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    Clinical Trial Results:
    A 24-WEEK, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, PLACEBO AND ACTIVE CONTROLLED, PARALLEL GROUP, DOSE RANGING STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 4 DOSES OF CHF 6001 DPI IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ON A BACKGROUND THERAPY.

    Summary
    EudraCT number
    2015-005548-32
    Trial protocol
    GB   DE   HU   PL   BG  
    Global end of trial date
    09 Jan 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Jan 2019
    First version publication date
    25 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-06001AA1-01
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02986321
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A.
    Sponsor organisation address
    Via Palermo 26/A, Parma, Italy, 43122
    Public contact
    Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., +39 0521 2791, clinicaltrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., +39 0521 2791, clinicaltrials_info@chiesi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Oct 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to investigate the dose-response relationship of 4 doses of CHF 6001 dry powder inhaler (DPI) with respect to pre-dose forced expiratory volume in the 1st second (FEV1) after 12 weeks of treatment and to identify the optimal dose of CHF 6001 for further development in patients with moderate to severe COPD already treated with background therapy.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines, and following all other requirements of local laws. At all visits from screening onwards, concomitant medications and adverse events were recorded and physical examination of subjects was carried out. Vital signs were recorded pre-dose and pre-dose spirometry (including inspiratory capacity [IC], FEV1 and forced vital capacity [FVC]) was performed at screening, randomisation and all post-randomisation visits until the last treatment visit. Baseline Dyspnoea Index (BDI) was recorded at randomisation and Transition Dyspnoea Index (TDI) was recorded at all post-randomisation visits until the last treatment visit. COPD exacerbations were assessed at all post-randomisation visits. Subjects were provided with salbutamol as rescue medication. From screening, the electronic diary (eDiary) was completed by patients from home on a daily basis to record rescue medication use, compliance with background medication and study treatment, and COPD exacerbation-related outcomes (using the EXAcerbations of Chronic pulmonary disease Tool - Patient Reported Outcome [EXACT-PRO]/Respiratory Symptoms [E-RS] questionnaire). Health related quality of life was assessed at all visits over the randomised treatment period using the St. George's Respiratory Questionnaire (SGRQ). Blood collection for routine haematology and blood chemistry was performed at screening, randomisation, Week 12 and last treatment visits; thyroid functions were tested at screening. From screening, 12-lead electrocardiogram (ECG) parameters (heart rate [HR], Fridericia-corrected QT interval [QTcF], PR interval [PR] and QRS interval [QRS]) were recorded.
    Background therapy
    Patients received formoterol fumarate 12 µg (one inhalation twice daily, total daily dose 24 µg) as background medication during the two-week run-in period, which was continued at the same dose throughout the study. Patients also received salbutamol as rescue medication (dose of 100 µg pressured metered dose inhaler [pMDI] as needed [PRN], maximum of 8 puffs/day), to be used throughout the study.
    Evidence for comparator
    Budesonide (ICS)
    Actual start date of recruitment
    15 Dec 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
    Poland: 210
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Bulgaria: 126
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Hungary: 87
    Country: Number of subjects enrolled
    Russian Federation: 263
    Country: Number of subjects enrolled
    Ukraine: 425
    Worldwide total number of subjects
    1130
    EEA total number of subjects
    442
    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)
    554
    From 65 to 84 years
    573
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    Overall, 1593 patients were screened according to inclusion and exclusion criteria; of these, 1130 patients were randomised.

    Pre-assignment
    Screening details
    At screening, not more than 7 days after a pre-screening visit, inclusion/exclusion criteria were assessed. There were 463 screening failures (failure to meet randomisation criteria [418 patients], consent withdrawal [31 patients] , other reasons [5 patients], AEs [4 patients], protocol deviations [3 patients], lost to follow-up [2 patients]).

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Assessor, Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    An Interactive Response Technology (IRT) system was used to generate the randomisation list.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CHF 6001 800 μg
    Arm description
    Patients were randomised to receive CHF 6001 800 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 6001
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test product: CHF 6001 DPI NEXThaler®100 µg/actuation. Double-blind double-dummy design: During study visits patients in the CHF 6001 800 µg group received two boxes, each with two NEXThaler®s with CHF 6001 100 µg/actuation and a Budesonide DPI (Pulmicort® Turbohaler®) matched Placebo, one box to be used for morning administration and the other to be used for evening administration of study medication. Dose: 2 inhalations of CHF 6001 100 µg/actuation plus 2 inhalations of CHF 6001 100 µg/actuation plus 2 inhalations of Budesonide DPI matched Placebo, all twice daily (BID). Total daily dose: CHF 6001 800 µg. Mode of administration: Dry powder inhalation using DPIs (NEXThaler®, Pulmicort® Turbohaler®). Patients were trained in the use of DPIs with training kits containing a NEXThaler® and a Pulmicort® Turbohaler®, both with Placebo.

    Arm title
    CHF 6001 1600 μg
    Arm description
    Patients were randomised to receive CHF 6001 1600 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 6001
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test product: CHF 6001 DPI NEXThaler®400 µg/actuation. Double-blind double-dummy design: During study visits patients in the CHF 6001 1600 µg group received two boxes, each with a NEXThaler® with CHF 6001 400 µg/actuation, a NEXThaler® with CHF 6001 matched Placebo and a Budesonide DPI (Pulmicort® Turbohaler®) matched Placebo, one box to be used for morning administration and the other box to be used for evening administration of study medication. Dose: 2 inhalations of CHF 6001 400 µg/actuation plus 2 inhalations of CHF 6001 matched Placebo plus 2 inhalations of Budesonide DPI matched Placebo, all twice daily (BID). Total daily dose: CHF 6001 1600 µg. Mode of administration: Dry powder inhalation using DPIs (NEXThaler®, Pulmicort® Turbohaler®). Patients were trained in the use of DPIs with training kits containing a NEXThaler® and a Pulmicort® Turbohaler®, both with Placebo.

    Arm title
    CHF 6001 2400 µg
    Arm description
    Patients were randomised to receive CHF 6001 2400 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 6001
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test product: CHF 6001 DPI NEXThaler®300 µg/actuation. Double-blind double-dummy design: During study visits patients in the CHF 6001 2400 µg group received two boxes, each with two NEXThaler®s with CHF 6001 300 µg/actuation and a Budesonide DPI (Pulmicort® Turbohaler®) matched Placebo, one box to be used for morning administration and the other to be used for evening administration of study medication. Dose: 2 inhalations of CHF 6001 300 µg/actuation plus 2 inhalations of CHF 6001 300 µg/actuation plus 2 inhalations of Budesonide DPI matched Placebo, all twice daily (BID). Total daily dose: CHF 6001 2400 µg. Mode of administration: Dry powder inhalation using DPIs (NEXThaler®, Pulmicort® Turbohaler®). Patients were trained in the use of DPIs with training kits containing a NEXThaler® and a Pulmicort® Turbohaler®, both with Placebo.

    Arm title
    CHF 6001 3200 µg
    Arm description
    Patients were randomised to receive CHF 6001 3200 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 6001
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test product: CHF 6001 DPI NEXThaler®400 µg/actuation. Double-blind double-dummy design: During study visits patients in the CHF 6001 3200 µg group received two boxes, each with two NEXThaler®s with CHF 6001 400 µg/actuation and a Budesonide DPI (Pulmicort® Turbohaler®) matched Placebo, one box to be used for morning administration and the other to be used for evening administration of study medication. Dose: 2 inhalations of CHF 6001 400 µg/actuation plus 2 inhalations of CHF 6001 400 µg/actuation plus 2 inhalations of Budesonide DPI matched Placebo, all twice daily (BID). Total daily dose: CHF 6001 3200 µg. Mode of administration: Dry powder inhalation using DPIs (NEXThaler®, Pulmicort® Turbohaler®). Patients were trained in the use of DPIs with training kits containing a NEXThaler® and a Pulmicort® Turbohaler®, both with Placebo.

    Arm title
    Budesonide 800 µg
    Arm description
    Patients were randomised to receive Budesonide 800 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period
    Arm type
    Active comparator

    Investigational medicinal product name
    Budesonide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test product: Budesonide DPI Pulmicort® Turbohaler® 200 µg/actuation. Double-blind double-dummy design: During study visits, patients in the Budesonide 800 µg group received two boxes, each with two NEXThaler®s with CHF 6001 matched Placebo and a Budesonide DPI (Pulmicort® Turbohaler®) 200 µg/actuation, one box to be used for morning administration and the other to be used for evening administration of study medication. Dose: 2 inhalations of CHF 6001 matched Placebo plus 2 inhalations of CHF 6001 matched Placebo plus 2 inhalations of Budesonide DPI 200 µg/actuation, all twice daily (BID). Total daily dose: Budesonide 800 µg. Mode of administration: Dry powder inhalation using DPIs (NEXThaler®, Pulmicort® Turbohaler®). Patients were trained in the use of DPIs with training kits containing a NEXThaler® and a Pulmicort® Turbohaler®, both with Placebo.

    Arm title
    Placebo
    Arm description
    Patients were randomised to receive Placebo for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test product: Matched Placebo. Double-blind double-dummy design: During study visits patients in the Placebo group received two boxes, each with two CHF 6001 DPI NEXThaler® matched Placebos and a Budesonide DPI (Pulmicort® Turbohaler®) matched Placebo, one box to be used for morning administration and the other to be used for evening administration of study medication. Dose: 2 inhalations of CHF 6001 matched Placebo plus 2 inhalations of CHF 6001 matched Placebo plus 2 inhalations of Budesonide DPI matched Placebo, all twice daily (BID). Total daily dose: Not applicable. Mode of administration: Dry powder inhalation using DPIs (NEXThaler®, Pulmicort® Turbohaler®). Patients were trained in the use of DPIs with training kits containing a NEXThaler® and a Pulmicort® Turbohaler®, both with Placebo.

    Number of subjects in period 1
    CHF 6001 800 μg CHF 6001 1600 μg CHF 6001 2400 µg CHF 6001 3200 µg Budesonide 800 µg Placebo
    Started
    190
    179
    188
    193
    187
    193
    Completed
    175
    162
    176
    173
    175
    177
    Not completed
    15
    17
    12
    20
    12
    16
         Protocol deviation
    -
    2
    -
    -
    -
    -
         Lack of efficacy
    2
    1
    2
    3
    4
    1
         Adverse event, serious fatal
    1
    1
    1
    2
    -
    -
         Adverse event, non-fatal
    3
    2
    3
    6
    2
    5
         Consent withdrawn by subject
    7
    10
    5
    5
    4
    7
         Lost to follow-up
    -
    -
    -
    -
    1
    -
         No reason specified
    2
    1
    1
    4
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CHF 6001 800 μg
    Reporting group description
    Patients were randomised to receive CHF 6001 800 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period.

    Reporting group title
    CHF 6001 1600 μg
    Reporting group description
    Patients were randomised to receive CHF 6001 1600 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period

    Reporting group title
    CHF 6001 2400 µg
    Reporting group description
    Patients were randomised to receive CHF 6001 2400 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period

    Reporting group title
    CHF 6001 3200 µg
    Reporting group description
    Patients were randomised to receive CHF 6001 3200 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period

    Reporting group title
    Budesonide 800 µg
    Reporting group description
    Patients were randomised to receive Budesonide 800 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period

    Reporting group title
    Placebo
    Reporting group description
    Patients were randomised to receive Placebo for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period

    Reporting group values
    CHF 6001 800 μg CHF 6001 1600 μg CHF 6001 2400 µg CHF 6001 3200 µg Budesonide 800 µg Placebo Total
    Number of subjects
    190 179 188 193 187 193 1130
    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)
    94 80 90 104 91 95 554
        From 65-84 years
    96 98 98 89 95 97 573
        85 years and over
    0 1 0 0 1 1 3
    Gender categorical
    Units: Subjects
        Female
    57 50 57 58 55 60 337
        Male
    133 129 131 135 132 133 793

    End points

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    End points reporting groups
    Reporting group title
    CHF 6001 800 μg
    Reporting group description
    Patients were randomised to receive CHF 6001 800 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period.

    Reporting group title
    CHF 6001 1600 μg
    Reporting group description
    Patients were randomised to receive CHF 6001 1600 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period

    Reporting group title
    CHF 6001 2400 µg
    Reporting group description
    Patients were randomised to receive CHF 6001 2400 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period

    Reporting group title
    CHF 6001 3200 µg
    Reporting group description
    Patients were randomised to receive CHF 6001 3200 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period

    Reporting group title
    Budesonide 800 µg
    Reporting group description
    Patients were randomised to receive Budesonide 800 μg for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period

    Reporting group title
    Placebo
    Reporting group description
    Patients were randomised to receive Placebo for 24 weeks, following the 2-week run-in period during which they received background medication (formoterol fumarate 24 μg/day) and rescue medication (salbutamol, as required). Patients continued to receive the background and rescue medications throughout the treatment period

    Subject analysis set title
    CHF 6001 800 μg - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intention-to-treat (ITT) population was defined as all randomised patients who received at least one dose of the study medication and with at least one available evaluation of efficacy after the baseline.

    Subject analysis set title
    CHF 6001 1600 μg - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intention-to-treat (ITT) population was defined as all randomised patients who received at least one dose of the study medication and with at least one available evaluation of efficacy after the baseline.

    Subject analysis set title
    CHF 6001 2400 μg - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intention-to-treat (ITT) population was defined as all randomised patients who received at least one dose of the study medication and with at least one available evaluation of efficacy after the baseline.

    Subject analysis set title
    CHF 6001 3200 μg - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intention-to-treat (ITT) population was defined as all randomised patients who received at least one dose of the study medication and with at least one available evaluation of efficacy after the baseline.

    Subject analysis set title
    Budesonide 800 μg - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intention-to-treat (ITT) population was defined as all randomised patients who received at least one dose of the study medication and with at least one available evaluation of efficacy after the baseline.

    Subject analysis set title
    Placebo - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intention-to-treat (ITT) population was defined as all randomised patients who received at least one dose of the study medication and with at least one available evaluation of efficacy after the baseline.

    Primary: Change from baseline in morning pre-dose FEV1 at Week 12

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    End point title
    Change from baseline in morning pre-dose FEV1 at Week 12
    End point description
    Morning pre-dose forced expiratory volume in the first second (FEV1).
    End point type
    Primary
    End point timeframe
    Baseline (pre-dose at the randomisation visit, Week 0) to Week 12.
    End point values
    CHF 6001 800 μg - ITT CHF 6001 1600 μg - ITT CHF 6001 2400 μg - ITT CHF 6001 3200 μg - ITT Budesonide 800 μg - ITT Placebo - ITT
    Number of subjects analysed
    177 [1]
    166 [2]
    178 [3]
    178 [4]
    178 [5]
    176 [6]
    Units: Litres
        least squares mean (confidence interval 95%)
    -0.004 (-0.037 to 0.028)
    0.011 (-0.022 to 0.044)
    0.004 (-0.029 to 0.036)
    -0.024 (-0.057 to 0.008)
    -0.002 (-0.035 to 0.030)
    -0.006 (-0.039 to 0.026)
    Notes
    [1] - Number of patients in the ITT population = 190, number of patients with available data = 177
    [2] - Number of patients in the ITT population = 179, number of patients with available data = 166
    [3] - Number of patients in the ITT population = 188, number of patients with available data = 178
    [4] - Number of patients in the ITT population = 193, number of patients with available data = 178
    [5] - Number of patients in the ITT population = 187, number of patients with available data = 178
    [6] - Number of patients in the ITT population = 193, number of patients with available data = 176
    Statistical analysis title
    Adjusted mean difference in CFB FEV1 at Week 12
    Statistical analysis description
    The CFB in pre-dose morning FEV1 was analysed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction and sites pooled by country as effects and baseline FEV1 value and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo were estimated by the model. Comparisons with Budesonide were also provided.
    Comparison groups
    CHF 6001 800 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    353
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.932
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.002
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.044
         upper limit
    0.048
    Statistical analysis title
    Adjusted mean difference in CFB FEV1 at Week 12
    Statistical analysis description
    The CFB in pre-dose morning FEV1 was analysed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction and sites pooled by country as effects and baseline FEV1 value and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo were estimated by the model. Comparisons with Budesonide were also provided.
    Comparison groups
    CHF 6001 1600 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    342
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.47
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.017
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.029
         upper limit
    0.064
    Statistical analysis title
    Adjusted mean difference in CFB FEV1 at Week 12
    Statistical analysis description
    The CFB in pre-dose morning FEV1 was analysed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction and sites pooled by country as effects and baseline FEV1 value and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo were estimated by the model. Comparisons with Budesonide were also provided.
    Comparison groups
    CHF 6001 2400 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    354
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.673
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.036
         upper limit
    0.056
    Statistical analysis title
    Adjusted mean difference in CFB FEV1 at Week 12
    Statistical analysis description
    The CFB in pre-dose morning FEV1 was analysed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction and sites pooled by country as effects and baseline FEV1 value and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo were estimated by the model. Comparisons with Budesonide were also provided.
    Comparison groups
    CHF 6001 3200 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    354
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.433
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.018
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.064
         upper limit
    0.027

    Secondary: TDI score at Week 3

    Close Top of page
    End point title
    TDI score at Week 3
    End point description
    The Baseline Dyspnoea Index (BDI)/Transition Dyspnoea Index (TDI) is a clinical rating used to measure the impact of dyspnoea on three domains: functional impairment, magnitude of task and magnitude of effort. The BDI focal scores were recorded at the randomisation visit (Week 0) and TDI focal scores were recorded at all post-randomisation visits (Week 3, Week 6, Week 12, Week 18 and Week 24). A TDI focal score ≥ 1 is considered the minimal clinically important difference (MCID) for this instrument.
    End point type
    Secondary
    End point timeframe
    Week 3
    End point values
    CHF 6001 800 μg - ITT CHF 6001 1600 μg - ITT CHF 6001 2400 μg - ITT CHF 6001 3200 μg - ITT Budesonide 800 μg - ITT Placebo - ITT
    Number of subjects analysed
    181 [7]
    172 [8]
    183 [9]
    185 [10]
    181 [11]
    187 [12]
    Units: TDI focal scores
        least squares mean (confidence interval 95%)
    0.84 (0.51 to 1.17)
    0.74 (0.39 to 1.08)
    0.65 (0.32 to 0.98)
    0.58 (0.25 to 0.91)
    0.89 (0.56 to 1.22)
    0.73 (0.40 to 1.06)
    Notes
    [7] - Number of patients in the ITT population = 190, number of patients with available data = 181
    [8] - Number of patients in the ITT population = 179, number of patients with available data = 172
    [9] - Number of patients in the ITT population = 188, number of patients with available data = 183
    [10] - Number of patients in the ITT population = 193, number of patients with available data = 185
    [11] - Number of patients in the ITT population = 187, number of patients with available data = 181
    [12] - Number of patients in the ITT population = 193, number of patients with available data = 187
    Statistical analysis title
    Adjusted mean difference in TDI focal scores
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 800 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.645
    Method
    Linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.36
         upper limit
    0.57
    Statistical analysis title
    Adjusted mean difference in TDI focal scores
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 1600 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.968
    Method
    Linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.47
         upper limit
    0.48
    Statistical analysis title
    Adjusted mean difference in TDI focal scores
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 2400 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.753
    Method
    Linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.54
         upper limit
    0.39
    Statistical analysis title
    Adjusted mean difference in TDI focal scores
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 3200 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.537
    Method
    Linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.62
         upper limit
    0.32

    Secondary: TDI score at Week 6

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    End point title
    TDI score at Week 6
    End point description
    The Baseline Dyspnoea Index (BDI)/Transition Dyspnoea Index (TDI) is a clinical rating used to measure the impact of dyspnoea on three domains: functional impairment, magnitude of task and magnitude of effort. The BDI focal scores were recorded at the randomisation visit (Week 0) and TDI focal scores were recorded at all post-randomisation visits (Week 3, Week 6, Week 12, Week 18 and Week 24). A TDI focal score ≥ 1 is considered the minimal clinically important difference (MCID) for this instrument.
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    CHF 6001 800 μg - ITT CHF 6001 1600 μg - ITT CHF 6001 2400 μg - ITT CHF 6001 3200 μg - ITT Budesonide 800 μg - ITT Placebo - ITT
    Number of subjects analysed
    183 [13]
    168 [14]
    181 [15]
    184 [16]
    179 [17]
    186 [18]
    Units: TDI focal scores
        least squares mean (confidence interval 95%)
    1.28 (0.96 to 1.61)
    1.14 (0.79 to 1.48)
    1.17 (0.83 to 1.50)
    1.09 (0.75 to 1.42)
    1.44 (1.11 to 1.77)
    1.15 (0.82 to 1.48)
    Notes
    [13] - Number of patients in the ITT population = 190, number of patients with available data = 183
    [14] - Number of patients in the ITT population = 179, number of patients with available data = 168
    [15] - Number of patients in the ITT population = 188, number of patients with available data = 181
    [16] - Number of patients in the ITT population = 193, number of patients with available data = 184
    [17] - Number of patients in the ITT population = 187, number of patients with available data = 179
    [18] - Number of patients in the ITT population = 193, number of patients with available data = 186
    Statistical analysis title
    Adjusted mean difference in TDI focal scores
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 800 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.574
    Method
    Linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.33
         upper limit
    0.6
    Statistical analysis title
    Adjusted mean difference in TDI focal scores
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 1600 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    354
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.957
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.49
         upper limit
    0.46
    Statistical analysis title
    Adjusted mean difference in TDI focal score
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 2400 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.945
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.45
         upper limit
    0.49
    Statistical analysis title
    Adjusted mean difference in TDI focal score
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 3200 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.793
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.53
         upper limit
    0.41

    Secondary: TDI score at Week 12

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    End point title
    TDI score at Week 12
    End point description
    The Baseline Dyspnoea Index (BDI)/Transition Dyspnoea Index (TDI) is a clinical rating used to measure the impact of dyspnoea on three domains: functional impairment, magnitude of task and magnitude of effort. The BDI focal scores were recorded at the randomisation visit (Week 0) and TDI focal scores were recorded at all post-randomisation visits (Week 3, Week 6, Week 12, Week 18 and Week 24). A TDI focal score ≥ 1 is considered the minimal clinically important difference (MCID) for this instrument.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    CHF 6001 800 μg - ITT CHF 6001 1600 μg - ITT CHF 6001 2400 μg - ITT CHF 6001 3200 μg - ITT Budesonide 800 μg - ITT Placebo - ITT
    Number of subjects analysed
    179 [19]
    164 [20]
    178 [21]
    182 [22]
    180 [23]
    178 [24]
    Units: TDI focal scores
        least squares mean (confidence interval 95%)
    1.23 (0.88 to 1.57)
    1.21 (0.84 to 1.57)
    1.15 (0.80 to 1.50)
    0.99 (0.64 to 1.34)
    1.03 (0.68 to 1.37)
    1.21 (0.86 to 1.56)
    Notes
    [19] - Number of patients in the ITT population = 190, number of patients with available data = 179
    [20] - Number of patients in the ITT population = 179, number of patients with available data = 164
    [21] - Number of patients in the ITT population = 188, number of patients with available data = 178
    [22] - Number of patients in the ITT population = 193, number of patients with available data = 182
    [23] - Number of patients in the ITT population = 187, number of patients with available data = 180
    [24] - Number of patients in the ITT population = 193, number of patients with available data = 178
    Statistical analysis title
    Adjusted mean difference in TDI focal scores
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 800 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.948
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.48
         upper limit
    0.51
    Statistical analysis title
    Adjusted mean difference in TDI focal scores
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 1600 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    342
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.988
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.51
         upper limit
    0.5
    Statistical analysis title
    Adjusted mean difference in TDI focal score
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 2400 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.82
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.55
         upper limit
    0.44
    Statistical analysis title
    Adjusted mean difference in TDI focal score
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 3200 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    360
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.387
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.72
         upper limit
    0.28

    Secondary: TDI score at Week 18

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    End point title
    TDI score at Week 18
    End point description
    The Baseline Dyspnoea Index (BDI)/Transition Dyspnoea Index (TDI) is a clinical rating used to measure the impact of dyspnoea on three domains: functional impairment, magnitude of task and magnitude of effort. The BDI focal scores were recorded at the randomisation visit (Week 0) and TDI focal scores were recorded at all post-randomisation visits (Week 3, Week 6, Week 12, Week 18 and Week 24). A TDI focal score ≥ 1 is considered the minimal clinically important difference (MCID) for this instrument.
    End point type
    Secondary
    End point timeframe
    Week 18
    End point values
    CHF 6001 800 μg - ITT CHF 6001 1600 μg - ITT CHF 6001 2400 μg - ITT CHF 6001 3200 μg - ITT Budesonide 800 μg - ITT Placebo - ITT
    Number of subjects analysed
    178 [25]
    164 [26]
    178 [27]
    172 [28]
    177 [29]
    178 [30]
    Units: TDI focal scores
        least squares mean (confidence interval 95%)
    1.09 (0.74 to 1.45)
    1.14 (0.76 to 1.52)
    1.07 (0.71 to 1.43)
    1.11 (0.73 to 1.48)
    1.19 (0.83 to 1.55)
    0.96 (0.60 to 1.32)
    Notes
    [25] - Number of patients in the ITT population = 190, number of patients with available data = 178
    [26] - Number of patients in the ITT population = 179, number of patients with available data = 164
    [27] - Number of patients in the ITT population = 188, number of patients with available data = 178
    [28] - Number of patients in the ITT population = 193, number of patients with available data = 172
    [29] - Number of patients in the ITT population = 187, number of patients with available data = 177
    [30] - Number of patients in the ITT population = 193, number of patients with available data = 178
    Statistical analysis title
    Adjusted mean difference in TDI focal scores
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 800 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.606
    Method
    Linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.37
         upper limit
    0.64
    Statistical analysis title
    Adjusted mean difference in TDI focal score
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 1600 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    342
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.496
    Method
    Linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.34
         upper limit
    0.7
    Statistical analysis title
    Adjusted mean difference in TDI focal score
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 2400 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.678
    Method
    Linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    0.62
    Statistical analysis title
    Adjusted mean difference in TDI focal score
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 3200 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.582
    Method
    Linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.37
         upper limit
    0.66

    Secondary: TDI score at Week 24

    Close Top of page
    End point title
    TDI score at Week 24
    End point description
    The Baseline Dyspnoea Index (BDI)/Transition Dyspnoea Index (TDI) is a clinical rating used to measure the impact of dyspnoea on three domains: functional impairment, magnitude of task and magnitude of effort. The BDI focal scores were recorded at the randomisation visit (Week 0) and TDI focal scores were recorded at all post-randomisation visits (Week 3, Week 6, Week 12, Week 18 and Week 24). A TDI focal score ≥ 1 is considered the minimal clinically important difference (MCID) for this instrument.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    CHF 6001 800 μg - ITT CHF 6001 1600 μg - ITT CHF 6001 2400 μg - ITT CHF 6001 3200 μg - ITT Budesonide 800 μg - ITT Placebo - ITT
    Number of subjects analysed
    175 [31]
    159 [32]
    175 [33]
    172 [34]
    174 [35]
    177 [36]
    Units: TDI focal scores
        least squares mean (confidence interval 95%)
    1.54 (1.19 to 1.90)
    1.28 (0.90 to 1.65)
    1.49 (1.13 to 1.85)
    1.44 (1.08 to 1.81)
    1.49 (1.13 to 1.84)
    1.46 (1.11 to 1.82)
    Notes
    [31] - Number of patients in the ITT population = 190, number of patients with available data = 175
    [32] - Number of patients in the ITT population = 179, number of patients with available data = 159
    [33] - Number of patients in the ITT population = 188, number of patients with available data = 175
    [34] - Number of patients in the ITT population = 193, number of patients with available data = 172
    [35] - Number of patients in the ITT population = 187, number of patients with available data = 174
    [36] - Number of patients in the ITT population = 193, number of patients with available data = 177
    Statistical analysis title
    Adjusted mean difference in TDI focal scores
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 800 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.758
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.42
         upper limit
    0.58
    Statistical analysis title
    Adjusted mean difference in TDI focal scores
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 1600 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.484
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    0.33
    Statistical analysis title
    Adjusted mean difference in TDI focal scores
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 2400 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.922
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.48
         upper limit
    0.53
    Statistical analysis title
    Adjusted mean difference in TDI focal scores
    Statistical analysis description
    The TDI focal scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, BDI score at randomisation (Week 0) and BDI score by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 3200 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.939
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.53
         upper limit
    0.49

    Secondary: TDI response

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    End point title
    TDI response
    End point description
    TDI focal scores were recorded at all post-randomisation visits (Week 3, Week 6, Week 12, Week 18 and Week 24) . A TDI response is defined as TDI focal score ≥ 1 unit. TDI response was assessed at each post-randomisation visit. Patients with TDI focal score < 1 unit or with missing data at any visit were classed as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 3, Week 6, Week 12, Week 18, Week 24.
    End point values
    CHF 6001 800 μg - ITT CHF 6001 1600 μg - ITT CHF 6001 2400 μg - ITT CHF 6001 3200 μg - ITT Budesonide 800 μg - ITT Placebo - ITT
    Number of subjects analysed
    190 [37]
    179 [38]
    188 [39]
    193 [40]
    187 [41]
    193 [42]
    Units: Patients
    number (not applicable)
        Week 3
    85
    74
    70
    84
    85
    80
        Week 6
    94
    83
    83
    94
    95
    88
        Week 12
    90
    78
    84
    80
    86
    93
        Week 18
    83
    81
    81
    80
    85
    86
        Week 24
    96
    77
    90
    88
    95
    100
    Notes
    [37] - ITT population
    [38] - ITT population
    [39] - ITT population
    [40] - ITT population
    [41] - ITT population
    [42] - ITT population
    No statistical analyses for this end point

    Secondary: Change from baseline to Week 3 in SGRQ total score

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    End point title
    Change from baseline to Week 3 in SGRQ total score
    End point description
    The St. George's Respiratory Questionnaire (SGRQ) is used to measure health-related quality of life. Decrease in SGRQ total scores indicates improvement. Baseline SGRQ total score was recorded at the randomisation visit (Week 0) and SGRQ total scores were recorded at all post-randomisation visits (Week 3, Week 6, Week 12, Week 18 and Week 24). The minimal clinically important difference (MCID) for this instrument is a decrease from baseline of ≥ 4 units.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 3.
    End point values
    CHF 6001 800 μg - ITT CHF 6001 1600 μg - ITT CHF 6001 2400 μg - ITT CHF 6001 3200 μg - ITT Budesonide 800 μg - ITT Placebo - ITT
    Number of subjects analysed
    184 [43]
    173 [44]
    185 [45]
    186 [46]
    183 [47]
    189 [48]
    Units: SGRQ total scores
        least squares mean (confidence interval 95%)
    -1.49 (-3.08 to 0.10)
    -2.90 (-4.53 to -1.26)
    -2.37 (-3.95 to -0.79)
    -2.87 (-4.44 to -1.30)
    -3.46 (-5.05 to -1.87)
    -3.51 (-5.07 to -1.94)
    Notes
    [43] - Number of patients in the ITT population = 190, number of patients with available data = 184
    [44] - Number of patients in the ITT population = 179, number of patients with available data = 173
    [45] - Number of patients in the ITT population = 188, number of patients with available data = 185
    [46] - Number of patients in the ITT population = 193, number of patients with available data = 186
    [47] - Number of patients in the ITT population = 187, number of patients with available data = 183
    [48] - Number of patients in the ITT population = 193, number of patients with available data = 189
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The change from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 800 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    373
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.075
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    2.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.21
         upper limit
    4.25
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The changes from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 1600 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.594
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.65
         upper limit
    2.88
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The changes from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 2400 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.314
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    1.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.08
         upper limit
    3.37
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The changes from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 3200 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.572
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.58
         upper limit
    2.86

    Secondary: Change from baseline to Week 6 in SGRQ total score

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    End point title
    Change from baseline to Week 6 in SGRQ total score
    End point description
    The St. George's Respiratory Questionnaire (SGRQ) is used to measure health-related quality of life. Decrease in SGRQ total scores indicates improvement. Baseline SGRQ total score was recorded at the randomisation visit (Week 0) and SGRQ total scores were recorded at all post-randomisation visits (Week 3, Week 6, Week 12, Week 18 and Week 24). The minimal clinically important difference (MCID) for this instrument is a decrease from baseline of ≥ 4 units.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    CHF 6001 800 μg - ITT CHF 6001 1600 μg - ITT CHF 6001 2400 μg - ITT CHF 6001 3200 μg - ITT Budesonide 800 μg - ITT Placebo - ITT
    Number of subjects analysed
    181 [49]
    170 [50]
    184 [51]
    182 [52]
    182 [53]
    184 [54]
    Units: SGRQ total scores
        least squares mean (confidence interval 95%)
    -2.21 (-3.92 to -0.50)
    -5.21 (-6.96 to -3.45)
    -4.12 (-5.82 to -2.43)
    -4.82 (-6.52 to -3.12)
    -5.32 (-7.03 to -3.62)
    -5.42 (-7.11 to -3.73)
    Notes
    [49] - Number of patients in the ITT population = 190, number of patients with available data = 181
    [50] - Number of patients in the ITT population = 179, number of patients with available data = 170
    [51] - Number of patients in the ITT population = 188, number of patients with available data = 184
    [52] - Number of patients in the ITT population = 193, number of patients with available data = 182
    [53] - Number of patients in the ITT population = 187, number of patients with available data = 182
    [54] - Number of patients in the ITT population = 193, number of patients with available data = 184
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The changes from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 800 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.009
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    3.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    5.61
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The changes from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 1600 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    354
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.865
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.23
         upper limit
    2.65
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The changes from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 2400 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.289
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    3.69
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The changes from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 3200 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.624
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    2.99

    Secondary: Change from baseline to Week 12 in SGRQ total score

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    End point title
    Change from baseline to Week 12 in SGRQ total score
    End point description
    The St. George's Respiratory Questionnaire (SGRQ) is used to measure health-related quality of life. Decrease in SGRQ total scores indicates improvement. Baseline SGRQ total score was recorded at the randomisation visit (Week 0) and SGRQ total scores were recorded at all post-randomisation visits (Week 3, Week 6, Week 12, Week 18 and Week 24). The minimal clinically important difference (MCID) for this instrument is a decrease from baseline of ≥ 4 units.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    CHF 6001 800 μg - ITT CHF 6001 1600 μg - ITT CHF 6001 2400 μg - ITT CHF 6001 3200 μg - ITT Budesonide 800 μg - ITT Placebo - ITT
    Number of subjects analysed
    176 [55]
    167 [56]
    179 [57]
    180 [58]
    180 [59]
    179 [60]
    Units: SGRQ total scores
        least squares mean (confidence interval 95%)
    -4.53 (-6.43 to -2.62)
    -6.62 (-8.57 to -4.66)
    -4.58 (-6.47 to -2.69)
    -6.38 (-8.26 to -4.50)
    -5.56 (-7.45 to -3.67)
    -6.17 (-8.06 to -4.29)
    Notes
    [55] - Number of patients in the ITT population = 190, number of patients with available data = 176
    [56] - Number of patients in the ITT population = 179, number of patients with available data = 167
    [57] - Number of patients in the ITT population = 188, number of patients with available data = 179
    [58] - Number of patients in the ITT population = 193, number of patients with available data = 180
    [59] - Number of patients in the ITT population = 187, number of patients with available data = 180
    [60] - Number of patients in the ITT population = 193, number of patients with available data = 179
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The change from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 800 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    355
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.227
    Method
    Linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    1.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.03
         upper limit
    4.33
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The change from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 1600 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.75
    Method
    Linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.15
         upper limit
    2.27
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The change from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 2400 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.241
    Method
    Linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    1.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.07
         upper limit
    4.26
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The change from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 3200 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.879
    Method
    Linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.87
         upper limit
    2.46

    Secondary: Change from baseline to Week 18 in SGRQ total score

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    End point title
    Change from baseline to Week 18 in SGRQ total score
    End point description
    The St. George's Respiratory Questionnaire (SGRQ) is used to measure health-related quality of life. Decrease in SGRQ total scores indicates improvement. Baseline SGRQ total score was recorded at the randomisation visit (Week 0) and SGRQ total scores were recorded at all post-randomisation visits (Week 3, Week 6, Week 12, Week 18 and Week 24). The minimal clinically important difference (MCID) for this instrument is a decrease from baseline of ≥ 4 units.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 18
    End point values
    CHF 6001 800 μg - ITT CHF 6001 1600 μg - ITT CHF 6001 2400 μg - ITT CHF 6001 3200 μg - ITT Budesonide 800 μg - ITT Placebo - ITT
    Number of subjects analysed
    176 [61]
    163 [62]
    179 [63]
    176 [64]
    176 [65]
    178 [66]
    Units: SGRQ total scores
        least squares mean (confidence interval 95%)
    -6.04 (-7.98 to -4.09)
    -7.93 (-9.94 to -5.92)
    -5.18 (-7.11 to -3.25)
    -6.09 (-8.02 to -4.15)
    -5.91 (-7.85 to -3.97)
    -6.50 (-8.42 to -4.57)
    Notes
    [61] - Number of patients in the ITT population = 190, number of patients with available data = 176
    [62] - Number of patients in the ITT population = 179, number of patients with available data = 163
    [63] - Number of patients in the ITT population = 188, number of patients with available data = 179
    [64] - Number of patients in the ITT population = 193, number of patients with available data = 176
    [65] - Number of patients in the ITT population = 187, number of patients with available data = 176
    [66] - Number of patients in the ITT population = 193, number of patients with available data = 178
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The change from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 800 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    354
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.742
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.28
         upper limit
    3.2
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The change from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 1600 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.313
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    -1.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.22
         upper limit
    1.35
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The change from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 2400 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.344
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    1.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.41
         upper limit
    4.05
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The change from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 3200 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    354
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.769
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.32
         upper limit
    3.14

    Secondary: Change from baseline to Week 24 in SGRQ total score

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    End point title
    Change from baseline to Week 24 in SGRQ total score
    End point description
    The St. George's Respiratory Questionnaire (SGRQ) is used to measure health-related quality of life. Decrease in SGRQ total scores indicates improvement. Baseline SGRQ total score was recorded at the randomisation visit (Week 0) and SGRQ total scores were recorded at all post-randomisation visits (Week 3, Week 6, Week 12, Week 18 and Week 24). The minimal clinically important difference (MCID) for this instrument is a decrease from baseline of ≥ 4 units.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    CHF 6001 800 μg - ITT CHF 6001 1600 μg - ITT CHF 6001 2400 μg - ITT CHF 6001 3200 μg - ITT Budesonide 800 μg - ITT Placebo - ITT
    Number of subjects analysed
    172 [67]
    162 [68]
    175 [69]
    173 [70]
    176 [71]
    177 [72]
    Units: SGRQ total scores
        least squares mean (confidence interval 95%)
    -5.54 (-7.64 to -3.43)
    -8.06 (-10.24 to -5.89)
    -5.95 (-8.04 to -3.86)
    -6.96 (-9.06 to -4.87)
    -7.11 (-9.20 to -5.02)
    -7.48 (-9.57 to -5.40)
    Notes
    [67] - Number of patients in the ITT population = 190, number of patients with available data = 172
    [68] - Number of patients in the ITT population = 179, number of patients with available data = 162
    [69] - Number of patients in the ITT population = 188, number of patients with available data = 175
    [70] - Number of patients in the ITT population = 193, number of patients with available data = 173
    [71] - Number of patients in the ITT population = 187, number of patients with available data = 176
    [72] - Number of patients in the ITT population = 193, number of patients with available data = 177
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The change from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 800 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.198
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    1.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.02
         upper limit
    4.91
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The change from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 1600 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    339
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.705
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.59
         upper limit
    2.43
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The change from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 2400 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.307
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    1.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.42
         upper limit
    4.49
    Statistical analysis title
    Adjusted mean difference in CFB, SGRQ total score
    Statistical analysis description
    The change from baseline (CFB) in SGRQ total scores were analysed using a linear MMRM including treatment, visit, treatment by visit interaction and sites pooled by country as effects, baseline (pre-dose at Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 3200 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.73
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.43
         upper limit
    3.47

    Secondary: SGRQ response

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    End point title
    SGRQ response
    End point description
    SGRQ response is defined as a decrease from baseline in SGRQ total score ≥ 4 units. Baseline SGRQ total scores were recorded at the randomisation visit (Week 0), and SGRQ total scores were recorded at all post-randomisation visits (Week 3, Week 6, Week 12, Week 18 and Week 24). Patients with decrease from baseline in SGRQ score ≥ 4 units at any visit were classed as responders. Patients with a decrease from baseline in SGRQ total score < 4 units or with missing data at any visit, were classed as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 3, Week 6, Week 12, Week 18 and Week 24.
    End point values
    CHF 6001 800 μg - ITT CHF 6001 1600 μg - ITT CHF 6001 2400 μg - ITT CHF 6001 3200 μg - ITT Budesonide 800 μg - ITT Placebo - ITT
    Number of subjects analysed
    190 [73]
    179 [74]
    188 [75]
    193 [76]
    187 [77]
    193 [78]
    Units: Patients
    number (not applicable)
        Week 3
    83
    71
    81
    74
    92
    88
        Week 6
    80
    90
    90
    92
    93
    95
        Week 12
    93
    96
    87
    97
    95
    90
        Week 18
    98
    95
    101
    102
    92
    97
        Week 24
    91
    98
    94
    90
    93
    92
    Notes
    [73] - ITT population
    [74] - ITT population
    [75] - ITT population
    [76] - ITT population
    [77] - ITT population
    [78] - ITT population
    No statistical analyses for this end point

    Secondary: CFB to the entire treatment period in average E-RS total score

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    End point title
    CFB to the entire treatment period in average E-RS total score
    End point description
    The EXAcerbations of Chronic pulmonary disease Tool (EXACT) collects patient-reported outcomes (PRO) data in order to capture frequency, severity and time course of COPD exacerbations. Digital platform technology was used for data collection in this study. Average EXACT-Respiratory Symptoms (E-RS) scores were recorded during the 2-week run-in period (baseline) and over the entire treatment period of 24 weeks. Change from baseline (CFB) over the entire treatment period was analysed. A decrease from baseline in average E-RS scores ≥ 2.0 is the minimal clinically important difference (MCID) for this instrument.
    End point type
    Secondary
    End point timeframe
    Baseline (run-in period) to 24 weeks treatment period.
    End point values
    CHF 6001 800 μg - ITT CHF 6001 1600 μg - ITT CHF 6001 2400 μg - ITT CHF 6001 3200 μg - ITT Budesonide 800 μg - ITT Placebo - ITT
    Number of subjects analysed
    187 [79]
    176 [80]
    186 [81]
    187 [82]
    184 [83]
    193 [84]
    Units: Average E-RS total scores
        least squares mean (confidence interval 95%)
    -1.53 (-2.21 to -0.94)
    -2.41 (-3.01 to -1.80)
    -1.89 (-2.48 to -1.31)
    -2.07 (-2.66 to -1.48)
    -2.35 (-2.94 to -1.76)
    -2.12 (-2.79 to -1.63)
    Notes
    [79] - Number of patients in the ITT population = 190, number of patients with available data = 187
    [80] - Number of patients in the ITT population = 179, number of patients with available data = 176
    [81] - Number of patients in the ITT population = 188, number of patients with available data = 186
    [82] - Number of patients in the ITT population = 193, number of patients with available data = 187
    [83] - Number of patients in the ITT population = 187, number of patients with available data = 184
    [84] - Number of patients in the ITT population = 193, number of patients with available data = 193
    Statistical analysis title
    Adjusted mean difference in CFB, E-RS total score
    Statistical analysis description
    Analysis of change from baseline (CFB) to the entire treatment period in average E-RS total scores was based on a linear mixed model for repeated measures (MMRM) including treatment, inter-Visit period, treatment by inter-Visit period interaction and Pooled Country as fixed effects, and baseline value and baseline by inter-Visit period interaction as covariates. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo are presented.
    Comparison groups
    CHF 6001 800 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    380
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.105
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.14
         upper limit
    1.5
    Statistical analysis title
    Adjusted mean difference in CFB, E-RS total score
    Statistical analysis description
    Analysis of change from baseline (CFB) to the entire treatment period in average E-RS total scores was based on a linear mixed model for repeated measures (MMRM) including treatment, inter-Visit period, treatment by inter-Visit period interaction and Pooled Country as fixed effects, and baseline value and baseline by inter-Visit period interaction as covariates. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo are presented.
    Comparison groups
    CHF 6001 1600 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.647
    Method
    lnear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.03
         upper limit
    0.64
    Statistical analysis title
    Adjusted mean difference in CFB, E-RS total score
    Statistical analysis description
    Analysis of change from baseline (CFB) to the entire treatment period in average E-RS total scores was based on a linear mixed model for repeated measures (MMRM) including treatment, inter-Visit period, treatment by inter-Visit period interaction and Pooled Country as fixed effects, and baseline value and baseline by inter-Visit period interaction as covariates. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo are presented.
    Comparison groups
    CHF 6001 2400 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.451
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.51
         upper limit
    1.14
    Statistical analysis title
    Adjusted mean difference in CFB, E-RS total score
    Statistical analysis description
    Analysis of change from baseline (CFB) to the entire treatment period in average E-RS total scores was based on a linear mixed model for repeated measures (MMRM) including treatment, inter-Visit period, treatment by inter-Visit period interaction and Pooled Country as fixed effects, and baseline value and baseline by inter-Visit period interaction as covariates. Adjusted mean differences (95% CIs) between the CHF 6001 treatments and Placebo are presented.
    Comparison groups
    CHF 6001 3200 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    380
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.737
    Method
    linear MMRM
    Parameter type
    Adjusted mean difference
    Point estimate
    0.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.68
         upper limit
    0.97

    Secondary: E-RS response

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    End point title
    E-RS response
    End point description
    Average E-RS total scores were recorded during the run-in period (baseline) and for each inter-visit period over the treatment period of 24 weeks. The proportion of patients with a decrease from baseline in average E-RS total score ≥ 2.0 were classed as responders; patients with a decrease from baseline in average E-RS total score < 2.0 units or with missing data for any inter-visit period were classed as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline (two-week run-in period) and inter-visit periods Week 1 to Week 3, Week 4 to Week 6, Week 7 to Week 12, Week 13 to Week 18 and Week 19 to Week 24.
    End point values
    CHF 6001 800 μg - ITT CHF 6001 1600 μg - ITT CHF 6001 2400 μg - ITT CHF 6001 3200 μg - ITT Budesonide 800 μg - ITT Placebo - ITT
    Number of subjects analysed
    190 [85]
    179 [86]
    188 [87]
    193 [88]
    187 [89]
    193 [90]
    Units: Patients
    number (not applicable)
        Week 1 to Week 3
    58
    65
    54
    58
    60
    62
        Week 4 to Week 6
    73
    82
    62
    82
    76
    73
        Week 7 to Week 12
    78
    86
    72
    87
    89
    81
        Week 13 to Week 18
    74
    84
    83
    77
    90
    93
        Week 19 to Week 24
    79
    94
    80
    82
    86
    89
    Notes
    [85] - ITT population
    [86] - ITT population
    [87] - ITT population
    [88] - ITT population
    [89] - ITT population
    [90] - ITT population
    No statistical analyses for this end point

    Secondary: Moderate and severe COPD exacerbation rate over 24 weeks of treatment

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    End point title
    Moderate and severe COPD exacerbation rate over 24 weeks of treatment
    End point description
    The rate of moderate or severe COPD exacerbations was evaluated over 24 weeks of treatment. Exacerbations were classified as moderate or severe as per European Medicines Agency (EMA)/Committee for Medicinal Products for Human Use (CHMP) guideline definitions. A moderate exacerbation was defined as a sustained worsening of the patient's condition that required treatment with systemic (oral/IV/IM) corticosteroids and/or antibiotics. A severe exacerbation was defined as one that required hospitalisation or resulted in death. The recognition of potential COPD exacerbations was optimised by the daily reporting of worsened symptoms through the EXAcerbations of Chronic pulmonary disease Tool - Patient Reported Outcome (EXACT-PRO) questionnaire.
    End point type
    Secondary
    End point timeframe
    Baseline to 24 weeks.
    End point values
    CHF 6001 800 μg - ITT CHF 6001 1600 μg - ITT CHF 6001 2400 μg - ITT CHF 6001 3200 μg - ITT Budesonide 800 μg - ITT Placebo - ITT
    Number of subjects analysed
    190 [91]
    179 [92]
    188 [93]
    193 [94]
    187 [95]
    193 [96]
    Units: Adjusted exacerbation rate/patient/year
        number (confidence interval 95%)
    0.563 (0.414 to 0.764)
    0.585 (0.428 to 0.799)
    0.593 (0.440 to 0.801)
    0.487 (0.351 to 0.675)
    0.415 (0.292 to 0.589)
    0.681 (0.514 to 0.902)
    Notes
    [91] - ITT population
    [92] - ITT population
    [93] - ITT population
    [94] - ITT population
    [95] - ITT population
    [96] - ITT population
    Statistical analysis title
    Adjusted exacerbation rate ratio
    Statistical analysis description
    The rate of moderate and severe COPD exacerbations over 24 weeks of treatment was analysed using a negative binomial model including treatment and sites pooled by country as factors and logarithm of time into the study as an offset. Adjusted rate ratios (95% CIs) for CHF 6001 treatments over Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 800 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    383
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.367
    Method
    Negative binomial model
    Parameter type
    Adjusted rate ratio
    Point estimate
    0.826
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.546
         upper limit
    1.251
    Statistical analysis title
    Adjusted exacerbation rate ratio
    Statistical analysis description
    The rate of moderate and severe COPD exacerbations over 24 weeks of treatment was analysed using a negative binomial model including treatment and sites pooled by country as factors and logarithm of time into the study as an offset. Adjusted rate ratios (95% CIs) for CHF 6001 treatments over Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 1600 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.479
    Method
    Negative binomial model
    Parameter type
    Adjusted rate ratio
    Point estimate
    0.859
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.565
         upper limit
    1.307
    Statistical analysis title
    Adjusted exacerbation rate ratio
    Statistical analysis description
    The rate of moderate and severe COPD exacerbations over 24 weeks of treatment was analysed using a negative binomial model including treatment and sites pooled by country as factors and logarithm of time into the study as an offset. Adjusted rate ratios (95% CIs) for CHF 6001 treatments over Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 2400 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.51
    Method
    Negative binomial model
    Parameter type
    Adjusted rate ratio
    Point estimate
    0.871
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.578
         upper limit
    1.313
    Statistical analysis title
    Adjusted exacerbation rate ratio
    Statistical analysis description
    The rate of moderate and severe COPD exacerbations over 24 weeks of treatment was analysed using a negative binomial model including treatment and sites pooled by country as factors and logarithm of time into the study as an offset. Adjusted rate ratios (95% CIs) for CHF 6001 treatments over Placebo estimated by the model are presented.
    Comparison groups
    CHF 6001 3200 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    386
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.127
    Method
    Negative binomial model
    Parameter type
    Adjusted rate ratio
    Point estimate
    0.715
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.465
         upper limit
    1.1

    Secondary: Time to first moderate or severe COPD exacerbation

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    End point title
    Time to first moderate or severe COPD exacerbation
    End point description
    The number of patients at risk of a moderate or severe COPD exacerbation is presented.
    End point type
    Secondary
    End point timeframe
    Baseline to 24 weeks
    End point values
    CHF 6001 800 μg - ITT CHF 6001 1600 μg - ITT CHF 6001 2400 μg - ITT CHF 6001 3200 μg - ITT Budesonide 800 μg - ITT Placebo - ITT
    Number of subjects analysed
    190 [97]
    179 [98]
    188 [99]
    193 [100]
    187 [101]
    193 [102]
    Units: Patients
        number (not applicable)
    37
    36
    42
    35
    32
    49
    Notes
    [97] - ITT population
    [98] - ITT population
    [99] - ITT population
    [100] - ITT population
    [101] - ITT population
    [102] - ITT population
    Statistical analysis title
    Hazard ratio - time to first exacerbation
    Statistical analysis description
    The time to first moderate or severe COPD exacerbation was analysed using Cox proportional hazard regression model including treatment and sites pooled by country as factors. The hazard ratios (95% CIs) for the CHF 6001 treatment groups (versus Placebo) are presented.
    Comparison groups
    CHF 6001 800 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    383
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Cox proportional hazard regression model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.731
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.477
         upper limit
    1.12
    Statistical analysis title
    Hazard ratio - time to first exacerbation
    Statistical analysis description
    The time to first moderate or severe COPD exacerbation was analysed using Cox proportional hazard regression model including treatment and sites pooled by country as factors. The hazard ratios (95% CIs) for the CHF 6001 treatment groups (versus Placebo) are presented.
    Comparison groups
    CHF 6001 1600 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Cox proportional hazard regression model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.768
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.499
         upper limit
    1.181
    Statistical analysis title
    Hazard ratio - time to first exacerbation
    Statistical analysis description
    The time to first moderate or severe COPD exacerbation was analysed using Cox proportional hazard regression model including treatment and sites pooled by country as factors. The hazard ratios (95% CIs) for the CHF 6001 treatment groups (versus Placebo) are presented.
    Comparison groups
    CHF 6001 2400 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Cox proportional hazard regression model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.829
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.549
         upper limit
    1.252
    Statistical analysis title
    Hazard ratio - time to first exacerbation
    Statistical analysis description
    The time to first moderate or severe COPD exacerbation was analysed using Cox proportional hazard regression model including treatment and sites pooled by country as factors. The hazard ratios (95% CIs) for the CHF 6001 treatment groups (versus Placebo) are presented.
    Comparison groups
    CHF 6001 3200 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    386
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Cox proportional hazard regression model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.693
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.449
         upper limit
    1.07

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were reported from the time of patient informed consent to study completion or discontinuation.
    Adverse event reporting additional description
    Treatment-emergent adverse events (TEAEs) were defined as AEs starting on or after the first randomised study medication intake.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    CHF 6001 800 μg - Safety
    Reporting group description
    The Safety population was defined as all randomised patients who received at least one dose of study medication.

    Reporting group title
    CHF 6001 1600 μg - Safety
    Reporting group description
    The Safety population was defined as all randomised patients who received at least one dose of the study medication.

    Reporting group title
    CHF 6001 2400 µg - Safety
    Reporting group description
    The Safety population was defined as all randomised patients who received at least one dose of the study medication.

    Reporting group title
    CHF 6001 3200 µg - Safety
    Reporting group description
    The Safety population was defined as all randomised patients who received at least one dose of the study medication.

    Reporting group title
    Budesonide 800 µg - Safety
    Reporting group description
    The Safety population was defined as all randomised patients who received at least one dose of the study medication.

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

    Serious adverse events
    CHF 6001 800 μg - Safety CHF 6001 1600 μg - Safety CHF 6001 2400 µg - Safety CHF 6001 3200 µg - Safety Budesonide 800 µg - Safety Placebo - Safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 190 (5.79%)
    13 / 179 (7.26%)
    12 / 188 (6.38%)
    7 / 193 (3.63%)
    10 / 187 (5.35%)
    7 / 193 (3.63%)
         number of deaths (all causes)
    1
    1
    1
    2
    0
    0
         number of deaths resulting from adverse events
    1
    1
    1
    2
    0
    0
    Vascular disorders
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 190 (0.00%)
    0 / 179 (0.00%)
    1 / 188 (0.53%)
    0 / 193 (0.00%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 190 (0.00%)
    0 / 179 (0.00%)
    0 / 188 (0.00%)
    0 / 193 (0.00%)
    1 / 187 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 190 (0.00%)
    0 / 179 (0.00%)
    0 / 188 (0.00%)
    1 / 193 (0.52%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 190 (0.00%)
    0 / 179 (0.00%)
    0 / 188 (0.00%)
    1 / 193 (0.52%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 190 (0.00%)
    0 / 179 (0.00%)
    0 / 188 (0.00%)
    0 / 193 (0.00%)
    1 / 187 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 179 (0.00%)
    0 / 188 (0.00%)
    0 / 193 (0.00%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 190 (0.00%)
    0 / 179 (0.00%)
    1 / 188 (0.53%)
    0 / 193 (0.00%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 179 (0.56%)
    0 / 188 (0.00%)
    0 / 193 (0.00%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 179 (0.56%)
    0 / 188 (0.00%)
    0 / 193 (0.00%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 179 (0.00%)
    0 / 188 (0.00%)
    0 / 193 (0.00%)
    0 / 187 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    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
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 190 (0.00%)
    0 / 179 (0.00%)
    1 / 188 (0.53%)
    0 / 193 (0.00%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 190 (0.00%)
    0 / 179 (0.00%)
    0 / 188 (0.00%)
    1 / 193 (0.52%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 179 (0.56%)
    0 / 188 (0.00%)
    1 / 193 (0.52%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 179 (0.56%)
    0 / 188 (0.00%)
    0 / 193 (0.00%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 179 (0.56%)
    0 / 188 (0.00%)
    0 / 193 (0.00%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    6 / 190 (3.16%)
    7 / 179 (3.91%)
    7 / 188 (3.72%)
    2 / 193 (1.04%)
    5 / 187 (2.67%)
    5 / 193 (2.59%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
    0 / 7
    0 / 2
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 179 (0.00%)
    0 / 188 (0.00%)
    0 / 193 (0.00%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 179 (0.00%)
    0 / 188 (0.00%)
    0 / 193 (0.00%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 179 (0.56%)
    0 / 188 (0.00%)
    1 / 193 (0.52%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal stenosis
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 179 (0.00%)
    0 / 188 (0.00%)
    0 / 193 (0.00%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 190 (0.00%)
    0 / 179 (0.00%)
    1 / 188 (0.53%)
    0 / 193 (0.00%)
    1 / 187 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 179 (0.56%)
    0 / 188 (0.00%)
    0 / 193 (0.00%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 179 (0.56%)
    0 / 188 (0.00%)
    0 / 193 (0.00%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Infections and infestations
    Infectious pleural effusion
         subjects affected / exposed
    0 / 190 (0.00%)
    0 / 179 (0.00%)
    0 / 188 (0.00%)
    0 / 193 (0.00%)
    1 / 187 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 190 (0.53%)
    1 / 179 (0.56%)
    1 / 188 (0.53%)
    0 / 193 (0.00%)
    1 / 187 (0.53%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia escherichia
         subjects affected / exposed
    0 / 190 (0.00%)
    0 / 179 (0.00%)
    1 / 188 (0.53%)
    0 / 193 (0.00%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 190 (0.00%)
    0 / 179 (0.00%)
    0 / 188 (0.00%)
    1 / 193 (0.52%)
    0 / 187 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3.5%
    Non-serious adverse events
    CHF 6001 800 μg - Safety CHF 6001 1600 μg - Safety CHF 6001 2400 µg - Safety CHF 6001 3200 µg - Safety Budesonide 800 µg - Safety Placebo - Safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    86 / 190 (45.26%)
    90 / 179 (50.28%)
    91 / 188 (48.40%)
    83 / 193 (43.01%)
    89 / 187 (47.59%)
    101 / 193 (52.33%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    42 / 190 (22.11%)
    41 / 179 (22.91%)
    54 / 188 (28.72%)
    43 / 193 (22.28%)
    39 / 187 (20.86%)
    58 / 193 (30.05%)
         occurrences all number
    68
    58
    66
    60
    56
    75
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 190 (5.26%)
    7 / 179 (3.91%)
    7 / 188 (3.72%)
    11 / 193 (5.70%)
    10 / 187 (5.35%)
    8 / 193 (4.15%)
         occurrences all number
    14
    8
    8
    15
    12
    10
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 190 (3.68%)
    14 / 179 (7.82%)
    11 / 188 (5.85%)
    12 / 193 (6.22%)
    9 / 187 (4.81%)
    13 / 193 (6.74%)
         occurrences all number
    10
    16
    11
    15
    10
    13

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Oct 2016
    There were three versions of the clinical study protocol. Version 1.0 was never used, and initial submissions were done with Version 2.0. Based on the Medicines and Healthcare products Regulatory Agency (MHRA) comments, there was one substantial protocol amendment, with the following main changes implemented further to the initial protocol version: - The thyroid function tests were added at the screening visit to confirm the exclusion of the uncontrolled thyroid disease as per exclusion criterion #16; - Monitoring of psychiatric adverse events was specified (including update of the physical examination section). The first Competent Authority approval of Version 3.0 was received on 27 October 2016.

    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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