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    Clinical Trial Results:
    A single-dose, open-label, randomized, 2-way cross-over, clinical pharmacology study of CHF 1535 35/4 NEXThaler® (DPI fixed combination of beclometasone dipropionate (BDP) 35 µg plus formoterol fumarate (FF) 4 µg versus the free combination of licensed BDP DPI and FF DPI in asthmatic children

    Summary
    EudraCT number
    		 2015-005152-10
    Trial protocol
    		 DK  
    Global end of trial date
    08 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Feb 2018
    First version publication date
    01 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-01535BB1-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A.
    Sponsor organisation address
    Via Palermo 26/A, Parma, Italy,
    Public contact
    Clinical Trial Transparency,, Clinical Trial Transparency,, clinicaltrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency,, Clinical Trial Transparency,, clinicaltrials_info@chiesi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000548-PIP01-09
    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
    24 Oct 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluate the systemic exposure to B17MP (an active metabolite of BDP) as AUC (0-t), after inhalation of CHF 1535 35/4 NEXThaler® in comparison with a free combination of licensed products of BDP DPI and FF DPI in children with asthma. AUC (0-t)=Area under the plasma drug concentration-time curve, calculated to the last quantifiable data point BDP=Beclometasone dipropionate B17MP=Beclometasone-17-monopropionate (an active metabolite of BDP) Cmax =Maximum plasma concentration DPI=Dry powder inhaler FF=Formoterol fumarate
    Protection of trial subjects
    The study was conducted according to the clinical study protocol, the current International Council for Harmonization (ICH) Good Clinical Practice (GCP) guidelines, any local guidelines, and the Declaration of Helsinki (1964 and amendments). Adverse events and vital signs were recorded at all visits (from screening onward). All new clinically relevant abnormalities or relevant changes at the following visits, in the medical opinion of the Investigator, were reported as AEs in the case report form (CRF). All described PK and safety assessments were performed according to accepted standard methods.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Aug 2016
    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: 26
    Worldwide total number of subjects
    26
    EEA total number of subjects
    26
    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)
    26
    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
    		 Children (male and female) with diagnosed asthma were screened according to the study inclusion and exclusion criteria. Overall, 28 subjects were screened; of these, 26 were randomized to treatment.

    Pre-assignment
    Screening details
    		 Subjects attended a screening visit (2 to 21 days prior to randomisation), study entry criteria were checked; consent form signed. Eligible subjects were randomised into the study, which comprised of 2 treatment sequences that were separated by a wash-out period (min 7 days, max 3 weeks).

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Fixed combination BDP/FF
    Arm description
    		 Fixed combination BDP/FF 35/4 μg (total dose: BDP/FF 140/16 μg) During the treatment, the children remained at the clinical center. They arrived at the clinical site in the morning and left on the same day, after the 8 h post-dose assessments have been performed for each treatment sequence. In the morning, the subjects inhaled a single dose (4 inhalations) of CHF 1535 using the NEXThaler®.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CHF 1535 35/4μg NEXThaler®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fixed combination of beclometasone dipropionate (BDP) 35 μg + formoterol fumarate (FF) 4 μg. CHF 1535 35/4 μg NEXThaler® per inhalation (total dose: BDP/FF 140/16 μg) A single dose was administered. 4 (four) inhalations of CHF 1535 35/4 µg via the NEXThaler® dry powder inhaler, as a fixed combination of beclometasone dipropionate 35 μg/unit dose plus formoterol fumarate 4 μg/unit dose.

    Arm title
    		 Free combination BDP+FF
    Arm description
    		 Free combination BDP 100 μg and FF 6 μg (total dose: BDP 200 µg + FF 24 µg) During the treatment period, the children remained at the clinical center. They arrived at the clinical site in the morning and left on the same day, after the 8 h post-dose assessments have been performed for each study period. In the morning, the subjects inhaled a single dose of BDP (2 inhalations; total dose: 200 μg) and of FF (4 inhalations total dose: 24 μg).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Beclomethasone Dipropionate (BDP)
    Investigational medicinal product code
    Other name
    Clenil® Pulvinal®
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Beclometasone dipropionate (BDP) dry powder inhaler (DPI) BDP 100 μg dry powder per unit dose (Clenil® Pulvinal®) A single dose was administered. 2 (two) inhalations of BDP 100 μg (total dose: 200 µg) via a DPI.

    Investigational medicinal product name
    Formoterol Fumarate (FF)
    Investigational medicinal product code
    Other name
    Oxis® Turbohaler®
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol fumarate (FF) Dry powder inhaler (DPI) FF 6 μg per unit dose inhalation dry powder (Oxis® Turbohaler®) A single dose was administered. 4 (four) inhalations of FF 6 μg (total dose: 24 µg) via a DPI.

    Number of subjects in period 1
    		Fixed combination BDP/FF Free combination BDP+FF
    Started
    12
    14
    Completed
    12
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fixed combination BDP/FF
    Reporting group description
    		 Fixed combination BDP/FF 35/4 μg (total dose: BDP/FF 140/16 μg) During the treatment, the children remained at the clinical center. They arrived at the clinical site in the morning and left on the same day, after the 8 h post-dose assessments have been performed for each treatment sequence. In the morning, the subjects inhaled a single dose (4 inhalations) of CHF 1535 using the NEXThaler®.

    Reporting group title
    Free combination BDP+FF
    Reporting group description
    		 Free combination BDP 100 μg and FF 6 μg (total dose: BDP 200 µg + FF 24 µg) During the treatment period, the children remained at the clinical center. They arrived at the clinical site in the morning and left on the same day, after the 8 h post-dose assessments have been performed for each study period. In the morning, the subjects inhaled a single dose of BDP (2 inhalations; total dose: 200 μg) and of FF (4 inhalations total dose: 24 μg).

    Reporting group values
    		 Fixed combination BDP/FF Free combination BDP+FF Total
    Number of subjects
    		 12 14 26
    Age categorical
    Safety population
    Units: Subjects
        Children (2-11 years)
    		 12 14 26
    Age continuous
    Safety population
    Units: years
        arithmetic mean (standard deviation)
    		 8.6 ( 1.6 ) 8.9 ( 1.7 ) -
    Gender categorical
    Safety population
    Units: Subjects
        Female
    		 6 5 11
        Male
    		 6 9 15
    Race
    Safety population
    Units: Subjects
        White
    		 12 12 24
        Other
    		 0 2 2
    Body mass index (BMI)
    Safety population
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 16.833 ( 2.355 ) 17.207 ( 2.299 ) -
    Asthma history
    Units: years
        arithmetic mean (standard deviation)
    		 4.87 ( 2.78 ) 6.96 ( 2.10 ) -

    End points

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    End points reporting groups
    Reporting group title
    Fixed combination BDP/FF
    Reporting group description
    		 Fixed combination BDP/FF 35/4 μg (total dose: BDP/FF 140/16 μg) During the treatment, the children remained at the clinical center. They arrived at the clinical site in the morning and left on the same day, after the 8 h post-dose assessments have been performed for each treatment sequence. In the morning, the subjects inhaled a single dose (4 inhalations) of CHF 1535 using the NEXThaler®.

    Reporting group title
    Free combination BDP+FF
    Reporting group description
    		 Free combination BDP 100 μg and FF 6 μg (total dose: BDP 200 µg + FF 24 µg) During the treatment period, the children remained at the clinical center. They arrived at the clinical site in the morning and left on the same day, after the 8 h post-dose assessments have been performed for each study period. In the morning, the subjects inhaled a single dose of BDP (2 inhalations; total dose: 200 μg) and of FF (4 inhalations total dose: 24 μg).

    Subject analysis set title
    Fixed combination BDP/FF
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    PK analysis set = All subjects from the safety population excluding subjects without any valid PK measurement or with major protocol deviations significantly affecting PK in at least one treatment sequence.

    Subject analysis set title
    Free combination BDP+FF
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    PK analysis set = All subjects from the safety population excluding subjects without any valid PK measurement or with major protocol deviations significantly affecting PK in at least one treatment sequence.

    Primary: 1_B17MP: AUC (0-t)

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    End point title
    		 1_B17MP: AUC (0-t)
    End point description
    Determine the pharmacokinetic parameter AUC (0-t) for B17MP (an active metabolite of BDP). AUC (0-t)=Area under the plasma drug concentration-time curve calculated to the last quantifiable data point BDP=Beclometasone dipropionate B17MP=Beclometasone-17-monopropionate
    End point type
    Primary
    End point timeframe
    Pre-dose (baseline) and post-dose at 15, 30 min, 1, 2, 4, 6, and 8 h
    End point values
    		 Fixed combination BDP/FF Free combination BDP+FF
    Number of subjects analysed
    26 [1]
    26 [2]
    Units: h.pg/mL
        arithmetic mean (standard deviation)
    1285.66 ( 309.77 )
    854.76 ( 251.30 )
    Notes
    [1] - PK population
    [2] - PK Population
    Statistical analysis title
    		 B17MP: AUC (0-t)
    Statistical analysis description
    Subjects in this analysis: N=26 (cross-over study design). The value N=52, shown below is generated automatically by the EudraCT database system and is due to an innate error of the EudraCT database system.
    Comparison groups
    Fixed combination BDP/FF v Free combination BDP+FF
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Adjusted geometric mean ratio
    Point estimate
    152.5
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 141.1
         upper limit
    		 164.81
    Notes
    [3] - Log transformed PK parameters (AUC0-t, Cmax) were analysed by an ANOVA model with fixed terms for sequence, patient-within-sequence, period, and treatment. Adjusted geometric mean ratio and its 90% confidence interval was calculated by the anti-log of the least squared (LS) means difference and the corresponding 90% CI.

    Secondary: 2_B17MP: Cmax

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    End point title
    		 2_B17MP: Cmax
    End point description
    Determine the pharmacokinetic parameter Cmax for B17MP (an active metabolite of BDP). BDP=Beclometasone dipropionate B17MP=Beclometasone-17-monopropionate Cmax=Maximum plasma concentration
    End point type
    Secondary
    End point timeframe
    Pre-dose (baseline) and post-dose at 15, 30 min, 1, 2, 4, 6, and 8 h
    End point values
    		 Fixed combination BDP/FF Free combination BDP+FF
    Number of subjects analysed
    26 [4]
    26 [5]
    Units: pg/mL
        arithmetic mean (standard deviation)
    447.01 ( 154.86 )
    239.41 ( 79.75 )
    Notes
    [4] - PK population
    [5] - PK population
    Statistical analysis title
    		 B17MP: Cmax
    Statistical analysis description
    Subjects in this analysis: N=26 (cross-over study design). The value N=52, shown below is generated automatically by the EudraCT database system and is due to an innate error of the EudraCT database system.
    Comparison groups
    Fixed combination BDP/FF v Free combination BDP+FF
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Adjusted geometric mean ratio
    Point estimate
    183.82
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 163.18
         upper limit
    		 207.07
    Notes
    [6] - Log transformed PK parameters (AUC0-t, Cmax) were analysed by an ANOVA model with fixed terms for sequence, patient-within-sequence, period, and treatment. Adjusted geometric mean ratio and its 90% confidence interval was calculated by the anti-log of the least squared (LS) means difference and the corresponding 90% CI.

    Secondary: 3_Formoterol: AUC (0-t)

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    End point title
    		 3_Formoterol: AUC (0-t)
    End point description
    Determine the pharmacokinetic parameter AUC (0-t) for formoterol. AUC (0-t) =Area under the plasma drug concentration-time curve calculated to the last quantifiable data point
    End point type
    Secondary
    End point timeframe
    Pre-dose (baseline) and post-dose at 15, 30 min, 1, 2, 4, 6, and 8 h
    End point values
    		 Fixed combination BDP/FF Free combination BDP+FF
    Number of subjects analysed
    26 [7]
    23 [8]
    Units: h.pg/mL
        arithmetic mean (standard deviation)
    82.13 ( 26.24 )
    95.03 ( 44.02 )
    Notes
    [7] - PK population
    [8] - PK population
    Statistical analysis title
    		 Formoterol: AUC (0-t)
    Statistical analysis description
    Subjects in this analysis: N=26 (cross-over study design). The value N=49, shown below is generated automatically by the EudraCT database system and is due to an innate error of the EudraCT database system.
    Comparison groups
    Fixed combination BDP/FF v Free combination BDP+FF
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    Method
    Parameter type
    		 Adjusted geometric mean ratio
    Point estimate
    91.51
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 84
         upper limit
    		 99.69
    Notes
    [9] - Log transformed PK parameters (AUC0-t, Cmax) were analysed by an ANOVA model with fixed terms for sequence, patient-within-sequence, period, and treatment. Adjusted geometric mean ratio and its 90% confidence interval was calculated by the anti-log of the least squared (LS) means difference and the corresponding 90% CI.

    Secondary: 4_Formoterol: Cmax

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    End point title
    		 4_Formoterol: Cmax
    End point description
    Determine the pharmacokinetic parameter Cmax for formoterol. Cmax=Maximum plasma concentration
    End point type
    Secondary
    End point timeframe
    Pre-dose (baseline) and post-dose at 15, 30 min, 1, 2, 4, 6, and 8 h
    End point values
    		 Fixed combination BDP/FF Free combination BDP+FF
    Number of subjects analysed
    26 [10]
    26 [11]
    Units: pg/mL
        arithmetic mean (standard deviation)
    36.01 ( 13.15 )
    33.85 ( 18.51 )
    Notes
    [10] - PK population
    [11] - PK population
    Statistical analysis title
    		 Formoterol: Cmax
    Statistical analysis description
    Subjects in this analysis: N=26 (cross-over study design). The value N=52, shown below is generated automatically by the EudraCT database system and is due to an innate error of the EudraCT database system.
    Comparison groups
    Fixed combination BDP/FF v Free combination BDP+FF
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [12]
    Method
    Parameter type
    		 Adjusted geometric mean ratio
    Point estimate
    114.57
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 99.81
         upper limit
    		 131.5
    Notes
    [12] - Log transformed PK parameters (AUC0-t, Cmax) were analysed by an ANOVA model with fixed terms for sequence, patient-within-sequence, period, and treatment. Adjusted geometric mean ratio and its 90% confidence interval was calculated by the anti-log of the least squared (LS) means difference and the corresponding 90% CI.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing the informed consent until the end of the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Fixed combination CHF 1535 (BDP/FF)
    Reporting group description
    		 -

    Reporting group title
    Free combination (BDP+FF)
    Reporting group description
    		 -

    Serious adverse events
    		 Fixed combination CHF 1535 (BDP/FF) Free combination (BDP+FF)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Fixed combination CHF 1535 (BDP/FF) Free combination (BDP+FF)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 26 (7.69%)
    General disorders and administration site conditions
    Catheter site discolouration
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Glycosuria
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Mar 2016
    Changes versus the previous version of the protocol were implemented to limit assessments only to those deemed to be necessary and to minimize children’s stress and improve their compliance to the study; this amendment included reducing the number of blood sample collections and of vital sign testing procedures, and removing the Holter monitoring.

    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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