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    Clinical Trial Results:
    A 52-week, double-blind, randomized, multinational, multicentre, 2-arm parallel-group, active-controlled clinical trial of fixed combination of beclometasone dipropionate plus formoterol fumarate plus glycopyrrolate bromide administered via pMDI (CHF 5993) versus fixed combination of beclometasone dipropionate plus formoterol fumarate administered via pMDI in patients with chronic obstructive pulmonary disease

    Summary
    EudraCT number
    2013-001057-27
    Trial protocol
    GB   BE   HU   DE   IT   CZ   SK   PL   BG  
    Global end of trial date
    14 Jan 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Feb 2017
    First version publication date
    10 Feb 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-1207-PR-0091
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01917331
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    TRILOGY: TRILOGY
    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
    23 May 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • Demonstrate superiority of CHF 5993 pMDI over CHF 1535 pMDI in terms of lung function (change from baseline in pre-dose and 2-hour post-dose morning FEV1 at Week 26). • Demonstrate superiority of CHF 5993 pMDI over CHF 1535 pMDI in terms of dyspnea (Transition Dyspnea Index focal score at Week 26). CHF 5993 = Fixed combination of BDP and FF and GB CHF 1535=Fixed combination of BDP and FF BDP = Beclomethasone dipropionate COPD=Chronic obstructive pulmonary disease FF=Formoterol fumarate GB=Glycopyrronium bromide pMDI=Pressurised metered dose inhaler
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practices (GCP) guidelines, and national legal requirements. At all visits, from screening onward, concomitant medications, adverse events and vital signs were recorded, COPD exacerbations were assessed and 12-lead electrocardiogram (ECG) and physical examinations were performed. Treatment compliance was evaluated on the basis of the information recorded daily by the patient on the digital platform.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 53
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Romania: 105
    Country: Number of subjects enrolled
    Russian Federation: 320
    Country: Number of subjects enrolled
    Ukraine: 224
    Country: Number of subjects enrolled
    Poland: 113
    Country: Number of subjects enrolled
    Slovakia: 33
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Bulgaria: 92
    Country: Number of subjects enrolled
    Czech Republic: 208
    Country: Number of subjects enrolled
    Germany: 63
    Country: Number of subjects enrolled
    Hungary: 103
    Country: Number of subjects enrolled
    Italy: 23
    Worldwide total number of subjects
    1368
    EEA total number of subjects
    767
    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)
    739
    From 65 to 84 years
    627
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    Overall, 1812 patients were screened according to inclusion and exclusion criteria; of these 1368 patients were randomized.

    Pre-assignment
    Screening details
    Pre-screening visit was at most 1 week before the screening visit when inclusion/exclusion criteria were assessed and the run-in period of 2 weeks started. During the run-in period patients stopped their current treatment and received an open-label CHF 1535 pMDI to take as 2 puffs bid for 2 weeks (BDP 400 μg/FF 24 μg daily).

    Period 1
    Period 1 title
    Overall trial (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
    Interactive Response Technology was used to assign study medication kits in order to have an inventory control and patient dosing tracking. In addition, the IRT maintained quantities, kit numbers, drug types,batch/code number, expiration dates and it monitored inventory levels at all sites and managed the drug re-supply. The canisters/actuators of CHF 5993 pMDI and CHF 1535 pMDI were of identical appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment A - fixed combination CHF 5993 100/6/12.5μg
    Arm description
    Treatment A: CHF 5993 pMDI: Patients followed a schedule of 2 puffs of CHF 5993 100/6/12.5 μg bid. Therefore, the total daily dose was BDP/FF/GB 400/24/50 μg; BDP=Beclomethasone dipropionate GB=Glycopyrronium bromide FF=Formoterol fumarate CHF 5993 pMDI=Fixed combination of BDP 50μg, FF 6 μg, GB 12.5µg per metered dose
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 5993 100/6/12.5 μg
    Investigational medicinal product code
    Other name
    BDP/FF/GB, Fixed combination of beclomethasone dipropionate, formoterol fumarate, Glycopyrronium bromide
    Pharmaceutical forms
    Pressurised inhalation, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Dose: BDP 100 μg, FF 6 μg, GB 12.5 μg per actuation, 2 puffs bid (twice daily). Total daily dose: BDP 400 μg, FF 24 μg, GB 50 μg. Mode of administration: pMDI using a standard actuator. If patients inhaled their usual COPD pMDI treatments with a spacer device, they were provided with the AeroChamber Plus™ to be used when taking the pMDI study treatments.

    Arm title
    Treatment B - fixed combination CHF 1535 100/6μg
    Arm description
    Treatment B: CHF 1535 pMDI: Patients followed a schedule of 2 puffs of CHF 1535 100/6 μg bid. Therefore, the total daily dose was BDP/FF 400/24 μg. BDP=Beclomethasone dipropionate FF=Formoterol fumarate CHF 1535 pMDI=Fixed combination of BDP 100μg, FF 6 μg,
    Arm type
    Active comparator

    Investigational medicinal product name
    CHF 1535 100/6 μg
    Investigational medicinal product code
    Other name
    BDP/FF, Fixed combination of beclomethasone dipropionate and formoterol fumarate
    Pharmaceutical forms
    Pressurised inhalation, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Dose: BDP 100 μg, FF 6 μg per actuation, 2 puffs bid. (twice daily). Total daily dose: BDP 400 μg, FF 24 μg. Mode of administration: pMDI using a standard actuator. If patients inhaled their usual COPD pMDI treatments with a spacer device, they were provided with the AeroChamber Plus™ to be used when taking the pMDI study treatments.

    Number of subjects in period 1
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Started
    687
    681
    Completed
    602
    579
    Not completed
    85
    102
         Protocol deviation
    2
    3
         Other
    -
    2
         Lack of efficacy
    3
    6
         Adverse event, serious fatal
    13
    15
         Adverse event, non-fatal
    20
    17
         Consent withdrawn by subject
    45
    54
         Lost to follow-up
    2
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment A - fixed combination CHF 5993 100/6/12.5μg
    Reporting group description
    Treatment A: CHF 5993 pMDI: Patients followed a schedule of 2 puffs of CHF 5993 100/6/12.5 μg bid. Therefore, the total daily dose was BDP/FF/GB 400/24/50 μg; BDP=Beclomethasone dipropionate GB=Glycopyrronium bromide FF=Formoterol fumarate CHF 5993 pMDI=Fixed combination of BDP 50μg, FF 6 μg, GB 12.5µg per metered dose

    Reporting group title
    Treatment B - fixed combination CHF 1535 100/6μg
    Reporting group description
    Treatment B: CHF 1535 pMDI: Patients followed a schedule of 2 puffs of CHF 1535 100/6 μg bid. Therefore, the total daily dose was BDP/FF 400/24 μg. BDP=Beclomethasone dipropionate FF=Formoterol fumarate CHF 1535 pMDI=Fixed combination of BDP 100μg, FF 6 μg,

    Reporting group values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg Total
    Number of subjects
    687 681 1368
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    391 348 739
        From 65-84 years
    295 332 627
        85 years and over
    1 1 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.3 ± 7.9 63.8 ± 8.2 -
    Gender categorical
    Units: Subjects
        Female
    178 154 332
        Male
    509 527 1036
    Race
    Units: Subjects
        Other
    3 1 4
        White
    684 680 1364

    End points

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    End points reporting groups
    Reporting group title
    Treatment A - fixed combination CHF 5993 100/6/12.5μg
    Reporting group description
    Treatment A: CHF 5993 pMDI: Patients followed a schedule of 2 puffs of CHF 5993 100/6/12.5 μg bid. Therefore, the total daily dose was BDP/FF/GB 400/24/50 μg; BDP=Beclomethasone dipropionate GB=Glycopyrronium bromide FF=Formoterol fumarate CHF 5993 pMDI=Fixed combination of BDP 50μg, FF 6 μg, GB 12.5µg per metered dose

    Reporting group title
    Treatment B - fixed combination CHF 1535 100/6μg
    Reporting group description
    Treatment B: CHF 1535 pMDI: Patients followed a schedule of 2 puffs of CHF 1535 100/6 μg bid. Therefore, the total daily dose was BDP/FF 400/24 μg. BDP=Beclomethasone dipropionate FF=Formoterol fumarate CHF 1535 pMDI=Fixed combination of BDP 100μg, FF 6 μg,

    Primary: 1_Change from baseline in pre-dose morning FEV1 at week 26

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    End point title
    1_Change from baseline in pre-dose morning FEV1 at week 26
    End point description
    FEV1=Forced expiratory volume in the 1st second. It is the volume of air that can be forced out in one second after taking a deep breath.
    End point type
    Primary
    End point timeframe
    Baseline to Week 26.
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    642 [1]
    616 [2]
    Units: litre(s)
        least squares mean (confidence interval 95%)
    0.082 (0.062 to 0.102)
    0.001 (-0.019 to 0.021)
    Notes
    [1] - ITT population; Change from baseline available;
    [2] - ITT population; Change from baseline available;
    Statistical analysis title
    Adjusted mean difference between treatment groups
    Comparison groups
    Treatment B - fixed combination CHF 1535 100/6μg v Treatment A - fixed combination CHF 5993 100/6/12.5μg
    Number of subjects included in analysis
    1258
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.001
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.081
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.052
         upper limit
    0.109
    Notes
    [3] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and baseline value and baseline by visit interaction as covariates. Treatment A (CHF 5993 pMDI) - Treatment B (CHF 1535 pMDI)

    Primary: 2_Change from baseline to 2-hour post-dose value of FEV1 at Week 26

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    End point title
    2_Change from baseline to 2-hour post-dose value of FEV1 at Week 26
    End point description
    Change from baseline to 2-hour post-dose value of FEV1 at Week 26.
    End point type
    Primary
    End point timeframe
    Baseline to 2-hour post-dose at Week 26.
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    631 [4]
    609 [5]
    Units: litre(s)
        least squares mean (confidence interval 95%)
    0.261 (0.24 to 0.283)
    0.145 (0.123 to 0.166)
    Notes
    [4] - ITT population; Change from baseline available;
    [5] - ITT population; Change from baseline available;
    Statistical analysis title
    Adjusted mean difference between treatment groups
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1240
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    < 0.001
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.117
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.086
         upper limit
    0.147
    Notes
    [6] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, Country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and baseline value and baseline by visit interaction as covariates. Treatment A (CHF 5993 pMDI) - Treatment B (CHF 1535 pMDI)

    Primary: 3_TDI focal score at Week 26

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    End point title
    3_TDI focal score at Week 26
    End point description
    TDI focal score is a symptom-based variable, used to assess breathlessness and the impact of intervention. The BDI/TDI is a clinical rating method based on a validated instrument, developed to measure the impact of dyspnoea on three domains: functional impairment, magnitude of task, and magnitude of effort. The BDI scores range from 0 (very severe impairment) to 4 (no impairment) for each domain with the baseline focal score consisting of the sum of each domain (i.e. from 0 to 12). Change from baseline in dyspnoea severity was measured using the TDI. TDI score ranges from -3 (major deterioration) to +3 (major improvement) for each domain with the TDI focal score consisting in the sum of each domain (i.e. from -9 to +9). BDI and TDI are based on validated questionnaires. BDI focal score is the baseline value from which TDI focal score is assessed. BDI=Baseline Dyspnoea Index TDI=Transition Dyspnoea Index
    End point type
    Primary
    End point timeframe
    Baseline to Week 26.
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    642 [7]
    619 [8]
    Units: score
        least squares mean (confidence interval 95%)
    1.71 (1.5 to 1.92)
    1.5 (1.29 to 1.71)
    Notes
    [7] - ITT population; Change from baseline available;
    [8] - ITT population; Change from baseline available;
    Statistical analysis title
    Adjusted mean difference between treatment groups
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1261
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.16
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.08
         upper limit
    0.51
    Notes
    [9] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and baseline value and baseline by visit interaction as covariates. Treatment A (CHF 5993 pMDI) - Treatment B (CHF 1535 pMDI)

    Secondary: 4_Change from baseline in pre-dose morning FEV1 at all study visits

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    End point title
    4_Change from baseline in pre-dose morning FEV1 at all study visits
    End point description
    Change from baseline in pre-dose morning FEV1 at all study visits. Shown are the number of subjects included in the model and the number of subjects with available results at the indicated week (Wk).
    End point type
    Secondary
    End point timeframe
    Baseline and each study visit (Week 4, 12, 26, 40, 52).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    681 [10]
    670 [11]
    Units: litre(s)
    least squares mean (confidence interval 95%)
        Week 4
    0.093 (0.076 to 0.109)
    0.022 (0.005 to 0.039)
        Week 12
    0.078 (0.06 to 0.096)
    0.01 (-0.008 to 0.028)
        Week 26
    0.082 (0.062 to 0.102)
    0.001 (-0.019 to 0.021)
        Week 40
    0.095 (0.073 to 0.116)
    0.018 (-0.004 to 0.04)
        Week 52
    0.071 (0.05 to 0.093)
    0.008 (-0.014 to 0.03)
    Notes
    [10] - ITT population (analysed) Wk 04 n=679 Wk 12 n=660 Wk 26 n=642 Wk 40 n=622 Wk 52 n=606
    [11] - ITT population (analysed) Wk 04 n=669 Wk 12 n=654 Wk 26 n=616 Wk 40 n=597 Wk 52 n=578
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 4
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 4. The number of subjects in this analysis shown (1351) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects in this analysis with available data is 1348: n (CHF 5993 pMDI)=679 n (CHF 1535 pMDI)=669
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [12]
    P-value
    < 0.001
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.071
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.047
         upper limit
    0.094
    Notes
    [12] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates. CHF 5993 pMDI - CHF 1535 pMDI
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 12
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 12. The number of subjects in this analysis shown (1351) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects in this analysis with available data is 1314: n (CHF 5993 pMDI)=660 n (CHF 1535 pMDI)=654
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    < 0.001
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.068
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.042
         upper limit
    0.094
    Notes
    [13] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates. CHF 5993 pMDI - CHF 1535 pMDI
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 26
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 26. The number of subjects in this analysis shown (1351) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects in this analysis with available data is 1258: n (CHF 5993 pMDI)=642 n (CHF 1535 pMDI)=616
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [14]
    P-value
    < 0.001
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.081
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.052
         upper limit
    0.109
    Notes
    [14] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates. CHF 5993 pMDI - CHF 1535 pMDI
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 40
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 40. The number of subjects in this analysis shown (1351) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects in this analysis with available data is 1219: n (CHF 5993 pMDI)=622 n (CHF 1535 pMDI)=597
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    < 0.001
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.077
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.046
         upper limit
    0.108
    Notes
    [15] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates. CHF 5993 pMDI - CHF 1535 pMDI
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 52
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 52. The number of subjects in this analysis shown (1351) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects in this analysis with available data is 1184: n (CHF 5993 pMDI)=606 n (CHF 1535 pMDI)=578
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [16]
    P-value
    < 0.001
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.063
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.032
         upper limit
    0.094
    Notes
    [16] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates. CHF 5993 pMDI - CHF 1535 pMDI

    Secondary: 5_Change from baseline to the average over the treatment period in pre-dose morning FEV1

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    End point title
    5_Change from baseline to the average over the treatment period in pre-dose morning FEV1
    End point description
    Change from baseline to the average over the treatment period in pre-dose morning FEV1. Shown are the number of subjects included in the model and the number of subjects with available results at the indicated week (Wk).
    End point type
    Secondary
    End point timeframe
    Baseline to the overall treatment period (Week 4 to Week 52).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    681 [17]
    670 [18]
    Units: litre(s)
        least squares mean (confidence interval 95%)
    0.084 (0.067 to 0.1)
    0.012 (-0.005 to 0.029)
    Notes
    [17] - ITT population; Change from baseline available;
    [18] - ITT population; Change from baseline available;
    Statistical analysis title
    Adjusted mean difference between treatment groups.
    Statistical analysis description
    Adjusted mean difference between treatment groups.
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    < 0.001
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.072
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.048
         upper limit
    0.096
    Notes
    [19] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and baseline value and baseline by visit interaction as covariates. CHF 5993 pMDI - CHF 1535 pMDI

    Secondary: 6_FEV1 response (change from baseline in pre-dose morning FEV1 ≥100 mL) at Week 26 and Week 52

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    End point title
    6_FEV1 response (change from baseline in pre-dose morning FEV1 ≥100 mL) at Week 26 and Week 52
    End point description
    FEV1 response is defined as a change from baseline in pre-dose morning FEV1 ≥100 mL. If the change from baseline was <100 mL, the patient was classed as a non-responder in terms of FEV1. Subjects with missing pre-dose morning FEV1 value at the relevant time points were also classified as non-responders. Results are shown as the number of responders for the comparison of CHF 5993 pMDI vs CHF 1535 pMDI.
    End point type
    Secondary
    End point timeframe
    Baseline to study visit at Week 26, Week 52.
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    687 [20]
    680 [21]
    Units: subject
        Week 26
    287
    165
        Week 52
    259
    158
    Notes
    [20] - ITT population
    [21] - ITT population
    Statistical analysis title
    Btw grp analysis, change in FEV1 ≥100 mL, Wk 26
    Statistical analysis description
    Between group analysis (change from baseline in pre-dose morning FEV1 ≥100 mL, Week 26). CHF 5993 pMDI / CHF 1535 pMDI
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [22]
    P-value
    < 0.001
    Method
    Logistic model
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.299
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.817
         upper limit
    2.91
    Notes
    [22] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors and the baseline FEV1 value as a covariate.
    Statistical analysis title
    Btw grp analysis, change in FEV1 ≥100 mL, Wk 52
    Statistical analysis description
    Between group analysis (change from baseline in pre-dose morning FEV1 ≥100 mL, Week 52). CHF 5993 pMDI / CHF 1535 pMDI
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    < 0.001
    Method
    Logistic model
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.061
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.621
         upper limit
    2.62
    Notes
    [23] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors and the baseline FEV1 value as a covariate.

    Secondary: 7_Change from baseline to 2-hour post-dose value of FEV1 at all study visits

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    End point title
    7_Change from baseline to 2-hour post-dose value of FEV1 at all study visits
    End point description
    Change from baseline to 2-hour post-dose value of FEV1 at all study visits. Shown are the number of subjects included in the model and the number of subjects with available results at the indicated week (Wk).
    End point type
    Secondary
    End point timeframe
    Baseline to 2-hour post-dose at each study visit (Week 0, 4, 12, 26, 40, 52).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    686 [24]
    679 [25]
    Units: litre(s)
    least squares mean (confidence interval 95%)
        Week 0
    0.215 (0.203 to 0.228)
    0.138 (0.126 to 0.15)
        Week 4
    0.268 (0.25 to 0.286)
    0.153 (0.135 to 0.171)
        Week 12
    0.261 (0.241 to 0.281)
    0.146 (0.125 to 0.166)
        Week 26
    0.261 (0.24 to 0.283)
    0.145 (0.123 to 0.166)
        Week 40
    0.253 (0.23 to 0.275)
    0.15 (0.127 to 0.174)
        Week 52
    0.249 (0.226 to 0.273)
    0.146 (0.122 to 0.17)
    Notes
    [24] - ITT population (analysed) W 0 n=683 W 4 n=675 W 12 n=657 W 26 n=631 W 40 n=615 W 52 n=598
    [25] - ITT population (analysed) W 0 n=674 W 4 n=660 W 12 n=648 W 26 n=609 W 40 n=590 W 52 n=575
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 0
    Statistical analysis description
    Adjusted mean differences between treatments in 2-hour post-dose FEV1 at Week 0. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1365) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1357: n (CHF 5993 p65) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below.
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1365
    Analysis specification
    Pre-specified
    Analysis type
    superiority [26]
    P-value
    < 0.001
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.077
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.06
         upper limit
    0.095
    Notes
    [26] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 4
    Statistical analysis description
    Adjusted mean differences between treatments in 2-hour post-dose FEV1 at Week 4. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1365) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1335: n (CHF 5993 pMDI)=675 n (CHF 1535 pMDI)=660
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1365
    Analysis specification
    Pre-specified
    Analysis type
    superiority [27]
    P-value
    < 0.001
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.116
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.09
         upper limit
    0.141
    Notes
    [27] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 12
    Statistical analysis description
    Adjusted mean differences between treatments in 2-hour post-dose FEV1 at Week 12. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1365) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1305: n (CHF 5993 pMDI)=657 n (CHF 1535 pMDI)=648
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1365
    Analysis specification
    Pre-specified
    Analysis type
    superiority [28]
    P-value
    < 0.001
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.116
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.087
         upper limit
    0.144
    Notes
    [28] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 26
    Statistical analysis description
    Adjusted mean differences between treatments in 2-hour post-dose FEV1 at Week 26. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1365) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1240: n (CHF 5993 pMDI)=631 n (CHF 1535 pMDI)=609
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1365
    Analysis specification
    Pre-specified
    Analysis type
    superiority [29]
    P-value
    < 0.001
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.117
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.086
         upper limit
    0.147
    Notes
    [29] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 40
    Statistical analysis description
    Adjusted mean differences between treatments in 2-hour post-dose FEV1 at Week 40. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1365) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1205: n (CHF 5993 pMDI)=615 n (CHF 1535 pMDI)=590
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1365
    Analysis specification
    Pre-specified
    Analysis type
    superiority [30]
    P-value
    < 0.001
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.102
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.07
         upper limit
    0.135
    Notes
    [30] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 52
    Statistical analysis description
    Adjusted mean differences between treatments in 2-hour post-dose FEV1 at Week 52. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1365) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1173: n (CHF 5993 pMDI)=598 n (CHF 1535 pMDI)=575
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1365
    Analysis specification
    Pre-specified
    Analysis type
    superiority [31]
    P-value
    < 0.001
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.103
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.069
         upper limit
    0.137
    Notes
    [31] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

    Secondary: 8_Change from pre-dose to 2-hour post-dose value of FEV1 at all study visits

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    End point title
    8_Change from pre-dose to 2-hour post-dose value of FEV1 at all study visits
    End point description
    Change from pre-dose to 2-hour post-dose value of FEV1 at all study visits. The number of patients shown represents the ITT population; change from baseline for available patients at the specified week (Wk) for the comparison of CHF 5993 pMDI vs CHF 1535 pMDI. Shown are the number of subjects included in the ITT population and the number of subjects with available results at the indicated week (Wk).
    End point type
    Secondary
    End point timeframe
    Pre-dose to 2-hour post-dose at each study visit (Week 4, 12, 26, 40, 52).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    687 [32]
    680 [33]
    Units: litre(s)
    least squares mean (confidence interval 95%)
        Week 4
    0.177 (0.165 to 0.189)
    0.13 (0.118 to 0.143)
        Week 12
    0.183 (0.171 to 0.194)
    0.138 (0.126 to 0.149)
        Week 26
    0.18 (0.169 to 0.192)
    0.149 (0.138 to 0.161)
        Week 40
    0.159 (0.147 to 0.171)
    0.138 (0.125 to 0.15)
        Week 52
    0.18 (0.167 to 0.193)
    0.146 (0.133 to 0.159)
    Notes
    [32] - ITT population Wk 04 n=674 Wk 12 n=658 Wk 26 n=632 Wk 40 n=616 Wk 52 n=599
    [33] - ITT population Wk 04 n=661 Wk 12 n=648 Wk 26 n=610 Wk 40 n=591 Wk 52 n=575
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 4
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 4. The number of subjects in this analysis shown (1367) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1355. n (CHF 5993 pMDI)=674 n (CHF 1535 pMDI)=661 CHF 5993 pMDI vs CHF 1535 pMDI
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [34]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0.046
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.029
         upper limit
    0.064
    Notes
    [34] - Analysis is based on an ANCOVA model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and the pre-dose value at the visit as a covariate.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 12
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 12. The number of subjects in this analysis shown (1367) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1306. n (CHF 5993 pMDI)=658 n (CHF 1535 pMDI)=648 CHF 5993 pMDI vs CHF 1535 pMDI
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [35]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0.045
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.029
         upper limit
    0.062
    Notes
    [35] - Analysis is based on an ANCOVA model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and the pre-dose value at the visit as a covariate.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 26
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 26. The number of subjects in this analysis shown (1367) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1242. n (CHF 5993 pMDI)=632 n (CHF 1535 pMDI)=610 CHF 5993 pMDI vs CHF 1535 pMDI
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [36]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0.031
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.015
         upper limit
    0.047
    Notes
    [36] - Analysis is based on an ANCOVA model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and the pre-dose value at the visit as a covariate.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 40
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 40. The number of subjects in this analysis shown (1367) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1207. n (CHF 5993 pMDI)=616 n (CHF 1535 pMDI)=591 CHF 5993 pMDI vs CHF 1535 pMDI
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [37]
    P-value
    = 0.013
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0.022
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.005
         upper limit
    0.039
    Notes
    [37] - Analysis is based on an ANCOVA model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and the pre-dose value at the visit as a covariate.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 52
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 52. The number of subjects in this analysis shown (1367) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1174. n (CHF 5993 pMDI)=599 n (CHF 1535 pMDI)=575 CHF 5993 pMDI vs CHF 1535 pMDI
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [38]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0.034
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.016
         upper limit
    0.052
    Notes
    [38] - Analysis is based on an ANCOVA model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and the pre-dose value at the visit as a covariate.

    Secondary: 9_TDI focal score at all study visits

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    End point title
    9_TDI focal score at all study visits
    End point description
    TDI focal score is a symptom-based variable, used to assess breathlessness and the impact of intervention. The BDI/TDI is a clinical rating method based on a validated instrument, developed to measure the impact of dyspnoea on three domains: functional impairment, magnitude of task, and magnitude of effort. The BDI scores range from 0 (very severe impairment) to 4 (no impairment) for each domain with the baseline focal score consisting of the sum of each domain (i.e. from 0 to 12). Change from baseline in dyspnoea severity was measured using the TDI. TDI score ranges from -3 (major deterioration) to +3 (major improvement) for each domain with the TDI focal score consisting in the sum of each domain (i.e. from -9 to +9). BDI and TDI are based on validated questionnaires. BDI focal score is the baseline value from which TDI focal score is assessed. BDI=Baseline Dyspnoea Index TDI=Transition Dyspnoea Index
    End point type
    Secondary
    End point timeframe
    Baseline and each study visit (Week 4, 12, 26, 40, 52).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    687 [39]
    680 [40]
    Units: score
    least squares mean (confidence interval 95%)
        Week 4
    1.54 (1.35 to 1.72)
    1.12 (0.94 to 1.31)
        Week 12
    1.77 (1.58 to 1.97)
    1.39 (1.19 to 1.58)
        Week 26
    1.71 (1.5 to 1.92)
    1.5 (1.29 to 1.71)
        Week 40
    1.8 (1.58 to 2.01)
    1.65 (1.43 to 1.86)
        Week 52
    2.03 (1.81 to 2.25)
    1.81 (1.59 to 2.04)
    Notes
    [39] - ITT population (analysed) Wk 04 n=680 Wk 12 n=661 Wk 26 n=642 Wk 40 n=622 Wk 52 n=608
    [40] - ITT population (analysed) Wk 04 n=672 Wk 12 n=651 Wk 26 n=619 Wk 40 n=596 Wk 52 n=579
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 4
    Statistical analysis description
    Adjusted mean differences between treatments for TDI focal score at Week 4. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1367) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1352: n (CHF 5993 pMDI)=680 n (CHF 1535 pMDI)=672
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [41]
    P-value
    = 0.002
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.15
         upper limit
    0.68
    Notes
    [41] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 12
    Statistical analysis description
    Adjusted mean differences between treatments for TDI focal score at Week 12. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1367) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1312: n (CHF 5993 pMDI)=661 n (CHF 1535 pMDI)=651
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [42]
    P-value
    = 0.007
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.11
         upper limit
    0.66
    Notes
    [42] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 26
    Statistical analysis description
    Adjusted mean differences between treatments for TDI focal score at Week 26. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1367) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1261: n (CHF 5993 pMDI)=642 n (CHF 1535 pMDI)=619
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [43]
    P-value
    = 0.16
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.08
         upper limit
    0.51
    Notes
    [43] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 40
    Statistical analysis description
    Adjusted mean differences between treatments for TDI focal score at Week 40. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1367) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1218: n (CHF 5993 pMDI)=622 n (CHF 1535 pMDI)=596
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [44]
    P-value
    = 0.343
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.16
         upper limit
    0.45
    Notes
    [44] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 52
    Statistical analysis description
    Adjusted mean differences between treatments for TDI focal score at Week 52. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1367) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1187: n (CHF 5993 pMDI)=608 n (CHF 1535 pMDI)=579
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [45]
    P-value
    = 0.186
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.53
    Notes
    [45] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

    Secondary: 10_TDI response (focal score ≥1) at Week 26 and Week 52

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    End point title
    10_TDI response (focal score ≥1) at Week 26 and Week 52
    End point description
    TDI response is defined as a TDI focal score ≥1. If the TDI focal score was <1, the patient was classified as a non-responder in terms of TDI. Patients with missing TDI focal score at the relevant time points were also classed as non-responders. Results are shown as the number of responders for the comparison of CHF 5993 pMDI vs CHF 1535 pMDI. TDI=Transition Dyspnoea Index
    End point type
    Secondary
    End point timeframe
    Week 26, Week 52.
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    687 [46]
    680 [47]
    Units: subjects
        Week 26
    394
    352
        Week 52
    370
    354
    Notes
    [46] - ITT population
    [47] - ITT population
    Statistical analysis title
    Between group analysis (TDI score ≥1, Week 26)
    Statistical analysis description
    Between treatment group analysis for subjects with a TDI focal score ≥1 at Week 26. CHF 5993 pMDI vs CHF 1535 pMDI
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [48]
    P-value
    = 0.027
    Method
    Logistic model
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.029
         upper limit
    1.594
    Notes
    [48] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as factors and the baseline TDI focal score value as a covariate.
    Statistical analysis title
    Between group analysis (TDI score ≥1, Week 52)
    Statistical analysis description
    Between treatment group analysis for subjects with a TDI focal score ≥1 at Week 52. CHF 5993 pMDI vs CHF 1535 pMDI
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [49]
    P-value
    = 0.43
    Method
    Logistic model
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.093
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.877
         upper limit
    1.362
    Notes
    [49] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as factors and the baseline TDI focal score value as a covariate.

    Secondary: 11_Change from baseline in Saint George’s respiratory questionnaire (SGRQ) at all study visits: Total Score

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    End point title
    11_Change from baseline in Saint George’s respiratory questionnaire (SGRQ) at all study visits: Total Score
    End point description
    SGRQ Total Score. SGRQ is a questionnaire developed to measure health in chronic airflow limitation. SGRQ questionnaire was completed by the patient at all study visits (Week 0 baseline, 4, 12, 26, 40, 52). In this study, the Total Score for SGRQ was calculated, whereby lower scores correspond to better health. Moreover, 3 component scores of SGRQ were calculated: Symptoms, Activity, and Impacts on daily life. Change from baseline in SGRQ Total Score was calculated and presented for this end point. Shown are the number of subjects included in the model and the number of subjects with available results at the indicated week (Wk). SGRQ=Saint George’s respiratory questionnaire
    End point type
    Secondary
    End point timeframe
    Baseline and each study visit (Week 4, 12, 26, 40, 52).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    658 [50]
    644 [51]
    Units: score
    least squares mean (confidence interval 95%)
        Week 4
    -3.66 (-4.41 to -2.91)
    -2.19 (-2.96 to -1.43)
        Week 12
    -4.7 (-5.58 to -3.81)
    -2.66 (-3.55 to -1.77)
        Week 26
    -4.76 (-5.69 to -3.83)
    -3.43 (-4.38 to -2.47)
        Week 40
    -5.48 (-6.49 to -4.47)
    -4.08 (-5.11 to -3.05)
        Week 52
    -5.12 (-6.18 to -4.06)
    -3.43 (-4.51 to -2.35)
    Notes
    [50] - ITT population (analysed) Wk 04 n=628 Wk 12 n=601 Wk 26 n=594 Wk 40 n=572 Wk 52 n=559
    [51] - ITT population (analysed) Wk 04 n=607 Wk 12 n=597 Wk 26 n=558 Wk 40 n=545 Wk 52 n=532
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 4
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 4. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1302) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1235: n (CHF 5993 pMDI)=628 n (CHF 1535 pMDI)=607
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1302
    Analysis specification
    Pre-specified
    Analysis type
    superiority [52]
    P-value
    = 0.007
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -1.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.54
         upper limit
    -0.39
    Notes
    [52] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 12
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 12. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1302) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1198: n (CHF 5993 pMDI)=601 n (CHF 1535 pMDI)=597
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1302
    Analysis specification
    Pre-specified
    Analysis type
    superiority [53]
    P-value
    = 0.002
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -2.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.3
         upper limit
    -0.78
    Notes
    [53] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 26
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 26. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1302) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1152: n (CHF 5993 pMDI)=594 n (CHF 1535 pMDI)=558
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1302
    Analysis specification
    Pre-specified
    Analysis type
    superiority [54]
    P-value
    = 0.051
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -1.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.66
         upper limit
    0.01
    Notes
    [54] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 40
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 40. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1302) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1117: n (CHF 5993 pMDI)=572 n (CHF 1535 pMDI)=545
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1302
    Analysis specification
    Pre-specified
    Analysis type
    superiority [55]
    P-value
    = 0.057
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.85
         upper limit
    0.04
    Notes
    [55] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 52
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 52. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1302) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1091: n (CHF 5993 pMDI)=559 n (CHF 1535 pMDI)=532
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1302
    Analysis specification
    Pre-specified
    Analysis type
    superiority [56]
    P-value
    = 0.029
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -1.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.2
         upper limit
    -0.17
    Notes
    [56] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

    Secondary: 12_Change from baseline in Saint George’s respiratory questionnaire (SGRQ) at all study visits: Symptoms Score

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    End point title
    12_Change from baseline in Saint George’s respiratory questionnaire (SGRQ) at all study visits: Symptoms Score
    End point description
    SGRQ Symptoms Score. SGRQ is a questionnaire developed to measure health in chronic airflow limitation. SGRQ questionnaire was completed by the patient at all study visits (Week 0 baseline, 4, 12, 26, 40, 52). In this study, the Total Score for SGRQ was calculated, whereby lower scores correspond to better health. Moreover, 3 component scores of SGRQ were calculated: Symptoms, Activity, and Impacts on daily life. Change from baseline in SGRQ Symptoms Score was calculated and presented for this end point. Shown are the number of subjects included in the model and the number of subjects with available results at the indicated week (Wk). SGRQ=Saint George’s respiratory questionnaire
    End point type
    Secondary
    End point timeframe
    Baseline and each study visit (Week 4, 12, 26, 40, 52).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    674 [57]
    664 [58]
    Units: score
    least squares mean (confidence interval 95%)
        Week 4
    -5.02 (-6.1 to -3.95)
    -3.83 (-4.92 to -2.75)
        Week 12
    -5.09 (-6.29 to -3.89)
    -4.56 (-5.77 to -3.34)
        Week 26
    -6.8 (-8.06 to -5.53)
    -5.17 (-6.46 to -3.88)
        Week 40
    -8.35 (-9.73 to -6.96)
    -7.12 (-8.53 to -5.71)
        Week 52
    -8.22 (-9.67 to -6.77)
    -7.26 (-8.74 to -5.78)
    Notes
    [57] - ITT population (analysed) Wk 04 n=652 Wk 12 n=636 Wk 26 n=620 Wk 40 n=601 Wk 52 n=584
    [58] - ITT population (analysed) Wk 04 n=637 Wk 12 n=629 Wk 26 n=589 Wk 40 n=576 Wk 52 n=558
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 4
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 4. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1338) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1289: n (CHF 5993 pMDI)=652 n (CHF 1535 pMDI)=637
    Comparison groups
    Treatment B - fixed combination CHF 1535 100/6μg v Treatment A - fixed combination CHF 5993 100/6/12.5μg
    Number of subjects included in analysis
    1338
    Analysis specification
    Pre-specified
    Analysis type
    superiority [59]
    P-value
    = 0.126
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -1.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.72
         upper limit
    0.34
    Notes
    [59] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 12
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 12. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1338) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1265: n (CHF 5993 pMDI)=636 n (CHF 1535 pMDI)=629
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1338
    Analysis specification
    Pre-specified
    Analysis type
    superiority [60]
    P-value
    = 0.54
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -0.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.24
         upper limit
    1.17
    Notes
    [60] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 26
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 26. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1338) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1209: n (CHF 5993 pMDI)=620 n (CHF 1535 pMDI)=589
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1338
    Analysis specification
    Pre-specified
    Analysis type
    superiority [61]
    P-value
    = 0.077
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -1.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.44
         upper limit
    0.17
    Notes
    [61] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 40
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 40. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1338) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1177: n (CHF 5993 pMDI)=601 n (CHF 1535 pMDI)=576
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1338
    Analysis specification
    Pre-specified
    Analysis type
    superiority [62]
    P-value
    = 0.224
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -1.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.21
         upper limit
    0.75
    Notes
    [62] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 52
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 52. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1338) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1142: n (CHF 5993 pMDI)=584 n (CHF 1535 pMDI)=558
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1338
    Analysis specification
    Pre-specified
    Analysis type
    superiority [63]
    P-value
    = 0.364
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.03
         upper limit
    1.11
    Notes
    [63] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

    Secondary: 13_Change from baseline in Saint George’s respiratory questionnaire (SGRQ) at all study visits: Impacts Score

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    End point title
    13_Change from baseline in Saint George’s respiratory questionnaire (SGRQ) at all study visits: Impacts Score
    End point description
    SGRQ Impacts Score. SGRQ is a questionnaire developed to measure health in chronic airflow limitation. SGRQ questionnaire was completed by the patients at all study visits (Week 0 baseline, 4, 12, 26, 40, 52). In this study, the Total Score for SGRQ was calculated, whereby lower scores correspond to better health. Moreover, 3 component scores of SGRQ were calculated: Symptoms, Activity, and Impacts on daily life. Change from baseline in SGRQ Impacts Score was calculated and presented for this end point. Shown are the number of subjects included in the model and the number of subjects with available results at the indicated week (Wk). SGRQ=Saint George’s respiratory questionnaire
    End point type
    Secondary
    End point timeframe
    Baseline and each study visit (Week 4, 12, 26, 40, 52).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    678 [64]
    668 [65]
    Units: score
    least squares mean (confidence interval 95%)
        Week 4
    -3.44 (-4.34 to -2.54)
    -2.29 (-3.2 to -1.38)
        Week 12
    -4.65 (-5.69 to -3.62)
    -2.72 (-3.76 to -1.68)
        Week 26
    -4.88 (-5.96 to -3.8)
    -3.5 (-4.6 to -2.39)
        Week 40
    -5.33 (-6.45 to -4.2)
    -3.75 (-4.89 to -2.6)
        Week 52
    -4.68 (-5.85 to -3.51)
    -2.59 (-3.79 to -1.4)
    Notes
    [64] - ITT population (analysed) Wk 04 n=668 Wk 12 n=641 Wk 26 n=627 Wk 40 n=608 Wk 52 n=590
    [65] - ITT population (analysed) Wk 04 n=654 Wk 12 n=636 Wk 26 n=594 Wk 40 n=576 Wk 52 n=559
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 4
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 4. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1346) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1322: n (CHF 5993 pMDI)=668 n (CHF 1535 pMDI)=654
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1346
    Analysis specification
    Pre-specified
    Analysis type
    superiority [66]
    P-value
    = 0.077
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -1.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.43
         upper limit
    0.13
    Notes
    [66] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 12
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 12. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1346) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1277: n (CHF 5993 pMDI)=641 n (CHF 1535 pMDI)=636
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1346
    Analysis specification
    Pre-specified
    Analysis type
    superiority [67]
    P-value
    = 0.01
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -1.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.4
         upper limit
    -0.46
    Notes
    [67] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 26
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 26. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1346) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1221: n (CHF 5993 pMDI)=627 n (CHF 1535 pMDI)=594
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1346
    Analysis specification
    Pre-specified
    Analysis type
    superiority [68]
    P-value
    = 0.079
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -1.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.93
         upper limit
    0.16
    Notes
    [68] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 40
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 40. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1346) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1284: n (CHF 5993 pMDI)=608 n (CHF 1535 pMDI)=576
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1346
    Analysis specification
    Pre-specified
    Analysis type
    superiority [69]
    P-value
    = 0.054
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -1.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.19
         upper limit
    0.03
    Notes
    [69] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 52
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 52. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1346) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1149: n (CHF 5993 pMDI)=590 n (CHF 1535 pMDI)=559
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1346
    Analysis specification
    Pre-specified
    Analysis type
    superiority [70]
    P-value
    = 0.015
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -2.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.76
         upper limit
    -0.41
    Notes
    [70] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

    Secondary: 14_Change from baseline in Saint George’s respiratory questionnaire (SGRQ) at all study visits: Activity Score

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    End point title
    14_Change from baseline in Saint George’s respiratory questionnaire (SGRQ) at all study visits: Activity Score
    End point description
    SGRQ Activity Score. SGRQ is a questionnaire developed to measure health in chronic airflow limitation. SGRQ questionnaire was completed by the patients at all study visits (Week 0 baseline, 4, 12, 26, 40, 52). In this study, the Total Score for SGRQ was calculated, whereby lower scores correspond to better health. Moreover, 3 component scores of SGRQ were calculated: Symptoms, Activity, and Impacts on daily life. Change from baseline in SGRQ Activity Score was calculated and presented for this end point. Shown are the number of subjects included in the model and the number of subjects with available results at the indicated week (Wk). SGRQ=Saint George’s respiratory questionnaire
    End point type
    Secondary
    End point timeframe
    Baseline and each study visit (Week 4, 12, 26, 40, 52).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    672 [71]
    661 [72]
    Units: score
    least squares mean (confidence interval 95%)
        Week 4
    -2.69 (-3.65 to -1.73)
    -1.21 (-2.18 to -0.24)
        Week 12
    -3.93 (-5.03 to -2.83)
    -1.35 (-2.46 to -0.24)
        Week 26
    -3.88 (-5.01 to -2.75)
    -2.17 (-3.33 to -1.02)
        Week 40
    -4.35 (-5.54 to -3.15)
    -2.74 (-3.96 to -1.51)
        Week 52
    -4.26 (-5.49 to -3.02)
    -2.95 (-4.21 to -1.68)
    Notes
    [71] - ITT population (analysed) Wk 04 n=659 Wk 12 n=626 Wk 26 n=616 Wk 40 n=596 Wk 52 n=583
    [72] - ITT population (analysed) Wk 4 n=639 Wk 12 n=621 Wk 26 n=585 Wk 40 n=562 Wk 52 n=554
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 4
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 4. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1333) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1298: n (CHF 5993 pMDI)=659 n (CHF 1535 pMDI)=639
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1333
    Analysis specification
    Pre-specified
    Analysis type
    superiority [73]
    P-value
    = 0.034
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -1.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.84
         upper limit
    -0.11
    Notes
    [73] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 12
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 12. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1333) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1247: n (CHF 5993 pMDI)=626 n (CHF 1535 pMDI)=621
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1333
    Analysis specification
    Pre-specified
    Analysis type
    superiority [74]
    P-value
    = 0.001
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -2.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.14
         upper limit
    -1.01
    Notes
    [74] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 26
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 26. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1333) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1201: n (CHF 5993 pMDI)=616 n (CHF 1535 pMDI)=585
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1333
    Analysis specification
    Pre-specified
    Analysis type
    superiority [75]
    P-value
    = 0.039
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -1.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.33
         upper limit
    -0.09
    Notes
    [75] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 40
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 40. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1333) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1158: n (CHF 5993 pMDI)=596 n (CHF 1535 pMDI)=562
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1333
    Analysis specification
    Pre-specified
    Analysis type
    superiority [76]
    P-value
    = 0.065
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -1.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.32
         upper limit
    -0.1
    Notes
    [76] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups Wk 52
    Statistical analysis description
    Adjusted mean difference between treatment groups at Week 52. CHF 5993 pMDI vs CHF 1535 pMDI The number of subjects in this analysis shown (1333) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1158: n (CHF 5993 pMDI)=596 n (CHF 1535 pMDI)=562
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1333
    Analysis specification
    Pre-specified
    Analysis type
    superiority [77]
    P-value
    = 0.145
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -1.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.08
         upper limit
    0.45
    Notes
    [77] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

    Secondary: 15_SGRQ response (change from baseline in Total score ≤-4) at Week 26 and Week 52

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    End point title
    15_SGRQ response (change from baseline in Total score ≤-4) at Week 26 and Week 52
    End point description
    SGRQ response is defined as a change from baseline in SGRQ total score ≤ -4. If the change from baseline was > -4, the patient was classed as a non-responder in terms of SGRQ. Patients with missing change from baseline at the relevant time points were also classified as non-responders. Results are shown as the number of responders for the comparison of CHF 5993 pMDI vs CHF 1535 pMDI. SGRQ=Saint George’s respiratory questionnaire
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26, Week 52.
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    687 [78]
    680 [79]
    Units: subject
        Week 26
    321
    246
        Week 52
    297
    244
    Notes
    [78] - ITT population
    [79] - ITT population
    Statistical analysis title
    Btw grp analysis, change in SGRQ score ≤-4, Wk 26
    Statistical analysis description
    SGRQ response = Subjects with a change from baseline in Total Score ≤-4, at week 26. Between group analysis (change from baseline in SGRQ Total score ≤-4, Week 26). CHF 5993 pMDI / CHF 1535 pMDI
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [80]
    P-value
    < 0.001
    Method
    Logistic model
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.521
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.211
         upper limit
    1.911
    Notes
    [80] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors and the baseline SGRQ total score value as a covariate.
    Statistical analysis title
    Btw grp analysis, change in SGRQ score ≤-4, Wk 52
    Statistical analysis description
    SGRQ response = Subjects with a change from baseline in Total Score ≤-4, at week 52. Between group analysis (change from baseline in SGRQ Total score ≤-4, Week 52). CHF 5993 pMDI / CHF 1535 pMDI
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [81]
    P-value
    = 0.014
    Method
    Logistic model
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.327
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.06
         upper limit
    1.661
    Notes
    [81] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors and the baseline SGRQ total score value as a covariate.

    Secondary: 16_Change from baseline for percentage of days without intake of rescue medication

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    End point title
    16_Change from baseline for percentage of days without intake of rescue medication
    End point description
    Days without intake of rescue medication. Change from baseline to each inter-visit period and for the entire treatment period (Week 1-52) in the percentage of days without intake of rescue medication. Shown are the number of subjects included in the model and the number of subjects with available results at the indicated week (Wk).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4, 12, 26, 40, 52.
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    653 [82]
    645 [83]
    Units: days
    least squares mean (confidence interval 95%)
        Week 1-4
    6.67 (4.89 to 8.44)
    2.46 (0.67 to 4.25)
        Week 5-12
    6.23 (4.19 to 8.27)
    3.18 (1.12 to 5.24)
        Week 13-26
    5.49 (3.3 to 7.67)
    2.4 (0.19 to 4.6)
        Week 27-40
    4.39 (2.07 to 6.72)
    2.79 (0.43 to 5.15)
        Week 41-52
    3.82 (1.45 to 6.19)
    1.24 (-1.17 to 3.65)
        Week 1-52
    5.01 (3.05 to 6.98)
    2.36 (0.37 to 4.35)
    Notes
    [82] - ITT population W 1-4 n=645 W 5-12 n=642 W 13-26 n=627 W 27-40 n=601 W 41-52 n=578 W 1-52 n=650
    [83] - ITT population W 1-4 n=637 W 5-12 n=629 W 13-26 n=610 W 27-40 n=572 W 41-52 n=552 W 1-52 n=640
    Statistical analysis title
    Adjusted mean difference btw treat groups W 1-4
    Statistical analysis description
    Adjusted mean difference between treatment groups during Week 1-4. CHF 5993 pMDI - CHF 1535 pMDI The number of subjects in this analysis shown (1298) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1282: n (CHF 5993 pMDI)=645 n (CHF 1535 pMDI)=637
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1298
    Analysis specification
    Pre-specified
    Analysis type
    superiority [84]
    P-value
    = 0.001
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    4.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.69
         upper limit
    6.73
    Notes
    [84] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups W 5-12
    Statistical analysis description
    Adjusted mean difference between treatment groups during Week 5-12. CHF 5993 pMDI - CHF 1535 pMDI The number of subjects in this analysis shown (1298) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1271: n (CHF 5993 pMDI)=642 n (CHF 1535 pMDI)=629
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1298
    Analysis specification
    Pre-specified
    Analysis type
    superiority [85]
    P-value
    = 0.039
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    3.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.15
         upper limit
    5.95
    Notes
    [85] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups W 13-26
    Statistical analysis description
    Adjusted mean difference between treatment groups during Week 13-26. CHF 5993 pMDI - CHF 1535 pMDI The number of subjects in this analysis shown (1298) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1237: n (CHF 5993 pMDI)=627 n (CHF 1535 pMDI)=610
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1298
    Analysis specification
    Pre-specified
    Analysis type
    superiority [86]
    P-value
    = 0.051
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    3.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.02
         upper limit
    6.2
    Notes
    [86] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups W 27-40
    Statistical analysis description
    Adjusted mean difference between treatment groups during Week 27-40. CHF 5993 pMDI - CHF 1535 pMDI The number of subjects in this analysis shown (1298) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1173: n (CHF 5993 pMDI)=601 n (CHF 1535 pMDI)=572
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1298
    Analysis specification
    Pre-specified
    Analysis type
    superiority [87]
    P-value
    = 0.342
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.71
         upper limit
    4.91
    Notes
    [87] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups W 41-52
    Statistical analysis description
    Adjusted mean difference between treatment groups during Week 41-52. CHF 5993 pMDI - CHF 1535 pMDI The number of subjects in this analysis shown (1298) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1130: n (CHF 5993 pMDI)=578 n (CHF 1535 pMDI)=552
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1298
    Analysis specification
    Pre-specified
    Analysis type
    superiority [88]
    P-value
    = 0.134
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    2.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    5.97
    Notes
    [88] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups W 1-52
    Statistical analysis description
    Adjusted mean difference between treatment groups during Week 1-52. CHF 5993 pMDI - CHF 1535 pMDI The number of subjects in this analysis shown (1298) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1290: n (CHF 5993 pMDI)=650 n (CHF 1535 pMDI)=640
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1298
    Analysis specification
    Pre-specified
    Analysis type
    superiority [89]
    P-value
    = 0.063
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    2.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.14
         upper limit
    5.45
    Notes
    [89] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates.

    Secondary: 17_Change from baseline for the average use of rescue medication

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    End point title
    17_Change from baseline for the average use of rescue medication
    End point description
    Average use of rescue medication. Change from baseline to each inter-visit period and for the entire treatment period (Week 1-52) in the average use of rescue medication (number of puffs/day). Shown are the number of subjects included in the model and the number of subjects with available results at the indicated week (Wk).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4, 12, 26, 40, 52.
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    653 [90]
    645 [91]
    Units: puffs/day
    least squares mean (confidence interval 95%)
        Week 1-4
    -0.29 (-0.38 to -0.2)
    -0.07 (-0.17 to 0.02)
        Week 5-12
    -0.25 (-0.36 to -0.14)
    -0.06 (-0.17 to 0.05)
        Week 13-26
    -0.21 (-0.32 to -0.09)
    -0.02 (-0.14 to 0.1)
        Week 27-40
    -0.09 (-0.22 to 0.04)
    0.02 (-0.11 to 0.15)
        Week 41-52
    -0.04 (-0.17 to 0.09)
    0.07 (-0.07 to 0.21)
        Week 1-52
    -0.15 (-0.26 to -0.04)
    0 (-0.11 to 0.12)
    Notes
    [90] - ITT population W 1-4 n=645 W 5-12 n=642 W 13-26 n=627 W 27-40 n=601 W 41-52 n=578 W 1-52 n=650
    [91] - ITT population W 1-4 n=637 W 5-12 n=629 W 13-26 n=610 W 27-40 n=572 W 41-52 n=552 W 1-52 n=640
    Statistical analysis title
    Adjusted mean difference btw treat groups W 1-4
    Statistical analysis description
    Adjusted mean difference between treatment groups during Week 1-4. CHF 5993 pMDI - CHF 1535 pMDI The number of subjects in this analysis shown (1298) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1282: n (CHF 5993 pMDI)=645 n (CHF 1535 pMDI)=637
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1298
    Analysis specification
    Pre-specified
    Analysis type
    superiority [92]
    P-value
    = 0.001
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.34
         upper limit
    -0.08
    Notes
    [92] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups W 5-12
    Statistical analysis description
    Adjusted mean difference between treatment groups during Week 5-12. CHF 5993 pMDI - CHF 1535 pMDI The number of subjects in this analysis shown (1298) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1271: n (CHF 5993 pMDI)=642 n (CHF 1535 pMDI)=629
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1298
    Analysis specification
    Pre-specified
    Analysis type
    superiority [93]
    P-value
    = 0.016
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.35
         upper limit
    -0.04
    Notes
    [93] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups W 13-26
    Statistical analysis description
    Adjusted mean difference between treatment groups during Week 13-26. CHF 5993 pMDI - CHF 1535 pMDI The number of subjects in this analysis shown (1298) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1237: n (CHF 5993 pMDI)=627 n (CHF 1535 pMDI)=610
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1298
    Analysis specification
    Pre-specified
    Analysis type
    superiority [94]
    P-value
    = 0.029
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.35
         upper limit
    -0.02
    Notes
    [94] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups W 27-40
    Statistical analysis description
    Adjusted mean difference between treatment groups during Week 27-40. CHF 5993 pMDI - CHF 1535 pMDI The number of subjects in this analysis shown (1298) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1173: n (CHF 5993 pMDI)=601 n (CHF 1535 pMDI)=572
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1298
    Analysis specification
    Pre-specified
    Analysis type
    superiority [95]
    P-value
    = 0.225
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.29
         upper limit
    0.07
    Notes
    [95] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups W 41-52
    Statistical analysis description
    Adjusted mean difference between treatment groups during Week 41-52. CHF 5993 pMDI - CHF 1535 pMDI The number of subjects in this analysis shown (1298) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1130: n (CHF 5993 pMDI)=578 n (CHF 1535 pMDI)=552
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1298
    Analysis specification
    Pre-specified
    Analysis type
    superiority [96]
    P-value
    = 0.262
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.08
    Notes
    [96] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates.
    Statistical analysis title
    Adjusted mean difference btw treat groups W 1-52
    Statistical analysis description
    Adjusted mean difference between treatment groups during Week 1-52. CHF 5993 pMDI - CHF 1535 pMDI The number of subjects in this analysis shown (1298) is due to an innate error within the EudraCT database. The correct number of participating subjects is shown below. The total number of subjects with available data in this analysis is 1290: n (CHF 5993 pMDI)=650 n (CHF 1535 pMDI)=640
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1298
    Analysis specification
    Pre-specified
    Analysis type
    superiority [97]
    P-value
    = 0.062
    Method
    Mixed model for repeated measures
    Parameter type
    Mean difference (net)
    Point estimate
    -0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.31
         upper limit
    0.01
    Notes
    [97] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates.

    Secondary: 18_Moderate and severe COPD exacerbation rate over 52 weeks of treatment

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    End point title
    18_Moderate and severe COPD exacerbation rate over 52 weeks of treatment
    End point description
    Rate of moderate or severe COPD exacerbation. Evaluate the rate of moderate or severe COPD exacerbation over 52 weeks of treatment. Data are presented as Adjusted Exacerbation Rate per Patient per Year (95% CI). Shown are the number of subjects included in the model and the number of subjects with available results. COPD=Chronic obstructive pulmonary disease
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52 (entire treatment period).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    687 [98]
    680 [99]
    Units: exacerbation/patient/year
        number (confidence interval 95%)
    0.41 (0.358 to 0.469)
    0.53 (0.468 to 0.6)
    Notes
    [98] - ITT population
    [99] - ITT population
    Statistical analysis title
    Adjusted rate ratio for mod and sev exacerbations
    Statistical analysis description
    Adjusted rate ratio for moderate and severe exacerbations. CHF 5993 pMDI / CHF 1535 pMDI
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [100]
    P-value
    = 0.005
    Method
    Negative binomial model
    Parameter type
    Adjusted Rate Ratio
    Point estimate
    0.773
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.647
         upper limit
    0.924
    Notes
    [100] - Analysis is based on a negative binomial model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as fixed effects, and log-time on study as an offset.

    Secondary: 19_Time to first moderate or severe COPD exacerbation

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    End point title
    19_Time to first moderate or severe COPD exacerbation
    End point description
    Time to first moderate or severe COPD exacerbation. Shown are the number of subjects included in the model and the number of subjects with available results. COPD=Chronic obstructive pulmonary disease
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52 (entire treatment period).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    678 [101]
    680 [102]
    Units: Subjects, at least 1 mod or sev exacerbt
    214
    240
    Notes
    [101] - ITT population
    [102] - ITT population
    Statistical analysis title
    Time to first moderate or severe COPD exacerbation
    Comparison groups
    Treatment A - fixed combination CHF 5993 100/6/12.5μg v Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects included in analysis
    1358
    Analysis specification
    Pre-specified
    Analysis type
    superiority [103]
    P-value
    = 0.02
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.803
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.668
         upper limit
    0.967
    Notes
    [103] - Analysis is based on a Cox proportional hazards model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at Screening as factors. CHF 5993 pMDI / CHF 1535 pMDI

    Secondary: 20_Vital signs: Systolic blood pressure

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    End point title
    20_Vital signs: Systolic blood pressure
    End point description
    Systolic Blood Pressure. Results represent changes from baseline (Week 0, pre-dose), on Week 26 and Week 52 (pre-dose and 10-minute post-dose). Shown are the number of subjects included in the safety population and the number of subjects with available results.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4, 12, 26, 40, 52 (data shown are for Week 26 and Week 52).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    687 [104]
    680 [105]
    Units: mmHg
    arithmetic mean (confidence interval 95%)
        Week 0, 10 min post-dose
    -0.8 (-1.4 to -0.3)
    -0.7 (-1.2 to -0.1)
        Week 26, pre-dose
    0.3 (-0.6 to 1.2)
    -0.5 (-1.4 to 0.4)
        Week 26, 10 min post-dose
    -1 (-1.9 to -0.1)
    -1.9 (-2.8 to -1.1)
        Week 52, pre-dose
    -0.2 (-1.2 to 0.7)
    -1.3 (-2.3 to -0.2)
        Week 52, 10 min post-dose
    -1.2 (-2.2 to -0.3)
    -2 (-3 to -1)
    Notes
    [104] - Safety pop W 0 post n=683 W 26 pre n=643 W 26 post n=633 W 52 pre n=608 W 52 post n=603
    [105] - Safety pop W 0 post n=679 W 26 pre n=619 W 26 post n=612 W 52 pre n=579 W 52 post n=576
    No statistical analyses for this end point

    Secondary: 21_Vital signs: Diastolic blood pressure

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    End point title
    21_Vital signs: Diastolic blood pressure
    End point description
    Diastolic Blood Pressure. Results represent changes from baseline (Week 0, pre-dose), on Week 26 and Week 52 (pre-dose and 10-minute post-dose). Shown are the number of subjects included in the safety population and the number of subjects with available results.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4, 12, 26, 40, 52 (data shown are for Week 26 and Week 52).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    687 [106]
    680 [107]
    Units: mmHg
    arithmetic mean (confidence interval 95%)
        Week 0, 10 min post-dose
    -0.5 (-0.9 to 0)
    -0.3 (-0.7 to 0.1)
        Week 26, pre-dose
    -0.3 (-1 to 0.4)
    0.4 (-0.2 to 1)
        Week 26, 10 min post-dose
    -1 (-1.6 to -0.3)
    -0.5 (-1.2 to 0.1)
        Week 52, pre-dose
    -0.5 (-1.2 to 0.2)
    -0.1 (-0.7 to 0.6)
        Week 52, 10 min post-dose
    -1.4 (-2.1 to -0.7)
    -0.6 (-1.2 to 0.1)
    Notes
    [106] - Safety pop W 0 post n=683 W 26 pre n=643 W 26 post n=633 W 52 pre n=608 W 52 post n=603
    [107] - Safety pop W 0 post n=679 W 26 pre n=619 W 26 post n=612 W 52 pre n=579 W 52 post n=576
    No statistical analyses for this end point

    Secondary: 22_Vital signs: Body mass index

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    End point title
    22_Vital signs: Body mass index
    End point description
    Body Mass Index. Results represent changes from baseline (Week 0), on Week 26 and Week 52. Shown are the number of subjects included in the safety population and the number of subjects with available results.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4, 12, 26, 40, 52 (data shown are for Week 26 and Week 52).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    687 [108]
    680 [109]
    Units: kg/m2
    arithmetic mean (confidence interval 95%)
        Week 26
    0.17 (0.09 to 0.25)
    -0.02 (-0.09 to 0.06)
        Week 52
    0.12 (0 to 0.23)
    -0.05 (-0.15 to 0.05)
    Notes
    [108] - Safety population Wk 26 n=643 Wk 52 n=608
    [109] - Safety population Wk 26 n=620 Wk 52 n=579
    No statistical analyses for this end point

    Secondary: 23_Electrocardiogram parameters: Heart rate

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    End point title
    23_Electrocardiogram parameters: Heart rate
    End point description
    Heart Rate. Results represent changes from baseline (Week 0, pre-dose), on Week 26 and Week 52 (pre-dose and 10-minute post-dose). Shown are the number of subjects included in the safety population and the number of subjects with available results.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4, 12, 26, 40, 52 (data shown are for Week 26 and Week 52).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    687 [110]
    680 [111]
    Units: bpm
    arithmetic mean (standard deviation)
        Week 0, 10 min post-dose
    -2.68 ± 5.71
    -3.03 ± 5.43
        Week 26, pre-dose
    -0.28 ± 10.56
    -0.24 ± 11.52
        Week 26, 10 min post-dose
    -2.01 ± 10.92
    -1.99 ± 11.42
        Week 52, pre-dose
    0.56 ± 11.05
    0.56 ± 11.22
        Week 52, 10 min post-dose
    -0.71 ± 10.93
    -0.66 ± 11.63
    Notes
    [110] - Safety pop W 0 post n=658 W 26 pre n=618 W 26 post n=611 W 52 pre n=588 W 52 post n=583
    [111] - Safety pop W 0 post n=656 W 26 pre n=597 W 26 post n=592 W 52 pre n=557 W 52 post n=554
    No statistical analyses for this end point

    Secondary: 24_Electrocardiogram parameters: QTcF interval

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    End point title
    24_Electrocardiogram parameters: QTcF interval
    End point description
    QTcF (Fridericia’s Corrected QT Interval). Results represent changes from baseline (Week 0, pre-dose), on Week 26 and Week 52 (pre-dose and 10-minute post-dose). Shown are the number of subjects included in the safety population and the number of subjects with available results.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4, 12, 26, 40, 52 (data shown are for Week 26 and Week 52).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    687 [112]
    680 [113]
    Units: msec
    arithmetic mean (standard deviation)
        Week 0, 10 min post-dose
    -0.55 ± 10.68
    -0.27 ± 11.11
        Week 26, pre-dose
    0.38 ± 14.08
    0.76 ± 15.76
        Week 26, 10 min post-dose
    -0.09 ± 14.41
    -0.38 ± 15.97
        Week 52, pre-dose
    -0.08 ± 14.43
    -0.96 ± 16.31
        Week 52, 10 min post-dose
    0.07 ± 14.26
    -1.1 ± 16.36
    Notes
    [112] - Safety pop W 0 post n=657 W 26 pre n=618 W 26 post n=611 W 52 pre n=589 W 52 post n=583
    [113] - Safety pop W 0 post n=656 W 26 pre n=597 W 26 post n=592 W 52 pre n=557 W 52 post n=554
    No statistical analyses for this end point

    Secondary: 25_Electrocardiogram parameters: PR interval

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    End point title
    25_Electrocardiogram parameters: PR interval
    End point description
    PR Interval. Results represent changes from baseline (Week 0, pre-dose), on Week 26 and Week 52 (pre-dose and 10-minute post-dose). Shown are the number of subjects included in the safety population and the number of subjects with available results.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4, 12, 26, 40, 52 (data shown are for Week 26 and Week 52).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    687 [114]
    680 [115]
    Units: msec
    arithmetic mean (standard deviation)
        Week 0, 10 min post-dose
    -0.65 ± 8.1
    -0.67 ± 7.74
        Week 26, pre-dose
    -1.14 ± 12.82
    -0.23 ± 11.18
        Week 26, 10 min post-dose
    -1.17 ± 12.49
    -0.98 ± 11.08
        Week 52, pre-dose
    -0.35 ± 12.68
    -1.52 ± 12.89
        Week 52, 10 min post-dose
    -1.28 ± 13.31
    -2.08 ± 12.22
    Notes
    [114] - Safety pop W 0 post n=658 W 26 pre n=618 W 26 post n=611 W 52 pre n=589 W 52 post n=583
    [115] - Safety pop W 0 post n=656 W 26 pre n=597 W 26 post n=592 W 52 pre n=557 W 52 post n=554
    No statistical analyses for this end point

    Secondary: 26_Electrocardiogram parameters: QRS interval

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    End point title
    26_Electrocardiogram parameters: QRS interval
    End point description
    QRS interval. Results represent changes from baseline (Week 0, pre-dose), on Week 26 and Week 52 (pre-dose and 10-minute post-dose). Shown are the number of subjects included in the safety population and the number of subjects with available results.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4, 12, 26, 40, 52 (data shown are for Week 26 and Week 52).
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    687 [116]
    680 [117]
    Units: msec
    arithmetic mean (standard deviation)
        Week 0, 10 min post-dose
    0.1 ± 4.72
    0.38 ± 4.57
        Week 26, pre-dose
    -0.71 ± 6.91
    -0.17 ± 6.46
        Week 26, 10 min post-dose
    -0.19 ± 6.74
    -0.39 ± 6.71
        Week 52, pre-dose
    -0.58 ± 7.76
    -0.33 ± 7.69
        Week 52, 10 min post-dose
    -0.24 ± 7.48
    -0.06 ± 7.67
    Notes
    [116] - Safety pop W 0 post n=658 W 26 pre n=618 W 26 post n=611 W 52 pre n=589 W 52 post n=583
    [117] - Safety pop W 0 post n=656 W 26 pre n=597 W 26 post n=592 W 52 pre n=557 W 52 post n=554
    No statistical analyses for this end point

    Secondary: 27_Holter electrocardiogram parameter: 24-h Average heart rate

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    End point title
    27_Holter electrocardiogram parameter: 24-h Average heart rate
    End point description
    Holter electrocardiogram parameter: 24-h Average heart rate values. Results represent change from baseline (Week 0, pre-dose), to Week 26 and Week 52. Shown are the number of subjects included in the safety population and the number of subjects with available results.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26, Week 52.
    End point values
    Treatment A - fixed combination CHF 5993 100/6/12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Number of subjects analysed
    67 [118]
    71 [119]
    Units: bmp
    arithmetic mean (standard deviation)
        Week 26
    0.3 ± 7.27
    -0.68 ± 10.77
        Week 52
    0.45 ± 6.87
    -0.3 ± 9.09
    Notes
    [118] - Holter subset population Wk 26 n=60 Wk 52 n=58
    [119] - Holter subset population Wk 26 n=62 Wk 52 n=56
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from the time of patient informed consent signature to study completion or discontinuation.
    Adverse event reporting additional description
    Data represent treatment-emergent adverse events (i.e. events that occurred after the first randomised study drug intake).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Treatment A - fixed combination CHF 5993 100/6 /12.5μg
    Reporting group description
    -

    Reporting group title
    Treatment B - fixed combination CHF 1535 100/6μg
    Reporting group description
    -

    Serious adverse events
    Treatment A - fixed combination CHF 5993 100/6 /12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    106 / 687 (15.43%)
    123 / 680 (18.09%)
         number of deaths (all causes)
    15
    16
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic thrombosis
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral artery aneurysm
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leriche syndrome
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 687 (0.15%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal tract adenoma
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal cancer stage III
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    1 / 687 (0.15%)
    2 / 680 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung neoplasm
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    3 / 687 (0.44%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm of conjunctiva
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic gastric cancer
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Device malfunction
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 687 (0.00%)
    2 / 680 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Psychiatric disorders
    Alcohol abuse
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hip fracture
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poisoning
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural fistula
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 687 (0.00%)
    3 / 680 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 687 (0.15%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 687 (0.44%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 687 (0.15%)
    2 / 680 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Cardiac failure
         subjects affected / exposed
    4 / 687 (0.58%)
    3 / 680 (0.44%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Cardiac failure acute
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 687 (0.15%)
    3 / 680 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Myocardial ischaemia
         subjects affected / exposed
    0 / 687 (0.00%)
    4 / 680 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sick sinus syndrome
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachyarrhythmia
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 687 (0.15%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    66 / 687 (9.61%)
    75 / 680 (11.03%)
         occurrences causally related to treatment / all
    0 / 87
    0 / 86
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    Chronic respiratory failure
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cyst
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 687 (0.29%)
    2 / 680 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 687 (0.15%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Vocal cord leukoplakia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haemorrhagic disorder
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic thrombocytopenic purpura
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 687 (0.00%)
    2 / 680 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic erosive gastritis
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernial eventration
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 687 (0.15%)
    2 / 680 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    2 / 687 (0.29%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Abnormal loss of weight
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    0 / 687 (0.00%)
    1 / 680 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    14 / 687 (2.04%)
    6 / 680 (0.88%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 687 (0.15%)
    0 / 680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Treatment A - fixed combination CHF 5993 100/6 /12.5μg Treatment B - fixed combination CHF 1535 100/6μg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    330 / 687 (48.03%)
    341 / 680 (50.15%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    159 / 687 (23.14%)
    184 / 680 (27.06%)
         occurrences all number
    212
    274
    Nasopharyngitis
         subjects affected / exposed
    39 / 687 (5.68%)
    38 / 680 (5.59%)
         occurrences all number
    50
    45

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/27598678
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