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    Clinical Trial Results:
    A comparative study to assess a fixed-dose combination of Budesonide-Salmeterol versus Serevent® Diskus® 50 μg + Pulmicort® Turbuhaler® 100 µg co-administrated in asthmatic children: single dose, cross-over, randomized, 3-treatment

    Summary
    EudraCT number
    		 2020-003404-14
    Trial protocol
    		 BG  
    Global end of trial date
    26 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Oct 2021
    First version publication date
    31 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BUSAL-SD201
    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
    Clinical Trial Information, Laboratoires SMB S.A., 32 2411 48 28, DptClinique@smb.be
    Scientific contact
    Clinical Trial Information, Laboratoires SMB S.A., 32 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
    01 Jul 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Apr 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to assess and compare the systemic exposure of budesonide and salmeterol after administration of the study products (two dosages of Budesonide-Salmeterol fixed dose combination versus Serevent® Diskus® 50 μg + Pulmicort® Turbuhaler® 100 µg co-administration) using Cmax, AUC∞, AUC0-30min, AUC0-2h, tmax and t1/2.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki “Ethical principles for medical research involving human volunteer”, reviewed during the 64th WMA General Assembly, Fortaleza, 2013, in compliance with the approved protocol, Good Clinical Practices (GCP) and applicable regulatory requirements
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Mar 2021
    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: 14
    Worldwide total number of subjects
    14
    EEA total number of subjects
    14
    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)
    14
    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
    		 -

    Pre-assignment
    Screening details
    		 The screening period was maximum 21 days, the volunteers were randomised according to the inclusion/exclusion criteria, blood and urine analysis, physical test and medical history.

    Period 1
    Period 1 title
    Cross over phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This pharmacokinetic study was a partially blinded study as blindness was maintained only between the both dosages of Budesonide/salmeterol combination.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Pulmicort 100µg + Serevent 50µg
    Arm description
    		 Serevent Diskus 50 µg + Pulmicort Turbuhaler 100 µg co-administration, one dose taken by inhalation via the inhalers, containing 50 µg of salmeterol and 100 µg of budesonide respectively
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Budesonide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One dose taken by inhalation via the inhaler containing 100 µg of budesonide

    Investigational medicinal product name
    salmeterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One dose taken by inhalation via the inhaler containing 50 µg of salmeterol

    Arm title
    		 BUSAL 75/25µg
    Arm description
    		 Budesonide-Salmeterol 75-25 µg (DPI), one capsule taken by inhalation via the Vertical-Haler®, containing 75 µg of budesonide and 25 µg of salmeterol xinafoate
    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 taken by inhalation via the Vertical-Haler®, containing 75 µg of budesonide and 25 µg of salmeterol xinafoate

    Arm title
    		 BUSAL 66/22µg
    Arm description
    		 Budesonide-Salmeterol 66/22 µg (DPI), one capsule taken by inhalation via the Vertical-Haler®, containing 66 µg of budesonide and 22 µg of salmeterol xinafoate
    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 taken by inhalation via the Vertical-Haler containing 66 µg of budesonide and 22 µg of salmeterol xinafoate

    Number of subjects in period 1
    		Pulmicort 100µg + Serevent 50µg BUSAL 75/25µg BUSAL 66/22µg
    Started
    14
    14
    14
    Completed
    14
    14
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cross over phase
    Reporting group description
    		 After being screened, 14 subejcts were randomised in this study and 14 subjects completed the study. The safety and demographic data were analysed with14 subjects and the pharmacokinetic endpoints were analysed with 14 subjects according the SAP.

    Reporting group values
    		 Cross over phase Total
    Number of subjects
    		 14 14
    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)
    		 14 14
        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)
    		 9.29 ± 1.68 -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 5 5

    End points

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    End points reporting groups
    Reporting group title
    Pulmicort 100µg + Serevent 50µg
    Reporting group description
    		 Serevent Diskus 50 µg + Pulmicort Turbuhaler 100 µg co-administration, one dose taken by inhalation via the inhalers, containing 50 µg of salmeterol and 100 µg of budesonide respectively

    Reporting group title
    BUSAL 75/25µg
    Reporting group description
    		 Budesonide-Salmeterol 75-25 µg (DPI), one capsule taken by inhalation via the Vertical-Haler®, containing 75 µg of budesonide and 25 µg of salmeterol xinafoate

    Reporting group title
    BUSAL 66/22µg
    Reporting group description
    		 Budesonide-Salmeterol 66/22 µg (DPI), one capsule taken by inhalation via the Vertical-Haler®, containing 66 µg of budesonide and 22 µg of salmeterol xinafoate

    Primary: Budesonide Cmax

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    End point title
    		 Budesonide Cmax
    End point description
    End point type
    Primary
    End point timeframe
    Period I, period II and Perido III
    End point values
    		 Pulmicort 100µg + Serevent 50µg BUSAL 75/25µg BUSAL 66/22µg
    Number of subjects analysed
    14
    14
    14
    Units: ng/ml
        arithmetic mean (standard deviation)
    95.02 ± 77.94
    190.92 ± 78.34
    135.02 ± 67.10
    Statistical analysis title
    		 T1 vs T2
    Comparison groups
    Pulmicort 100µg + Serevent 50µg v BUSAL 75/25µg
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    243
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 167.23
         upper limit
    		 353.14
    Statistical analysis title
    		 T1vsT3
    Comparison groups
    Pulmicort 100µg + Serevent 50µg v BUSAL 66/22µg
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    173.23
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 109.43
         upper limit
    		 274.21

    Primary: Budesonide AUCt

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    End point title
    		 Budesonide AUCt
    End point description
    End point type
    Primary
    End point timeframe
    Period I, period II and period III
    End point values
    		 Pulmicort 100µg + Serevent 50µg BUSAL 75/25µg BUSAL 66/22µg
    Number of subjects analysed
    14
    14
    14
    Units: ng/ml*min
        arithmetic mean (standard deviation)
    199.51 ± 179.33
    398.60 ± 139.10
    321.09 ± 112.63
    Statistical analysis title
    		 T1 vs T2
    Comparison groups
    Pulmicort 100µg + Serevent 50µg v BUSAL 75/25µg
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 GMR
    Point estimate
    279.96
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 164.7
         upper limit
    		 475.89
    Statistical analysis title
    		 T1 vs T3
    Comparison groups
    Pulmicort 100µg + Serevent 50µg v BUSAL 66/22µg
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 GMR
    Point estimate
    235.82
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 134.92
         upper limit
    		 412.17

    Primary: Salmeterol Cmax

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    End point title
    		 Salmeterol Cmax
    End point description
    End point type
    Primary
    End point timeframe
    PI, PII and PIII
    End point values
    		 Pulmicort 100µg + Serevent 50µg BUSAL 75/25µg BUSAL 66/22µg
    Number of subjects analysed
    14
    14
    14
    Units: ng/ml
        arithmetic mean (standard deviation)
    109.37 ± 61.00
    141.74 ± 58.68
    115.89 ± 55.61
    Statistical analysis title
    		 T1 vs T2
    Comparison groups
    Pulmicort 100µg + Serevent 50µg v BUSAL 75/25µg
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 GMR
    Point estimate
    137.98
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 111.14
         upper limit
    		 171.3
    Statistical analysis title
    		 T1 vs T3
    Comparison groups
    Pulmicort 100µg + Serevent 50µg v BUSAL 66/22µg
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 GMR
    Point estimate
    110.95
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 88.78
         upper limit
    		 138.66

    Primary: Salmeterol AUCt

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    End point title
    		 Salmeterol AUCt
    End point description
    End point type
    Primary
    End point timeframe
    PI, PII and PIII
    End point values
    		 Pulmicort 100µg + Serevent 50µg BUSAL 75/25µg BUSAL 66/22µg
    Number of subjects analysed
    14
    14
    14
    Units: ng/ml*h
        arithmetic mean (standard deviation)
    174.83 ± 68.58
    158.10 ± 51.97
    132.19 ± 55.66
    Statistical analysis title
    		 T1 vs T2
    Comparison groups
    Pulmicort 100µg + Serevent 50µg v BUSAL 75/25µg
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 GMR
    Point estimate
    92.37
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 76.73
         upper limit
    		 111.19
    Statistical analysis title
    		 T1 vs T3
    Comparison groups
    Pulmicort 100µg + Serevent 50µg v BUSAL 66/22µg
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 GMR
    Point estimate
    75.36
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 64.59
         upper limit
    		 87.91

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Screening, period I, period II, period III and end of study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Pulmicort 100µg + Serevent 50µg
    Reporting group description
    		 Serevent Diskus 50 mg + Pulmicort Turbuhaler 100 µg co-administration, one dose taken by inhalation via the inhalers, containing 50 µg of salmeterol and 100 µg of budesonide respectively

    Reporting group title
    BUSAL 75/25µg
    Reporting group description
    		 Budesonide-Salmeterol 75-25 mg (DPI), one capsule taken by inhalation via the Vertical-Haler®, containing 75 µg of budesonide and 25 µg of salmeterol xinafoate

    Reporting group title
    BUSAL 66/22
    Reporting group description
    		 Budesonide-Salmeterol 66/22 mg (DPI), one capsule taken by inhalation via the Vertical-Haler®, containing 66 µg of budesonide and 22 µg of salmeterol xinafoate

    Serious adverse events
    		 Pulmicort 100µg + Serevent 50µg BUSAL 75/25µg BUSAL 66/22
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (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: 5%
    Non-serious adverse events
    		 Pulmicort 100µg + Serevent 50µg BUSAL 75/25µg BUSAL 66/22
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (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 adverse event were reported in the BUSALSD201 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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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