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    Clinical Trial Results:
    A 52-week, Double Blind, Double dummy, Randomized, Multinational, Multicentre, 2-arm Parallel Group, active Controlled Clinical Trial of fixed combination of beclometasone dipropionate plus formoterol fumarate plus Glycopyrronium bromide administered via pMDI (CHF 5993) versus indacaterol/glycopyrronium (Ultibro®) via DPI in patients with Chronic Obstructive Pulmonary Disease

    Summary
    EudraCT number
    		 2014-001704-22
    Trial protocol
    		 LV   PT   HU   CZ   RO   DK   DE   AT   NO   PL   FR   BG   HR   IT  
    Global end of trial date
    10 Jul 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Apr 2018
    First version publication date
    29 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-05993AA1-08
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02579850
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 TRIBUTE: Tribute
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A.
    Sponsor organisation address
    Via Palermo 26/A, Parma, Italy, 43122
    Public contact
    Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., ClinicalTrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., ClinicalTrials_info@chiesi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of CHF 5993 pMDI over Indacaterol/GB in terms of moderate and severe COPD exacerbation rate over 52 weeks of treatment.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, with the Good Clinical Practice (GCP) guidelines in force during study conduct, and following all other requirements of local laws. At all visits, from screening onwards, concomitant medication, adverse events (AEs) and vital signs were recorded, COPD exacerbations were assessed, pre-dose spirometry (including forced expiratory volume in the 1st second [FEV1] and forced vital capacity [FVC]), and physical examinations were carried out. From screening, the electronic diary (eDiary) was completed to record rescue medication use, compliance with treatment and COPD exacerbation-related outcomes (using the EXAcerbations of chronic pulmonary disease tool-patient reported outcome [EXACT-PRO] questionnaire). Furthermore, 12-lead electrocardiogram (ECG) parameters: heart rate (HR), Fridericia corrected QT interval (QTcF), PR interval (PR), and QRS interval (QRS) were collected at screening, Week 26 and Week 52 of treatment.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 May 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 205
    Country: Number of subjects enrolled
    Portugal: 16
    Country: Number of subjects enrolled
    Romania: 217
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Croatia: 30
    Country: Number of subjects enrolled
    Austria: 25
    Country: Number of subjects enrolled
    Bulgaria: 311
    Country: Number of subjects enrolled
    Czech Republic: 154
    Country: Number of subjects enrolled
    Denmark: 15
    Country: Number of subjects enrolled
    Germany: 76
    Country: Number of subjects enrolled
    Hungary: 86
    Country: Number of subjects enrolled
    Latvia: 177
    Country: Number of subjects enrolled
    Argentina: 64
    Country: Number of subjects enrolled
    Chile: 25
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Mexico: 100
    Worldwide total number of subjects
    1532
    EEA total number of subjects
    1343
    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)
    765
    From 65 to 84 years
    766
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Overall, 2103 patients were screened according to inclusion and exclusion criteria; of these, 1532 patients were randomised.

    Pre-assignment
    Screening details
    		 At the screening visit, inclusion/exclusion criteria were assessed. There were 571 screening failures. The screening visit was followed by a 2-week, open-label, run-in period during which patients self-administered indacaterol/glycopyrronium bromide (GB) (85/43 μg/day, one capsule, once daily [od]).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CHF 5993 pMDI (100/6/12.5 μg)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    CHF 5993 pMDI (100/6/12.5 μg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pressurised inhalation, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test product: CHF 5993 pMDI, fixed-dose combination of beclometasone dipropionate (BDP) + formoterol fumarate (FF) + glycopyrronium bromide (GB). Dose: BDP 100 μg, FF 6 μg, GB 12.5 μg per actuation, 2 puffs, twice daily (bid). Total daily dose: BDP 400 μg, FF 24 μg, GB 50 μg. Mode of administration: pMDI using a standard actuator. Double-dummy design: patients in the CHF 5993 pMDI (100/6/12.5 μg) group received pMDI inhalers with CHF 5993 pMDI 100/6/12.5 μg and Breezhaler® inhalers with indacaterol/GB-matched placebo. Patients were trained with training kits containing placebo in the proper use of pMDI.

    Arm title
    		 Indacaterol/GB (85/43 μg)
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Indacaterol/GB (85/43 μg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Reference product: Indacaterol/GB. Dose: Indacaterol 85 μg, GB 43 µg, 1 inhalation, once daily (od). Total daily dose: Indacaterol 85 μg, GB 43 µg. Mode of administration: DPI, Breezhaler® inhaler. Double-dummy design: patients in the Indacaterol/GB (85/43 μg) group received DPI inhalers (Breezhaler®) with indacaterol/GB 85/43 μg and pMDI inhalers with CHF 5993-matched placebo. Patients were trained with training kits containing placebo in the proper use of the Breezhaler® inhaler for the inhalation of DPI in capsule.

    Number of subjects in period 1
    		CHF 5993 pMDI (100/6/12.5 μg) Indacaterol/GB (85/43 μg)
    Started
    764
    768
    Completed
    666
    648
    Not completed
    98
    120
         Adverse event, serious fatal
    15
    20
         Consent withdrawn by subject
    42
    51
         Adverse event, non-fatal
    23
    26
         Other
    1
    3
         Lost to follow-up
    4
    3
         Lack of efficacy
    7
    12
         Protocol deviation
    6
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CHF 5993 pMDI (100/6/12.5 μg)
    Reporting group description
    		 -

    Reporting group title
    Indacaterol/GB (85/43 μg)
    Reporting group description
    		 -

    Reporting group values
    		 CHF 5993 pMDI (100/6/12.5 μg) Indacaterol/GB (85/43 μg) Total
    Number of subjects
    		 764 768 1532
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 389 376 765
        From 65-84 years
    		 374 392 766
        85 years and over
    		 1 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.4 ± 7.7 64.5 ± 7.7 -
    Gender categorical
    Units: Subjects
        Female
    		 216 216 432
        Male
    		 548 552 1100

    End points

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    End points reporting groups
    Reporting group title
    CHF 5993 pMDI (100/6/12.5 μg)
    Reporting group description
    		 -

    Reporting group title
    Indacaterol/GB (85/43 μg)
    Reporting group description
    		 -

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

    Subject analysis set title
    Indacaterol/GB (85/43 μg) - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intention-to-Treat (ITT) population was defined as all randomised patients who received at least one dose of study treatment and with at least one available evaluation of efficacy after baseline.

    Subject analysis set title
    CHF 5993 pMDI (100/6/12.5 μg) - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per-Protocol (PP) population was defined as all patients from the ITT population without any major protocol violations (e.g. inclusion/exclusion criteria not respected, poor compliance, non-permitted medications).

    Subject analysis set title
    Indacaterol/GB (85/43 μg) - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per-Protocol (PP) population was defined as all patients from the ITT population without any major protocol violations (e.g. inclusion/exclusion criteria not respected, poor compliance, non-permitted medications).

    Primary: Moderate and severe COPD exacerbation rate over 52 weeks of treatment

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    End point title
    		 Moderate and severe COPD exacerbation rate over 52 weeks of treatment
    End point description
    Rate of moderate and severe COPD exacerbations evaluated over 52 weeks of treatment. The exacerbations were classified as moderate or severe as per EMA/Committee for Medicinal Products for Human Use (CHMP) guidelines definitions. A moderate COPD exacerbation was defined as a sustained worsening of the patient’s condition which required treatment with systemic corticosteroids and/or antibiotics, a severe exacerbation was one which led to hospitalisation or death. The recognition of exacerbations was facilitated by the daily recording of symptoms through the EXACT-PRO. Data are presented as adjusted exacerbation rate per patient per year.
    End point type
    Primary
    End point timeframe
    Baseline to Week 52
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) - ITT Indacaterol/GB (85/43 μg) - ITT CHF 5993 pMDI (100/6/12.5 μg) - PP Indacaterol/GB (85/43 μg) - PP
    Number of subjects analysed
    764
    768
    742
    737
    Units: Exacerbation/patient/year
        number (confidence interval 95%)
    0.504 (0.447 to 0.569)
    0.595 (0.530 to 0.668)
    0.486 (0.430 to 0.551)
    0.573 (0.508 to 0.645)
    Statistical analysis title
    		 Adjusted exacerbation rate ratio - ITT population
    Statistical analysis description
    The number of moderate and severe COPD exacerbations was analysed using a negative binomial model including treatment, country, number of COPD exacerbations during the previous year (1, >1), severity of airflow limitation and smoking status as fixed effects and log-time on study in years as an offset. The adjusted exacerbation rate in each treatment group and the adjusted rate ratio (CHF 5993 pMDI / Indacaterol/GB) with associated 95% Wald confidence intervals (CIs) were estimated by the model.
    Comparison groups
    CHF 5993 pMDI (100/6/12.5 μg) - ITT v Indacaterol/GB (85/43 μg) - ITT
    Number of subjects included in analysis
    1532
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.043
    Method
    		 Negative binomial model
    Parameter type
    		 Adjusted rate ratio
    Point estimate
    0.848
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.723
         upper limit
    		 0.995
    Notes
    [1] - Superiority of CHF 5993 pMDI over indacaterol/GB was demonstrated if the upper limit of the 95% CI for the adjusted exacerbation rate ratio was <1.
    Statistical analysis title
    		 Adjusted exacerbation rate ratio - PP population
    Statistical analysis description
    The number of moderate and severe COPD exacerbations was analysed using a negative binomial model including treatment, country, number of COPD exacerbations during the previous year (1, >1), severity of airflow limitation and smoking status as fixed effects and log-time on study in years as an offset. The adjusted exacerbation rate in each treatment group and the adjusted rate ratio (CHF 5993 pMDI / Indacaterol/GB) with associated 95% Wald confidence intervals (CIs) were estimated by the model.
    Comparison groups
    CHF 5993 pMDI (100/6/12.5 μg) - PP v Indacaterol/GB (85/43 μg) - PP
    Number of subjects included in analysis
    1479
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.05
    Method
    		 Negative binomial model
    Parameter type
    		 Adjusted rate ratio
    Point estimate
    0.849
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.721
         upper limit
    		 1
    Notes
    [2] - Superiority of CHF 5993 pMDI over indacaterol/GB was demonstrated if the upper limit of the 95% CI for the adjusted exacerbation rate ratio was <1.

    Secondary: Severe COPD exacerbation rate over 52 weeks of treatment

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    End point title
    		 Severe COPD exacerbation rate over 52 weeks of treatment
    End point description
    Rate of severe COPD exacerbations evaluated over 52 weeks of treatment. The exacerbations were classified as moderate or severe as per EMA/CHMP guidelines definitions. A severe exacerbation was one which led to hospitalisation or death. The recognition of exacerbations was facilitated by the daily recording of symptoms through the EXACT-PRO. Data are presented as adjusted exacerbation rate per patient per year.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) - ITT Indacaterol/GB (85/43 μg) - ITT
    Number of subjects analysed
    764
    768
    Units: Exacerbation/patient/year
        number (confidence interval 95%)
    0.074 (0.055 to 0.099)
    0.094 (0.072 to 0.123)
    Statistical analysis title
    		 Adjusted exacerbation rate ratio
    Statistical analysis description
    The number of severe COPD exacerbations was analysed using a negative binomial model including treatment, country, number of COPD exacerbations during the previous year (1, >1), severity of airflow limitation and smoking status as fixed effects and log-time on study in years as an offset. The adjusted exacerbation rate in each treatment group and the adjusted rate ratio (CHF 5993 pMDI / Indacaterol/GB) with associated 95% Wald confidence intervals (CIs) were estimated by the model.
    Comparison groups
    CHF 5993 pMDI (100/6/12.5 μg) - ITT v Indacaterol/GB (85/43 μg) - ITT
    Number of subjects included in analysis
    1532
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.189
    Method
    		 Negative binomial model
    Parameter type
    		 Adjusted rate ratio
    Point estimate
    0.787
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.551
         upper limit
    		 1.125
    Notes
    [3] - Superiority of CHF 5993 pMDI over indacaterol/GB was demonstrated if the upper limit of the 95% CI for the adjusted exacerbation rate ratio was <1.

    Secondary: Moderate COPD exacerbation rate over 52 weeks of treatment

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    End point title
    		 Moderate COPD exacerbation rate over 52 weeks of treatment
    End point description
    Rate of moderate COPD exacerbations evaluated over 52 weeks of treatment. The exacerbations were classified as moderate or severe as per EMA/CHMP guidelines definitions. A moderate COPD exacerbation was defined as a sustained worsening of the patient’s condition which required treatment with systemic corticosteroids and/or antibiotics. The recognition of exacerbations was facilitated by the daily recording of symptoms through the EXACT-PRO. Data are presented as adjusted exacerbation rate per patient per year.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) - ITT Indacaterol/GB (85/43 μg) - ITT
    Number of subjects analysed
    764
    768
    Units: Exacerbation/patient/year
        number (confidence interval 95%)
    0.408 (0.356 to 0.468)
    0.471 (0.413 to 0.537)
    Statistical analysis title
    		 Adjusted exacerbation rate ratio
    Statistical analysis description
    The number of moderate COPD exacerbations was analysed using a negative binomial model including treatment, country, number of COPD exacerbations during the previous year (1, >1), severity of airflow limitation and smoking status as fixed effects and log-time on study in years as an offset. The adjusted exacerbation rate in each treatment group and the adjusted rate ratio (CHF 5993 pMDI / Indacaterol/GB) with associated 95% Wald confidence intervals (CIs) were estimated by the model.
    Comparison groups
    CHF 5993 pMDI (100/6/12.5 μg) - ITT v Indacaterol/GB (85/43 μg) - ITT
    Number of subjects included in analysis
    1532
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.118
    Method
    		 Negative binomial model
    Parameter type
    		 Adjusted rate ratio
    Point estimate
    0.866
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.723
         upper limit
    		 1.037
    Notes
    [4] - Superiority of CHF 5993 pMDI over indacaterol/GB was demonstrated if the upper limit of the 95% CI for the adjusted exacerbation rate ratio was <1.

    Secondary: Time to first severe COPD exacerbation

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    End point title
    		 Time to first severe COPD exacerbation
    End point description
    The number of patients experiencing a severe exacerbation during the 52-week treatment period is presented.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) - ITT Indacaterol/GB (85/43 μg) - ITT
    Number of subjects analysed
    764
    768
    Units: patients
    62
    69
    Statistical analysis title
    		 Time to first exacerbation (hazard ratio)
    Statistical analysis description
    Time to first severe COPD exacerbation was analysed using a regression model including treatment, country, number of COPD exacerbations during the previous year. Shown is the hazard ratio for CHF 5339 pMDI / Indacaterol/GB.
    Comparison groups
    CHF 5993 pMDI (100/6/12.5 μg) - ITT v Indacaterol/GB (85/43 μg) - ITT
    Number of subjects included in analysis
    1532
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.405
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.864
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.613
         upper limit
    		 1.219

    Secondary: Time to first moderate or severe COPD exacerbation

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    End point title
    		 Time to first moderate or severe COPD exacerbation
    End point description
    The number of patients experiencing a moderate or severe exacerbation during the 52-week treatment period is presented.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) - ITT Indacaterol/GB (85/43 μg) - ITT
    Number of subjects analysed
    764
    768
    Units: patients
    273
    288
    Statistical analysis title
    		 Time to first exacerbation (hazard ratio)
    Statistical analysis description
    Time to first moderate or severe COPD exacerbation was analysed using a regression model including treatment, country, number of COPD exacerbations during the previous year. Shown is the hazard ratio for CHF 5339 pMDI / Indacaterol/GB.
    Comparison groups
    CHF 5993 pMDI (100/6/12.5 μg) - ITT v Indacaterol/GB (85/43 μg) - ITT
    Number of subjects included in analysis
    1532
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.219
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.901
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.763
         upper limit
    		 1.064

    Secondary: Change from baseline in SGRQ total score at Week 52

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    End point title
    		 Change from baseline in SGRQ total score at Week 52
    End point description
    St. George’s Respiratory Questionnaire (SGRQ) total score. SGRQ is a questionnaire developed to measure health in chronic airflow limitation. The total score for SGRQ was calculated, whereby lower scores correspond to better health. Data are presented as least squares mean change from baseline at Week 52. Shown are the number of patients in the ITT population (N) and the number of patients with available results (n).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) - ITT Indacaterol/GB (85/43 μg) - ITT
    Number of subjects analysed
    760 [5]
    763 [6]
    Units: SGRQ total score
        least squares mean (confidence interval 95%)
    -3.49 (-4.36 to -2.63)
    -1.85 (-2.72 to -0.98)
    Notes
    [5] - N=764; n=760
    [6] - N=768; n=763
    Statistical analysis title
    		 LS mean difference in change from baseline in SGRQ
    Statistical analysis description
    Least squares mean difference in change from baseline in SGRQ total score at Week 52.
    Comparison groups
    CHF 5993 pMDI (100/6/12.5 μg) - ITT v Indacaterol/GB (85/43 μg) - ITT
    Number of subjects included in analysis
    1523
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.009
    Method
    		 Mixed model for repeated measures
    Parameter type
    		 Least squares mean difference
    Point estimate
    -1.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.87
         upper limit
    		 -0.42
    Notes
    [7] - Change from baseline in SGRQ total score at Week 52 analysed using a linear mixed model for repeated measures (MMRM) including treatment, country, visit, treatment by visit interaction, number of COPD exacerbations during the previous year (1, > 1), severity of airflow limitation and smoking status as fixed effects, and baseline and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed.

    Secondary: SGRQ response at Week 26

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    End point title
    		 SGRQ response at Week 26
    End point description
    SGRQ response was 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 total score. Patients with missing data at Week 26 were considered as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) - ITT Indacaterol/GB (85/43 μg) - ITT
    Number of subjects analysed
    764
    768
    Units: patients
        Responder
    310
    292
    No statistical analyses for this end point

    Secondary: SGRQ response at Week 52

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    End point title
    		 SGRQ response at Week 52
    End point description
    SGRQ response was 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 total score. Patients with missing data at Week 52 were considered as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) - ITT Indacaterol/GB (85/43 μg) - ITT
    Number of subjects analysed
    764
    768
    Units: patients
        Responders
    311
    279
    No statistical analyses for this end point

    Secondary: Change from baseline in pre-dose morning FEV1 over 52 weeks of treatment

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    End point title
    		 Change from baseline in pre-dose morning FEV1 over 52 weeks of treatment
    End point description
    Change from baseline in pre-dose morning FEV1 over 52 weeks of treatment. FEV1 is the volume of air that can be forced out in the first second after taking a deep breath. Data are presented as LS mean change from baseline averaged over 52 weeks of treatment. Shown are the number of patients in the ITT population (N) and the number of patients with available results (n).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) - ITT Indacaterol/GB (85/43 μg) - ITT
    Number of subjects analysed
    757 [8]
    760 [9]
    Units: litre(s)
        least squares mean (confidence interval 95%)
    -0.003 (-0.016 to 0.010)
    -0.026 (-0.039 to -0.013)
    Notes
    [8] - N=764; n=757
    [9] - N=768; n=760
    Statistical analysis title
    		 LS mean difference in change from baseline
    Comparison groups
    Indacaterol/GB (85/43 μg) - ITT v CHF 5993 pMDI (100/6/12.5 μg) - ITT
    Number of subjects included in analysis
    1517
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.018
    Method
    		 Mixed model for repeated measures
    Parameter type
    		 Least squares mean difference
    Point estimate
    0.022
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.004
         upper limit
    		 0.04
    Notes
    [10] - Changes from baseline in pre-dose morning FEV1 were analysed using a linear MMRM including treatment, country, visit, treatment by visit interaction, number of COPD exacerbations during the previous year (1, > 1), severity of airflow limitation and smoking status as fixed effects, and baseline and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed.

    Secondary: FEV1 response at Week 26

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    End point title
    		 FEV1 response at Week 26
    End point description
    FEV1 response was 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. Patients with missing data at Week 26 were considered as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) - ITT Indacaterol/GB (85/43 μg) - ITT
    Number of subjects analysed
    764
    768
    Units: patients
        Responders
    176
    156
    No statistical analyses for this end point

    Secondary: FEV1 response at Week 52

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    End point title
    		 FEV1 response at Week 52
    End point description
    FEV1 response was 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. Patients with missing data at Week 52 were considered as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) - ITT Indacaterol/GB (85/43 μg) - ITT
    Number of subjects analysed
    764
    768
    Units: patients
        Responders
    145
    125
    No statistical analyses for this end point

    Secondary: Change from baseline in pre-dose morning FVC over 52 weeks of treatment

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    End point title
    		 Change from baseline in pre-dose morning FVC over 52 weeks of treatment
    End point description
    Change from baseline in pre-dose morning FVC over 52 weeks of treatment. FVC is the volume of air that can be forced out after taking a deep breath. Data are presented as LS mean change from baseline over 52 weeks. Shown are the number of patients in the ITT population (N) and the number of patients with available results (n).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) - ITT Indacaterol/GB (85/43 μg) - ITT
    Number of subjects analysed
    757 [11]
    760 [12]
    Units: litre(s)
        least squares mean (confidence interval 95%)
    -0.058 (-0.082 to -0.034)
    -0.082 (-0.106 to -0.058)
    Notes
    [11] - N=764; n=757
    [12] - N=768; n=760
    No statistical analyses for this end point

    Secondary: Change from baseline in CAT score at Week 52

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    End point title
    		 Change from baseline in CAT score at Week 52
    End point description
    The COPD assessment test (CAT) is a questionnaire developed to measure manifestations of COPD, lower scores correspond to better health. Data are presented as arithmetic mean change from baseline. Shown are the number of patients included in the ITT population (N) and the number of patients with available results for each visit (n).
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment (Week 52)
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) - ITT Indacaterol/GB (85/43 μg) - ITT
    Number of subjects analysed
    700 [13]
    704 [14]
    Units: CAT score
        arithmetic mean (standard deviation)
    -0.8 ± 5.8
    -0.6 ± 6.2
    Notes
    [13] - N=764; n=700
    [14] - N=768; n=704
    No statistical analyses for this end point

    Secondary: Change from baseline in E-RS score over 52 weeks of treatment

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    End point title
    		 Change from baseline in E-RS score over 52 weeks of treatment
    End point description
    The Exacerbations of Chronic Pulmonary Disease Tool – Respiratory Symptoms (E-RS) is a derivative of the EXACT-PRO questionnaire, developed to evaluate the effect of treatment on respiratory symptom severity in patients with COPD, i.e. to test the extent to which treatments improve respiratory symptoms also when patients are stable/non exacerbating. Higher scores correspond to a more severe health status. Data are presented as arithmetic mean change from baseline over the entire treatment period (Week 1-52). Shown are the number of patients in the ITT population (N) and the number of patients with available results (n).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) - ITT Indacaterol/GB (85/43 μg) - ITT
    Number of subjects analysed
    755 [15]
    761 [16]
    Units: E-RS score
        arithmetic mean (standard deviation)
    -0.72 ± 3.85
    -0.44 ± 4.02
    Notes
    [15] - N=764; n=755
    [16] - N=768; n=761
    No statistical analyses for this end point

    Secondary: Change from baseline in percentage of days, night and complete days (day + night) without rescue medication over the entire treatment period

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    End point title
    		 Change from baseline in percentage of days, night and complete days (day + night) without rescue medication over the entire treatment period
    End point description
    Change from baseline in percentage of days, nights and complete days (day + night) without rescue medication over the entire treatment period. Rescue medication use was recorded daily and averaged over the entire treatment period. Data are presented as arithmetic mean change from baseline over the entire treatment period (Week 1-52). Shown are the number of patients in the ITT population (N) and the number of patients with available results for each category (n).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52 (entire treatment period)
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) - ITT Indacaterol/GB (85/43 μg) - ITT
    Number of subjects analysed
    752 [17]
    756 [18]
    Units: Percentage
    arithmetic mean (standard deviation)
        Days
    5.64 ± 29.30
    6.86 ± 31.10
        Nights
    8.66 ± 31.40
    6.79 ± 31.48
        Complete days
    8.39 ± 29.41
    9.42 ± 31.46
    Notes
    [17] - N=764; Days n=755; Nights n=757; Complete days n=752
    [18] - N=768; Days n=761; Nights n=761; Complete days n=756
    No statistical analyses for this end point

    Secondary: Change from baseline in EXACT-PRO nocturnal symptoms score averaged over the treatment period

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    End point title
    		 Change from baseline in EXACT-PRO nocturnal symptoms score averaged over the treatment period
    End point description
    The EXACT-PRO is a validated, patient-reported outcome measure to evaluate exacerbation-related outcomes of COPD treatment using an electronic real-time-based technology. The patient’s health status is correlated to the global score meaning higher score corresponds to more severe health status. The EXACT-PRO item 13, was completed to verify the status of patients’ nocturnal symptoms. Data are presented as arithmetic mean change from baseline over the entire treatment period (Week 1-52). Shown are the number of patients in the ITT population (N) and the number of patients with available results (n).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) - ITT Indacaterol/GB (85/43 μg) - ITT
    Number of subjects analysed
    757 [19]
    761 [20]
    Units: score
        arithmetic mean (standard deviation)
    -0.05 ± 0.50
    -0.04 ± 0.48
    Notes
    [19] - N=764, n=757
    [20] - N=768, n=761
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were reported from the time of patient informed consent signature to study completion or discontinuation.
    Adverse event reporting additional description
    Treatment-emergent AEs (TEAEs) were defined as AEs with date of first randomised study medication intake ≤ AE onset date ≤ date of completion/discontinuation.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    CHF 5993 pMDI (100/6/12.5 μg)
    Reporting group description
    		 -

    Reporting group title
    Indacaterol/GB (85/43 μg)
    Reporting group description
    		 -

    Serious adverse events
    		 CHF 5993 pMDI (100/6/12.5 μg) Indacaterol/GB (85/43 μg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    117 / 764 (15.31%)
    130 / 768 (16.93%)
         number of deaths (all causes)
    16
    21
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct cancer
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    2 / 764 (0.26%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hodgkin's disease
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lip squamous cell carcinoma
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 764 (0.13%)
    2 / 768 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma stage IV
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    4 / 764 (0.52%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 764 (0.13%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine carcinoma metastatic
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Phyllodes tumour
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectosigmoid cancer
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (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 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Essential hypertension
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral artery occlusion
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 764 (0.13%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         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
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
    Additional description: The PT “death” corresponds to cases where the cause of death was unknown.
         subjects affected / exposed
    2 / 764 (0.26%)
    3 / 768 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Facial pain
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 764 (0.00%)
    3 / 768 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Sudden death
         subjects affected / exposed
    1 / 764 (0.13%)
    2 / 768 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 764 (0.26%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    1 / 764 (0.13%)
    2 / 768 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
    Additional description: COPD is the PT for the reported “COPD exacerbation”.
         subjects affected / exposed
    61 / 764 (7.98%)
    69 / 768 (8.98%)
         occurrences causally related to treatment / all
    0 / 75
    0 / 94
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Chronic respiratory failure
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (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 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 764 (0.26%)
    2 / 768 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Respiratory distress
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 764 (0.13%)
    3 / 768 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 764 (0.13%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         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 / 764 (0.00%)
    1 / 768 (0.13%)
         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
    1 / 764 (0.13%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Post procedural complication
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (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
    Porphyria non-acute
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 764 (0.00%)
    5 / 768 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    Aortic valve stenosis
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    0 / 764 (0.00%)
    5 / 768 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Atrial flutter
         subjects affected / exposed
    0 / 764 (0.00%)
    3 / 768 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 764 (0.13%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 764 (0.13%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 764 (0.13%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 764 (0.13%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    2 / 764 (0.26%)
    2 / 768 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 764 (0.13%)
    3 / 768 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         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 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery occlusion
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid sinus syndrome
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         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
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    2 / 764 (0.26%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 764 (0.13%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Diabetic coma
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         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
    1 / 764 (0.13%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (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
    Anaemia
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy mediastinal
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    2 / 764 (0.26%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerulonephritis chronic
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 764 (0.00%)
    2 / 768 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periostitis
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (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
    Appendicitis
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 764 (0.00%)
    2 / 768 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 764 (0.13%)
    2 / 768 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    16 / 764 (2.09%)
    10 / 768 (1.30%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 10
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory tract infection bacterial
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Metabolic disorder
         subjects affected / exposed
    0 / 764 (0.00%)
    1 / 768 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 764 (0.13%)
    0 / 768 (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: 2%
    Non-serious adverse events
    		 CHF 5993 pMDI (100/6/12.5 μg) Indacaterol/GB (85/43 μg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    453 / 764 (59.29%)
    471 / 768 (61.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 764 (1.96%)
    22 / 768 (2.86%)
         occurrences all number
    16
    24
    Nervous system disorders
    Headache
         subjects affected / exposed
    44 / 764 (5.76%)
    35 / 768 (4.56%)
         occurrences all number
    50
    39
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
    Additional description: Chronic obstructive pulmonary disease is the PT for the reported “COPD exacerbation”
         subjects affected / exposed
    231 / 764 (30.24%)
    239 / 768 (31.12%)
         occurrences all number
    369
    407
    Cough
         subjects affected / exposed
    13 / 764 (1.70%)
    21 / 768 (2.73%)
         occurrences all number
    14
    25
    Dyspnoea
         subjects affected / exposed
    21 / 764 (2.75%)
    21 / 768 (2.73%)
         occurrences all number
    25
    23
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    21 / 764 (2.75%)
    23 / 768 (2.99%)
         occurrences all number
    21
    27
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    43 / 764 (5.63%)
    37 / 768 (4.82%)
         occurrences all number
    56
    41

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29429593
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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