aerobec Autohaler (also known as QVAR Autohaler), containing the ICS Beclometasone, was included in the study for exploratory purposes to evaluate potential differences in suppressive effects between different ICS / device combinations and to serve as a positive control. The Autohaler is a breath-actuated pressurised metered dose inhaler approved for use in children aged 5 and above in Denmark and multiple other EU member states.
    Actual start date of recruitment
    24 Feb 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 48
    Worldwide total number of subjects
    48
    EEA total number of subjects
    48
    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)
    48
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    All 48 subjects were randomised in one site in Denmark between 10 Mar 2014 and 27 Mar 2014.

    Pre-assignment
    Screening details
    A total of 48 subjects provided written informed consent and were screened and, as no subjects failed screening, all 48 subjects were randomised into the study. Two subjects discontinued early from the study due to subject’s choice.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Assessor [1]
    Blinding implementation details
    The assessor undertaking lower leg measurements via knemometry was blinded to study treatment (the “assessing” investigator). A different “treating” investigator was responsible for supervising study treatment.The subject and treating investigator were open to the treatment being taken during each treatment period. The study team, including persons involved in conducting the analysis of the study, remained blinded to the treatments patients were randomised to until after study database lock.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Flutiform
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Flutiform
    Investigational medicinal product code
    Other name
    Fluticasone/ formoterol
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    50/5 µg, 2 puffs, Q12h

    Arm title
    Fluticasone
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Flixotide
    Investigational medicinal product code
    Other name
    Fluticasone propionate
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    50 µg, 2 puffs, Q12h

    Arm title
    Beclometasone
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Beclometasone
    Investigational medicinal product code
    Other name
    QVAR
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    50 µg, 2 puffs, Q12h

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: The investigator and patient were un-blinded. The Assessor taking the measurements was blinded and therefore the single blinded description. The system does not allow us to enter this without giving the warning.
    Number of subjects in period 1
    Flutiform Fluticasone Beclometasone
    Started
    48
    48
    48
    Run-in
    48
    48
    48
    Treatment Period 1
    48
    48
    48
    Wash-out Period 1
    48
    48
    48
    Treatment Period 2
    48
    48
    48
    Wash-out Period 2
    48
    48
    48
    Treatment Period 3
    48
    48
    46
    Post Study
    48
    48
    46
    Completed
    48
    48
    46
    Not completed
    0
    0
    2
         Consent withdrawn by subject
    -
    -
    2

    Baseline characteristics

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

    Reporting group values
    Overall Period Total
    Number of subjects
    48 48
    Age categorical
    Units: Subjects
        Children (5-11)
    48 48
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    0 0
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    8.7 ± 1.65 -
    Gender categorical
    Units: Subjects
        Female
    10 10
        Male
    38 38
    Subject analysis sets

    Subject analysis set title
    Randomised Population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All subjects who were randomised to a treatment sequence.

    Subject analysis set title
    Full Analysis Population
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomised subjects who received at least one dose of investigational medicinal product (IMP) and had a valid baseline and at least one valid post-baseline lower leg growth rate value

    Subject analysis set title
    Per Protocol Population
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All overall Full Analysis Population subjects without major protocol deviations.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population was defined as all randomised subjects who received at least one dose of study medication (IMP).

    Subject analysis sets values
    Randomised Population Full Analysis Population Per Protocol Population Safety Population
    Number of subjects
    48
    48
    38
    48
    Age categorical
    Units: Subjects
        Children (5-11)
    48
    48
    38
    48
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    0
    0
    0
    0
        From 65-84 years
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    8.7 ± 1.65
    8.7 ± 1.65
    8.8 ± 1.54
    8.7 ± 1.65
    Gender categorical
    Units: Subjects
        Female
    10
    10
    8
    10
        Male
    38
    38
    30
    38

    End points

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    End points reporting groups
    Reporting group title
    Flutiform
    Reporting group description
    -

    Reporting group title
    Fluticasone
    Reporting group description
    -

    Reporting group title
    Beclometasone
    Reporting group description
    -

    Subject analysis set title
    Randomised Population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All subjects who were randomised to a treatment sequence.

    Subject analysis set title
    Full Analysis Population
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomised subjects who received at least one dose of investigational medicinal product (IMP) and had a valid baseline and at least one valid post-baseline lower leg growth rate value

    Subject analysis set title
    Per Protocol Population
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All overall Full Analysis Population subjects without major protocol deviations.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population was defined as all randomised subjects who received at least one dose of study medication (IMP).

    Primary: Difference in mean lower leg growth rate (LLGR) between Flutiform and Fluticasone treatments

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    End point title
    Difference in mean lower leg growth rate (LLGR) between Flutiform and Fluticasone treatments [1]
    End point description
    Measurement of lower leg growth (LLG) using the knemometer was taken at each visit by an assessor who was blinded to the study treatment. Knemometry measurements at visits 1 to 7 were taken at the same time (+/- 1 hour) on the same day of the week whenever possible, corresponding to the beginning and the end of each treatment or wash-out period. For each subject LLG in each period (run-in, treatment, washout) was calculated as the change in LLL during the respective period. The primary analysis was based on LLG in treatment period.
    End point type
    Primary
    End point timeframe
    Each Treatment Phase was 14 days, separated by 14 days for the wash-out period.
    Notes
    [1] - 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: Each endpoint listed compares 2 out of the 3 arms in the baseline period. The 3 endpoints include reporting statistics for all 3 arms.
    End point values
    Flutiform Fluticasone
    Number of subjects analysed
    30
    30
    Units: mm/week
        least squares mean (confidence interval 95%)
    0.417 (0.349 to 0.486)
    0.423 (0.355 to 0.491)
    Statistical analysis title
    Non-inferiority of Flutiform versus Fluticasone
    Statistical analysis description
    The null hypothesis was: -0.2 > µFlutiform - µfluticasone The mean lower leg growth rate during treatment (mm/week) was analysed using an Analysis of Covariance (ANCOVA) model, with fixed terms for treatment, period, treatment sequence, baseline lower leg growth rate and FEV1% predicted value at baseline and subject within sequence as a random effect.
    Comparison groups
    Flutiform v Fluticasone
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    P-value
    < 0.001 [3]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.006
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.095
         upper limit
    0.084
    Notes
    [2] - A non-inferiority margin of -0.2mm/week was used, based on an estimated placebo growth rate of 0.4mm/week, the observation, that 25 to 50% reduction in short-term lower leg growth rate translates to a reduction in medium term growth rate of between 0.5 to 1.5cm/year, and considering the technical error margin of 0.1mm associated with knemometry. The intended power for the test of non-inferiority of Flutiform versus Fluticasone was set to 90%.
    [3] - The null hypothesis was tested with a one-sided significance level of 0.025 (being equivalent to a two-sided test at a 0.05 level of significance).

    Primary: Difference in mean lower leg growth rate (LLGR) between Flutiform and Beclometasone treatments

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    End point title
    Difference in mean lower leg growth rate (LLGR) between Flutiform and Beclometasone treatments [4]
    End point description
    Measurement of lower leg growth using the knemometer was taken at each visit by an assessor who was blinded to the study treatment. Knemometry measurements at visits 1 to 7 were taken at the same time (+/- 1 hour) on the same day of the week whenever possible, corresponding to the beginning and the end of each treatment or wash-out period. For each subject LLG in each period (run-in, treatment, washout) was calculated as the change in LLL during the respective period. The primary analysis was based on LLG in treatment period.
    End point type
    Primary
    End point timeframe
    Each Treatment Phase was 14 days, separated by 14 days for the wash-out period.
    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: Each endpoint listed compares 2 out of the 3 arms in the baseline period. The 3 endpoints include reporting statistics for all 3 arms.
    End point values
    Flutiform Beclometasone
    Number of subjects analysed
    28
    28
    Units: mm/week
        least squares mean (confidence interval 95%)
    0.385 (0.29 to 0.48)
    0.269 (0.174 to 0.364)
    Statistical analysis title
    Superiority of Flutiform versus Beclometasone
    Statistical analysis description
    The null hypothesis was that the difference in means is 0 mm/week The mean lower leg growth rate during treatment (mm/week) was analysed using an Analysis of Covariance (ANCOVA) model, with fixed terms for treatment, period, treatment sequence, baseline growth rate and FEV1% predicted value at baseline and subject within sequence as a random effect.
    Comparison groups
    Flutiform v Beclometasone
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.057 [6]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.116
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.004
         upper limit
    0.235
    Notes
    [5] - A difference of 0 mm/week was used.
    [6] - 2-sided p-value of treatment comparison based on the null hypothesis that the difference in means is 0 mm/week.

    Primary: Difference in mean lower leg growth rate (LLGR) between Fluticasone and Beclometasone treatments

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    End point title
    Difference in mean lower leg growth rate (LLGR) between Fluticasone and Beclometasone treatments [7]
    End point description
    Measurement of lower leg growth using the knemometer was taken at each visit by an assessor who was blinded to the study treatment. Knemometry measurements at visits 1 to 7 were taken at the same time (+/- 1 hour) on the same day of the week whenever possible, corresponding to the beginning and the end of each treatment or wash-out period. For each subject LLG in each period (run-in, treatment, washout) was calculated as the change in LLL during the respective period. The primary analysis was based on LLG in treatment period.
    End point type
    Primary
    End point timeframe
    Each Treatment Phase was 14 days, separated by 14 days for the wash-out period.
    Notes
    [7] - 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: Each endpoint listed compares 2 out of the 3 arms in the baseline period. The 3 endpoints include reporting statistics for all 3 arms.
    End point values
    Fluticasone Beclometasone
    Number of subjects analysed
    34
    34
    Units: mm/week
        least squares mean (confidence interval 95%)
    0.399 (0.337 to 0.46)
    0.235 (0.174 to 0.296)
    Statistical analysis title
    Superiorty of Fluticasone versus Beclometasone
    Statistical analysis description
    The null hypothesis was that the difference in means is 0 mm/week.
    Comparison groups
    Beclometasone v Fluticasone
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    < 0.001 [9]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.163
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.078
         upper limit
    0.249
    Notes
    [8] - The mean lower leg growth rate during treatment (mm/week) was analysed using an Analysis of Covariance (ANCOVA) model, with fixed terms for treatment, period, treatment sequence, baseline lower leg growth rate and FEV1% predicted value at baseline and subject within sequence as a random effect.
    [9] - 2-sided p-value of treatment comparison based on the null hypothesis that the difference in means is 0 mm/week.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were recorded from the point at which the Informed Consent was signed until 7 days after the subject left the study. This included new AEs that were reported in the 7 days following the subject’s completion/discontinuation visit.
    Adverse event reporting additional description
    Any AE that was still ongoing 7 days after the completion/discontinuation visit had an outcome of ‘ongoing’ in the CRF; SAEs were followed until the event resolved or the event or sequelae stabilized. A treatment emergent AE was defined as any AE with an onset date on or after the first dose of IMP, or worsened after the first dose of IMP.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Flutiform
    Reporting group description
    -

    Reporting group title
    Fluticasone
    Reporting group description
    -

    Reporting group title
    Beclometasone
    Reporting group description
    -

    Serious adverse events
    Flutiform Fluticasone Beclometasone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Flutiform Fluticasone Beclometasone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 48 (8.33%)
    3 / 48 (6.25%)
    3 / 46 (6.52%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 48 (4.17%)
    1 / 46 (2.17%)
         occurrences all number
    1
    2
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    2
    0
    0
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
         occurrences all number
    0
    1
    0
    Tonsillitis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Anger
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
         occurrences all number
    0
    1
    0
    Restlessness
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Eye infection
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    0
    1

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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