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    Clinical Trial Results:
    A multicenter, randomised, double blind, placebo-controlled, incomplete block, 3-way cross-over study to evaluate the efficacy and safety of 4 doses of glycopyrronium bromide DPI in moderate to severe patients with chronic obstructive pulmonary disease (COPD)

    Summary
    EudraCT number
    2015-000558-40
    Trial protocol
    DE   HU   CZ   RO  
    Global end of trial date
    06 Feb 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    31 Jan 2018
    First version publication date
    31 Jan 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-06302AA1-01
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02680197
    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., ClinicalTrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., 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
    28 Aug 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to identify the optimal dose of CHF 5259 glycopyrronium bromide (GB) to be further developed for the treatment of patients with COPD.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements. There was no anticipated benefit for patients receiving placebo. However, patients were closely monitored and the risks for patients were minimised by measures such as training of patients in the early recognition of COPD exacerbations and on appropriate early actions to be taken, including contacting the investigator if their condition was worsening, and discontinuation in case of disease worsening. Moreover, patients received placebo only for a maximum of one out the three treatment periods and had access to rescue medication as needed throughout the study.
    Background therapy
    If the patient was receiving treatment with inhaled corticosteroid (ICS) in combination with a bronchodilator (long-acting β2 agonist [LABA] or long-acting muscarinic agonist [LAMA]) at the time of informed consent signature, the combination was discontinued at screening and an equipotent daily dose of Flixotide® Accuhaler® DPI 250 μg/actuation was prescribed according to the Global Initiative for asthma pocket guide for health professionals. This background treatment was maintained for the entire run-in period and the remainder of the study.
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Feb 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Romania: 31
    Country: Number of subjects enrolled
    Czech Republic: 88
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Hungary: 64
    Worldwide total number of subjects
    202
    EEA total number of subjects
    202
    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)
    118
    From 65 to 84 years
    84
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Overall, 202 patients were randomised into one of the ten treatment sequences (Sequence A-C-D [n=20], Sequence E-D-B [n=20], Sequence C-B-E [n=20], Sequence D-E-C [n=20], Sequence B-C-A [n=20], Sequence B-A-D [n=20], Sequence A-D-E [n=20], Sequence D-B-C [n=21], Sequence E-A-B [n=20], Sequence C-E-A [n=21]) and 178 patients completed the study.

    Pre-assignment
    Screening details
    This study comprised a pre-screening visit, occurring no more than seven days prior to a screening visit. A total of 262 patients were screened, 202 (77.1%) were randomised and 60 (22.9%) failed screening due to inclusion/exclusion criteria (51 patients), consent withdrawal (3 patients), adverse events (2 patients) and other reasons (4 patients)

    Period 1
    Period 1 title
    Overall trial by sequence (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    At randomisation, patients in each centre were centrally assigned to one of the ten treatment sequences by the interactive response technology system using a list-based randomisation algorithm. 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 A-C-D
    Arm description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment A = CHF 5259 DPI 12.5 µg; Treatment C = CHF 5259 DPI 50 µg; Treatment D = CHF 5259 DPI 100 µg.
    Arm type
    Experimental - experimental - experimental

    Investigational medicinal product name
    Glycopyrronium Bromide
    Investigational medicinal product code
    CHF 5259
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study medication was administered using NEXThaler® technology (Dry Powder Inhaler, DPI). The study treatment kit for each period contained two inhalers. During each four-week treatment period, the study medication was administered twice daily by inhaling one puff from each inhaler every morning and one puff from each inhaler every evening, adding up to four puffs per day: Treatment A = CHF 5259 DPI 12.5 µg (1 inhalation of CHF 5259 DPI 6.25 µg and 1 inhalation of placebo twice daily); Treatment C = CHF 5259 DPI 50 µg (2 inhalations of CHF 5259 DPI 12.5 µg twice daily); Treatment D = CHF 5259 DPI 100 µg (2 inhalations of CHF 5259 DPI 25 µg twice daily).

    Arm title
    Sequence E-D-B
    Arm description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment E = Placebo; Treatment D = CHF 5259 DPI 100 µg; Treatment B = CHF 5259 DPI 25 µg.
    Arm type
    Placebo - experimental - experimental

    Investigational medicinal product name
    Glycopyrronium Bromide
    Investigational medicinal product code
    CHF 5259
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study medication was administered using NEXThaler® technology (Dry Powder Inhaler, DPI). The study treatment kit for each period contained two inhalers. During each four-week treatment period, the study medication was administered twice daily by inhaling one puff from each inhaler every morning and one puff from each inhaler every evening, adding up to four puffs per day: Treatment B = CHF 5259 DPI 25 µg (2 inhalations of CHF 5259 DPI 6.25 µg twice daily); Treatment D = CHF 5259 DPI 100 µg (2 inhalations of CHF 5259 DPI 25 µg twice daily).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study medication was administered using NEXThaler® technology (Dry Powder Inhaler, DPI). The study treatment kit for each period contained two inhalers. During each four-week treatment period, the study medication was administered twice daily by inhaling one puff from each inhaler every morning and one puff from each inhaler every evening, adding up to four puffs per day: Treatment E = Placebo (2 inhalations of placebo twice daily).

    Arm title
    Sequence C-B-E
    Arm description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment C = CHF 5259 DPI 50 µg; Treatment B = CHF 5259 DPI 25 µg; Treatment E = Placebo.
    Arm type
    Experimental - experimental - placebo

    Investigational medicinal product name
    Glycopyrronium Bromide
    Investigational medicinal product code
    CHF 5259
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study medication was administered using NEXThaler® technology (Dry Powder Inhaler, DPI). The study treatment kit for each period contained two inhalers. During each four-week treatment period, the study medication was administered twice daily by inhaling one puff from each inhaler every morning and one puff from each inhaler every evening, adding up to four puffs per day: Treatment B = CHF 5259 DPI 25 µg (2 inhalations of CHF 5259 DPI 6.25 µg twice daily); Treatment C = CHF 5259 DPI 50 µg (2 inhalations of CHF 5259 DPI 12.5 µg twice daily).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study medication was administered using NEXThaler® technology (Dry Powder Inhaler, DPI). The study treatment kit for each period contained two inhalers. During each four-week treatment period, the study medication was administered twice daily by inhaling one puff from each inhaler every morning and one puff from each inhaler every evening, adding up to four puffs per day: Treatment E = Placebo (2 inhalations of placebo twice daily).

    Arm title
    Sequence D-E-C
    Arm description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment D = CHF 5259 DPI 100 µg; Treatment E = Placebo; Treatment C = CHF 5259 DPI 50 µg.
    Arm type
    Experimental - placebo - experimental

    Investigational medicinal product name
    Glycopyrronium Bromide
    Investigational medicinal product code
    CHF 5259
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study medication was administered using NEXThaler® technology (Dry Powder Inhaler, DPI). The study treatment kit for each period contained two inhalers. During each four-week treatment period, the study medication was administered twice daily by inhaling one puff from each inhaler every morning and one puff from each inhaler every evening, adding up to four puffs per day: Treatment C = CHF 5259 DPI 50 µg (2 inhalations of CHF 5259 DPI 12.5 µg twice daily); Treatment D = CHF 5259 DPI 100 µg (2 inhalations of CHF 5259 DPI 25 µg twice daily).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study medication was administered using NEXThaler® technology (Dry Powder Inhaler, DPI). The study treatment kit for each period contained two inhalers. During each four-week treatment period, the study medication was administered twice daily by inhaling one puff from each inhaler every morning and one puff from each inhaler every evening, adding up to four puffs per day: Treatment E = Placebo (2 inhalations of placebo twice daily).

    Arm title
    Sequence B-C-A
    Arm description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment B = CHF 5259 DPI 25 µg; Treatment C = CHF 5259 DPI 50 µg; Treatment A = CHF 5259 DPI 12.5 µg.
    Arm type
    Experimental - experimental - experimental

    Investigational medicinal product name
    Glycopyrronium Bromide
    Investigational medicinal product code
    CHF 5259
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study medication was administered using NEXThaler® technology (Dry Powder Inhaler, DPI). The study treatment kit for each period contained two inhalers. During each four-week treatment period, the study medication was administered twice daily by inhaling one puff from each inhaler every morning and one puff from each inhaler every evening, adding up to four puffs per day: Treatment A = CHF 5259 DPI 12.5 µg (1 inhalation of CHF 5259 DPI 6.25 µg and 1 inhalation of placebo twice daily); Treatment B = CHF 5259 DPI 25 µg (2 inhalations of CHF 5259 DPI 6.25 µg twice daily); Treatment C = CHF 5259 DPI 50 µg (2 inhalations of CHF 5259 DPI 12.5 µg twice daily).

    Arm title
    Sequence B-A-D
    Arm description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment B = CHF 5259 DPI 25 µg; Treatment A = CHF 5259 DPI 12.5 µg; Treatment D = CHF 5259 DPI 100 µg;
    Arm type
    Experimental - experimental - experimental

    Investigational medicinal product name
    Glycopyrronium Bromide
    Investigational medicinal product code
    CHF 5259
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study medication was administered using NEXThaler® technology (Dry Powder Inhaler, DPI). The study treatment kit for each period contained two inhalers. During each four-week treatment period, the study medication was administered twice daily by inhaling one puff from each inhaler every morning and one puff from each inhaler every evening, adding up to four puffs per day: Treatment A = CHF 5259 DPI 12.5 µg (1 inhalation of CHF 5259 DPI 6.25 µg and 1 inhalation of placebo twice daily); Treatment B = CHF 5259 DPI 25 µg (2 inhalations of CHF 5259 DPI 6.25 µg twice daily); Treatment D = CHF 5259 DPI 100 µg (2 inhalations of CHF 5259 DPI 25 µg twice daily).

    Arm title
    Sequence A-D-E
    Arm description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment A = CHF 5259 DPI 12.5 µg; Treatment D = CHF 5259 DPI 100 µg; Treatment E = Placebo.
    Arm type
    Experimental - experimental - placebo

    Investigational medicinal product name
    Glycopyrronium Bromide
    Investigational medicinal product code
    CHF 5259
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study medication was administered using NEXThaler® technology (Dry Powder Inhaler, DPI). The study treatment kit for each period contained two inhalers. During each four-week treatment period, the study medication was administered twice daily by inhaling one puff from each inhaler every morning and one puff from each inhaler every evening, adding up to four puffs per day: Treatment A = CHF 5259 DPI 12.5 µg (1 inhalation of CHF 5259 DPI 6.25 µg and 1 inhalation of placebo twice daily); Treatment D = CHF 5259 DPI 100 µg (2 inhalations of CHF 5259 DPI 25 µg twice daily).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study medication was administered using NEXThaler® technology (Dry Powder Inhaler, DPI). The study treatment kit for each period contained two inhalers. During each four-week treatment period, the study medication was administered twice daily by inhaling one puff from each inhaler every morning and one puff from each inhaler every evening, adding up to four puffs per day: Treatment E = Placebo (2 inhalations of placebo twice daily).

    Arm title
    Sequence D-B-C
    Arm description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment D = CHF 5259 DPI 100 µg; Treatment B = CHF 5259 DPI 25 µg; Treatment C = CHF 5259 DPI 50 µg.
    Arm type
    Experimental - experimental - experimental

    Investigational medicinal product name
    Glycopyrronium Bromide
    Investigational medicinal product code
    CHF 5259
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study medication was administered using NEXThaler® technology (Dry Powder Inhaler, DPI). The study treatment kit for each period contained two inhalers. During each four-week treatment period, the study medication was administered twice daily by inhaling one puff from each inhaler every morning and one puff from each inhaler every evening, adding up to four puffs per day: Treatment B = CHF 5259 DPI 25 µg (2 inhalations of CHF 5259 DPI 6.25 µg twice daily); Treatment C = CHF 5259 DPI 50 µg (2 inhalations of CHF 5259 DPI 12.5 µg twice daily); Treatment D = CHF 5259 DPI 100 µg (2 inhalations of CHF 5259 DPI 25 µg twice daily).

    Arm title
    Sequence E-A-B
    Arm description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment E = Placebo; Treatment A = CHF 5259 DPI 12.5 µg; Treatment B = CHF 5259 DPI 25 µg.
    Arm type
    Placebo - experimental - experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study medication was administered using NEXThaler® technology (Dry Powder Inhaler, DPI). The study treatment kit for each period contained two inhalers. During each four-week treatment period, the study medication was administered twice daily by inhaling one puff from each inhaler every morning and one puff from each inhaler every evening, adding up to four puffs per day: Treatment E = Placebo (2 inhalations of placebo twice daily).

    Investigational medicinal product name
    Glycopyrronium Bromide
    Investigational medicinal product code
    CHF 5259
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study medication was administered using NEXThaler® technology (Dry Powder Inhaler, DPI). The study treatment kit for each period contained two inhalers. During each four-week treatment period, the study medication was administered twice daily by inhaling one puff from each inhaler every morning and one puff from each inhaler every evening, adding up to four puffs per day: Treatment A = CHF 5259 DPI 12.5 µg (1 inhalation of CHF 5259 DPI 6.25 µg and 1 inhalation of placebo twice daily); Treatment B = CHF 5259 DPI 25 µg (2 inhalations of CHF 5259 DPI 6.25 µg twice daily).

    Arm title
    Sequence C-E-A
    Arm description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment C = CHF 5259 DPI 50 µg; Treatment E = Placebo; Treatment A = CHF 5259 DPI 12.5 µg.
    Arm type
    Experimental - placebo - experimental

    Investigational medicinal product name
    Glycopyrronium Bromide
    Investigational medicinal product code
    CHF 5259
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study medication was administered using NEXThaler® technology (Dry Powder Inhaler, DPI). The study treatment kit for each period contained two inhalers. During each four-week treatment period, the study medication was administered twice daily by inhaling one puff from each inhaler every morning and one puff from each inhaler every evening, adding up to four puffs per day: Treatment A = CHF 5259 DPI 12.5 µg (1 inhalation of CHF 5259 DPI 6.25 µg and 1 inhalation of placebo twice daily); Treatment C = CHF 5259 DPI 50 µg (2 inhalations of CHF 5259 DPI 12.5 µg twice daily).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study medication was administered using NEXThaler® technology (Dry Powder Inhaler, DPI). The study treatment kit for each period contained two inhalers. During each four-week treatment period, the study medication was administered twice daily by inhaling one puff from each inhaler every morning and one puff from each inhaler every evening, adding up to four puffs per day: Treatment E = Placebo (2 inhalations of placebo twice daily).

    Number of subjects in period 1
    Sequence A-C-D Sequence E-D-B Sequence C-B-E Sequence D-E-C Sequence B-C-A Sequence B-A-D Sequence A-D-E Sequence D-B-C Sequence E-A-B Sequence C-E-A
    Started
    20
    20
    20
    20
    20
    20
    20
    21
    20
    21
    Completed
    17
    15
    16
    20
    17
    18
    17
    20
    17
    21
    Not completed
    3
    5
    4
    0
    3
    2
    3
    1
    3
    0
         Other (family problems)
    -
    -
    -
    -
    -
    -
    -
    -
    1
    -
         Adverse event, non-fatal
    2
    3
    2
    -
    2
    2
    2
    1
    -
    -
         Consent withdrawn by subject
    1
    2
    2
    -
    -
    -
    1
    -
    2
    -
         Lost to follow-up
    -
    -
    -
    -
    1
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence A-C-D
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment A = CHF 5259 DPI 12.5 µg; Treatment C = CHF 5259 DPI 50 µg; Treatment D = CHF 5259 DPI 100 µg.

    Reporting group title
    Sequence E-D-B
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment E = Placebo; Treatment D = CHF 5259 DPI 100 µg; Treatment B = CHF 5259 DPI 25 µg.

    Reporting group title
    Sequence C-B-E
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment C = CHF 5259 DPI 50 µg; Treatment B = CHF 5259 DPI 25 µg; Treatment E = Placebo.

    Reporting group title
    Sequence D-E-C
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment D = CHF 5259 DPI 100 µg; Treatment E = Placebo; Treatment C = CHF 5259 DPI 50 µg.

    Reporting group title
    Sequence B-C-A
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment B = CHF 5259 DPI 25 µg; Treatment C = CHF 5259 DPI 50 µg; Treatment A = CHF 5259 DPI 12.5 µg.

    Reporting group title
    Sequence B-A-D
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment B = CHF 5259 DPI 25 µg; Treatment A = CHF 5259 DPI 12.5 µg; Treatment D = CHF 5259 DPI 100 µg;

    Reporting group title
    Sequence A-D-E
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment A = CHF 5259 DPI 12.5 µg; Treatment D = CHF 5259 DPI 100 µg; Treatment E = Placebo.

    Reporting group title
    Sequence D-B-C
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment D = CHF 5259 DPI 100 µg; Treatment B = CHF 5259 DPI 25 µg; Treatment C = CHF 5259 DPI 50 µg.

    Reporting group title
    Sequence E-A-B
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment E = Placebo; Treatment A = CHF 5259 DPI 12.5 µg; Treatment B = CHF 5259 DPI 25 µg.

    Reporting group title
    Sequence C-E-A
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment C = CHF 5259 DPI 50 µg; Treatment E = Placebo; Treatment A = CHF 5259 DPI 12.5 µg.

    Reporting group values
    Sequence A-C-D Sequence E-D-B Sequence C-B-E Sequence D-E-C Sequence B-C-A Sequence B-A-D Sequence A-D-E Sequence D-B-C Sequence E-A-B Sequence C-E-A Total
    Number of subjects
    20 20 20 20 20 20 20 21 20 21 202
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0 0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    8 12 14 12 12 10 14 12 12 12 118
        From 65-84 years
    12 8 6 8 8 10 6 9 8 9 84
        85 years and over
    0 0 0 0 0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    64.3 ± 7.5 60.4 ± 7 62 ± 6.6 59.5 ± 9.3 64 ± 8.8 64.7 ± 7.8 61.5 ± 6.3 62.9 ± 6.5 63.3 ± 7.9 64 ± 6.5 -
    Gender categorical
    Units: Subjects
        Female
    8 7 6 10 9 8 6 10 9 6 79
        Male
    12 13 14 10 11 12 14 11 11 15 123

    End points

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    End points reporting groups
    Reporting group title
    Sequence A-C-D
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment A = CHF 5259 DPI 12.5 µg; Treatment C = CHF 5259 DPI 50 µg; Treatment D = CHF 5259 DPI 100 µg.

    Reporting group title
    Sequence E-D-B
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment E = Placebo; Treatment D = CHF 5259 DPI 100 µg; Treatment B = CHF 5259 DPI 25 µg.

    Reporting group title
    Sequence C-B-E
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment C = CHF 5259 DPI 50 µg; Treatment B = CHF 5259 DPI 25 µg; Treatment E = Placebo.

    Reporting group title
    Sequence D-E-C
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment D = CHF 5259 DPI 100 µg; Treatment E = Placebo; Treatment C = CHF 5259 DPI 50 µg.

    Reporting group title
    Sequence B-C-A
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment B = CHF 5259 DPI 25 µg; Treatment C = CHF 5259 DPI 50 µg; Treatment A = CHF 5259 DPI 12.5 µg.

    Reporting group title
    Sequence B-A-D
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment B = CHF 5259 DPI 25 µg; Treatment A = CHF 5259 DPI 12.5 µg; Treatment D = CHF 5259 DPI 100 µg;

    Reporting group title
    Sequence A-D-E
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment A = CHF 5259 DPI 12.5 µg; Treatment D = CHF 5259 DPI 100 µg; Treatment E = Placebo.

    Reporting group title
    Sequence D-B-C
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment D = CHF 5259 DPI 100 µg; Treatment B = CHF 5259 DPI 25 µg; Treatment C = CHF 5259 DPI 50 µg.

    Reporting group title
    Sequence E-A-B
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment E = Placebo; Treatment A = CHF 5259 DPI 12.5 µg; Treatment B = CHF 5259 DPI 25 µg.

    Reporting group title
    Sequence C-E-A
    Reporting group description
    Patients were randomised to receive three out of five different possible treatments (total daily doses of 12.5 µg, 25 µg, 50 µg and 100 µg of CHF 5259 DPI or matched placebo given twice daily) during three treatment periods. Treatment periods lasted four weeks each and were separated by three-week wash-out periods. Treatment C = CHF 5259 DPI 50 µg; Treatment E = Placebo; Treatment A = CHF 5259 DPI 12.5 µg.

    Subject analysis set title
    A) CHF 5259 DPI 12.5 µg - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Treatment A = CHF 5259 DPI 12.5 µg; The ITT population was defined as all randomised patients who received at least one dose of the study treatment and with available evaluation of efficacy (primary or secondary efficacy variables) in at least two treatment periods.

    Subject analysis set title
    B) CHF 5259 DPI 25 µg - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Treatment B = CHF 5259 DPI 25 µg; The ITT population was defined as all randomised patients who received at least one dose of the study treatment and with available evaluation of efficacy (primary or secondary efficacy variables) in at least two treatment periods.

    Subject analysis set title
    C) CHF 5259 DPI 50 µg - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Treatment C = CHF 5259 DPI 50 µg; The ITT population was defined as all randomised patients who received at least one dose of the study treatment and with available evaluation of efficacy (primary or secondary efficacy variables) in at least two treatment periods.

    Subject analysis set title
    D) CHF 5259 DPI 100 µg - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Treatment D = CHF 5259 DPI 100 µg; The ITT population was defined as all randomised patients who received at least one dose of the study treatment and with available evaluation of efficacy (primary or secondary efficacy variables) in at least two treatment periods.

    Subject analysis set title
    E) Placebo - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Treatment E = Placebo; The ITT population was defined as all randomised patients who received at least one dose of the study treatment and with available evaluation of efficacy (primary or secondary efficacy variables) in at least two treatment periods.

    Primary: FEV1 AUC0-12h on Day 28

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    End point title
    FEV1 AUC0-12h on Day 28
    End point description
    Forced expiratory volume in the 1st second (FEV1) area under the curve between 0 and 12 hours (AUC0-12h) normalised by time was calculated based on the actual times using the linear trapezoidal rule. Results for FVC were comparable to those observed with FEV1
    End point type
    Primary
    End point timeframe
    FEV1, assessed in each treatment period at 15 min, 30 min, 45 min and 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 11.5 h and 12 h post-morning dose, was used to calculate FEV1 area under the curve between 0-12 h (AUC0-12h) on Day 28.
    End point values
    A) CHF 5259 DPI 12.5 µg - ITT B) CHF 5259 DPI 25 µg - ITT C) CHF 5259 DPI 50 µg - ITT D) CHF 5259 DPI 100 µg - ITT E) Placebo - ITT
    Number of subjects analysed
    104 [1]
    106 [2]
    112 [3]
    108 [4]
    103 [5]
    Units: litre(s)
        least squares mean (confidence interval 95%)
    1.505 (1.483 to 1.528)
    1.517 (1.495 to 1.539)
    1.535 (1.513 to 1.556)
    1.579 (1.557 to 1.601)
    1.392 (1.369 to 1.414)
    Notes
    [1] - ITT population, available for change from baseline (complete ITT population n=113)
    [2] - ITT population, available for change from baseline (complete ITT population n=110)
    [3] - ITT population, available for change from baseline (complete ITT population n=117)
    [4] - ITT population, available for change from baseline (complete ITT population n=112)
    [5] - ITT population, available for change from baseline (complete ITT population n=108)
    Statistical analysis title
    CHF 5259 DPI 12.5 µg vs. placebo
    Statistical analysis description
    The value N=207, shown below, is generated automatically and is due to innate error of the EudraCT database system
    Comparison groups
    A) CHF 5259 DPI 12.5 µg - ITT v E) Placebo - ITT
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.114
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.074
         upper limit
    0.154
    Statistical analysis title
    CHF 5259 DPI 25 µg vs. placebo
    Statistical analysis description
    The value N=209, shown below, is generated automatically and is due to innate error of the EudraCT database system
    Comparison groups
    B) CHF 5259 DPI 25 µg - ITT v E) Placebo - ITT
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.125
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.085
         upper limit
    0.166
    Statistical analysis title
    CHF 5259 DPI 50 µg vs. placebo
    Statistical analysis description
    The value N=215, shown below, is generated automatically and is due to innate error of the EudraCT database system
    Comparison groups
    C) CHF 5259 DPI 50 µg - ITT v E) Placebo - ITT
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.143
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.104
         upper limit
    0.183
    Statistical analysis title
    CHF 5259 DPI 100 µg vs. placebo
    Statistical analysis description
    The value N=211, shown below, is generated automatically and is due to innate error of the EudraCT database system
    Comparison groups
    D) CHF 5259 DPI 100 µg - ITT v E) Placebo - ITT
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.187
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.147
         upper limit
    0.228

    Secondary: Change from baseline in morning pre-dose FEV1 on Day 28

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    End point title
    Change from baseline in morning pre-dose FEV1 on Day 28
    End point description
    Morning pre-dose FEV1 was defined as the mean of 45 min and 10 min pre-dose measurements. Baseline was defined as the mean of 45 min and 10 min pre-dose measurements on Day 1.
    End point type
    Secondary
    End point timeframe
    The change from baseline in morning pre-dose FEV1 was analysed on Day 28.
    End point values
    A) CHF 5259 DPI 12.5 µg - ITT B) CHF 5259 DPI 25 µg - ITT C) CHF 5259 DPI 50 µg - ITT D) CHF 5259 DPI 100 µg - ITT E) Placebo - ITT
    Number of subjects analysed
    111 [6]
    109 [7]
    115 [8]
    109 [9]
    107 [10]
    Units: litre(s)
        least squares mean (confidence interval 95%)
    0.084 (0.059 to 0.109)
    0.072 (0.047 to 0.097)
    0.097 (0.073 to 0.122)
    0.136 (0.111 to 0.162)
    -0.023 (-0.048 to 0.003)
    Notes
    [6] - ITT population, available for change from baseline
    [7] - ITT population, available for change from baseline
    [8] - ITT population, available for change from baseline
    [9] - ITT population, available for change from baseline
    [10] - ITT population, available for change from baseline
    Statistical analysis title
    CHF 5259 DPI 12.5 µg vs. placebo
    Statistical analysis description
    The value N=218, shown below, is generated automatically and is due to innate error of the EudraCT database system
    Comparison groups
    A) CHF 5259 DPI 12.5 µg - ITT v E) Placebo - ITT
    Number of subjects included in analysis
    218
    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
    0.07
         upper limit
    0.142
    Statistical analysis title
    CHF 5259 DPI 25 µg vs. placebo
    Statistical analysis description
    The value N=216, shown below, is generated automatically and is due to innate error of the EudraCT database system
    Comparison groups
    B) CHF 5259 DPI 25 µg - ITT v E) Placebo - ITT
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.095
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.058
         upper limit
    0.131
    Statistical analysis title
    CHF 5259 DPI 50 µg vs. placebo
    Statistical analysis description
    The value N=222, shown below, is generated automatically and is due to innate error of the EudraCT database system
    Comparison groups
    C) CHF 5259 DPI 50 µg - ITT v E) Placebo - ITT
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.084
         upper limit
    0.155
    Statistical analysis title
    CHF 5259 DPI 100 µg vs. placebo
    Statistical analysis description
    The value N=216, shown below, is generated automatically and is due to innate error of the EudraCT database system
    Comparison groups
    D) CHF 5259 DPI 100 µg - ITT v E) Placebo - ITT
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.159
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.123
         upper limit
    0.195

    Secondary: Change from baseline in trough FEV1 at 12 h on Day 28

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    End point title
    Change from baseline in trough FEV1 at 12 h on Day 28
    End point description
    Trough FEV1 was defined as the mean of 11.5 h and 12 h post-dose measurements. Baseline was defined as the mean of 45 min and 10 min pre-dose measurements on Day 1.
    End point type
    Secondary
    End point timeframe
    The change from baseline in trough FEV1 at 12 h was analysed on Day 28.
    End point values
    A) CHF 5259 DPI 12.5 µg - ITT B) CHF 5259 DPI 25 µg - ITT C) CHF 5259 DPI 50 µg - ITT D) CHF 5259 DPI 100 µg - ITT E) Placebo - ITT
    Number of subjects analysed
    104 [11]
    106 [12]
    112 [13]
    108 [14]
    103 [15]
    Units: litre(s)
        least squares mean (confidence interval 95%)
    0.052 (0.024 to 0.08)
    0.07 (0.042 to 0.097)
    0.092 (0.066 to 0.119)
    0.132 (0.105 to 0.159)
    -0.025 (-0.053 to 0.003)
    Notes
    [11] - ITT population, available for change from baseline
    [12] - ITT population, available for change from baseline
    [13] - ITT population, available for change from baseline
    [14] - ITT population, available for change from baseline
    [15] - ITT population, available for change from baseline
    Statistical analysis title
    CHF 5259 DPI 12.5 µg vs. placebo
    Statistical analysis description
    The value N=207, shown below, is generated automatically and is due to innate error of the EudraCT database system
    Comparison groups
    A) CHF 5259 DPI 12.5 µg - ITT v E) Placebo - ITT
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.077
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.037
         upper limit
    0.116
    Statistical analysis title
    CHF 5259 DPI 25 µg vs. placebo
    Statistical analysis description
    The value N=209, shown below, is generated automatically and is due to innate error of the EudraCT database system
    Comparison groups
    B) CHF 5259 DPI 25 µg - ITT v E) Placebo - ITT
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.094
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.055
         upper limit
    0.134
    Statistical analysis title
    CHF 5259 DPI 50 µg vs. placebo
    Statistical analysis description
    The value N=215, shown below, is generated automatically and is due to innate error of the EudraCT database system
    Comparison groups
    C) CHF 5259 DPI 50 µg - ITT v E) Placebo - ITT
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.117
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.078
         upper limit
    0.156
    Statistical analysis title
    CHF 5259 DPI 100 µg vs. placebo
    Statistical analysis description
    The value N=211, shown below, is generated automatically and is due to innate error of the EudraCT database system
    Comparison groups
    D) CHF 5259 DPI 100 µg - ITT v E) Placebo - ITT
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.157
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.117
         upper limit
    0.196

    Secondary: Change from baseline in peak0-4h FEV1 on Day 28

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    End point title
    Change from baseline in peak0-4h FEV1 on Day 28
    End point description
    Peak0-4h FEV1 was defined as the maximum FEV1 value from 15 min to 4 h post-dose. Baseline was defined as the mean of 45 min and 10 min pre-dose measurements on Day 1.
    End point type
    Secondary
    End point timeframe
    The change from baseline in peak0-4h FEV1 was analysed on Day 28.
    End point values
    A) CHF 5259 DPI 12.5 µg - ITT B) CHF 5259 DPI 25 µg - ITT C) CHF 5259 DPI 50 µg - ITT D) CHF 5259 DPI 100 µg - ITT E) Placebo - ITT
    Number of subjects analysed
    111 [16]
    109 [17]
    115 [18]
    109 [19]
    107 [20]
    Units: litre(s)
        least squares mean (confidence interval 95%)
    0.24 (0.214 to 0.265)
    0.25 (0.225 to 0.276)
    0.269 (0.244 to 0.294)
    0.31 (0.284 to 0.336)
    0.105 (0.079 to 0.131)
    Notes
    [16] - ITT population, available for change from baseline
    [17] - ITT population, available for change from baseline
    [18] - ITT population, available for change from baseline
    [19] - ITT population, available for change from baseline
    [20] - ITT population, available for change from baseline
    Statistical analysis title
    CHF 5259 DPI 12.5 µg vs. placebo
    Statistical analysis description
    The value N=218, shown below, is generated automatically and is due to innate error of the EudraCT database system
    Comparison groups
    A) CHF 5259 DPI 12.5 µg - ITT v E) Placebo - ITT
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.135
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.098
         upper limit
    0.172
    Statistical analysis title
    CHF 5259 DPI 25 µg vs. placebo
    Statistical analysis description
    The value N=216, shown below, is generated automatically and is due to innate error of the EudraCT database system
    Comparison groups
    B) CHF 5259 DPI 25 µg - ITT v E) Placebo - ITT
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.145
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.108
         upper limit
    0.183
    Statistical analysis title
    CHF 5259 DPI 50 µg vs. placebo
    Statistical analysis description
    The value N=222, shown below, is generated automatically and is due to innate error of the EudraCT database system
    Comparison groups
    C) CHF 5259 DPI 50 µg - ITT v E) Placebo - ITT
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.163
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.127
         upper limit
    0.2
    Statistical analysis title
    CHF 5259 DPI 100 µg vs. placebo
    Statistical analysis description
    The value N=216, shown below, is generated automatically and is due to innate error of the EudraCT database system
    Comparison groups
    D) CHF 5259 DPI 100 µg - ITT v E) Placebo - ITT
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    0.204
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.167
         upper limit
    0.242

    Secondary: TDI focal score on Day 28

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    End point title
    TDI focal score on Day 28
    End point description
    Dyspnoea at baseline was assessed with the Baseline Dyspnoea Index (BDI) , which covers three domains: functional impairment, magnitude of task and magnitude of effort with the values added for a combined focal score. The BDI scores ranged from 0 (very severe impairment) to 4 (no impairment) for each domain with the baseline focal score consisting of the sum of each domain (0 to 12). The changes from baseline were measured by the Transition Dyspnoea Index (TDI) score which ranged from -3 (major deterioration) to +3 (major improvement) for each domain, with the TDI focal score consisting of the sum of each domain (-9 to +9).
    End point type
    Secondary
    End point timeframe
    TDI was assessed in the morning of Day 28 of each treatment period or in case of ET visit. (BDI was assessed in the morning of Day 1 of each treatment period.)
    End point values
    A) CHF 5259 DPI 12.5 µg - ITT B) CHF 5259 DPI 25 µg - ITT C) CHF 5259 DPI 50 µg - ITT D) CHF 5259 DPI 100 µg - ITT E) Placebo - ITT
    Number of subjects analysed
    113 [21]
    110 [22]
    117 [23]
    111 [24]
    108 [25]
    Units: unit(s)
        arithmetic mean (confidence interval 95%)
    1.372 (0.878 to 1.865)
    1.718 (1.264 to 2.173)
    1.462 (1.000 to 1.923)
    2.036 (1.559 to 2.513)
    0.750 (0.266 to 1.234)
    Notes
    [21] - ITT population, available for change from baseline
    [22] - ITT population, available for change from baseline
    [23] - ITT population, available for change from baseline
    [24] - ITT population, available for change from baseline
    [25] - ITT population, available for change from baseline
    No statistical analyses for this end point

    Secondary: TDI focal score responders on Day 28

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    End point title
    TDI focal score responders on Day 28
    End point description
    Responders were patients with a TDI focal score ≥1 on Day 28. Real non-responders were patients with a TDI focal score <1 on Day 28. Non-responders due to missing values were patients with a missing TDI focal score on Day 28.
    End point type
    Secondary
    End point timeframe
    TDI focal score responders were analysed on Day 28.
    End point values
    A) CHF 5259 DPI 12.5 µg - ITT B) CHF 5259 DPI 25 µg - ITT C) CHF 5259 DPI 50 µg - ITT D) CHF 5259 DPI 100 µg - ITT E) Placebo - ITT
    Number of subjects analysed
    113 [26]
    110 [27]
    117 [28]
    112 [29]
    108 [30]
    Units: patients
        Responders
    59
    67
    65
    71
    48
        Real non-responders
    54
    43
    52
    40
    60
        Non-responders due to missing values
    0
    0
    0
    1
    0
    Notes
    [26] - ITT population
    [27] - ITT population
    [28] - ITT population
    [29] - ITT population
    [30] - ITT population
    No statistical analyses for this end point

    Secondary: Number of patients using rescue medication

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    End point title
    Number of patients using rescue medication
    End point description
    End point type
    Secondary
    End point timeframe
    Number of patients who used rescue medication at least once during the treatment period.
    End point values
    A) CHF 5259 DPI 12.5 µg - ITT B) CHF 5259 DPI 25 µg - ITT C) CHF 5259 DPI 50 µg - ITT D) CHF 5259 DPI 100 µg - ITT E) Placebo - ITT
    Number of subjects analysed
    113 [31]
    110 [32]
    117 [33]
    112 [34]
    108 [35]
    Units: patients
    81
    80
    87
    77
    89
    Notes
    [31] - ITT population
    [32] - ITT population
    [33] - ITT population
    [34] - ITT population
    [35] - ITT population
    No statistical analyses for this end point

    Secondary: Days with rescue medication administration during the treatment period (%)

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    End point title
    Days with rescue medication administration during the treatment period (%)
    End point description
    The percentage of days with intake of rescue medication was calculated as: (number of days with rescue medication intake / number of days with available data) * 100.
    End point type
    Secondary
    End point timeframe
    Treatment period.
    End point values
    A) CHF 5259 DPI 12.5 µg - ITT B) CHF 5259 DPI 25 µg - ITT C) CHF 5259 DPI 50 µg - ITT D) CHF 5259 DPI 100 µg - ITT E) Placebo - ITT
    Number of subjects analysed
    107 [36]
    104 [37]
    113 [38]
    110 [39]
    103 [40]
    Units: days (%)
        arithmetic mean (confidence interval 95%)
    46.332 (38.517 to 54.147)
    48.844 (41.158 to 56.530)
    49.006 (41.679 to 56.334)
    36.572 (29.446 to 43.697)
    59.452 (51.847 to 67.058)
    Notes
    [36] - ITT population, available for change from baseline
    [37] - ITT population, available for change from baseline
    [38] - ITT population, available for change from baseline
    [39] - ITT population, available for change from baseline
    [40] - ITT population, available for change from baseline
    No statistical analyses for this end point

    Secondary: Average use of rescue medication during the treatment period (puffs/day)

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    End point title
    Average use of rescue medication during the treatment period (puffs/day)
    End point description
    The average use of rescue medication was calculated as total number of puffs / number of days with available data.
    End point type
    Secondary
    End point timeframe
    Treatment period.
    End point values
    A) CHF 5259 DPI 12.5 µg - ITT B) CHF 5259 DPI 25 µg - ITT C) CHF 5259 DPI 50 µg - ITT D) CHF 5259 DPI 100 µg - ITT E) Placebo - ITT
    Number of subjects analysed
    107 [41]
    104 [42]
    113 [43]
    110 [44]
    103 [45]
    Units: puffs/day
        arithmetic mean (confidence interval 95%)
    1.358 (1.018 to 1.698)
    1.331 (1.003 to 1.659)
    1.130 (0.868 to 1.392)
    1.085 (0.753 to 1.416)
    1.831 (1.448 to 2.214)
    Notes
    [41] - ITT population, available for change from baseline
    [42] - ITT population, available for change from baseline
    [43] - ITT population, available for change from baseline
    [44] - ITT population, available for change from baseline
    [45] - ITT population, available for change from baseline
    No statistical analyses for this end point

    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 (follow-up call included).
    Adverse event reporting additional description
    All AEs starting on or after the time of first study treatment intake and before the last visit in Treatment Period 3 or the early termination visit (as applicable) were classified as treatment emergent AEs (TEAEs). TEAEs were assigned to the last study medication received.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    A) CHF 5259 DPI 12.5 µg - Safety
    Reporting group description
    Treatment A = CHF 5259 DPI 12.5 µg; The Safety population was defined as all randomised patients who received at least one dose of the study medication.

    Reporting group title
    B) CHF 5259 DPI 25 µg - Safety
    Reporting group description
    Treatment B = CHF 5259 DPI 25 µg; The Safety population was defined as all randomised patients who received at least one dose of the study medication.

    Reporting group title
    C) CHF 5259 DPI 50 µg - Safety
    Reporting group description
    Treatment C = CHF 5259 DPI 50 µg; The Safety population was defined as all randomised patients who received at least one dose of the study medication.

    Reporting group title
    D) CHF 5259 DPI 100 µg - Safety
    Reporting group description
    Treatment D = CHF 5259 DPI 100 µg; The Safety population was defined as all randomised patients who received at least one dose of the study medication.

    Reporting group title
    E) Placebo - Safety
    Reporting group description
    Treatment E = placebo; The Safety population was defined as all randomised patients who received at least one dose of the study medication.

    Serious adverse events
    A) CHF 5259 DPI 12.5 µg - Safety B) CHF 5259 DPI 25 µg - Safety C) CHF 5259 DPI 50 µg - Safety D) CHF 5259 DPI 100 µg - Safety E) Placebo - Safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 116 (0.86%)
    1 / 111 (0.90%)
    0 / 119 (0.00%)
    2 / 112 (1.79%)
    2 / 115 (1.74%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Limb traumatic amputation
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 111 (0.00%)
    0 / 119 (0.00%)
    0 / 112 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Small cell lung cancer extensive stage
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 111 (0.00%)
    0 / 119 (0.00%)
    0 / 112 (0.00%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 111 (0.00%)
    0 / 119 (0.00%)
    2 / 112 (1.79%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Psoriatic arthropathy
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 111 (0.90%)
    0 / 119 (0.00%)
    0 / 112 (0.00%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    A) CHF 5259 DPI 12.5 µg - Safety B) CHF 5259 DPI 25 µg - Safety C) CHF 5259 DPI 50 µg - Safety D) CHF 5259 DPI 100 µg - Safety E) Placebo - Safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 116 (14.66%)
    18 / 111 (16.22%)
    13 / 119 (10.92%)
    15 / 112 (13.39%)
    16 / 115 (13.91%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    4 / 116 (3.45%)
    1 / 111 (0.90%)
    1 / 119 (0.84%)
    1 / 112 (0.89%)
    3 / 115 (2.61%)
         occurrences all number
    4
    1
    1
    1
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 116 (4.31%)
    7 / 111 (6.31%)
    3 / 119 (2.52%)
    1 / 112 (0.89%)
    1 / 115 (0.87%)
         occurrences all number
    5
    7
    3
    1
    1

    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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