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    Clinical Trial Results:
    A 12-Week Study to Evaluate the Efficacy and Safety of Fluticasone Furoate/Vilanterol Inhalation Powder (FF/VI) 100/25 mcg Once Daily Compared with Vilanterol Inhalation Powder (VI) 25 mcg Once Daily in Subjects with Chronic Obstructive Pulmonary Disease (COPD)

    Summary
    EudraCT number
    		 2013-004548-44
    Trial protocol
    		 BG   PL   RO  
    Global end of trial date
    08 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jun 2016
    First version publication date
    30 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    200820
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02105974
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, +1 8664357343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, +1 8664357343,
    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
    14 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the contribution on lung function (as measured by trough forced expiratory volume in one second [FEV1]) of fluticasone furoate (FF) 100 mcg to the FF/vilanterol (VI) 100/25 mcg QD combination by comparison of the latter with VI 25 mcg QD and the safety of FF/VI 100/25 mcg QD over a 12-week treatment period in subjects with COPD. ELLIPTA™ is a registered trademark of GlaxoSmithKline.
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Apr 2014
    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
    United States: 284
    Country: Number of subjects enrolled
    Germany: 223
    Country: Number of subjects enrolled
    Japan: 653
    Country: Number of subjects enrolled
    Korea, Republic of: 135
    Country: Number of subjects enrolled
    Poland: 145
    Country: Number of subjects enrolled
    Romania: 182
    Country: Number of subjects enrolled
    Russian Federation: 250
    Country: Number of subjects enrolled
    South Africa: 116
    Country: Number of subjects enrolled
    Taiwan: 78
    Country: Number of subjects enrolled
    Ukraine: 220
    Country: Number of subjects enrolled
    Bulgaria: 137
    Worldwide total number of subjects
    2423
    EEA total number of subjects
    687
    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)
    1074
    From 65 to 84 years
    1325
    85 years and over
    24

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 238 sites. Participants (par) with a history of chronic obstructive pulmonary disease (COPD) meeting eligibility criteria at screening were enrolled in a 2-week, single-blind (placebo) run-in period to obtain baseline use of albuterol (salbutamol), COPD symptom scores and disease stability.

    Pre-assignment
    Screening details
    		 Par meeting continuation criteria during the run-in period were randomized (1:1) to receive FF/VI 100/25 µg QD or VI 25 µg QD. Of the 2423 par screened, 1622 were randomized. 1620 received at least one dose of double-blind study medication and comprised the Intent-to-Treat population.

    Period 1
    Period 1 title
    2 Week, Single-blind Run-in period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Arm title
    		 Placebo Run-In
    Arm description
    		 Participants received placebo once daily (QD) in the morning for 2 weeks. In addition, participants were provided an inhaled short-acting beta2-receptor agonist (SABA), albuterol (salbutamol) (metered dose inhaler [MDI] or nebules) or oxitropium bromide (applicable sites in Japan), to be used as a rescue medication for relief of chronic obstructive pulmonary disease (COPD) symptoms during the Run-in and Treatment Periods.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo QD
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    QD in the morning via DPI

    Number of subjects in period 1
    		Placebo Run-In
    Started
    2265
    Completed
    1622
    Not completed
    643
         Study closed/terminated
    1
         Consent withdrawn by subject
    23
         Adverse event, non-fatal
    6
         Did not meet inclusion/exclusion criteria
    603
         Lost to follow-up
    2
         Investigator discretion
    8
    Period 2
    Period 2 title
    12 Week (Wk) Treatment Period (TP)
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 FF/VI 100/25 µg QD
    Arm description
    		 Participants received fluticasone furoate/vilaterol (FF/VI) 100/25 microgram(µg) inhalation via a dry powder inhaler (DPI) once daily (QD) in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler [MDI] or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone furoate/vilanterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Single dose of combination of FF 100 microgram (µg) and VI 25 µg in morning via ELLIPTA for 12 weeks

    Arm title
    		 VI 25 µg QD
    Arm description
    		 Participants received VI 25 µg inhalation QD via a DPI in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler [MDI] or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vilanterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Single dose of VI 25 µg in morning via ELLIPTA for 12 weeks

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Eligible participants (par.) at screening entered a 2-week, single-blind placebo run-in period (RIP) to obtain Baseline assessments of albuterol (salbutamol) use, COPD symptom scores and disease stability. At the end of the RIP, par. meeting the continuation criteria entered the double-blind treatment period (TP) of 24 weeks (Wk).
    Number of subjects in period 2 [2] [3]
    		FF/VI 100/25 µg QD VI 25 µg QD
    Started
    806
    814
    Completed the treatment (trt) period
    764
    754 [4]
    Completed
    764
    756
    Not completed
    42
    58
         Physician decision
    7
    4
         Adverse event, non-fatal
    14
    18
         Participant reached stopping criteria
    1
    2
         Withdrawal by Subject
    12
    18
         Lost to follow-up
    -
    1
         Lack of efficacy
    6
    9
         Protocol deviation
    2
    6
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 2,423 par were consented for the study, of whom 158 were withdrawn during the Pre-Screen period. A total of 2,265 par were screened, of whom 1,622 were randomized; 1,620 received at least one dose of double-blind study medication and comprised the Intent-to-Treat (ITT) Population.
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Of the 1622 subjects who completed period 1, 2 subjects were randomized in error and were not included as starting period 2.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Subjects (756) were considered to have completed the study if they attended the last clinic visit (Visit 7), had a follow-up phone contact and did not have an early withdrawal visit. Subjects were considered to have completed the treatment period (754) if they attended the last clinic visit (Visit 7) and did not withdraw at the visit and had an exposure stop date on or after the day prior to Visit 7.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FF/VI 100/25 µg QD
    Reporting group description
    		 Participants received fluticasone furoate/vilaterol (FF/VI) 100/25 microgram(µg) inhalation via a dry powder inhaler (DPI) once daily (QD) in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler [MDI] or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods.

    Reporting group title
    VI 25 µg QD
    Reporting group description
    		 Participants received VI 25 µg inhalation QD via a DPI in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler [MDI] or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods.

    Reporting group values
    		 FF/VI 100/25 µg QD VI 25 µg QD Total
    Number of subjects
    		 806 814 1620
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.3 ( 8.58 ) 65.4 ( 9.02 ) -
    Gender categorical
    Units: Subjects
        Female
    		 201 189 390
        Male
    		 605 625 1230
    Race
    Units: Subjects
        African American/African Heritage
    		 6 10 16
        Asian - East Asian Heritage
    		 77 77 154
        Asian - Japanese Heritage
    		 185 185 370
        White - White/Caucasian/European Heritage
    		 538 541 1079
        Mixed Race
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Placebo Run-In
    Reporting group description
    		 Participants received placebo once daily (QD) in the morning for 2 weeks. In addition, participants were provided an inhaled short-acting beta2-receptor agonist (SABA), albuterol (salbutamol) (metered dose inhaler [MDI] or nebules) or oxitropium bromide (applicable sites in Japan), to be used as a rescue medication for relief of chronic obstructive pulmonary disease (COPD) symptoms during the Run-in and Treatment Periods.
    Reporting group title
    FF/VI 100/25 µg QD
    Reporting group description
    		 Participants received fluticasone furoate/vilaterol (FF/VI) 100/25 microgram(µg) inhalation via a dry powder inhaler (DPI) once daily (QD) in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler [MDI] or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods.

    Reporting group title
    VI 25 µg QD
    Reporting group description
    		 Participants received VI 25 µg inhalation QD via a DPI in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler [MDI] or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods.

    Primary: Mean change from baseline (BL) in Clinic Visit trough (pre-bronchodilator and pre-dose) FEV1 (to evaluate the contribution of FF), on Treatment Day 84 (visit 7, week 12)

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    End point title
    		 Mean change from baseline (BL) in Clinic Visit trough (pre-bronchodilator and pre-dose) FEV1 (to evaluate the contribution of FF), on Treatment Day 84 (visit 7, week 12)
    End point description
    Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled from the lungs in one second. Trough FEV1 measurements were taken electronically by spirometry on Days 2, 14, 28, 56 and 84. BL was defined as the mean of the two assessments made 30 minutes pre-dose and immediately pre-dose on Treatment Day 1. Trough FEV1 was defined as the mean of the FEV1 values obtained 23 and 24 hours after previous morning's dosing. Change from BL was calculated as the average at each visit minus the BL value. Analysis was performed using a repeated measures model with covariates of treatment, reversibility status (stratum), baseline, Region, Day by Baseline, and Day by treatment interactions.
    End point type
    Primary
    End point timeframe
    Baseline to Day 84. Number of par. presented represent those with data available at the time point being presented; however, all par. in the ITT Population without missing covariate information and with at least one post BL measurement are included.
    End point values
    		 FF/VI 100/25 µg QD VI 25 µg QD
    Number of subjects analysed
    759
    749
    Units: Liter
        least squares mean (standard error)
    0.116 ( 0.0074 )
    0.082 ( 0.0075 )
    Statistical analysis title
    		 STATISTICAL ANALYSIS 1
    Comparison groups
    FF/VI 100/25 µg QD v VI 25 µg QD
    Number of subjects included in analysis
    1508
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least squares mean difference
    Point estimate
    0.034
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.014
         upper limit
    		 0.055
    Notes
    [1] - Restricted maximum likelihood (REML)-based repeated measures approach (MMRM)

    Secondary: Percentage of rescue-free 24-hour periods over the entire 12-week treatment period

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    End point title
    		 Percentage of rescue-free 24-hour periods over the entire 12-week treatment period
    End point description
    Par were given a Daily Diary for completion each morning and prior to taking study medication (single- and double-blind), supplemental medication albuterol [salbutamol] (if received) or oxitropium bromide (applicable sites in Japan) and ipratropium (if applicable) starting from the morning following the Screening Visit (Week-2) through Week 12 (Visit 7). Par recorded the number of occasions supplemental albuterol/salbutamol or oxitropium bromide used over the previous 24 hours and any medical problems that they had experienced and any medication used to treat these medical problems over the previous 24 hours. Rescue-free 24-hour periods are defined as the 24-hour periods in which the rescue medication was not used. The percentage of such 24-hour periods are summarized for the entire treatment period (12 weeks). Analysis was performed using an analysis of covariance (ANCOVA) model with covariates of treatment, reversibility status (stratum), baseline (week -1) and region.
    End point type
    Secondary
    End point timeframe
    BL (Week -1), Week 1 to Week 12. Only those participants with at least 1 on treatment rescue medication measurement during the treatment period and without missing covariate information were analyzed.
    End point values
    		 FF/VI 100/25 µg QD VI 25 µg QD
    Number of subjects analysed
    801
    802
    Units: Percentage of rescue-free periods
        least squares mean (standard error)
    47.03 ( 1.07 )
    44.41 ( 1.069 )
    Statistical analysis title
    		 STATISTICAL ANALYSIS 1
    Comparison groups
    FF/VI 100/25 µg QD v VI 25 µg QD
    Number of subjects included in analysis
    1603
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.084
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    2.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.35
         upper limit
    		 5.59

    Secondary: Time to First On-treatment Moderate or Severe COPD Exacerbation

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    End point title
    		 Time to First On-treatment Moderate or Severe COPD Exacerbation
    End point description
    Time to first on-treatment exacerbation was analysed using a Cox proportional hazards model with terms for treatment, reversibility status and percent predicted FEV1 at screening. Exacerbation of COPD is defined by a worsening of symptoms requiring additional treatment. Moderate COPD exacerbation is worsening symptoms of COPD that require treatment with antibiotics and/or systemic corticosteroids. Severe COPD exacerbation is worsening symptoms of COPD that require treatment with in-patient hospitalization. The number of participants with On-Treatment moderate or severe COPD exacerbations are presented.
    End point type
    Secondary
    End point timeframe
    From the start of double blind study medication until visit 7 (week 12)/Early withdrawal
    End point values
    		 FF/VI 100/25 µg QD VI 25 µg QD
    Number of subjects analysed
    806
    814
    Units: Participants
        number (not applicable)
    69
    114
    Statistical analysis title
    		 STATISTICAL ANALYSIS 2
    Comparison groups
    FF/VI 100/25 µg QD v VI 25 µg QD
    Number of subjects included in analysis
    1620
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [2]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.78
    Notes
    [2] - Nominal p-value

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of double-blind (DB) study treatment (Visit 2) through the follow up contact (up to 13 weeks).
    Adverse event reporting additional description
    On-treatment AE or SAE is defined as an AE with an onset date on or after the start date of DB study medication, but not later than one day after the last dose of DB study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    VI 25 µg QD
    Reporting group description
    		 Participants received VI 25 µg inhalation QD via a DPI in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler (MDI) or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods.

    Reporting group title
    FF/VI 100/25 µg QD
    Reporting group description
    		 Participants received fluticasone furoate/vilaterol (FF/VI) 100/25 microgram(µg) inhalation via a dry powder inhaler (DPI) once daily (QD) in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler (MDI) or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods.

    Serious adverse events
    		 VI 25 µg QD FF/VI 100/25 µg QD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 814 (4.30%)
    27 / 806 (3.35%)
         number of deaths (all causes)
    3
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 814 (0.12%)
    1 / 806 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    0 / 814 (0.00%)
    1 / 806 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    0 / 814 (0.00%)
    1 / 806 (0.12%)
         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 / 814 (0.00%)
    1 / 806 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral adenoma
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 814 (0.00%)
    2 / 806 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    17 / 814 (2.09%)
    10 / 806 (1.24%)
         occurrences causally related to treatment / all
    0 / 20
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic respiratory failure
         subjects affected / exposed
    0 / 814 (0.00%)
    1 / 806 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Epistaxis
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (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
    1 / 814 (0.12%)
    0 / 806 (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
    0 / 814 (0.00%)
    1 / 806 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    0 / 814 (0.00%)
    1 / 806 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (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
    Contusion
         subjects affected / exposed
    0 / 814 (0.00%)
    1 / 806 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 814 (0.12%)
    1 / 806 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 814 (0.00%)
    1 / 806 (0.12%)
         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
    1 / 814 (0.12%)
    0 / 806 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 814 (0.00%)
    1 / 806 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 814 (0.00%)
    1 / 806 (0.12%)
         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 / 814 (0.00%)
    2 / 806 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer
         subjects affected / exposed
    0 / 814 (0.00%)
    1 / 806 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (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 / 814 (0.12%)
    0 / 806 (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
    Pneumonia
         subjects affected / exposed
    4 / 814 (0.49%)
    2 / 806 (0.25%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 814 (0.00%)
    1 / 806 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 814 (0.00%)
    1 / 806 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 814 (0.12%)
    0 / 806 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 814 (0.00%)
    1 / 806 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 814 (0.00%)
    1 / 806 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 VI 25 µg QD FF/VI 100/25 µg QD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    64 / 814 (7.86%)
    72 / 806 (8.93%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 814 (2.33%)
    29 / 806 (3.60%)
         occurrences all number
    32
    49
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    48 / 814 (5.90%)
    49 / 806 (6.08%)
         occurrences all number
    53
    56

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

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

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