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    Clinical Trial Results:
    A SINGLE-DOSE, UNCONTROLLED, OPEN LABEL, NON-RANDOMIZED,CLINICAL PHARMACOLOGY STUDY OF CHF 5993 100/6/12.5 μg PMDI (FIXED COMBINATION OF BECLOMETASONE DIPROPIONATE PLUS FORMOTEROL FUMARATE PLUS GLYCOPYRRONIUM BROMIDE) IN ASTHMATIC ADOLESCENT PATIENTS AND ADULT PATIENTS

    Summary
    EudraCT number
    2019-002238-35
    Trial protocol
    PL  
    Global end of trial date
    04 Feb 2021

    Results information
    Results version number
    v2(current)
    This version publication date
    12 Nov 2021
    First version publication date
    18 Aug 2021
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Correction of the Paediatric regulatory details.

    Trial information

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    Trial identification
    Sponsor protocol code
    CLI-05993CB1-01
    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 Trasparency, Chiesi Farmaceutici S.p.A, clinicaltrials_info@chiesi.com
    Scientific contact
    Clinical Trial Trasparency, Chiesi Farmaceutici S.p.A, 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-001875-PIP02-18
    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
    23 Jul 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the systemic exposure to beclometasone 17-monopropionate (B17MP, active metabolite of beclometasone dipropionate [BDP]), formoterol, and glycopyrronium bromide [GB] as measured by the area under the plasma concentration-time curve (AUC) from 0 to the last quantifiable concentration (AUC0-t, index of total systemic exposure) after inhalation of CHF 5993 pressurised metered-dose inhaler (pMDI) in adolescent asthmatic patients in comparison to adult asthmatic patients.
    Protection of trial subjects
    This study was conducted in compliance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 Good Clinical Practices (GCP) guidelines, the Declaration of Helsinki (1964 and amendments) and other local regulations as applicable. The informed consent has been written separately in a language understandable to the adult and adolescent patients and/or patient’s legal representative (where applicable). Written informed consent was obtain by the Investigator from each patient or from the patient’s legal representative prior to any study related procedures taking place by using the latest EC/IRB approved version of the document.
    Background therapy
    CHF 5993 100/6/12.5 μg/actuation is an extra-fine fixed combination of an Inhaled corticosteroids (ICS), a Long-acting β2-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) containing Beclometasone Dipropionate (BDP) 100 μg/actuation plus Formoterol Fumarate (FF) 6 μg/actuation plus Glycopyrronium Bromide (GB) 12.5 μg/actuation has been developed as a hydrofluoroalkane (HFA) pressurised metered-dose inhaler (pMDI).
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Feb 2020
    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
    Poland: 80
    Worldwide total number of subjects
    80
    EEA total number of subjects
    80
    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)
    40
    Adults (18-64 years)
    40
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 82 asthmatic subjects divided into two age groups (41 adolescents and 41 adults) were screened, of which 80 were enrolled and treated (40 adolescents and 40 adults) and 2 subjects (1 adolescent and 1 adult) who failed screening.

    Pre-assignment
    Screening details
    Screening was performed from 28 to 21 days prior to the first administration of the study drug and the patient had been fasting for at least 10 hours, without smoking or nicotine-containing and had not engaged in strenuous activity in the 24 hours before the visit.The inclusion/exclusion criteria were assessed and there were 2 screening failures.

    Pre-assignment period milestones
    Number of subjects started
    82 [1]
    Number of subjects completed
    80

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    failure to meet Randomization Criteria: 1
    Reason: Number of subjects
    patient and parent’s fear for COVID-19: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: According to the protocol 40 adolescent asthmatic patients (for an outcome of 37 evaluable patients) and 40 adult asthmatic patients (for an outcome of 37 evaluable patients) were planned to be enrolled. To reach a target, a total of 41 adolescent patients and 41 adult patients were screened, of whom 1 adolescent patient and 1 adult patient were screening failures. Therefore 40 adolescent patients and 40 adult patients were enrolled and received the study drug.
    Period 1
    Period 1 title
    Treatment Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Adolescents (12-17 years)
    Arm description
    Adolescent asthmatic patients who have received one single-dose (consisting of 4 inhalation) of fixed combination CHF 5993 400/24/50 µg pMDI (400 μg BDP, 24 μg FF, and 50 μg GB).
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 5993 pMDI (100/6/12.5 μg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pressurised inhalation, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test product: CHF 5993 100/6/12.5 µg (BDP/FF/GB 100/6/12.5 μg per actuation) pMDI, fixed-dose combination of beclometasone dipropionate (BDP) + formoterol fumarate (FF) + glycopyrronium bromide (GB). The study medication was administered at clinical site on Day 1 as single dose by inhalation (4 inhalation in total) using the pMDI device, for a total dose of BDP 400 μg, FF 24 μg, GB 50 μg. The subjects were trainded to use the pMDI device with (Aerosol Inhalation Monitor) AIM ™ Vitalograph® at the screening visit and at pre-dose on Day 1. The subjects were trained also using the pMDI placebo devices at screening and at Day 1.

    Arm title
    Adults (18-64 years)
    Arm description
    Adult asthmatic patients who have received one single-dose (consisting of 4 inhalation) of fixed combination CHF 5993 400/24/50 µg pMDI (400 μg BDP, 24 μg FF, and 50 μg GB)
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 5993 pMDI (100/6/12.5 μg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pressurised inhalation, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test product: CHF 5993 100/6/12.5 µg (BDP/FF/GB 100/6/12.5 μg per actuation) pMDI, fixed-dose combination of beclometasone dipropionate (BDP) + formoterol fumarate (FF) + glycopyrronium bromide (GB). The study medication was administered at clinical site on Day 1 as single dose by inhalation (4 inhalation in total) using the pMDI device, for a total dose of BDP 400 μg, FF 24 μg, GB 50 μg. The subjectss were trainded to use the pMDI device with (Aerosol Inhalation Monitor) AIM ™ Vitalograph® at the screening visit and at pre-dose on Day 1. The subjects were trained also using the pMDI placebo devices at screening and at Day 1.

    Number of subjects in period 1
    Adolescents (12-17 years) Adults (18-64 years)
    Started
    40
    40
    Completed
    40
    40

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Adolescents (12-17 years)
    Reporting group description
    Adolescent asthmatic patients who have received one single-dose (consisting of 4 inhalation) of fixed combination CHF 5993 400/24/50 µg pMDI (400 μg BDP, 24 μg FF, and 50 μg GB).

    Reporting group title
    Adults (18-64 years)
    Reporting group description
    Adult asthmatic patients who have received one single-dose (consisting of 4 inhalation) of fixed combination CHF 5993 400/24/50 µg pMDI (400 μg BDP, 24 μg FF, and 50 μg GB)

    Reporting group values
    Adolescents (12-17 years) Adults (18-64 years) Total
    Number of subjects
    40 40 80
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    40 0 40
        Adults (18-64 years)
    0 40 40
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    14.8 ± 1.6 43.6 ± 14.7 -
    Gender categorical
    Units: Subjects
        Female
    15 26 41
        Male
    25 14 39
    Race
    Units: Subjects
        White
    40 40 80
    Subject analysis sets

    Subject analysis set title
    Adolescents (12-17 years) - Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Including all subjects who were enrolled and received at least one dose of study drug.

    Subject analysis set title
    Adults (18-64 years) - Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Including all subjects who were enrolled and received at least one dose of study drug.

    Subject analysis set title
    Adolescents (12-17 years) - PK
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PK population included all subjects from the safety set excluding subjects without any valid PK measurement and with major protocol deviation affecting PK evaluations.

    Subject analysis set title
    Adults (18-64 years)- PK
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PK population included all subjects from the safety set excluding subjects without any valid PK measurement and with major protocol deviation affecting PK evaluations.

    Subject analysis set title
    Adolescents (12-17 years) - PD
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PD population included all subjects from the safety set excluding subjects without any valid PD measurement and with major protocol deviations affecting PD evaluations.

    Subject analysis set title
    Adults (18-64 years)- PD
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PD population included all subjects from the safety set excluding subjects without any valid PD measurement and with major protocol deviations affecting PD evaluations.

    Subject analysis sets values
    Adolescents (12-17 years) - Safety Adults (18-64 years) - Safety Adolescents (12-17 years) - PK Adults (18-64 years)- PK Adolescents (12-17 years) - PD Adults (18-64 years)- PD
    Number of subjects
    40
    40
    40
    40
    38
    37
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    40
    0
    40
    0
    38
    0
        Adults (18-64 years)
    0
    40
    0
    40
    0
    37
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    14.8 ± 1.6
    43.6 ± 14.7
    14.8 ± 1.6
    43.6 ± 14.7
    14.7 ± 1.6
    43.4 ± 14.7
    Gender categorical
    Units: Subjects
        Female
    15
    26
    15
    26
    15
    24
        Male
    25
    14
    25
    14
    23
    13
    Race
    Units: Subjects
        White
    40
    40
    40
    40
    38
    37

    End points

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    End points reporting groups
    Reporting group title
    Adolescents (12-17 years)
    Reporting group description
    Adolescent asthmatic patients who have received one single-dose (consisting of 4 inhalation) of fixed combination CHF 5993 400/24/50 µg pMDI (400 μg BDP, 24 μg FF, and 50 μg GB).

    Reporting group title
    Adults (18-64 years)
    Reporting group description
    Adult asthmatic patients who have received one single-dose (consisting of 4 inhalation) of fixed combination CHF 5993 400/24/50 µg pMDI (400 μg BDP, 24 μg FF, and 50 μg GB)

    Subject analysis set title
    Adolescents (12-17 years) - Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Including all subjects who were enrolled and received at least one dose of study drug.

    Subject analysis set title
    Adults (18-64 years) - Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Including all subjects who were enrolled and received at least one dose of study drug.

    Subject analysis set title
    Adolescents (12-17 years) - PK
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PK population included all subjects from the safety set excluding subjects without any valid PK measurement and with major protocol deviation affecting PK evaluations.

    Subject analysis set title
    Adults (18-64 years)- PK
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PK population included all subjects from the safety set excluding subjects without any valid PK measurement and with major protocol deviation affecting PK evaluations.

    Subject analysis set title
    Adolescents (12-17 years) - PD
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PD population included all subjects from the safety set excluding subjects without any valid PD measurement and with major protocol deviations affecting PD evaluations.

    Subject analysis set title
    Adults (18-64 years)- PD
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PD population included all subjects from the safety set excluding subjects without any valid PD measurement and with major protocol deviations affecting PD evaluations.

    Primary: 1_AUC0-t for B17MP (active metabolite of BDP)

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    End point title
    1_AUC0-t for B17MP (active metabolite of BDP)
    End point description
    The AUC0-t for B17MP (the area under the plasma concentration-time curve from 0 to the last quantifiable concentration) was log-transformed and analysed using a linear model including patient group as fixed effects. Data was expressed as arithmetic mean with standard deviation.
    End point type
    Primary
    End point timeframe
    The AUC0-t for B17MP was studied for up to 10 h after administration of CHF 5993 400/24/50 μg pMDI for B17MP.
    End point values
    Adolescents (12-17 years) - PK Adults (18-64 years)- PK
    Number of subjects analysed
    40 [1]
    38 [2]
    Units: h·pg/mL
        arithmetic mean (standard deviation)
    3204 ± 909
    4027 ± 1022
    Notes
    [1] - PK population: number of patients/number of patients with data: 40/40
    [2] - PK population: number of patients/number of patients with data: 40/38
    Statistical analysis title
    1_B17MP AUC0-t ratio of adjusted geometric mean
    Statistical analysis description
    The ratio of adjusted geometric means (GMR) between patients groups (adolescent vs adult) was calculated with their 90% two sided confidence interval (CIs). Adult and adolecent total systemic exposure (AUC0-t) was assessed as comparable if the upper limit of CIs of the ratios (adolescent vs adult) was lower or equal to 125%.
    Comparison groups
    Adults (18-64 years)- PK v Adolescents (12-17 years) - PK
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.0006
    Method
    ANOVA
    Parameter type
    Ratio (%)
    Point estimate
    79.28
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    71.19
         upper limit
    88.29

    Primary: 1_AUC0-t for Formoterol (FF)

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    End point title
    1_AUC0-t for Formoterol (FF)
    End point description
    The AUC0-t for Formoterol (the area under the plasma concentration-time curve from 0 to the last quantifiable concentration) was log-transformed and analysed using a linear model including patient group as fixed effects.Data was expressed as arithmetic mean with standard deviation.
    End point type
    Primary
    End point timeframe
    The AUC0-t for Formoterol was studied for up to 10 h after administration of CHF 5993 400/24/50 μg pMDI for Formoterol.
    End point values
    Adolescents (12-17 years) - PK Adults (18-64 years)- PK
    Number of subjects analysed
    34 [3]
    37 [4]
    Units: h·pg/mL
        arithmetic mean (standard deviation)
    73.8 ± 21.8
    84.6 ± 26.6
    Notes
    [3] - PK population: number of patients/number of patients with data: 40/34
    [4] - PK population: number of patients/number of patients with data: 40/37
    Statistical analysis title
    1_FF AUC0-t ratio of adjusted geometric mean
    Statistical analysis description
    The ratios of adjusted geometric means (GMR) between patients groups (adolescent vs adult) was calculated with their 90% two sided confidence interval (CIs). Adult and adolecent total systemic exposure (AUC0-t) was assessed as comparable if the upper limit of CIs of the ratios (adolescent vs adult) was lower or equal to 125%.
    Comparison groups
    Adolescents (12-17 years) - PK v Adults (18-64 years)- PK
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.1339
    Method
    ANOVA
    Parameter type
    Ratio (%)
    Point estimate
    88.68
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    77.71
         upper limit
    101.2

    Primary: 1_AUC0-t for Glycopyrronium Bromide (GB)

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    End point title
    1_AUC0-t for Glycopyrronium Bromide (GB)
    End point description
    The AUC0-t for Glycopyrronium Bromide (the area under the plasma concentration-time curve from 0 to the last quantifiable concentration) was log-transformed and analysed using a linear model including patient group as fixed effects. Data was expressed as arithmetic mean with standard deviation.
    End point type
    Primary
    End point timeframe
    The AUC0-t for Glycopyrronium Bromide was studied for up to 10 h after administration of CHF 5993 400/24/50 μg pMDI for Glycopyrronium Bromide.
    End point values
    Adolescents (12-17 years) - PK Adults (18-64 years)- PK
    Number of subjects analysed
    40 [5]
    38 [6]
    Units: h·pg/mL
        arithmetic mean (standard deviation)
    74.5 ± 27.5
    90.1 ± 39.1
    Notes
    [5] - PK population: number of patients/number of patients with data: 40/40
    [6] - PK population: number of patients/number of patients with data: 40/38
    Statistical analysis title
    1_GB AUC0-t ratio of adjusted geometric mean
    Statistical analysis description
    The ratios of adjusted geometric means (GMR) between patients groups (adolescent vs adult) was calculated with their 90% two sided confidence interval (CIs). Adult and adolecent total systemic exposure (AUC0-t) was assessed as comparable if the upper limit of CIs of the ratios (adolescent vs adult) was lower or equal to 125%.
    Comparison groups
    Adults (18-64 years)- PK v Adolescents (12-17 years) - PK
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.1035
    Method
    ANOVA
    Parameter type
    Ratio (%)
    Point estimate
    85.49
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    72.96
         upper limit
    100.16

    Secondary: 2_Cmax for B17MP (active metabolite of BDP)

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    End point title
    2_Cmax for B17MP (active metabolite of BDP)
    End point description
    The Cmax for B17MP (the value ofthe maximum plasma concentration) was log-transformed and analysed using a linear model including patient group (adolescent or adult) as fixed effects.Data was expressed as arithmetic mean with standard deviation.
    End point type
    Secondary
    End point timeframe
    The Cmax for B17MP was studied for up to 10 h after administration of CHF 5993 400/24/50 μg pMDI for B17MP.
    End point values
    Adolescents (12-17 years) - PK Adults (18-64 years)- PK
    Number of subjects analysed
    40 [7]
    38 [8]
    Units: pg/mL
        arithmetic mean (standard deviation)
    831 ± 328
    1046 ± 455
    Notes
    [7] - PK population: number of patients/number of patients with data: 40/40
    [8] - PK population: numberof patients/number of patients with data: 40/38
    Statistical analysis title
    2_ B17MP Cmax ratio of adjusted geometric mean
    Statistical analysis description
    The ratios of adjusted geometric means (GMR) between patients groups (adolescent vs adult) was calculated with their 90% two sided confidence interval (CIs). Adult and adolecent maximum plasma concentration (Cmax) was assessed as comparable if the upper limit of CIs of the ratios (adolescent vs adult) was lower or equal to 125%.
    Comparison groups
    Adolescents (12-17 years) - PK v Adults (18-64 years)- PK
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.0401
    Method
    ANOVA
    Parameter type
    Ratio (%)
    Point estimate
    81.07
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    68.58
         upper limit
    95.84

    Secondary: 2_Cmax for Formoterol (FF)

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    End point title
    2_Cmax for Formoterol (FF)
    End point description
    The Cmax for Formoterol (the value of the maximum plasma concentration) was log-transformed and analysed using a linear model including patient group (adolescent or adult) as fixed effects. Data was expressed as arithmetic mean with standard deviation.
    End point type
    Secondary
    End point timeframe
    The Cmax for Formoterol was studied for up to 10 h after administration of CHF 5993 400/24/50 μg pMDI for Formoterol.
    End point values
    Adolescents (12-17 years) - PK Adults (18-64 years)- PK
    Number of subjects analysed
    36 [9]
    37 [10]
    Units: pg/mL
        arithmetic mean (standard deviation)
    20.9 ± 8.27
    27.2 ± 12.0
    Notes
    [9] - PK population: number of patients/number of patients with data: 40/36
    [10] - PK population: number of patients/number of patients with data: 40/37
    Statistical analysis title
    2_FF Cmax ratio of adjusted geometric mean
    Statistical analysis description
    The ratios of adjusted geometric means (GMR) between patients groups (adolescent vs adult) was calculated with their 90% two sided confidence interval (CIs). Adult and adolecent maximum plasma concentration (Cmax) was assessed as comparable if the upper limit of CIs of the ratios (adolescent vs adult) was lower or equal to 125%.
    Comparison groups
    Adolescents (12-17 years) - PK v Adults (18-64 years)- PK
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.032
    Method
    ANOVA
    Parameter type
    Ratio (%)
    Point estimate
    78.83
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    65.76
         upper limit
    94.49

    Secondary: 2_Cmax for Glycopyrronium Bromide (GB)

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    End point title
    2_Cmax for Glycopyrronium Bromide (GB)
    End point description
    The Cmax for Glycopyrronium Bromide (the value ofthe maximum plasma concentration) was log-transformed and analysed using a linear model including patient group (adolescent or adult) as fixed effects.Data were expressed as arithmetic mean with standard deviation.
    End point type
    Secondary
    End point timeframe
    The Cmax for Glycopyrronium Bromide was studied for up to 10 h after administration of CHF 5993 400/24/50 μg pMDI for Glycopyrronium Bromide.
    End point values
    Adolescents (12-17 years) - PK Adults (18-64 years)- PK
    Number of subjects analysed
    40 [11]
    38 [12]
    Units: pg/mL
        arithmetic mean (standard deviation)
    25.6 ± 15.2
    39.5 ± 31.7
    Notes
    [11] - PK population: number of patients/number of patients with data: 40/40
    [12] - PK population: number of patients/number of patients with data: 40/38
    Statistical analysis title
    2_GB Cmax ratio of adjusted geometric mean
    Statistical analysis description
    The ratios of adjusted geometric means (GMR) between patients groups (adolescent vs adult) was calculated with their 90% two sided confidence interval (CIs). Adult and adolecent maximum plasma concentration (Cmax) was assessed as comparable if the upper limit of CIs of the ratios (adolescent vs adult) was lower or equal to 125%.
    Comparison groups
    Adolescents (12-17 years) - PK v Adults (18-64 years)- PK
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.0583
    Method
    ANOVA
    Parameter type
    Ratio (%)
    Point estimate
    76
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    59.92
         upper limit
    96.39

    Secondary: 3_Glucose Serum Pharmacodynamic Parameter (Cmax)

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    End point title
    3_Glucose Serum Pharmacodynamic Parameter (Cmax)
    End point description
    The Cmax (value of maximum serum concentration of Glucose) data was expressed as arithmetic mean with standard deviation.
    End point type
    Secondary
    End point timeframe
    The Cmax of Glucose was studied in serum up to 4 h after administration of CHF 5993 400/24/50 μg pMDI.
    End point values
    Adolescents (12-17 years) - PD Adults (18-64 years)- PD
    Number of subjects analysed
    38 [13]
    37 [14]
    Units: millimole(s)/litre
        arithmetic mean (standard deviation)
    7.09 ± 1.49
    7.78 ± 1.60
    Notes
    [13] - PD population: number of patients/number of patients with data: 38/38
    [14] - PD population: number of patients/number of patients with data: 37/37
    No statistical analyses for this end point

    Secondary: 3_Glucose Serum Pharmacodynamic Parameter (t max)

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    End point title
    3_Glucose Serum Pharmacodynamic Parameter (t max)
    End point description
    The tmax (time of the maximum serum concentration of Glucose) data was expressed with median (minimum-maximum).
    End point type
    Secondary
    End point timeframe
    The tmax of Glucose was studied in serum up to 4 h after administration of CHF 5993 400/24/50 μg pMDI.
    End point values
    Adolescents (12-17 years) - PD Adults (18-64 years)- PD
    Number of subjects analysed
    38 [15]
    37 [16]
    Units: hour
        median (full range (min-max))
    4.0 (0.0 to 4.08)
    4.02 (2.02 to 4.05)
    Notes
    [15] - PD population: number of patients/number of patients with data: 38/38
    [16] - PD population: number of patients/number of patients with data: 37/37
    No statistical analyses for this end point

    Secondary: 3_Glucose Serum Pharmacodynamic Parameter (AUC0-2h)

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    End point title
    3_Glucose Serum Pharmacodynamic Parameter (AUC0-2h)
    End point description
    The AUC0-2h (the area under the serum concentration versus time curve observed from time 0 up to 2h time point) data was expressed as arithmetic mean with standard deviation.
    End point type
    Secondary
    End point timeframe
    The AUC0-2h of Glucose was studied in serum up to 4 h after administration of CHF 5993 400/24/50 μg pMDI.
    End point values
    Adolescents (12-17 years) - PD Adults (18-64 years)- PD
    Number of subjects analysed
    38 [17]
    37 [18]
    Units: h·mmol/L
        arithmetic mean (standard deviation)
    10.4 ± 0.923
    11.3 ± 1.20
    Notes
    [17] - PD population: number of patients/number of patients with data: 38/38
    [18] - PD population: number of patients/number of patients with data: 37/37
    No statistical analyses for this end point

    Secondary: 3_Potassium Serum Pharmacodynamic Parameter (Cmin)

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    End point title
    3_Potassium Serum Pharmacodynamic Parameter (Cmin)
    End point description
    The Cmin (value of minum Potassium serum level) data was expressed as arithmetic mean with standard deviation.
    End point type
    Secondary
    End point timeframe
    The Cmin of Potassium was studied in serum up to 4 h after administration of CHF 5993 400/24/50 μg pMDI.
    End point values
    Adolescents (12-17 years) - PD Adults (18-64 years)- PD
    Number of subjects analysed
    35 [19]
    36 [20]
    Units: millimole(s)/litre
        arithmetic mean (standard deviation)
    4.17 ± 0.370
    3.91 ± 0.306
    Notes
    [19] - PD population: number of patients/number of patients with data: 38/35
    [20] - PD population: number of patients/number of patients with data: 37/36
    No statistical analyses for this end point

    Secondary: 3_Potassium Serum Pharmacodynamic Parameter (t min)

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    End point title
    3_Potassium Serum Pharmacodynamic Parameter (t min)
    End point description
    The tmin (time of minimum Potassium serum level) data was expressed as median (minimum-maximum).
    End point type
    Secondary
    End point timeframe
    The tmin of Potassium was studied in serum up to 4 h after administration of CHF 5993 400/24/50 μg pMDI.
    End point values
    Adolescents (12-17 years) - PD Adults (18-64 years)- PD
    Number of subjects analysed
    35 [21]
    36 [22]
    Units: hour
        median (full range (min-max))
    2.0 (0.00 to 4.00)
    2.02 (0.00 to 4.05)
    Notes
    [21] - PD population: number of patients/number of patients with data: 38/35
    [22] - PD population: number of patients/number of patients with data: 37/36
    No statistical analyses for this end point

    Secondary: 3_Potassium Serum Pharmacodynamic Parameter (AUC0-2h)

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    End point title
    3_Potassium Serum Pharmacodynamic Parameter (AUC0-2h)
    End point description
    The AUC0-2h (the area under the serum concentration versus time curve observed from time 0 up to 2h time point) data was expressed as arithmetic mean with standard deviation.
    End point type
    Secondary
    End point timeframe
    The AUC0-2 of Potassium was studied in serum up to 4 h after administration of CHF 5993 400/24/50 μg pMDI.
    End point values
    Adolescents (12-17 years) - PD Adults (18-64 years)- PD
    Number of subjects analysed
    29 [23]
    36 [24]
    Units: h·mmol/L
        arithmetic mean (standard deviation)
    8.83 ± 0.584
    8.34 ± 0.629
    Notes
    [23] - PD population: number of patients/number of patients with data: 38/29
    [24] - PD population: number of patients/number of patients with data: 37/36
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs were recorded from the time of the Informed Consent signature until the patient's study partecipation ends.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Adolescents (12-17 years)
    Reporting group description
    40 adolescent patients treated with fixed combination of CHF 5993 400/24/50 µg pMDI

    Reporting group title
    Adults (18-64 years)
    Reporting group description
    40 adult patients treated with fixed combination of CHF 5993 400/24/50 µg pMDI

    Serious adverse events
    Adolescents (12-17 years) Adults (18-64 years)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 40 (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
    Adolescents (12-17 years) Adults (18-64 years)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 40 (0.00%)
    3 / 40 (7.50%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Non-cardiac Chest Pain
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2020
    The first revised CTP (version 2.0, dated 7 January 2020)was issued following feedback from the Competent Authority. The following changes were made: to document the change in Sponsor Medical Expert, to include a lower limit of body weight in the inclusion criteria, and to change the serum pregnancy test at screening to a urine pregnancy test. In addition, the timing of the screening and follow-up visits was updated, the allowed time deviation from theoretical post-dose times was added for PD assessments between 10 and 24 h post-dose, and the volume of blood samples for laboratory evaluations was reduced.
    10 Jun 2020
    The second revised CTP (version 3. 0, dated 24 April 2020) submitted on 30 April 2020 (silent/implicit approval from 10 June 2020) has been modified to: adjust the Hb value in the exclusion criteria to be in line with adolescent values, define time zero more clearly, better explain the ICF procedure, clarify when Holter recording should start, reduce the fasting period from 4 to 2 h post-dose and adjust the AUC of potassium and glucose accordingly, include reference to the Investigator's Brochure for CHF 5993 in the definition of predictability of AEs, and differentiate the required volume of blood samples for laboratory evaluations between adolescents and adults.

    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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