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    Clinical Trial Results:
    A pharmacokinetic and pharmacodynamic, randomised, single dose, cross-over, partially blinded study to compare the systemic exposure and the efficacy of a fixed-dose combination of Budesonide-Salmeterol DPI capsule 75-25 μg, Budesonide-Salmeterol DPI capsule 75-12.5 μg, Budesonide-Salmeterol DPI capsule 75-6.25 μg delivered by the Axahaler® versus Serevent® Diskus® 50 μg + Pulmicort® Turbohaler® 100µg co-administration in asthmatic children

    Summary
    EudraCT number
    		 2017-003330-91
    Trial protocol
    		 BG  
    Global end of trial date
    30 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Apr 2019
    First version publication date
    11 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BUSAL-II-17-1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Laboratoires SMB S.A.
    Sponsor organisation address
    26-28 rue de la pastorale, Brussels, Belgium,
    Public contact
    Marcereuil David, Laboratoires SMB S.A., 32 (0)2411 48 28, DptClinique@smb.be
    Scientific contact
    TREMEGE Mickaêl, Laboratoires SMB S.A., 32 (0)2411 48 28, DptClinique@smb.be
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the non-inferiority between budesonide-salmeterol DPI capsule 75/25µg and Serevent® Diskus® 50 μg + Pulmicort® Turbohaler® 100µg co-administration by measurement of the bronchodilating effect To assess and compare the systemic exposure of budesonide after administration of the two study products (budesonide-salmeterol DPI capsule 75/25µg versus Serevent® Diskus® 50 μg + Pulmicort® Turbohaler® 100µg co-administration) in asthmatic children aged from 6 to 11 years old, inclusive.
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practices (GCP), including International Conference on Harmonization (ICH) Guidelines, Directive 2001/20/EC of the European Parliament and the most recent version of the declaration of Helsinki (64th WMA General Assembly, Fortaleza, October 2013).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jan 2018
    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
    Bulgaria: 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
    		 The patients will be screened within 3 weeks prior to the randomization visit. Following all screening procedures, patients who satisfy all of the preliminary inclusion/exclusion criteria will be randomised in the study.

    Pre-assignment
    Screening details
    		 signed informed consent form by his/her parents Demographic data Asthma history Medical history and physical examination Vital signs/ECG Review of prior and conco Measurement of pulmonary function/reversibility test Lab tests Review IC/EC

    Period 1
    Period 1 title
    Study phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Data analyst, Carer, Assessor
    Blinding implementation details
    This is a partly blinded study. Indeed, as the double blind is not feasible due to the impossibility to obtain placebo from the reference products (Serevent® and Pulmicort®), the blind was maintained only for the two lower doses of the budesonide/salmeterol combination. The randomization procedure is applied in the study design to minimize the bias possibility as the investigator will not be able to predict the next treatment option for the sequential patient randomization in the trial

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 BUSAL 75/25µg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budesonide/salmeterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    one capsule a day by inhalation via the Axahaler ®, containing 75μg of budesonide and salmeterol

    Arm title
    		 BUSAL 75/12.5µg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budesonide/salmeterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    one capsule a day by inhalation via the Axahaler ®, containing budesonide and salmeterol

    Arm title
    		 BUSAL 75/6.25µg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budesonide/salmeterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    one capsule a day by inhalation via the Axahaler ®, containing 75μg of budesonide and salmeterol

    Arm title
    		 Serevent/pulmicort50/100µg
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Budesonide/salmeterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    SEREVENT® DISKUS® 50μg, one inhalation via the Diskus ®, each inhalation containing 50μg of salmeterol PULMICORT® TURBOHALER® 100μg, one inhalation taken by inhalation via the turbohaler ®, each inhalation containing 100μg of budesonide

    Number of subjects in period 1
    		BUSAL 75/25µg BUSAL 75/12.5µg BUSAL 75/6.25µg Serevent/pulmicort50/100µg
    Started
    48
    48
    48
    48
    Completed
    45
    45
    45
    45
    Not completed
    3
    3
    3
    3
         Consent withdrawn by subject
    2
    2
    2
    2
         Subject failed to demonstrate FEV1 stability
    1
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Study phase
    Reporting group description
    		 -

    Reporting group values
    		 Study phase Total
    Number of subjects
    		 48 48
    Age categorical
    Units: Subjects
        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)
    		 48 48
        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)
    		 9.30 ± 1.72 -
    Gender categorical
    Units: Subjects
        Female
    		 27 27
        Male
    		 21 21

    End points

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    End points reporting groups
    Reporting group title
    BUSAL 75/25µg
    Reporting group description
    		 -

    Reporting group title
    BUSAL 75/12.5µg
    Reporting group description
    		 -

    Reporting group title
    BUSAL 75/6.25µg
    Reporting group description
    		 -

    Reporting group title
    Serevent/pulmicort50/100µg
    Reporting group description
    		 -

    Primary: FEV1 AUC0-12h

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    End point title
    		 FEV1 AUC0-12h
    End point description
    End point type
    Primary
    End point timeframe
    Clinical assessments should always start in the morning between 07:00 and 10:00 a.m. with study treatment administration done at the same time as the first administration done at Visit 2. Pulmonary function tests will be performed at all visits
    End point values
    		 BUSAL 75/25µg BUSAL 75/12.5µg BUSAL 75/6.25µg Serevent/pulmicort50/100µg
    Number of subjects analysed
    45
    45
    45
    45
    Units: L/sec*h
        arithmetic mean (standard deviation)
    2.72 ± 1.09
    2.23 ± 1.12
    2.09 ± 1.09
    2.64 ± 1.42
    Statistical analysis title
    		 Non-inferiority analysis
    Comparison groups
    BUSAL 75/25µg v Serevent/pulmicort50/100µg
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0068 [1]
    Method
    		 t-test, 1-sided
    Parameter type
    		 ratio Test/reference
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 0.93
         upper limit
    		 -
    Notes
    [1] - Since the lower bound of the 95% CI of the ratio was over the non-inferiority threshold (0.90), the null hypothesis of inferiority was rejected. Therefore BUSAL75-25 µg was demonstrated to be non-inferior to Serevent 50 µg + Pulmicort 100 µg.

    Primary: Cmax

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    End point title
    		 Cmax [2]
    End point description
    End point type
    Primary
    End point timeframe
    The blood sampling were performed at various timepoints only after administration of BUSAL 75/25µg and Serevent/pulmicort 50/100µg.
    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: The objective was to assess and compare the systemic exposure of budesonide after administration of the two study products (budesonide-salmeterol DPI capsule 75/25µg versus Serevent® Diskus® 50 μg + Pulmicort® Turbohaler® 100µg co-administration). Therefore, only these two treatments were compared.
    End point values
    		 BUSAL 75/25µg Serevent/pulmicort50/100µg
    Number of subjects analysed
    43
    43
    Units: pg/ml
        arithmetic mean (standard deviation)
    229.67 ± 94.08
    145.43 ± 64.52
    Statistical analysis title
    		 Bioequivalence test
    Comparison groups
    BUSAL 75/25µg v Serevent/pulmicort50/100µg
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.65
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.45
         upper limit
    		 1.89

    Primary: AUCt

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    End point title
    		 AUCt [3]
    End point description
    End point type
    Primary
    End point timeframe
    The blood samplings were performed at various timepoints on peridos where BUSAL 75/25µg and Serevent/pulmicort were administered.
    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: The objective was to assess and compare the systemic exposure of budesonide after administration of the two study products (budesonide-salmeterol DPI capsule 75/25µg versus Serevent® Diskus® 50 μg + Pulmicort® Turbohaler® 100µg co-administration). Therefore, only these two treatments were compared.
    End point values
    		 BUSAL 75/25µg Serevent/pulmicort50/100µg
    Number of subjects analysed
    43
    43
    Units: pg/ml*min
        arithmetic mean (standard deviation)
    32347.27 ± 9414.34
    22627.58 ± 9862.86
    Statistical analysis title
    		 bioequivalence test
    Comparison groups
    BUSAL 75/25µg v Serevent/pulmicort50/100µg
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.5
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.32
         upper limit
    		 1.7

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Safety profile will be compared using: • Adverse events • Physical examination • Vital signs • 12 lead ECG • Tremor • Serum glucose and potassium measurements
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    BUSAL 75/25µg
    Reporting group description
    		 -

    Reporting group title
    BUSAL 75/12.5µg
    Reporting group description
    		 -

    Reporting group title
    BUSAL 75/6.25µg
    Reporting group description
    		 -

    Reporting group title
    Serevent/Pulmicort 50/100µg
    Reporting group description
    		 -

    Serious adverse events
    		 BUSAL 75/25µg BUSAL 75/12.5µg BUSAL 75/6.25µg Serevent/Pulmicort 50/100µg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 45 (0.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BUSAL 75/25µg BUSAL 75/12.5µg BUSAL 75/6.25µg Serevent/Pulmicort 50/100µg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 45 (0.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No non-serious adverse events superior to the frequency threshold were reported in this study.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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