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    Clinical Trial Results:
    A phase II, multicentre, randomised, double-blind, double-dummy, active-controlled, 3-way cross-over study to evaluate the efficacy of CHF 5993 administered via Dry Powder Inhaler (DPI) versus CHF 5993 via pressurized Metered Dose Inhaler (pMDI) and CHF 1535 pMDI in patients with chronic obstructive pulmonary disease

    Summary
    EudraCT number
    2017-004405-41
    Trial protocol
    DE   HU   CZ   BG   PL   IT  
    Global end of trial date
    06 Mar 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Mar 2020
    First version publication date
    20 Mar 2020
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    CLI-05993BA1-02
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03590379
    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 Trials Transparency, Chiesi Farmaceutici S.p.A., +39 05212791, clinicaltrials_info@chiesi.com
    Scientific contact
    Clinical Trials Transparency, Chiesi Farmaceutici S.p.A., +39 05212791, 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
    25 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the trial were: •To demonstrate the non-inferiority between CHF 5993 DPI and CHF 5993 pMDI in terms of forced expiratory volume in the 1st second (FEV1) area under the curve between 0 and 12 hours (AUC0-12h) normalised by time on Day 28; •To demonstrate the non-inferiority between CHF 5993 DPI and CHF 5993 pMDI in terms of trough FEV1 at 24 hours on Day 28.* *Minor changes to the wording of these objectives for clarification purposes, which did not alter the meaning, were made in this results posting compared to the protocol.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines and all other requirements of local laws. At all visits from screening to the end of the treatment period, concomitant medications and adverse events (AEs) were recorded and physical examination of patients was carried out (concomitant medications and AEs were additionally recorded at the follow-up call). Vital signs (pre-dose) and 12-lead electrocardiograms (ECGs) (pre-dose at screening, pre- and post-dose at all visits during the treatment period) were recorded. Spirometry was performed (pre- and post-bronchodilator FEV1 and forced vital capacity [FVC] at screening and pre-dose and serial post-dose spirometry [FEV1 and FVC] at randomisation and all post-randomisation visits during the treatment period). Patients completed the diary card at home daily from screening until the end of the treatment period. The St. George's Respiratory Questionnaire (SGRQ) was completed at randomisation and at all post-randomisation visits during the treatment period. Blood collection for routine haematology and blood chemistry was performed at screening and again at the end of the treatment period. Heart rate, Fridericia-corrected QT interval, PR interval and QRS interval were evaluated on 12-lead ECGs. Patients were provided with salbutamol as rescue medication.
    Background therapy
    -
    Evidence for comparator
    CHF 5993 DPI (beclometasone dipropionate [BDP]/formoterol fumarate [FF]/glycopyrronium bromide [GB] 100/6/12.5 μg/inhalation) was compared to CHF 5993 pMDI (BDP/FF/GB 100/6/12.5 μg/actuation) and to CHF 1535 pMDI (BDP/FF 100/6 μg/actuation). CHF 5993 pMDI was chosen as reference treatment as it contains the same active ingredients and is currently authorised as a maintenance treatment in adult patients with COPD who are not adequately treated by combinations of either an inhaled corticosteroid (ICS) and a long-acting β2 agonist (LABA) or a LABA and a long-acting muscarinic antagonist (LAMA). The aim of the study was to demonstrate non-inferiority of CHF 5993 DPI to CHF 5993 pMDI in accordance with the Orally Inhaled Products guideline. Superiority of the triple therapy CHF 5993 pMDI (ICS/LABA/LAMA) to double therapy with CHF 1535 pMDI (ICS/LABA) was tested to demonstrate assay sensitivity. CHF 1535 pMDI was chosen as reference treatment as it is currently marketed for the treatment of patients with COPD who have significant symptoms despite long-acting bronchodilator therapy.
    Actual start date of recruitment
    15 Jun 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 123
    Country: Number of subjects enrolled
    Bulgaria: 72
    Country: Number of subjects enrolled
    Czech Republic: 34
    Country: Number of subjects enrolled
    Germany: 25
    Country: Number of subjects enrolled
    Hungary: 105
    Country: Number of subjects enrolled
    Italy: 7
    Worldwide total number of subjects
    366
    EEA total number of subjects
    366
    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)
    175
    From 65 to 84 years
    191
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Overall, 449 patients were screened; 366 patients were randomised to one of six treatment sequences (Sequence ABC [n=63], Sequence CAB [n=60], Sequence BCA [n=60], Sequence ACB [n=62], Sequence BAC [n=60], Sequence CBA [n=61] [note: A=CHF 5993 DPI, B=CHF 5993 pMDI, C=CHF 1535 pMDI]); 342 patients completed the study.

    Pre-assignment
    Screening details
    At screening, no more than 7 days after a pre-screening visit, inclusion/exclusion criteria were assessed. A total of 83 patients failed screening due to: inclusion/exclusion criteria (66 patients), consent withdrawal (7 patients), other reasons (5 patients), adverse events (3 patients), death (1 patient) and lost to follow-up (1 patient).

    Period 1
    Period 1 title
    Period 1 (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
    At randomisation, patients were assigned to one of six treatment sequences using a balanced block randomisation scheme and a pre-established randomisation list. The randomisation list was provided to the labelling facility but was not available to patients, investigators, monitors or employees of the centre involved in the management of the study before unblinding of the data, unless in case of emergency.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sequence ABC
    Arm description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment A=CHF 5993 DPI; Treatment B=CHF 5993 pMDI; Treatment C=CHF 1535 pMDI.
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 5993 DPI
    Investigational medicinal product code
    CHF 5993 DPI
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study treatment kits for each period contained two DPI inhalers and two pMDI inhalers. Within the same period, patients receiving CHF 5993 DPI active were administered CHF 5993 pMDI placebo. Similarly, patients receiving CHF 5993 pMDI or CHF 1535 pMDI were administered CHF 5993 DPI placebo. Thus, each day during the treatment periods patients administered 2 inhalations from the first DPI and 2 puffs from the first pMDI in the morning, then 2 inhalations from the second DPI and 2 puffs from the second pMDI in the evening. Treatment A=CHF 5993 DPI (2 inhalations of CHF 5993 DPI and 2 puffs of CHF 5993 pMDI placebo twice daily [total daily dose: BDP/FF/GB 400/24/50 μg]); Treatment B=CHF 5993 pMDI (2 puffs of CHF 5993 pMDI and 2 inhalations of CHF 5993 DPI placebo twice daily [total daily dose: BDP/FF/GB 400/24/50 μg]); Treatment C=CHF 1535 pMDI (2 puffs of CHF 1535 pMDI and 2 inhalations of CHF 5993 DPI placebo twice daily [total daily dose: BDP/FF 400/24 μg]).

    Investigational medicinal product name
    CHF 5993 pMDI
    Investigational medicinal product code
    CHF 5993 pMDI
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study treatment kits for each period contained two DPI inhalers and two pMDI inhalers. Within the same period, patients receiving CHF 5993 DPI active were administered CHF 5993 pMDI placebo. Similarly, patients receiving CHF 5993 pMDI or CHF 1535 pMDI were administered CHF 5993 DPI placebo. Thus, each day during the treatment periods patients administered 2 inhalations from the first DPI and 2 puffs from the first pMDI in the morning, then 2 inhalations from the second DPI and 2 puffs from the second pMDI in the evening. Treatment A=CHF 5993 DPI (2 inhalations of CHF 5993 DPI and 2 puffs of CHF 5993 pMDI placebo twice daily [total daily dose: BDP/FF/GB 400/24/50 μg]); Treatment B=CHF 5993 pMDI (2 puffs of CHF 5993 pMDI and 2 inhalations of CHF 5993 DPI placebo twice daily [total daily dose: BDP/FF/GB 400/24/50 μg]); Treatment C=CHF 1535 pMDI (2 puffs of CHF 1535 pMDI and 2 inhalations of CHF 5993 DPI placebo twice daily [total daily dose: BDP/FF 400/24 μg]).

    Investigational medicinal product name
    CHF 1535 pMDI
    Investigational medicinal product code
    CHF 1535 pMDI
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study treatment kits for each period contained two DPI inhalers and two pMDI inhalers. Within the same period, patients receiving CHF 5993 DPI active were administered CHF 5993 pMDI placebo. Similarly, patients receiving CHF 5993 pMDI or CHF 1535 pMDI were administered CHF 5993 DPI placebo. Thus, each day during the treatment periods patients administered 2 inhalations from the first DPI and 2 puffs from the first pMDI in the morning, then 2 inhalations from the second DPI and 2 puffs from the second pMDI in the evening. Treatment A=CHF 5993 DPI (2 inhalations of CHF 5993 DPI and 2 puffs of CHF 5993 pMDI placebo twice daily [total daily dose: BDP/FF/GB 400/24/50 μg]); Treatment B=CHF 5993 pMDI (2 puffs of CHF 5993 pMDI and 2 inhalations of CHF 5993 DPI placebo twice daily [total daily dose: BDP/FF/GB 400/24/50 μg]); Treatment C=CHF 1535 pMDI (2 puffs of CHF 1535 pMDI and 2 inhalations of CHF 5993 DPI placebo twice daily [total daily dose: BDP/FF 400/24 μg]).

    Arm title
    Sequence CAB
    Arm description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment C=CHF 1535 pMDI; Treatment A=CHF 5993 DPI; Treatment B=CHF 5993 pMDI.
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 1535 pMDI
    Investigational medicinal product code
    CHF 1535 pMDI
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    See Sequence ABC.

    Investigational medicinal product name
    CHF 5993 DPI
    Investigational medicinal product code
    CHF 5993 DPI
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    See Sequence ABC.

    Investigational medicinal product name
    CHF 5993 pMDI
    Investigational medicinal product code
    CHF 5993 pMDI
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    See Sequence ABC.

    Arm title
    Sequence BCA
    Arm description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment B=CHF 5993 pMDI; Treatment C=CHF 1535 pMDI; Treatment A=CHF 5993 DPI.
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 5993 pMDI
    Investigational medicinal product code
    CHF 5993 pMDI
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    See Sequence ABC.

    Investigational medicinal product name
    CHF 1535 pMDI
    Investigational medicinal product code
    CHF 1535 pMDI
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    See Sequence ABC.

    Investigational medicinal product name
    CHF 5993 DPI
    Investigational medicinal product code
    CHF 5993 DPI
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    See Sequence ABC.

    Arm title
    Sequence ACB
    Arm description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment A=CHF 5993 DPI; Treatment C=CHF 1535 pMDI; Treatment B=CHF 5993 pMDI.
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 5993 DPI
    Investigational medicinal product code
    CHF 5993 DPI
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    See Sequence ABC.

    Investigational medicinal product name
    CHF 1535 pMDI
    Investigational medicinal product code
    CHF 1535 pMDI
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    See Sequence ABC.

    Investigational medicinal product name
    CHF 5993 pMDI
    Investigational medicinal product code
    CHF 5993 pMDI
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    See Sequence ABC.

    Arm title
    Sequence BAC
    Arm description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment B=CHF 5993 pMDI; Treatment A=CHF 5993 DPI; Treatment C=CHF 1535 pMDI.
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 5993 pMDI
    Investigational medicinal product code
    CHF 5993 pMDI
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    See Sequence ABC.

    Investigational medicinal product name
    CHF 5993 DPI
    Investigational medicinal product code
    CHF 5993 DPI
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    See Sequence ABC.

    Investigational medicinal product name
    CHF 1535 pMDI
    Investigational medicinal product code
    CHF 1535 pMDI
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    See Sequence ABC.

    Arm title
    Sequence CBA
    Arm description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment C=CHF 1535 pMDI; Treatment B=CHF 5993 pMDI; Treatment A=CHF 5993 DPI.
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 1535 pMDI
    Investigational medicinal product code
    CHF 1535 pMDI
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    See Sequence ABC.

    Investigational medicinal product name
    CHF 5993 pMDI
    Investigational medicinal product code
    CHF 5993 pMDI
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    See Sequence ABC.

    Investigational medicinal product name
    CHF 5993 DPI
    Investigational medicinal product code
    CHF 5993 DPI
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    See Sequence ABC.

    Number of subjects in period 1
    Sequence ABC Sequence CAB Sequence BCA Sequence ACB Sequence BAC Sequence CBA
    Started
    63
    60
    60
    62
    60
    61
    Completed
    60
    54
    56
    60
    57
    55
    Not completed
    3
    6
    4
    2
    3
    6
         Other: patient couldn't attend a planned visit
    -
    -
    -
    -
    1
    -
         Other: pre-planned intervention
    -
    -
    1
    -
    -
    -
         Other: investigator decision (compliance concerns)
    -
    1
    -
    -
    -
    -
         Other: non-compliance
    -
    1
    -
    -
    -
    -
         Adverse event, serious fatal
    -
    1
    -
    -
    -
    -
         Adverse event, non-fatal
    2
    1
    1
    1
    1
    1
         Consent withdrawn by subject
    1
    2
    2
    -
    1
    5
         Lost to follow-up
    -
    -
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence ABC
    Reporting group description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment A=CHF 5993 DPI; Treatment B=CHF 5993 pMDI; Treatment C=CHF 1535 pMDI.

    Reporting group title
    Sequence CAB
    Reporting group description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment C=CHF 1535 pMDI; Treatment A=CHF 5993 DPI; Treatment B=CHF 5993 pMDI.

    Reporting group title
    Sequence BCA
    Reporting group description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment B=CHF 5993 pMDI; Treatment C=CHF 1535 pMDI; Treatment A=CHF 5993 DPI.

    Reporting group title
    Sequence ACB
    Reporting group description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment A=CHF 5993 DPI; Treatment C=CHF 1535 pMDI; Treatment B=CHF 5993 pMDI.

    Reporting group title
    Sequence BAC
    Reporting group description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment B=CHF 5993 pMDI; Treatment A=CHF 5993 DPI; Treatment C=CHF 1535 pMDI.

    Reporting group title
    Sequence CBA
    Reporting group description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment C=CHF 1535 pMDI; Treatment B=CHF 5993 pMDI; Treatment A=CHF 5993 DPI.

    Reporting group values
    Sequence ABC Sequence CAB Sequence BCA Sequence ACB Sequence BAC Sequence CBA Total
    Number of subjects
    63 60 60 62 60 61 366
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0 0
        Adults (18-64 years)
    28 28 27 35 26 31 175
        From 65-84 years
    35 32 33 27 34 30 191
        85 years and over
    0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    65.9 ± 6.6 65.2 ± 6.7 65.4 ± 7.4 64.1 ± 6.9 64.6 ± 6.8 64.5 ± 7.1 -
    Gender categorical
    Units: Subjects
        Female
    26 22 25 30 25 23 151
        Male
    37 38 35 32 35 38 215

    End points

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    End points reporting groups
    Reporting group title
    Sequence ABC
    Reporting group description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment A=CHF 5993 DPI; Treatment B=CHF 5993 pMDI; Treatment C=CHF 1535 pMDI.

    Reporting group title
    Sequence CAB
    Reporting group description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment C=CHF 1535 pMDI; Treatment A=CHF 5993 DPI; Treatment B=CHF 5993 pMDI.

    Reporting group title
    Sequence BCA
    Reporting group description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment B=CHF 5993 pMDI; Treatment C=CHF 1535 pMDI; Treatment A=CHF 5993 DPI.

    Reporting group title
    Sequence ACB
    Reporting group description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment A=CHF 5993 DPI; Treatment C=CHF 1535 pMDI; Treatment B=CHF 5993 pMDI.

    Reporting group title
    Sequence BAC
    Reporting group description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment B=CHF 5993 pMDI; Treatment A=CHF 5993 DPI; Treatment C=CHF 1535 pMDI.

    Reporting group title
    Sequence CBA
    Reporting group description
    Patients were randomised to receive three different treatments during three treatment periods. Treatment periods each lasted 4 weeks (+/- 2 days) and were separated by 2-week wash-out periods. Treatment C=CHF 1535 pMDI; Treatment B=CHF 5993 pMDI; Treatment A=CHF 5993 DPI.

    Subject analysis set title
    A) CHF 5993 DPI - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Treatment A=CHF 5993 DPI; the Intention-to-treat (ITT) set 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
    A) CHF 5993 DPI - PP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Treatment A=CHF 5993 DPI; the Per protocol (PP) set was defined as all patients from the ITT set without any major protocol deviations (i.e. wrong inclusions, poor compliance, non-permitted medications).

    Subject analysis set title
    B) CHF 5993 pMDI - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Treatment B=CHF 5993 pMDI; the ITT set 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
    B) CHF 5993 pMDI - PP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Treatment B=CHF 5993 pMDI; the PP set was defined as all patients from the ITT set without any major protocol deviations (i.e. wrong inclusions, poor compliance, non-permitted medications).

    Subject analysis set title
    C) CHF 1535 pMDI - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Treatment C=CHF 1535 pMDI; the ITT set 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
    C) CHF 1535 pMDI - PP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Treatment C=CHF 1535 pMDI; the PP set was defined as all patients from the ITT set without any major protocol deviations (i.e. wrong inclusions, poor compliance, non-permitted medications).

    Primary: Change from baseline in FEV1 AUC0-12h normalised by time (L) on Day 28 - ITT set

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    End point title
    Change from baseline in FEV1 AUC0-12h normalised by time (L) on Day 28 - ITT set
    End point description
    FEV1 AUC0-12h normalised by time on Day 28 was calculated based on the actual times using the linear trapezoidal rule. The corresponding change from baseline in FEV1 AUC0-12h normalised by time on Day 28 was analysed using an analysis of covariance (ANCOVA) model with treatment, period and patient as fixed effects, and baseline FEV1 value as a covariate.
    End point type
    Primary
    End point timeframe
    Baseline (pre-dose on Day 1 of each treatment period) to Day 28. FEV1 was assessed at 45 and 10 minutes pre-dose and 10, 30 minutes and 1, 2, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and Day 28 (and also at 23.5 and 24 hours post-dose on Day 28).
    End point values
    A) CHF 5993 DPI - ITT B) CHF 5993 pMDI - ITT C) CHF 1535 pMDI - ITT
    Number of subjects analysed
    351 [1]
    351 [2]
    353 [3]
    Units: litre(s)
        least squares mean (confidence interval 95%)
    0.146 (0.136 to 0.157)
    0.167 (0.156 to 0.177)
    0.062 (0.051 to 0.072)
    Notes
    [1] - Number of patients in the ITT set = 354; Number of patients with available data = 351.
    [2] - Number of patients in the ITT set = 357; Number of patients with available data = 351.
    [3] - Number of patients in the ITT set = 357; Number of patients with available data = 353.
    Statistical analysis title
    CHF 5993 DPI v CHF 5993 pMDI ITT
    Statistical analysis description
    The value N=702, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    A) CHF 5993 DPI - ITT v B) CHF 5993 pMDI - ITT
    Number of subjects included in analysis
    702
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.007
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    -0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.035
         upper limit
    -0.006
    Statistical analysis title
    CHF 5993 pMDI v CHF 1535 pMDI ITT
    Statistical analysis description
    The value N=704, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    B) CHF 5993 pMDI - ITT v C) CHF 1535 pMDI - ITT
    Number of subjects included in analysis
    704
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.105
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.09
         upper limit
    0.12
    Statistical analysis title
    CHF 5993 DPI v CHF 1535 pMDI ITT
    Statistical analysis description
    The value N=704, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    A) CHF 5993 DPI - ITT v C) CHF 1535 pMDI - ITT
    Number of subjects included in analysis
    704
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.085
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.07
         upper limit
    0.099

    Primary: Change from baseline in FEV1 AUC0-12h normalised by time (L) on Day 28 - PP set

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    End point title
    Change from baseline in FEV1 AUC0-12h normalised by time (L) on Day 28 - PP set
    End point description
    FEV1 AUC0-12h normalised by time on Day 28 was calculated based on the actual times using the linear trapezoidal rule. The corresponding change from baseline in FEV1 AUC0-12h normalised by time on Day 28 was analysed using an ANCOVA model with treatment, period and patient as fixed effects, and baseline FEV1 value as a covariate.
    End point type
    Primary
    End point timeframe
    Baseline (pre-dose on Day 1 of each treatment period) to Day 28. FEV1 was assessed at 45 and 10 minutes pre-dose and 10, 30 minutes and 1, 2, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and Day 28 (and also at 23.5 and 24 hours post-dose on Day 28).
    End point values
    A) CHF 5993 DPI - PP B) CHF 5993 pMDI - PP C) CHF 1535 pMDI - PP
    Number of subjects analysed
    342 [4]
    342 [5]
    351 [6]
    Units: litre(s)
        least squares mean (confidence interval 95%)
    0.151 (0.140 to 0.162)
    0.173 (0.162 to 0.184)
    0.067 (0.056 to 0.077)
    Notes
    [4] - Number of patients in the PP set = 345; Number of patients with available data = 342.
    [5] - Number of patients in the PP set = 346; Number of patients with available data = 342.
    [6] - Number of patients in the PP set = 354; Number of patients with available data = 351.
    Statistical analysis title
    CHF 5993 DPI v CHF 5993 pMDI PP
    Statistical analysis description
    The value N=684, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    A) CHF 5993 DPI - PP v B) CHF 5993 pMDI - PP
    Number of subjects included in analysis
    684
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.004
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    -0.022
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.037
         upper limit
    -0.007
    Statistical analysis title
    CHF 5993 pMDI v CHF 1535 pMDI PP
    Statistical analysis description
    The value N=693, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    B) CHF 5993 pMDI - PP v C) CHF 1535 pMDI - PP
    Number of subjects included in analysis
    693
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.106
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.091
         upper limit
    0.121
    Statistical analysis title
    CHF 5993 DPI v CHF 1535 pMDI PP
    Statistical analysis description
    The value N=693, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    A) CHF 5993 DPI - PP v C) CHF 1535 pMDI - PP
    Number of subjects included in analysis
    693
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.084
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.069
         upper limit
    0.099

    Primary: Change from baseline in trough FEV1 at 24 hours (L) on Day 28 - ITT set

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    End point title
    Change from baseline in trough FEV1 at 24 hours (L) on Day 28 - ITT set
    End point description
    Trough FEV1 at 24 hours on Day 28 was defined as the mean of 23.5 and 24 hour post-dose measurements. Baseline was defined as the mean of 45 and 10 minute pre-dose measurements on Day 1. Change from baseline in trough FEV1 at 24 hours on Day 28 was analysed using the same model as for FEV1 AUC0-12h normalised by time on Day 28.
    End point type
    Primary
    End point timeframe
    The change from baseline in trough FEV1 was analysed on Day 28.
    End point values
    A) CHF 5993 DPI - ITT B) CHF 5993 pMDI - ITT C) CHF 1535 pMDI - ITT
    Number of subjects analysed
    351 [7]
    350 [8]
    351 [9]
    Units: litre(s)
        least squares mean (confidence interval 95%)
    -0.006 (-0.019 to 0.006)
    -0.009 (-0.021 to 0.003)
    -0.063 (-0.076 to -0.051)
    Notes
    [7] - Number of patients in the ITT set = 354; Number of patients with available data = 351.
    [8] - Number of patients in the ITT set = 357; Number of patients with available data = 350.
    [9] - Number of patients in the ITT set = 357; Number of patients with available data = 351.
    Statistical analysis title
    CHF 5993 DPI v CHF 5993 pMDI ITT
    Statistical analysis description
    The value N=701, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    A) CHF 5993 DPI - ITT v B) CHF 5993 pMDI - ITT
    Number of subjects included in analysis
    701
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.749
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.003
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.015
         upper limit
    0.02
    Statistical analysis title
    CHF 5993 pMDI v CHF 1535 pMDI ITT
    Statistical analysis description
    The value N=701, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    B) CHF 5993 pMDI - ITT v C) CHF 1535 pMDI - ITT
    Number of subjects included in analysis
    701
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.054
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.037
         upper limit
    0.072
    Statistical analysis title
    CHF 5993 DPI v CHF 1535 pMDI ITT
    Statistical analysis description
    The value N=702, shown below, is generated automatically and is due to innate error of the EudraCT database system
    Comparison groups
    A) CHF 5993 DPI - ITT v C) CHF 1535 pMDI - ITT
    Number of subjects included in analysis
    702
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.057
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.04
         upper limit
    0.074

    Primary: Change from baseline in trough FEV1 at 24 hours (L) on Day 28 - PP set

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    End point title
    Change from baseline in trough FEV1 at 24 hours (L) on Day 28 - PP set
    End point description
    Trough FEV1 at 24 hours on Day 28 was defined as the mean of 23.5 and 24 hour post-dose measurements. Baseline was defined as the mean of 45 and 10 minute pre-dose measurements on Day 1. Change from baseline in trough FEV1 at 24 hours on Day 28 was analysed using the same model as for FEV1 AUC0-12h normalised by time on Day 28.
    End point type
    Primary
    End point timeframe
    The change from baseline in trough FEV1 was analysed on Day 28.
    End point values
    A) CHF 5993 DPI - PP B) CHF 5993 pMDI - PP C) CHF 1535 pMDI - PP
    Number of subjects analysed
    341 [10]
    341 [11]
    348 [12]
    Units: litre(s)
        least squares mean (confidence interval 95%)
    -0.003 (-0.015 to 0.010)
    -0.006 (-0.018 to 0.007)
    -0.060 (-0.072 to -0.047)
    Notes
    [10] - Number of patients in the PP set = 345; Number of patients with available data = 341.
    [11] - Number of patients in the PP set = 346; Number of patients with available data = 341.
    [12] - Number of patients in the PP set = 354; Number of patients with available data = 348.
    Statistical analysis title
    CHF 5993 DPI v CHF 5993 pMDI PP
    Statistical analysis description
    The value N=682, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    A) CHF 5993 DPI - PP v B) CHF 5993 pMDI - PP
    Number of subjects included in analysis
    682
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.753
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.003
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.015
         upper limit
    0.02
    Statistical analysis title
    CHF 5993 pMDI v CHF 1535 pMDI PP
    Statistical analysis description
    The value N=689, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    B) CHF 5993 pMDI - PP v C) CHF 1535 pMDI - PP
    Number of subjects included in analysis
    689
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.054
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.037
         upper limit
    0.072
    Statistical analysis title
    CHF 5993 DPI v CHF 1535 pMDI PP
    Statistical analysis description
    The value N=689, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    A) CHF 5993 DPI - PP v C) CHF 1535 pMDI - PP
    Number of subjects included in analysis
    689
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.057
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.04
         upper limit
    0.074

    Secondary: Change from baseline in pre-dose morning FEV1 (L) on Day 28 - ITT set

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    End point title
    Change from baseline in pre-dose morning FEV1 (L) on Day 28 - ITT set
    End point description
    Pre-dose morning FEV1 on Day 28 was defined as the mean of 45 and 10 minute pre-dose measurements. Baseline was defined as the mean of 45 and 10 minute pre-dose measurements on Day 1. Change from baseline in pre-dose morning FEV1 on Day 28 was analysed using the same model as for FEV1 AUC0-12h normalised by time on Day 28.
    End point type
    Secondary
    End point timeframe
    The change from baseline in pre-dose morning FEV1 was analysed on Day 28.
    End point values
    A) CHF 5993 DPI - ITT B) CHF 5993 pMDI - ITT C) CHF 1535 pMDI - ITT
    Number of subjects analysed
    351 [13]
    352 [14]
    354 [15]
    Units: litre(s)
        least squares mean (confidence interval 95%)
    0.047 (0.034 to 0.060)
    0.056 (0.043 to 0.069)
    -0.025 (-0.038 to -0.012)
    Notes
    [13] - Number of patients in the ITT set = 354; Number of patients with available data = 351.
    [14] - Number of patients in the ITT set = 357; Number of patients with available data = 352.
    [15] - Number of patients in the ITT set = 357; Number of patients with available data = 354.
    Statistical analysis title
    CHF 5993 DPI v CHF 5993 pMDI ITT
    Statistical analysis description
    The value N=703, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    A) CHF 5993 DPI - ITT v B) CHF 5993 pMDI - ITT
    Number of subjects included in analysis
    703
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.363
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    -0.009
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.027
         upper limit
    0.01
    Statistical analysis title
    CHF 5993 pMDI v CHF 1535 pMDI ITT
    Statistical analysis description
    The value N=706, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    B) CHF 5993 pMDI - ITT v C) CHF 1535 pMDI - ITT
    Number of subjects included in analysis
    706
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.081
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.062
         upper limit
    0.099
    Statistical analysis title
    CHF 5993 DPI v CHF 1535 pMDI ITT
    Statistical analysis description
    The value N=705, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    A) CHF 5993 DPI - ITT v C) CHF 1535 pMDI - ITT
    Number of subjects included in analysis
    705
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.072
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.053
         upper limit
    0.09

    Secondary: Change from baseline in FEV1 AUC0-4h normalised by time (L) on Day 28 - ITT set

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    End point title
    Change from baseline in FEV1 AUC0-4h normalised by time (L) on Day 28 - ITT set
    End point description
    FEV1 AUC0-4h normalised by time on Day 28 was calculated based on the actual times using the linear trapezoidal rule. The corresponding change from baseline in FEV1 AUC0-4h normalised by time on Day 28 was analysed using the same model as for FEV1 AUC0-12h normalised by time on Day 28.
    End point type
    Secondary
    End point timeframe
    The change from baseline in FEV1 AUC0-4h normalised by time was analysed on Day 28.
    End point values
    A) CHF 5993 DPI - ITT B) CHF 5993 pMDI - ITT C) CHF 1535 pMDI - ITT
    Number of subjects analysed
    351 [16]
    352 [17]
    353 [18]
    Units: litre(s)
        least squares mean (confidence interval 95%)
    0.215 (0.204 to 0.227)
    0.241 (0.230 to 0.253)
    0.131 (0.120 to 0.143)
    Notes
    [16] - Number of patients in the ITT set = 354; Number of patients with available data = 351.
    [17] - Number of patients in the ITT set = 357; Number of patients with available data = 352.
    [18] - Number of patients in the ITT set = 357; Number of patients with available data = 353.
    Statistical analysis title
    CHF 5993 DPI v CHF 5993 pMDI ITT
    Statistical analysis description
    The value N=703, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    A) CHF 5993 DPI - ITT v B) CHF 5993 pMDI - ITT
    Number of subjects included in analysis
    703
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.002
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    -0.026
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.043
         upper limit
    -0.01
    Statistical analysis title
    CHF 5993 pMDI v CHF 1535 pMDI ITT
    Statistical analysis description
    The value N=705, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    B) CHF 5993 pMDI - ITT v C) CHF 1535 pMDI - ITT
    Number of subjects included in analysis
    705
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.094
         upper limit
    0.127
    Statistical analysis title
    CHF 5993 DPI v CHF 1535 pMDI ITT
    Statistical analysis description
    The value N=704, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    A) CHF 5993 DPI - ITT v C) CHF 1535 pMDI - ITT
    Number of subjects included in analysis
    704
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.084
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.068
         upper limit
    0.101

    Secondary: Change from baseline in FEV1 AUC0-12h normalised by time (L) on Day 1 - ITT set

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    End point title
    Change from baseline in FEV1 AUC0-12h normalised by time (L) on Day 1 - ITT set
    End point description
    FEV1 AUC0-12h normalised by time on Day 1 was calculated based on the actual times using the linear trapezoidal rule. The corresponding change from baseline in FEV1 AUC0-12h normalised by time on Day 1 was analysed using the same model as for FEV1 AUC0-12h normalised by time on Day 28.
    End point type
    Secondary
    End point timeframe
    The change from baseline in FEV1 AUC0-12h normalised by time was analysed on Day 1.
    End point values
    A) CHF 5993 DPI - ITT B) CHF 5993 pMDI - ITT C) CHF 1535 pMDI - ITT
    Number of subjects analysed
    351 [19]
    356 [20]
    354 [21]
    Units: litre(s)
        least squares mean (confidence interval 95%)
    0.162 (0.153 to 0.170)
    0.160 (0.151 to 0.169)
    0.086 (0.077 to 0.095)
    Notes
    [19] - Number of patients in the ITT set = 354; Number of patients with available data = 351.
    [20] - Number of patients in the ITT set = 357; Number of patients with available data = 356.
    [21] - Number of patients in the ITT set = 357; Number of patients with available data = 354.
    Statistical analysis title
    CHF 5993 DPI v CHF 5993 pMDI ITT
    Statistical analysis description
    The value N=707, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    A) CHF 5993 DPI - ITT v B) CHF 5993 pMDI - ITT
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.782
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.002
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.011
         upper limit
    0.014
    Statistical analysis title
    CHF 5993 pMDI v CHF 1535 pMDI ITT
    Statistical analysis description
    The value N=710, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    B) CHF 5993 pMDI - ITT v C) CHF 1535 pMDI - ITT
    Number of subjects included in analysis
    710
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.074
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.061
         upper limit
    0.086
    Statistical analysis title
    CHF 5993 DPI v CHF 1535 pMDI ITT
    Statistical analysis description
    The value N=705, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    A) CHF 5993 DPI - ITT v C) CHF 1535 pMDI - ITT
    Number of subjects included in analysis
    705
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.075
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.063
         upper limit
    0.088

    Secondary: Responder analysis on the change from baseline in pre-dose morning FEV1 on Day 28 - ITT set

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    End point title
    Responder analysis on the change from baseline in pre-dose morning FEV1 on Day 28 - ITT set
    End point description
    Responders were patients with a change from baseline in pre-dose morning FEV1 ≥ 100 mL on Day 28. Real non-responders were patients with a change from baseline in pre-dose morning FEV1 < 100 mL on Day 28. Non-responders due to missing values were patients with missing baseline values or missing data pre-dose on Day 28. FEV1 response on Day 28 was analysed using a conditional logistic regression model with treatment and period as fixed effects, patient as strata and baseline FEV1 as covariate.
    End point type
    Secondary
    End point timeframe
    FEV1 response was analysed on Day 28.
    End point values
    A) CHF 5993 DPI - ITT B) CHF 5993 pMDI - ITT C) CHF 1535 pMDI - ITT
    Number of subjects analysed
    354 [22]
    357 [23]
    357 [24]
    Units: patients
        Responders
    128
    125
    67
        Real non-responders
    223
    227
    287
        Non-responders due to missing values
    3
    5
    3
    Notes
    [22] - Number of patients in the ITT set.
    [23] - Number of patients in the ITT set.
    [24] - Number of patients in the ITT set.
    Statistical analysis title
    CHF 5993 DPI v CHF 5993 pMDI ITT
    Statistical analysis description
    The value N=711, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    A) CHF 5993 DPI - ITT v B) CHF 5993 pMDI - ITT
    Number of subjects included in analysis
    711
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.89
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.029
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.69
         upper limit
    1.533
    Statistical analysis title
    CHF 5993 pMDI v CHF 1535 pMDI ITT
    Statistical analysis description
    The value N=714, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    B) CHF 5993 pMDI - ITT v C) CHF 1535 pMDI - ITT
    Number of subjects included in analysis
    714
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.126
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.002
         upper limit
    4.88
    Statistical analysis title
    CHF 5993 DPI v CHF 1535 pMDI ITT
    Statistical analysis description
    The value N=711, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    A) CHF 5993 DPI - ITT v C) CHF 1535 pMDI - ITT
    Number of subjects included in analysis
    711
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.216
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.064
         upper limit
    5.01

    Secondary: Change from baseline in SGRQ total score on Day 28 - ITT set

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    End point title
    Change from baseline in SGRQ total score on Day 28 - ITT set
    End point description
    SGRQ is a questionnaire developed to measure health in chronic airflow limitation. The total score for SGRQ was calculated from several domains (symptoms, impacts and activity). Lower scores correspond to better health. The change from baseline in SGRQ total score on Day 28 was analysed using the same model as for FEV1 AUC0-12h normalised by time on Day 28, except that SGRQ total score was included as a covariate instead of baseline FEV1.
    End point type
    Secondary
    End point timeframe
    The change from baseline in SGRQ total score was analysed on Day 28.
    End point values
    A) CHF 5993 DPI - ITT B) CHF 5993 pMDI - ITT C) CHF 1535 pMDI - ITT
    Number of subjects analysed
    337 [25]
    340 [26]
    333 [27]
    Units: points
        least squares mean (confidence interval 95%)
    -0.82 (-1.56 to -0.08)
    -1.26 (-1.99 to -0.53)
    0.26 (-0.49 to 1.00)
    Notes
    [25] - Number of patients in the ITT set = 354; Number of patients with available data = 337.
    [26] - Number of patients in the ITT set = 357; Number of patients with available data = 340.
    [27] - Number of patients in the ITT set = 357; Number of patients with available data = 333.
    Statistical analysis title
    CHF 5993 DPI v CHF 5993 pMDI ITT
    Statistical analysis description
    The value N=677, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    A) CHF 5993 DPI - ITT v B) CHF 5993 pMDI - ITT
    Number of subjects included in analysis
    677
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.41
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    1.47
    Statistical analysis title
    CHF 5993 pMDI v CHF 1535 pMDI ITT
    Statistical analysis description
    The value N=673, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    B) CHF 5993 pMDI - ITT v C) CHF 1535 pMDI - ITT
    Number of subjects included in analysis
    673
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    -1.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.56
         upper limit
    -0.48
    Statistical analysis title
    CHF 5993 DPI v CHF 1535 pMDI ITT
    Statistical analysis description
    The value N=670, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    A) CHF 5993 DPI - ITT v C) CHF 1535 pMDI - ITT
    Number of subjects included in analysis
    670
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.042
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    -1.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.12
         upper limit
    -0.04

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The reporting period for AEs was from the signature of the informed consent form until the patient's participation in the study ended.
    Adverse event reporting additional description
    Treatment-emergent AEs (TEAEs) were defined as all AEs that started on or after date of first randomised study treatment intake and on or before 14 days after the date of the last randomised study treatment intake. TEAEs were assigned to the last study treatment received.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    A) CHF 5993 DPI - Safety
    Reporting group description
    Treatment A=CHF 5993 DPI; the Safety set was defined as all randomised patients who received at least one dose of study treatment.

    Reporting group title
    B) CHF 5993 pMDI - Safety
    Reporting group description
    Treatment B=CHF 5993 pMDI; the Safety set was defined as all randomised patients who received at least one dose of study treatment.

    Reporting group title
    C) CHF 1535 pMDI - Safety
    Reporting group description
    Treatment C=CHF 1535 pMDI; the Safety set was defined as all randomised patients who received at least one dose of study treatment.

    Serious adverse events
    A) CHF 5993 DPI - Safety B) CHF 5993 pMDI - Safety C) CHF 1535 pMDI - Safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 354 (1.13%)
    6 / 358 (1.68%)
    1 / 357 (0.28%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    1
    0
    Injury, poisoning and procedural complications
    Patella fracture
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 358 (0.00%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 358 (0.00%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 358 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 354 (0.00%)
    2 / 358 (0.56%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 358 (0.00%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 358 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 358 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis chronic
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 358 (0.00%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 354 (0.28%)
    2 / 358 (0.56%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 358 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 354 (0.28%)
    1 / 358 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1.5%
    Non-serious adverse events
    A) CHF 5993 DPI - Safety B) CHF 5993 pMDI - Safety C) CHF 1535 pMDI - Safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    53 / 354 (14.97%)
    62 / 358 (17.32%)
    55 / 357 (15.41%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    12 / 354 (3.39%)
    11 / 358 (3.07%)
    6 / 357 (1.68%)
         occurrences all number
    12
    11
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 354 (1.13%)
    7 / 358 (1.96%)
    2 / 357 (0.56%)
         occurrences all number
    4
    7
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    10 / 354 (2.82%)
    9 / 358 (2.51%)
    11 / 357 (3.08%)
         occurrences all number
    10
    10
    11

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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