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    Clinical Trial Results:
    A Multinational, Multicentre, Randomised, Open-Label, Active-Controlled, 26-Week, 2-Arm, Parallel Group Study to Evaluate the Non-Inferiority of Fixed Combination of Beclometasone Dipropionate Plus Formoterol Fumarate Plus Glycopyrronium Bromide Administered Via pMDI (CHF 5993) Versus Fixed Combination Of Fluticasone Furoate Plus Vilanterol Administered Via DPI (Relvar®) Plus Tiotropium Bromide (Spiriva®) for the Treatment of Patients With Chronic Obstructive Pulmonary Disease

    Summary
    EudraCT number
    		 2014-001487-35
    Trial protocol
    		 SE   GB   LT   NL   HU   DE   BE   PL  
    Global end of trial date
    05 Jan 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    17 Jun 2018
    First version publication date
    07 Jan 2018
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Correction of a typo mistake in the Serious Adverse Events section.

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-05993AA1-07
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02467452
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 TRISTAR: Tristar
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A.
    Sponsor organisation address
    Via Palermo 26/A, Parma, Italy, 43122
    Public contact
    Chiesi Farmaceutici S.p.A., Clinical Trial Transparency, ClinicalTrials_info@chiesi.com
    Scientific contact
    Chiesi Farmaceutici S.p.A., Clinical Trial Transparency, 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
    07 Aug 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the non-inferiority of CHF 5993 pMDI versus fixed combination of fluticasone furoate/vilanterol plus tiotropium in terms of quality of life (change from baseline in the St. George’s Respiratory Questionnaire [SGRQ] total score after 26 weeks of treatment).
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines, and national legal requirements. 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 night-time impact of COPD, rescue medication use and compliance with treatment. Furthermore, 12-lead electrocardiogram (ECG) parameters: heart rate (HR), Fridericia corrected QT interval (QTcF), PR interval (PR), and QRS interval (QRS) were evaluated at screening, Week 0 and Week 26 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
    Romania: 274
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Germany: 30
    Country: Number of subjects enrolled
    Hungary: 134
    Country: Number of subjects enrolled
    Lithuania: 65
    Country: Number of subjects enrolled
    Poland: 210
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Russian Federation: 388
    Country: Number of subjects enrolled
    South Africa: 33
    Country: Number of subjects enrolled
    Turkey: 13
    Worldwide total number of subjects
    1157
    EEA total number of subjects
    723
    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)
    619
    From 65 to 84 years
    536
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Overall, 1477 patients were screened according to inclusion and exclusion criteria; of these, 1157 patients were randomised.

    Pre-assignment
    Screening details
    		 At the screening visit, inclusion/exclusion criteria were assessed. The screening visit was followed by a 2-week, open-label, run-in period during which patients self-administered tiotropium (one 18 μg capsule inhaled, once daily [od]).

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    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. Patients were trained with training kits containing placebo in the proper use of pMDI.

    Arm title
    		 Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tiotropium (18 μg)
    Investigational medicinal product code
    Other name
    Spiriva®
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Reference product: Tiotropium bromide (Spiriva®). Dose: Tiotropium bromide 18 μg per capsule, 1 inhalation, od. Total daily dose: Tiotropium bromide 18 μg. Mode of administration: DPI, HandiHaler® inhaler. Patients were trained with training kits containing placebo in the proper use of the HandiHaler® inhaler for the inhalation of DPI in capsule.

    Investigational medicinal product name
    Fluticasone/vilanterol (100/25 μg)
    Investigational medicinal product code
    Other name
    Relvar®
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Reference product: Fluticasone furoate/vilanterol trifenatate (Relvar®). Dose: Fluticasone furoate 100 μg, vilanterol trifenatate 25 μg per pre-dispensed unit dose, 1 inhalation, od. Total daily dose: Fluticasone furoate 100 μg, vilanterol trifenatate 25 μg. Mode of administration: Dry powder inhaler (DPI), Ellipta® inhaler.

    Number of subjects in period 1
    		CHF 5993 pMDI (100/6/12.5 μg) Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Started
    578
    579
    Completed
    545
    549
    Not completed
    33
    30
         Adverse event, serious fatal
    3
    4
         Consent withdrawn by subject
    13
    9
         Adverse event, non-fatal
    6
    10
         Other
    4
    1
         Lost to follow-up
    2
    2
         Lack of efficacy
    2
    3
         Protocol deviation
    3
    1

    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
    Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Reporting group description
    		 -

    Reporting group values
    		 CHF 5993 pMDI (100/6/12.5 μg) Fluticasone/vilanterol + tiotropium (100/25 + 18 μg) Total
    Number of subjects
    		 578 579 1157
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 320 299 619
        From 65-84 years
    		 257 279 536
        85 years and over
    		 1 1 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.6 ( 7.7 ) 64.2 ( 7.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 133 150 283
        Male
    		 445 429 874

    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
    Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Reporting group description
    		 -

    Primary: Change from baseline in the SGRQ total score at Week 26

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    End point title
    		 Change from baseline in the SGRQ total score at Week 26
    End point description
    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 26 (95% Confidence Interval [CI]). Shown are the number of patients included in the model (Intention-to-Treat [ITT] population [N]; patients with available results [n]).
    End point type
    Primary
    End point timeframe
    Baseline to Week 26
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Number of subjects analysed
    553 [1]
    553 [2]
    Units: SGRQ total score
        least squares mean (confidence interval 95%)
    -6.77 (-7.91 to -5.64)
    -7.82 (-8.95 to -6.68)
    Notes
    [1] - N=577; n=553
    [2] - N=579; n=553
    Statistical analysis title
    		 LS mean diff in Δ from baseline in SGRQ at Week 26
    Statistical analysis description
    Least squares mean difference in change from baseline in SGRQ total score at Week 26. Primary efficacy analysis.
    Comparison groups
    CHF 5993 pMDI (100/6/12.5 μg) v Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Number of subjects included in analysis
    1106
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 = 0.204
    Method
    		 Mixed model for repeated measures
    Parameter type
    		 Least squares mean difference
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 2.65
    Notes
    [3] - Analysis is based on a linear mixed model for repeated measures (MMRM) 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. Non-inferiority of CHF 5993 pMDI relative to fluticasone/vilanterol + tiotropium was demonstrated by an upper confidence limit below 4 units.

    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) Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Number of subjects analysed
    577 [4]
    579 [5]
    Units: Subjects
        SGRQ responders
    295
    307
    Notes
    [4] - ITT population
    [5] - ITT population
    No statistical analyses for this end point

    Secondary: Change from baseline in the SGRQ total score at each visit

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    End point title
    		 Change from baseline in the SGRQ total score at each visit
    End point description
    SGRQ total score. Data are presented as arithmetic mean change from baseline at Week 4 and Week 12 (standard deviation; SD). Shown are the number of patients in the ITT population (N) and the number of patients with available results at each time point (n).
    End point type
    Secondary
    End point timeframe
    Baseline to study visits (Week 4, Week 12)
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Number of subjects analysed
    577 [6]
    579 [7]
    Units: SGRQ total score
    arithmetic mean (standard deviation)
        Week 4
    -5.04 ( 13.62 )
    -6.62 ( 12.37 )
        Week 12
    -6.29 ( 14.11 )
    -7.32 ( 13.87 )
    Notes
    [6] - N=577; Week 4 n=569; Week 12 n=565
    [7] - N=579; Week 4 n=577; Week 12 n=566
    No statistical analyses for this end point

    Secondary: Change from baseline in pre-dose morning FEV1 at Week 26

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    End point title
    		 Change from baseline in pre-dose morning FEV1 at Week 26
    End point description
    Change from baseline in pre-dose morning FEV1 at Week 26. FEV1 is the volume of air that can be forced out in the first second after taking a deep breath. Data are presented as arithmetic mean change from baseline at Week 26 (SD). 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 26
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Number of subjects analysed
    577 [8]
    579 [9]
    Units: Litres
        arithmetic mean (standard deviation)
    0.059 ( 0.245 )
    0.109 ( 0.252 )
    Notes
    [8] - N=577; n=553
    [9] - N=579; n=548
    No statistical analyses for this end point

    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) Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Number of subjects analysed
    577 [10]
    579 [11]
    Units: Subjects
        FEV1 responders
    211
    248
    Notes
    [10] - ITT population
    [11] - ITT population
    No statistical analyses for this end point

    Secondary: Change from baseline in pre-dose morning FVC at Week 26

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    End point title
    		 Change from baseline in pre-dose morning FVC at Week 26
    End point description
    Change from baseline in pre-dose morning FVC at Week 26. FVC is the volume of air that can be forced out after taking a deep breath. Data are presented as arithmetic mean change from baseline at Week 26 (SD). 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 26
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Number of subjects analysed
    577 [12]
    579 [13]
    Units: Litres
        arithmetic mean (standard deviation)
    0.03 ( 0.465 )
    0.096 ( 0.425 )
    Notes
    [12] - N=577; n=553
    [13] - N=579; n=548
    No statistical analyses for this end point

    Secondary: Change from baseline in the impact of night-time COPD symptoms on sleep quality over the entire treatment period

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    End point title
    		 Change from baseline in the impact of night-time COPD symptoms on sleep quality over the entire treatment period
    End point description
    Change from baseline in the impact of night-time COPD symptoms on sleep quality over the entire treatment period. Impacts were evaluated daily on a 7 point Likert scale and averaged over the entire treatment period. Data are presented as arithmetic mean change from baseline over the entire treatment period (Week 1-26) (SD). 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 26 (entire treatment period)
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Number of subjects analysed
    577 [14]
    579 [15]
    Units: Impact score
        arithmetic mean (standard deviation)
    -0.200 ( 0.793 )
    -0.224 ( 0.754 )
    Notes
    [14] - N=577; n=573
    [15] - N=579; n=573
    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, night 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 1-26) (SD). 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 26 (entire treatment period)
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Number of subjects analysed
    577 [16]
    579 [17]
    Units: Percentage of days
    arithmetic mean (standard deviation)
        Days
    12.94 ( 31.51 )
    13.94 ( 30.13 )
        Nights
    13.45 ( 28.50 )
    13.00 ( 30.61 )
        Complete days
    14.53 ( 30.51 )
    14.78 ( 29.67 )
    Notes
    [16] - N=577; Days n=575; Nights n=573; Complete days n=571
    [17] - N=579; Days n=573; Nights n=573; Complete days n=567
    No statistical analyses for this end point

    Secondary: COPD assessment test (CAT) score at baseline and Week 26

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    End point title
    		 COPD assessment test (CAT) score at baseline and Week 26
    End point description
    CAT score. CAT is a questionnaire developed to measure manifestations of COPD, lower scores correspond to better health. Data are presented as mean (SD). 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 Week 26
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Number of subjects analysed
    577 [18]
    579 [19]
    Units: CAT score
    arithmetic mean (standard deviation)
        Baseline
    21.8 ( 5.7 )
    21.8 ( 5.9 )
        Week 26
    19 ( 6.7 )
    18.4 ( 6.7 )
    Notes
    [18] - N=577; Baseline n=577; Week 26 n=559
    [19] - N=579; Baseline n=579; Week 26 n=560
    No statistical analyses for this end point

    Secondary: Rate of moderate and severe COPD exacerbation over 26 weeks of treatment

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    End point title
    		 Rate of moderate and severe COPD exacerbation over 26 weeks of treatment
    End point description
    Rate of moderate and severe COPD exacerbation evaluated over 26 weeks of treatment. 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. Data are presented as exacerbation rate per patient per year.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    End point values
    		 CHF 5993 pMDI (100/6/12.5 μg) Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Number of subjects analysed
    577 [20]
    579 [21]
    Units: Exacerbation/patient/year
        number (not applicable)
    0.516
    0.474
    Notes
    [20] - ITT population
    [21] - ITT population
    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.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    CHF 5993 pMDI (100/6/12.5 μg)
    Reporting group description
    		 -

    Reporting group title
    Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Reporting group description
    		 -

    Serious adverse events
    		 CHF 5993 pMDI (100/6/12.5 μg) Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    39 / 578 (6.75%)
    56 / 579 (9.67%)
         number of deaths (all causes)
    3
    5
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 578 (0.17%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         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
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant mediastinal neoplasm
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 578 (0.35%)
    0 / 579 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         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 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    21 / 578 (3.63%)
    31 / 579 (5.35%)
         occurrences causally related to treatment / all
    0 / 26
    0 / 39
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Nasal disorder
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 578 (0.17%)
    2 / 579 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (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 / 578 (0.17%)
    4 / 579 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 578 (0.17%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord disorder
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol abuse
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (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
    Chest injury
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (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 left ventricular failure
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    1 / 578 (0.17%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina pectoris
         subjects affected / exposed
    1 / 578 (0.17%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (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 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 578 (0.35%)
    0 / 579 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (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
    Cerebral ischaemia
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular encephalopathy
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eyelid cyst
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         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
    Leukoplakia
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (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
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle tightness
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    H1N1 influenza
         subjects affected / exposed
    0 / 578 (0.00%)
    2 / 579 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Appendicitis
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    Additional description: Pneumonia includes the preferred terms of bronchopneumonia, lobar pneumonia, pneumonia and pneumonia staphylococcal.
         subjects affected / exposed
    8 / 578 (1.38%)
    11 / 579 (1.90%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyelonephritis chronic
         subjects affected / exposed
    1 / 578 (0.17%)
    0 / 579 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 578 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         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) Fluticasone/vilanterol + tiotropium (100/25 + 18 μg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    241 / 578 (41.70%)
    230 / 579 (39.72%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 578 (2.25%)
    13 / 579 (2.25%)
         occurrences all number
    14
    15
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    10 / 578 (1.73%)
    12 / 579 (2.07%)
         occurrences all number
    11
    13
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    106 / 578 (18.34%)
    87 / 579 (15.03%)
         occurrences all number
    127
    103
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    26 / 578 (4.50%)
    17 / 579 (2.94%)
         occurrences all number
    28
    17
    Oral candidiasis
         subjects affected / exposed
    13 / 578 (2.25%)
    5 / 579 (0.86%)
         occurrences all number
    14
    5
    Respiratory tract infection viral
         subjects affected / exposed
    13 / 578 (2.25%)
    11 / 579 (1.90%)
         occurrences all number
    15
    14

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jun 2015
    There was one substantial general amendment, which comprised the following main changes: change of Sponsor Medical Expert; a rationale for the non-inferiority margin was required by the Regulatory Authorities in Sweden (LAKEMEDELSVERKET Medical Product Agency), and was added to the protocol section on determination of sample size; and an update of the list of forbidden concomitant treatments was required by the Regulatory Authorities in Hungary (the National Institute of Pharmacy and Nutrition). Co-administration of potent inhibitors of CYP34A (e.g. ketoconazole, ritonavir, clarithromycin, chloramphenicol and indinavir) was to be avoided with the comparator used in the study: Relvar® Ellipta®, as based on the relevant summary of product characteristics.

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

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