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    Clinical Trial Results:
    A 52 week, randomized, double blind, multinational, multicentre, active controlled, 2-arm parallel group trial comparing CHF 5993 100/6/12.5 µg pMDI (fixed combination of extrafine beclometasone dipropionate plus formoterol fumarate plus glycopyrronium bromide) to CHF 1535 100/6 µg pMDI (fixed combination of extrafine beclomethasone dipropionate plus formoterol fumarate) in patients with asthma uncontrolled on medium doses of inhaled corticosteroids in combination with long-acting ß2-agonists.

    Summary
    EudraCT number
    2015-000716-18
    Trial protocol
    GB   CZ   PT   SK   HU   LT   ES   PL  
    Global end of trial date
    17 May 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Jun 2019
    First version publication date
    13 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-05993AB1-03
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02676076
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A.
    Sponsor organisation address
    Via Palermo 26/A, Parma, Italy, 43122
    Public contact
    Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., +39 0521 2791, clinicaltrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., +39 0521 2791, clinicaltrials_info@chiesi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    17 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - To demonstrate the superiority of CHF 5993 pressurised metered dose inhaler (pMDI) 100/6/12.5 μg compared to CHF 1535 pMDI 100/6 μg in terms of change from baseline in pre-dose forced expiratory volume in the 1st second (FEV1) at Week 26; - To demonstrate the reduction of moderate and severe asthma exacerbations rate with CHF 5993 pMDI 100/6/12.5 μg compared to CHF 1535 pMDI 100/6 μg during the entire 52-week treatment period.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and following all other requirements of local laws. From screening to end of treatment, vital signs were recorded pre-dose at screening and pre- and post-dose at all visits during the treatment period; physical examination was performed at all visits; concomitant medications and adverse events (AEs) were recorded, and asthma exacerbations were assessed at all visits; lung function tests were performed (pre-dose for FEV1 and forced vital capacity from screening to end of treatment visits, pre-dose for inspiratory capacity and vital capacity and post-dose serial spirometry at all visits during the treatment period); 12-lead single electrocardiograms were recorded pre-dose at screening and pre- and post-dose at all visits during the treatment period (parameters evaluated included heart rate, PR interval, QRS interval and Fridericia-corrected QT interval). Patients completed the electronic diary from home twice daily from screening until the end of treatment to record asthma symptoms, treatment compliance and use of rescue medication, and used the electronic peakflowmeter to record peak expiratory flow twice daily from home from screening until the end of treatment. The Asthma Control Questionnaire© (ACQ)-7 was completed at screening and all visits during the treatment period. The EuroQuality of Life-5-Dimensional-3-Level questionnaire, and health economic and outcome assessments were competed at all visits during the treatment period. Blood samplings for haematology and blood chemistry were performed at screening, Week 26 and Week 52. Rescue medication (salbutamol 100 μg per inhalation) was used throughout the treatment period in case of absolute need; the maximum allowed dose was 8 inhalations/day (800 μg). An independent Data Safety Monitoring Board was established for independent scrutiny of the study and impartial safety insurance of patients.
    Background therapy
    -
    Evidence for comparator
    In this study, CHF 1535 pMDI 100/6 μg (beclometasone dipropionate [BDP]/formoterol fumarate [FF] 100/6 μg, total daily dose BDP/FF 400/24 μg, which is the marketed dose) was chosen as control treatment. The approved asthma indication of CHF 1535 pMDI 100/6 μg is in “patients not adequately controlled with inhaled corticosteroids (ICS) and ‘as needed’ inhaled rapid-acting ß2-agonist or patients already adequately controlled on both ICS and long-acting ß2-agonists (LABAs)”. In this study, although the population included patients with uncontrolled asthma while on medium doses of ICS in combination with LABAs, no safety risks were foreseen for this population as they were allowed to use inhaled salbutamol as rescue medication and they were closely and medically monitored during the entire study. The choice of comparator is in line with the scientific advice for the clinical development of CHF 5993 provided by the EMA.
    Actual start date of recruitment
    17 Feb 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 131
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Romania: 41
    Country: Number of subjects enrolled
    Slovakia: 15
    Country: Number of subjects enrolled
    Bulgaria: 96
    Country: Number of subjects enrolled
    Czech Republic: 107
    Country: Number of subjects enrolled
    Germany: 36
    Country: Number of subjects enrolled
    Hungary: 83
    Country: Number of subjects enrolled
    Argentina: 21
    Country: Number of subjects enrolled
    Belarus: 13
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Russian Federation: 361
    Country: Number of subjects enrolled
    Ukraine: 242
    Worldwide total number of subjects
    1155
    EEA total number of subjects
    518
    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)
    0
    Adults (18-64 years)
    950
    From 65 to 84 years
    205
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Overall, 1628 patients were screened according to inclusion and exclusion criteria; of these, 1155 patients were randomised.

    Pre-assignment
    Screening details
    At screening, within 7 days of a pre-screening visit, inclusion/exclusion criteria were assessed. There were 473 screening failures (failure to meet randomisation criteria [389 patients], consent withdrawal [58 patients], other reasons [17 patients], adverse events [4 patients], asthma exacerbations [4 patients], lost to follow-up [1 patient]).

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Assessor, Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    An Interactive Response Technology (IRT) system was used to assign patients to the treatment arms. The randomisation list was provided to the labelling facility. An additional copy of the Master Randomisation List was provided to the analytical laboratory performing the pharmacokinetic analyses on biological samples, that was unblinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CHF 5993 pMDI 100/6/12.5 μg
    Arm description
    Patients were randomised to receive CHF 5993 pMDI 100/6/12.5 μg 2 puffs twice daily (BID) (total daily dose: BDP/FF/glycopyrronium bromide [GB] 400/24/50 μg) for 52 weeks following a 2-week ± 2 days open-label run-in period of CHF 1535 pMDI 100/6 μg 2 puffs BID (total daily dose: BDP/FF 400/24 μg). Rescue medication (salbutamol 100 μg per inhalation) was used throughout the treatment period in case of absolute need; the maximum allowed dose was 8 inhalations/day (800 μg).
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 5993 pMDI 100/6/12.6 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 pMDI, fixed-dose combination of BDP/FF/GB. Dose: BDP 100 μg, FF 6 μg, GB 12.5 μg per actuation, 2 puffs BID. Total daily dose: BDP/FF/GB 400/24/50 μg. Mode of administration: pMDI using a standard actuator. Patients were trained in the proper use of the pMDI device. At Week 0, Week 12, Week 26 and Week 40, 2 kits of study treatment were dispensed to each patient, each consisting of one box containing two inhalers (numbered 1 and 2) which were to be used in the morning and in the evening. Each day during the 52-week treatment period, patients administered 1 puff from each pMDI inhaler in the morning and in the evening. If patients were used to inhaling their pMDI asthma medications with a spacer device, they used the AeroChamber Plus™ for inhaling the study treatment. Patients were trained in the proper use of this device, which was dispensed at screening, Week 0 and Week 26.

    Arm title
    CHF 1535 pMDI 100/6 μg
    Arm description
    Patients were randomised to receive CHF 1535 pMDI 100/6 μg 2 puffs BID (total daily dose: BDP/FF 400/24 μg) for 52 weeks following a 2-week ± 2 days open-label run-in period of CHF 1535 pMDI 100/6 μg 2 puffs BID (total daily dose: BDP/FF 400/24 μg). Rescue medication (salbutamol 100 μg per inhalation) was used throughout the treatment period in case of absolute need; the maximum allowed dose was 8 inhalations/day (800 μg).
    Arm type
    Active comparator

    Investigational medicinal product name
    CHF 1535 pMDI 100/6 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pressurised inhalation, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    CHF 1535 pMDI 100/6 μg containing BDP 100 μg and FF 6 μg. Dose: BDP 100 μg and FF 6 μg per actuation, 2 puffs BID. Total daily dose: BDP/FF 400/24 μg. Mode of administration: pMDI using a standard actuator. Patients were trained in the proper use of the pMDI device. At Week 0, Week 12, Week 26 and Week 40, 2 kits of study treatment were dispensed to each patient, each kit consisting of one box containing two inhalers (numbered 1 and 2) which were to be used in the morning and in the evening. Each day during the 52-week treatment period, patients administered 1 puff from each pMDI inhaler in the morning and in the evening. If patients were used to inhaling their pMDI asthma medications with a spacer device, they used the AeroChamber Plus™ for inhaling the study treatment. Patients were trained in the use of the AeroChamber Plus™ device, and this was dispensed at screening, Week 0 and Week 26.

    Number of subjects in period 1
    CHF 5993 pMDI 100/6/12.5 μg CHF 1535 pMDI 100/6 μg
    Started
    579
    576
    Completed
    542
    539
    Not completed
    37
    37
         Protocol violation
    7
    4
         Adverse event, serious fatal
    3
    -
         Adverse event, non-fatal
    -
    5
         Asthma exacerbation
    1
    -
         Consent withdrawn by subject
    22
    26
         Reason not specified
    2
    -
         Lost to follow-up
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CHF 5993 pMDI 100/6/12.5 μg
    Reporting group description
    Patients were randomised to receive CHF 5993 pMDI 100/6/12.5 μg 2 puffs twice daily (BID) (total daily dose: BDP/FF/glycopyrronium bromide [GB] 400/24/50 μg) for 52 weeks following a 2-week ± 2 days open-label run-in period of CHF 1535 pMDI 100/6 μg 2 puffs BID (total daily dose: BDP/FF 400/24 μg). Rescue medication (salbutamol 100 μg per inhalation) was used throughout the treatment period in case of absolute need; the maximum allowed dose was 8 inhalations/day (800 μg).

    Reporting group title
    CHF 1535 pMDI 100/6 μg
    Reporting group description
    Patients were randomised to receive CHF 1535 pMDI 100/6 μg 2 puffs BID (total daily dose: BDP/FF 400/24 μg) for 52 weeks following a 2-week ± 2 days open-label run-in period of CHF 1535 pMDI 100/6 μg 2 puffs BID (total daily dose: BDP/FF 400/24 μg). Rescue medication (salbutamol 100 μg per inhalation) was used throughout the treatment period in case of absolute need; the maximum allowed dose was 8 inhalations/day (800 μg).

    Reporting group values
    CHF 5993 pMDI 100/6/12.5 μg CHF 1535 pMDI 100/6 μg Total
    Number of subjects
    579 576 1155
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    473 477 950
        From 65-84 years
    106 99 205
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    52.6 ± 12.3 52.4 ± 12.3 -
    Gender categorical
    Units: Subjects
        Female
    358 355 713
        Male
    221 221 442
    Subject analysis sets

    Subject analysis set title
    CHF 5993 pMDI 100/6/12.5 μg - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intention-to-treat (ITT) population was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after baseline.

    Subject analysis set title
    CHF 1535 pMDI 100/6 μg - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The ITT population was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after baseline.

    Subject analysis set title
    CHF 5993 pMDI 100/6/12.5 μg - Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety population was defined as all randomised patients who received at least one dose of study treatment.

    Subject analysis set title
    CHF 1535 pMDI 100/6 μg - Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety population was defined as all randomised patients who received at least one dose of study treatment.

    Subject analysis set title
    CHF 5993 pMDI 100/6/12.5 μg and 200/6/12.5 μg - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    A pre-specified pooled analysis of the rate of severe asthma exacerbations over the 52-week treatment period was performed in the ITT population in two pivotal studies - CCD-05993AB1-03 (TRIMARAN) and CCD-05993AB2-02 (TRIGGER). The ITT population in each study was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary variables) after baseline. The present analysis set included patients from the CHF 5993 pMDI 100/6/12.5 μg (“CHF 5993 pMDI”) arm in Study CCD-05993AB1-03 (ITT population) and the CHF 5993 pMDI 200/6/12.5 μg (“CHF 5993 pMDI high strength [HS]") arm in Study CCD-05993AB2-02 (ITT population).

    Subject analysis set title
    CHF 1535 pMDI 100/6 μg and 200/6 μg - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    A pre-specified pooled analysis of severe asthma exacerbations over the 52-week treatment period was performed in the ITT populations of two pivotal studies - CCD-05993AB1-03 (TRIMARAN) and CCD-05993AB2-02 (TRIGGER). The ITT population in each study was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary variables) after baseline. The present analysis set included the CHF 1535 pMDI 100/6 μg ("CHF 1535 pMDI”) arm in Study CCD-05993AB1-03 (ITT population) and the CHF 1535 pMDI 200/6 μg (“CHF 1535 pMDI HS”) arm in Study CCD-05993AB2-02 (ITT population).

    Subject analysis sets values
    CHF 5993 pMDI 100/6/12.5 μg - ITT CHF 1535 pMDI 100/6 μg - ITT CHF 5993 pMDI 100/6/12.5 μg - Safety CHF 1535 pMDI 100/6 μg - Safety CHF 5993 pMDI 100/6/12.5 μg and 200/6/12.5 μg - ITT CHF 1535 pMDI 100/6 μg and 200/6 μg - ITT
    Number of subjects
    575
    574
    576
    574
    1146
    1145
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    52.6 ± 12.4
    52.5 ± 12.2
    52.6 ± 12.4
    52.5 ± 12.2
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    354
    353
    355
    353
        Male
    221
    221
    221
    221

    End points

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    End points reporting groups
    Reporting group title
    CHF 5993 pMDI 100/6/12.5 μg
    Reporting group description
    Patients were randomised to receive CHF 5993 pMDI 100/6/12.5 μg 2 puffs twice daily (BID) (total daily dose: BDP/FF/glycopyrronium bromide [GB] 400/24/50 μg) for 52 weeks following a 2-week ± 2 days open-label run-in period of CHF 1535 pMDI 100/6 μg 2 puffs BID (total daily dose: BDP/FF 400/24 μg). Rescue medication (salbutamol 100 μg per inhalation) was used throughout the treatment period in case of absolute need; the maximum allowed dose was 8 inhalations/day (800 μg).

    Reporting group title
    CHF 1535 pMDI 100/6 μg
    Reporting group description
    Patients were randomised to receive CHF 1535 pMDI 100/6 μg 2 puffs BID (total daily dose: BDP/FF 400/24 μg) for 52 weeks following a 2-week ± 2 days open-label run-in period of CHF 1535 pMDI 100/6 μg 2 puffs BID (total daily dose: BDP/FF 400/24 μg). Rescue medication (salbutamol 100 μg per inhalation) was used throughout the treatment period in case of absolute need; the maximum allowed dose was 8 inhalations/day (800 μg).

    Subject analysis set title
    CHF 5993 pMDI 100/6/12.5 μg - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intention-to-treat (ITT) population was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after baseline.

    Subject analysis set title
    CHF 1535 pMDI 100/6 μg - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The ITT population was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after baseline.

    Subject analysis set title
    CHF 5993 pMDI 100/6/12.5 μg - Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety population was defined as all randomised patients who received at least one dose of study treatment.

    Subject analysis set title
    CHF 1535 pMDI 100/6 μg - Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety population was defined as all randomised patients who received at least one dose of study treatment.

    Subject analysis set title
    CHF 5993 pMDI 100/6/12.5 μg and 200/6/12.5 μg - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    A pre-specified pooled analysis of the rate of severe asthma exacerbations over the 52-week treatment period was performed in the ITT population in two pivotal studies - CCD-05993AB1-03 (TRIMARAN) and CCD-05993AB2-02 (TRIGGER). The ITT population in each study was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary variables) after baseline. The present analysis set included patients from the CHF 5993 pMDI 100/6/12.5 μg (“CHF 5993 pMDI”) arm in Study CCD-05993AB1-03 (ITT population) and the CHF 5993 pMDI 200/6/12.5 μg (“CHF 5993 pMDI high strength [HS]") arm in Study CCD-05993AB2-02 (ITT population).

    Subject analysis set title
    CHF 1535 pMDI 100/6 μg and 200/6 μg - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    A pre-specified pooled analysis of severe asthma exacerbations over the 52-week treatment period was performed in the ITT populations of two pivotal studies - CCD-05993AB1-03 (TRIMARAN) and CCD-05993AB2-02 (TRIGGER). The ITT population in each study was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary variables) after baseline. The present analysis set included the CHF 1535 pMDI 100/6 μg ("CHF 1535 pMDI”) arm in Study CCD-05993AB1-03 (ITT population) and the CHF 1535 pMDI 200/6 μg (“CHF 1535 pMDI HS”) arm in Study CCD-05993AB2-02 (ITT population).

    Primary: Change from baseline in pre-dose FEV1 at Week 26

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    End point title
    Change from baseline in pre-dose FEV1 at Week 26
    End point description
    FEV1 is the forced expiratory volume in the first second. Change from baseline (CFB) in pre-dose morning FEV1 at Week 26 was analysed. Data are presented as adjusted means (least squares means) with their 95% confidence intervals (CIs).
    End point type
    Primary
    End point timeframe
    Baseline to Week 26.
    End point values
    CHF 5993 pMDI 100/6/12.5 μg - ITT CHF 1535 pMDI 100/6 μg - ITT
    Number of subjects analysed
    557 [1]
    553 [2]
    Units: Litres
        least squares mean (confidence interval 95%)
    0.185 (0.155 to 0.214)
    0.127 (0.098 to 0.157)
    Notes
    [1] - Number of patients in the ITT population = 575; Number of patients with available data = 557.
    [2] - Number of patients in the ITT population = 574; Number of patients with available data = 553.
    Statistical analysis title
    Adj. mean difference, CFB in pre-dose FEV1 Week 26
    Statistical analysis description
    The CFB in pre-dose FEV1 at Week 26 was analysed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction and country as fixed effects, and baseline value (Week 0, pre-dose) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted means in each treatment group, adjusted mean difference between treatments with 95% CIs and p-values were estimated.
    Comparison groups
    CHF 1535 pMDI 100/6 μg - ITT v CHF 5993 pMDI 100/6/12.5 μg - ITT
    Number of subjects included in analysis
    1110
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.008
    Method
    Linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.057
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.015
         upper limit
    0.099
    Notes
    [3] - Comparisons between treatments were conducted according to a hierarchical testing procedure to test the co-primary and key secondary efficacy endpoints. At step 1, both superiority tests on the co-primary endpoints had to be significant. For this endpoint, superiority of CHF 5993 pMDI 100/6/12.5 μg over CHF 1535 pMDI 100/6 μg was demonstrated if the lower limit of the confidence interval for the adjusted mean difference between treatments was > 0.

    Primary: Moderate and severe asthma exacerbation rate over the 52-week treatment period

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    End point title
    Moderate and severe asthma exacerbation rate over the 52-week treatment period
    End point description
    Severe asthma exacerbation - asthma worsening requiring initiation of treatment with systemic corticosteroids for at least 3 days (courses of corticosteroids separated by ≥ 1 week treated as separate severe exacerbations); requirement of an emergency room (ER) visit or hospitalisation was documented. Moderate asthma exacerbation - defined as ≥ 1 of the following criteria fulfilled and leading to a change in treatment (sustained increase of ≥ 1 puff of short acting β2-agonist [SABA] for 2 consecutive days): nocturnal awakening(s) due to asthma requiring SABA for 2 consecutive nights/increase of ≥ 0.75 from baseline in daily symptom score on 2 consecutive days; increase from baseline in occasions of SABA use on 2 consecutive days (minimum increase 4 puffs/day); ≥ 20% decrease in peak expiratory flow from baseline on at least 2 consecutive mornings/evenings or ≥ 20% decrease in FEV1 from baseline; visit to the ER/trial site for asthma treatment not requiring systemic corticosteroids.
    End point type
    Primary
    End point timeframe
    52-week treatment period.
    End point values
    CHF 5993 pMDI 100/6/12.5 μg - ITT CHF 1535 pMDI 100/6 μg - ITT
    Number of subjects analysed
    575
    574
    Units: Adjusted exacerbation rate/patient/year
        number (confidence interval 95%)
    1.825 (1.634 to 2.037)
    2.157 (1.937 to 2.402)
    Statistical analysis title
    Adjusted rate ratio, moderate/severe exacerbations
    Statistical analysis description
    The number of moderate and severe exacerbations during the 52-week treatment period was analysed using a negative binomial model including treatment, country, and number of exacerbations in the previous year (1 or > 1) as fixed effects, and log-time on study as an offset. Adjusted asthma exacerbation rates in each treatment group, adjusted rate ratios with their 95% CIs and p-values were estimated by the model.
    Comparison groups
    CHF 5993 pMDI 100/6/12.5 μg - ITT v CHF 1535 pMDI 100/6 μg - ITT
    Number of subjects included in analysis
    1149
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.033
    Method
    Negative binomial model
    Parameter type
    Adjusted rate ratio
    Point estimate
    0.846
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.725
         upper limit
    0.987
    Notes
    [4] - Comparisons between treatments were conducted according to a hierarchical testing procedure to test the co-primary and key secondary efficacy endpoints. At step 1, both superiority tests on the co-primary endpoints had to be significant. For this endpoint, superiority of CHF 5993 pMDI 100/6/12.5 μg over CHF 1535 pMDI 100/6 μg was demonstrated if the upper limit of the CI for the adjusted rate ratio between treatments was < 1.

    Secondary: Change from baseline in peak0-3h FEV1 at Week 26

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    End point title
    Change from baseline in peak0-3h FEV1 at Week 26
    End point description
    Peak0-3h FEV1 is the peak forced expiratory volume in the first second within 3 hours post-dose. The change from baseline in peak0-3h FEV1 at Week 26 was analysed. This was a key secondary efficacy endpoint. Data are presented as adjusted means (least squares means) with their 95% CIs.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26.
    End point values
    CHF 5993 pMDI 100/6/12.5 μg - ITT CHF 1535 pMDI 100/6 μg - ITT
    Number of subjects analysed
    553 [5]
    553 [6]
    Units: Litres
        least squares mean (confidence interval 95%)
    0.485 (0.453 to 0.516)
    0.401 (0.369 to 0.432)
    Notes
    [5] - Number of patients in the ITT population = 575; Number of patients with available data = 553.
    [6] - Number of patients in the ITT population = 574; Number of patients with available data = 553.
    Statistical analysis title
    Adj. mean difference in CFB, peak0-3h FEV1 Week 26
    Statistical analysis description
    The CFB in peak0-3h FEV1 at Week 26 was analysed using a linear MMRM including treatment, visit, treatment by visit interaction and country as fixed effects; baseline value (Week 0, pre-dose) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted means in each treatment group, adjusted mean difference between treatments, their 95% CIs and p-values were estimated.
    Comparison groups
    CHF 5993 pMDI 100/6/12.5 μg - ITT v CHF 1535 pMDI 100/6 μg - ITT
    Number of subjects included in analysis
    1106
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.001
    Method
    Linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.084
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.04
         upper limit
    0.129
    Notes
    [7] - The comparisons between treatments were conducted according to a hierarchical testing procedure. At step 1, both superiority tests on the two co-primary endpoints had to be significant. At step 2, superiority of CHF 5993 pMDI 100/6/12.5 μg over CHF 1535 pMDI 100/6 μg had to be demonstrated for the present key secondary efficacy endpoint. Superiority was demonstrated if the lower limit of the CI for the adjusted mean difference between treatments was > 0. Steps 3 and 4 followed in sequence.

    Secondary: Change from baseline in the average morning PEF measured by patients at home over the 26-week treatment period

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    End point title
    Change from baseline in the average morning PEF measured by patients at home over the 26-week treatment period
    End point description
    Patients monitored peak expiratory flow (PEF, litres/minute) twice a day (morning and evening) during the run-in period (baseline measurement) and the entire treatment period at home, using a portable ePeakflowmeter which was customised with a specific program according to the parameters required by the study protocol. Patients were trained on the purpose and technique of PEF home monitoring. During each measurement session, patients performed three blows before intake of run-in or study medication (as applicable), data were recorded on the device and automatically transmitted from home to the Vitalograph database on a daily basis. The change from baseline in the average morning PEF over the 26-week treatment period was analysed. This was a key secondary efficacy endpoint. Data are presented as adjusted means (least squares mean) with their 95% CIs.
    End point type
    Secondary
    End point timeframe
    26-week treatment period from Weeks 1 to 26.
    End point values
    CHF 5993 pMDI 100/6/12.5 μg - ITT CHF 1535 pMDI 100/6 μg - ITT
    Number of subjects analysed
    566 [8]
    569 [9]
    Units: Litres/minute
        least squares mean (confidence interval 95%)
    5.325 (1.921 to 8.729)
    -3.131 (-6.533 to 0.271)
    Notes
    [8] - Number of patients in the ITT population = 575; Number of patients with available data = 566.
    [9] - Number of patients in the ITT population = 574; Number of patients with available data = 569.
    Statistical analysis title
    Adj. mean difference, CFB in average morning PEF
    Statistical analysis description
    The CFB in average morning PEF over the 26-week treatment period was analysed using a linear MMRM which included treatment, inter-visit period, treatment by inter-visit period interaction and country as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates. Adjusted means in each treatment group, adjusted mean difference between treatments, 95% CIs and p-values were estimated.
    Comparison groups
    CHF 5993 pMDI 100/6/12.5 μg - ITT v CHF 1535 pMDI 100/6 μg - ITT
    Number of subjects included in analysis
    1135
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    < 0.001
    Method
    Linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    8.456
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.643
         upper limit
    13.269
    Notes
    [10] - Comparisons between treatments were conducted according to a hierarchical testing procedure. Step 1: both superiority (sup) tests on the co-primary endpoints had to be significant; Step 2: sup of CHF 5993 pMDI 100/6/12.5 μg over CHF 1535 pMDI 100/6 μg had to be demonstrated for CFB in peak0-3h FEV1 at Week 26; Step 3: sup (as in step 2) had to be demonstrated for the present endpoint (lower limit of the CI for the adjusted mean difference between treatments had to be > 0); Step 4 followed.

    Secondary: Severe asthma exacerbation rate over 52 weeks of treatment in a pre-specified pooled analysis of the two pivotal studies CCD-05993AB1-03 and CCD-05993AB2-02

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    End point title
    Severe asthma exacerbation rate over 52 weeks of treatment in a pre-specified pooled analysis of the two pivotal studies CCD-05993AB1-03 and CCD-05993AB2-02
    End point description
    A pre-specified pooled analysis of the rate of severe asthma exacerbations over the 52-week treatment period was performed in the ITT populations of two pivotal studies CCD-05993AB1-03 (present study, TRIMARAN) and CCD-05993AB2-02 (TRIGGER). The pooled analysis of the two studies was based on the following treatment groups: 1. CHF 5993 pMDI + CHF 5993 pMDI High Strength (HS), for which data from the CHF 5993 pMDI 100/6/12.5 μg (“CHF 5993 pMDI”) arm in Study CCD-05993AB1-03 and the CHF 5993 pMDI 200/6/12.5 μg (“CHF 5993 pMDI HS") arm in Study CCD-05993AB2-02 were pooled; 2. CHF 1535 pMDI + CHF 1535 pMDI HS, for which data from the CHF 1535 pMDI 100/6 μg ("CHF 1535 pMDI”) arm in Study CCD-05993AB1-03 and the CHF 1535 pMDI 200/6 μg (“CHF 1535 pMDI HS”) arm in Study CCD-05993AB2-02 were pooled. This was a key secondary efficacy endpoint.
    End point type
    Secondary
    End point timeframe
    52-week treatment period.
    End point values
    CHF 5993 pMDI 100/6/12.5 μg and 200/6/12.5 μg - ITT CHF 1535 pMDI 100/6 μg and 200/6 μg - ITT
    Number of subjects analysed
    1146
    1145
    Units: Adjusted exacerbation rate/patient/year
        number (confidence interval 95%)
    0.239 (0.206 to 0.276)
    0.310 (0.271 to 0.354)
    Statistical analysis title
    Adj. exacerbation rate ratio (severe exacerbation)
    Statistical analysis description
    The number of severe asthma exacerbations during the 52-week treatment period was analysed in the pooled data of the two pivotal studies using a negative binomial model including treatment, country, and number of exacerbations in the previous year (1 or > 1) as fixed effects, and log-time on study as an offset. The adjusted asthma exacerbation rates in each treatment group and the adjusted rate ratios with their 95% CIs and p-values were estimated by the model.
    Comparison groups
    CHF 5993 pMDI 100/6/12.5 μg and 200/6/12.5 μg - ITT v CHF 1535 pMDI 100/6 μg and 200/6 μg - ITT
    Number of subjects included in analysis
    2291
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.008
    Method
    Negative binomial model
    Parameter type
    Adjusted rate ratio
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.636
         upper limit
    0.933
    Notes
    [11] - Comparisons between treatments were conducted according to a hierarchical testing procedure. Step 1: superiority (sup) tests on the co-primary endpoints had to be significant; Steps 2, 3: sup of CHF 5993 pMDI 100/6/12.5 μg over CHF 1535 pMDI 100/6 μg had to be demonstrated for CFB in peak0-3h FEV1 (Week 26), then CFB in morning PEF over 26 weeks; Step 4 (present endpoint): sup of CHF 5993 pMDI over CHF 1535 pMDI was demonstrated if the upper limit of the CI for the adj. rate ratio was < 1.

    Secondary: Asthma Control Questionnaire©-7 response at Week 52

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    End point title
    Asthma Control Questionnaire©-7 response at Week 52
    End point description
    An ACQ-7 response was defined as change from baseline (Week 0, pre-dose) in ACQ-7 score ≤ -0.5; non-response was defined as change from baseline in ACQ-7 score >-0.5 or missing data. The ACQ-7 allows the identification of the adequacy of asthma control in individual patients. The first 6 items of the questionnaire refer to symptoms and rescue use in the previous 7 days (patients were asked to recall how their asthma had been during the previous week and to respond to the symptom and bronchodilator use questions on a 7-point scale with 0 = no impairment and 6 = maximum impairment); the 7th item (related to FEV1, completed by the clinical staff) was populated with the value of FEV1 % of predicted when reversibility was met at screening (Week -2) and considering the pre-dose FEV1 % of predicted taken at -15 minutes at visits during the treatment period. The ACQ-7 was completed at screening, and during the treatment period from Week 0 to Week 52.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52.
    End point values
    CHF 5993 pMDI 100/6/12.5 μg - ITT CHF 1535 pMDI 100/6 μg - ITT
    Number of subjects analysed
    575
    574
    Units: Patients
        number (not applicable)
    350
    340
    Statistical analysis title
    Odds ratio, ACQ-7 response at Week 52
    Statistical analysis description
    ACQ-7 response was compared between treatment groups using a logistic model including treatment and country as factors and the baseline value (Week 0) as covariate. The odds ratio for the treatment effects with their 95% CIs and corresponding p-values were estimated by the model.
    Comparison groups
    CHF 5993 pMDI 100/6/12.5 μg - ITT v CHF 1535 pMDI 100/6 μg - ITT
    Number of subjects included in analysis
    1149
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6
    Method
    Logistic model
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.072
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.843
         upper limit
    1.362

    Secondary: Time to first moderate or severe asthma exacerbation

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    End point title
    Time to first moderate or severe asthma exacerbation
    End point description
    The number of patients at risk of a moderate or severe asthma exacerbation is presented.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52.
    End point values
    CHF 5993 pMDI 100/6/12.5 μg - ITT CHF 1535 pMDI 100/6 μg - ITT
    Number of subjects analysed
    575 [12]
    574 [13]
    Units: Patients
    337
    379
    Notes
    [12] - Of 575 patients in the ITT population, 337 had a moderate/severe exacerbation.
    [13] - Of 574 patients in the ITT population, 379 had a moderate/severe exacerbation.
    Statistical analysis title
    Hazard ratio (time to 1st mod/severe exacerbation)
    Statistical analysis description
    Time to first moderate or severe asthma exacerbation was analysed using a Cox proportional hazards model including treatment, country and number of exacerbations in the previous year (1 or > 1) as factors.
    Comparison groups
    CHF 5993 pMDI 100/6/12.5 μg - ITT v CHF 1535 pMDI 100/6 μg - ITT
    Number of subjects included in analysis
    1149
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.022
    Method
    Cox proportional hazards analysis
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.842
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.727
         upper limit
    0.975

    Secondary: Time to first severe asthma exacerbation in the pooled analysis of the two pivotal studies CCD-05993AB1-03 and CCD-05993AB2-02

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    End point title
    Time to first severe asthma exacerbation in the pooled analysis of the two pivotal studies CCD-05993AB1-03 and CCD-05993AB2-02
    End point description
    The number of patients at risk of a severe asthma exacerbation is presented.
    End point type
    Secondary
    End point timeframe
    Baseline to 52 weeks for both studies in the pooled analysis.
    End point values
    CHF 5993 pMDI 100/6/12.5 μg and 200/6/12.5 μg - ITT CHF 1535 pMDI 100/6 μg and 200/6 μg - ITT
    Number of subjects analysed
    1146 [14]
    1145 [15]
    Units: Patients
    209
    257
    Notes
    [14] - Of 1146 patients in the ITT population, 209 had a severe exacerbation.
    [15] - Of 1145 patients in the ITT population, 257 had a severe exacerbation.
    Statistical analysis title
    Hazard ratio (time to 1st severe exacerbation)
    Statistical analysis description
    Time to first severe asthma exacerbation in the pooled data of the two pivotal studies CCD-05993AB1-03 and CCD-05993AB2-02 was analysed using a Cox proportional hazards model including treatment, country and number of exacerbations in the previous year (1 or > 1) as factors.
    Comparison groups
    CHF 5993 pMDI 100/6/12.5 μg and 200/6/12.5 μg - ITT v CHF 1535 pMDI 100/6 μg and 200/6 μg - ITT
    Number of subjects included in analysis
    2291
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.011
    Method
    Cox proportional hazards analysis
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.788
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.656
         upper limit
    0.946

    Secondary: Change from baseline in the percentage of asthma control days in each inter-visit period, over the 52-week treatment period

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    End point title
    Change from baseline in the percentage of asthma control days in each inter-visit period, over the 52-week treatment period
    End point description
    Patients recorded asthma symptom scores and use of rescue medication in the eDiary twice a day at home during the run-in (baseline values) and treatment periods; data were automatically transmitted daily to the Vitalograph database. Asthma symptoms (i.e. overall symptoms, cough, wheeze, chest tightness and breathlessness) were scored as follows: Morning (night-time asthma symptoms): 0 (no symptoms), 1 (mild - symptoms not causing awakening), 2 (moderate - discomfort enough to cause awakenings) and 3 (severe - causing awakenings for most of the night/did not sleep at all); Evening (daytime asthma symptoms): 0 (no symptoms), 1 (mild - aware of symptoms which could be easily tolerated), 2 (moderate - discomfort enough to cause interference with daily activity), 3 (severe - incapacitating with inability to work/take part in usual activity). Asthma control days were calculated as days (i.e. night-time + daytime) with a total asthma score of 0 and no rescue medication use.
    End point type
    Secondary
    End point timeframe
    52-week treatment period.
    End point values
    CHF 5993 pMDI 100/6/12.5 μg - ITT CHF 1535 pMDI 100/6 μg - ITT
    Number of subjects analysed
    574 [16]
    574 [17]
    Units: Percentage
        least squares mean (confidence interval 95%)
    16.395 (14.154 to 18.635)
    15.109 (12.863 to 17.355)
    Notes
    [16] - Number of patients in the ITT population = 575; Number of patients with available data = 574.
    [17] - Number of patients in the ITT population = 574; Number of patients with available data = 574.
    Statistical analysis title
    Adjusted mean difference - CFB over 52 weeks
    Statistical analysis description
    The CFB in percentage of asthma control days over the entire treatment period (Weeks 1-52) was analysed using a linear MMRM including treatment, inter-visit period, treatment by inter-visit period interaction and country as fixed effects, and baseline value (run-in period) and baseline by inter-visit period interaction and country as covariates.
    Comparison groups
    CHF 5993 pMDI 100/6/12.5 μg - ITT v CHF 1535 pMDI 100/6 μg - ITT
    Number of subjects included in analysis
    1148
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.427
    Method
    Linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    1.286
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.887
         upper limit
    4.459

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from the time of patient informed consent until study completion or discontinuation.
    Adverse event reporting additional description
    Treatment-emergent AEs (TEAEs) were defined as AEs with date of first randomised study treatment intake ≤ AE onset date ≤ date of completion/discontinuation.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    CHF 5993 pMDI 100/6/12.5 μg - Safety
    Reporting group description
    The Safety population was defined as all randomised patients who received at least one dose of study treatment.

    Reporting group title
    CHF 1535 pMDI 100/6 μg - Safety
    Reporting group description
    The Safety population was defined as all randomised patients who received at least one dose of study treatment.

    Serious adverse events
    CHF 5993 pMDI 100/6/12.5 μg - Safety CHF 1535 pMDI 100/6 μg - Safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 576 (4.86%)
    22 / 574 (3.83%)
         number of deaths (all causes)
    3
    0
         number of deaths resulting from adverse events
    3
    0
    Vascular disorders
    Aortic aneurysm rupture
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 576 (0.00%)
    1 / 574 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian artery stenosis
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    0 / 576 (0.00%)
    1 / 574 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Mantle cell lymphoma stage IV
         subjects affected / exposed
    0 / 576 (0.00%)
    1 / 574 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Limb crushing injury
         subjects affected / exposed
    0 / 576 (0.00%)
    1 / 574 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 576 (0.00%)
    1 / 574 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 576 (0.35%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 576 (0.17%)
    1 / 574 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 576 (0.00%)
    1 / 574 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 576 (0.00%)
    1 / 574 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    7 / 576 (1.22%)
    4 / 574 (0.70%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillar inflammation
         subjects affected / exposed
    0 / 576 (0.00%)
    1 / 574 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 576 (0.17%)
    1 / 574 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 576 (0.00%)
    1 / 574 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 576 (0.35%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 576 (0.00%)
    1 / 574 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Subcutaneous emphysema
         subjects affected / exposed
    0 / 576 (0.00%)
    1 / 574 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 576 (0.00%)
    2 / 574 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 576 (0.00%)
    1 / 574 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bursitis infective
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 576 (0.00%)
    1 / 574 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 576 (0.00%)
    1 / 574 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    1 / 576 (0.17%)
    0 / 574 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 576 (0.00%)
    3 / 574 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 576 (0.00%)
    1 / 574 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    CHF 5993 pMDI 100/6/12.5 μg - Safety CHF 1535 pMDI 100/6 μg - Safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    429 / 576 (74.48%)
    451 / 574 (78.57%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    16 / 576 (2.78%)
    9 / 574 (1.57%)
         occurrences all number
    22
    12
    Investigations
    Blood pressure increased
         subjects affected / exposed
    12 / 576 (2.08%)
    7 / 574 (1.22%)
         occurrences all number
    20
    14
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    334 / 576 (57.99%)
    377 / 574 (65.68%)
         occurrences all number
    1179
    1348
    Oropharyngeal pain
         subjects affected / exposed
    9 / 576 (1.56%)
    12 / 574 (2.09%)
         occurrences all number
    9
    13
    Nervous system disorders
    Headache
         subjects affected / exposed
    38 / 576 (6.60%)
    46 / 574 (8.01%)
         occurrences all number
    49
    52
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 576 (1.39%)
    14 / 574 (2.44%)
         occurrences all number
    8
    15
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    71 / 576 (12.33%)
    78 / 574 (13.59%)
         occurrences all number
    85
    98
    Respiratory tract infection viral
         subjects affected / exposed
    15 / 576 (2.60%)
    26 / 574 (4.53%)
         occurrences all number
    17
    30
    Bronchitis
         subjects affected / exposed
    18 / 576 (3.13%)
    22 / 574 (3.83%)
         occurrences all number
    22
    26
    Pharyngitis
         subjects affected / exposed
    12 / 576 (2.08%)
    16 / 574 (2.79%)
         occurrences all number
    12
    17
    Viral upper respiratory tract infection
         subjects affected / exposed
    12 / 576 (2.08%)
    16 / 574 (2.79%)
         occurrences all number
    14
    20
    Rhinitis
         subjects affected / exposed
    8 / 576 (1.39%)
    12 / 574 (2.09%)
         occurrences all number
    8
    13
    Sinusitis
         subjects affected / exposed
    6 / 576 (1.04%)
    12 / 574 (2.09%)
         occurrences all number
    6
    12

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jun 2016
    There was one substantial general amendment (protocol version 2.0, dated 12 May 2016) to clarify the nature of long-acting β2-agonist (LABA) daily doses in inclusion criterion #4.

    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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