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    Clinical Trial Results:
    AC4116136: A multicenter, randomized, double-blind, parallelgroup study to evaluate the efficacy and safety of the addition of umeclidinium bromide Inhalation Powder (62.5mcg) once-daily to fluticasone propionate/salmeterol (250/50mcg) twice-daily, umeclidinium bromide Inhalation Powder (125mcg) once-daily to fluticasone propionate/salmeterol (250/50mcg) twice-daily versus placebo to fluticasone propionate/salmeterol (250/50mcg) twice-daily over 12 weeks in subjects with COPD.

    Summary
    EudraCT number
    		 2012-001871-35
    Trial protocol
    		 CZ  
    Global end of trial date
    16 Aug 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2016
    First version publication date
    17 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC4116136
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01772147
    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, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    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
    02 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Aug 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to compare the efficacy and safety of the addition of UMEC (62.5mcg) once-daily to FSC (250/50mcg) twice-daily, UMEC (125mcg) once-daily to FSC (250/50mcg) twice-daily with placebo to FSC (250/50mcg) twice-daily over 12 weeks for the treatment of subjects with COPD.
    Protection of trial subjects
    Several measures were taken to protect trials subjects: these included adverse event monitoring throughout the study, frequent clinic visits (approximately every 4 weeks) to monitor subject status, exclusion of patients with clinically significant and uncontrolled medical conditions and/or ECG findings, and use of treatment arms where all patients received pharmacologic treatment that was appropriate for the disease and disease severity under study (e.g., patients on placebo received appropriate background therapy).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Jan 2013
    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: 120
    Country: Number of subjects enrolled
    Czech Republic: 170
    Country: Number of subjects enrolled
    Chile: 170
    Country: Number of subjects enrolled
    Korea, Republic of: 151
    Country: Number of subjects enrolled
    United States: 261
    Worldwide total number of subjects
    872
    EEA total number of subjects
    290
    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)
    408
    From 65 to 84 years
    455
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 606 participants met the eligibility criteria, were randomized, and received open-label fluticasone propionate and salmeterol (FSC) 250/50 micrograms (μg) for up to 12 Weeks during the Treatment Period

    Pre-assignment
    Screening details
    		 872 participants were enrolled in the trial and 608 were randomized to treatment. Of these, 606 participants comprised the Intent-to-Treat Population (participants randomized to treatment who received >=1 dose of randomized study medication in the treatment period).

    Period 1
    Period 1 title
    Overall Study (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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo QD + FSC 250/50 µg BID
    Arm description
    		 Participants received placebo once daily (QD) each morning via a dry powder inhaler (DPI) and FSC 250/50 µg twice daily (BID) (one inhalation each morning and one inhalation each evening) via a DPI for 12 weeks. Placebo was administered as a blinded study drug and FSC was open label.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Respiratory use
    Dosage and administration details
    Once daily via a dry powder inhaler

    Arm title
    		 UMEC 62.5 µg QD + FSC 250/50 µg BID
    Arm description
    		 Participants received umeclidinium bromide (UMEC) 62.5 µg QD each morning via a DPI and FSC 250/50 µg BID (one inhalation each morning and one inhalation each evening) via a DPI for 12 weeks. UMEC was administered as a blinded study drug and FSC was open label.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Umeclidinium bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Respiratory use
    Dosage and administration details
    62.5 µg once daily via a dry powder inhaler

    Arm title
    		 UMEC 125 µg QD + FSC 250/50 µg BID
    Arm description
    		 Participants received UMEC 125 µg QD each morning via a DPI and FSC 250/50 µg BID (one inhalation each morning and one inhalation each evening) via a DPI for 12 weeks. UMEC was administered as a blinded study drug and FSC was open label.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Umeclidinium bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Respiratory use
    Dosage and administration details
    125 µg once daily via a dry powder inhaler

    Number of subjects in period 1 [1]
    		Placebo QD + FSC 250/50 µg BID UMEC 62.5 µg QD + FSC 250/50 µg BID UMEC 125 µg QD + FSC 250/50 µg BID
    Started
    201
    203
    202
    Completed
    170
    178
    184
    Not completed
    31
    25
    18
         Adverse event, serious fatal
    1
    1
    -
         Consent withdrawn by subject
    7
    8
    4
         Adverse event, non-fatal
    12
    9
    6
         Lost to follow-up
    1
    -
    1
         Protocol deviation
    2
    1
    1
         Lack of efficacy
    8
    6
    6
    Notes
    [1] - 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: Although 872 participants were enrolled in the trial worldwide, only 608 were randomized to treatment. Of these, 606 participants comprised the Intent-to-Treat Population (participants randomized to treatment who received >=1 dose of randomized study medication in the treatment period).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo QD + FSC 250/50 µg BID
    Reporting group description
    		 Participants received placebo once daily (QD) each morning via a dry powder inhaler (DPI) and FSC 250/50 µg twice daily (BID) (one inhalation each morning and one inhalation each evening) via a DPI for 12 weeks. Placebo was administered as a blinded study drug and FSC was open label.

    Reporting group title
    UMEC 62.5 µg QD + FSC 250/50 µg BID
    Reporting group description
    		 Participants received umeclidinium bromide (UMEC) 62.5 µg QD each morning via a DPI and FSC 250/50 µg BID (one inhalation each morning and one inhalation each evening) via a DPI for 12 weeks. UMEC was administered as a blinded study drug and FSC was open label.

    Reporting group title
    UMEC 125 µg QD + FSC 250/50 µg BID
    Reporting group description
    		 Participants received UMEC 125 µg QD each morning via a DPI and FSC 250/50 µg BID (one inhalation each morning and one inhalation each evening) via a DPI for 12 weeks. UMEC was administered as a blinded study drug and FSC was open label.

    Reporting group values
    		 Placebo QD + FSC 250/50 µg BID UMEC 62.5 µg QD + FSC 250/50 µg BID UMEC 125 µg QD + FSC 250/50 µg BID Total
    Number of subjects
    		 201 203 202 606
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.7 ( 7.92 ) 64.5 ( 8.31 ) 65.5 ( 7.89 ) -
    Gender categorical
    Units: Subjects
        Female
    		 78 63 82 223
        Male
    		 123 140 120 383
    Race, Customized
    Units: Subjects
        African American/African Heritage
    		 3 5 4 12
        American Indian or Alaska Native
    		 0 1 0 1
        Japanese/East Asian/South East Asian Heritage
    		 37 33 27 97
        White
    		 161 164 171 496

    End points

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    End points reporting groups
    Reporting group title
    Placebo QD + FSC 250/50 µg BID
    Reporting group description
    		 Participants received placebo once daily (QD) each morning via a dry powder inhaler (DPI) and FSC 250/50 µg twice daily (BID) (one inhalation each morning and one inhalation each evening) via a DPI for 12 weeks. Placebo was administered as a blinded study drug and FSC was open label.

    Reporting group title
    UMEC 62.5 µg QD + FSC 250/50 µg BID
    Reporting group description
    		 Participants received umeclidinium bromide (UMEC) 62.5 µg QD each morning via a DPI and FSC 250/50 µg BID (one inhalation each morning and one inhalation each evening) via a DPI for 12 weeks. UMEC was administered as a blinded study drug and FSC was open label.

    Reporting group title
    UMEC 125 µg QD + FSC 250/50 µg BID
    Reporting group description
    		 Participants received UMEC 125 µg QD each morning via a DPI and FSC 250/50 µg BID (one inhalation each morning and one inhalation each evening) via a DPI for 12 weeks. UMEC was administered as a blinded study drug and FSC was open label.

    Primary: Change from Baseline in the trough forced expiratory volume in one second (FEV1) on Day 85

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    End point title
    		 Change from Baseline in the trough forced expiratory volume in one second (FEV1) on Day 85
    End point description
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 on Treatment Day 85 is defined as the mean of the FEV1 values obtained 23 and 24 hours after dosing on Treatment Day 84 (i.e., at Week 12). Baseline FEV1 is the mean of the two assessments made at -30 and -5 minutes (min) pre-dose on Treatment Day 1. Change from Baseline was calculated as the Day 85 value minus the Baseline value. Analysis was performed using a repeated measures model with covariates of treatment, Baseline (mean of the two assessments made at -30 and -5 min pre-dose on Treatment Day 1), smoking status, day, day by Baseline, and day by treatment interactions. Intent-to-Treat (ITT) Population: all participants randomized to treatment who received at least one dose of randomized study medication in the Treatment Period.
    End point type
    Primary
    End point timeframe
    Baseline and Day 85
    End point values
    		 Placebo QD + FSC 250/50 µg BID UMEC 62.5 µg QD + FSC 250/50 µg BID UMEC 125 µg QD + FSC 250/50 µg BID
    Number of subjects analysed
    200 [1]
    203 [2]
    202 [3]
    Units: Liters
        least squares mean (standard error)
    -0.001 ( 0.0136 )
    0.126 ( 0.0133 )
    0.147 ( 0.0132 )
    Notes
    [1] - Analysis included all subjects with at least one post-baseline non-missing trough assessment.
    [2] - Analysis included all subjects with at least one post-baseline non-missing trough assessment.
    [3] - Analysis included all subjects with at least one post-baseline non-missing trough assessment.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo QD + FSC 250/50 µg BID v UMEC 62.5 µg QD + FSC 250/50 µg BID
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 least squares mean
    Point estimate
    0.127
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.089
         upper limit
    		 0.164
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo QD + FSC 250/50 µg BID v UMEC 125 µg QD + FSC 250/50 µg BID
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 least squares mean
    Point estimate
    0.148
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.111
         upper limit
    		 0.185

    Secondary: Change from Baseline in 0-6 hour weighted mean FEV1 obtained post-dose at Day 84

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    End point title
    		 Change from Baseline in 0-6 hour weighted mean FEV1 obtained post-dose at Day 84
    End point description
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The weighted mean FEV1 was derived by calculating the area under the curve, and then dividing the value by the relevant time interval. The weighted mean was calculated using the 6-hour serial FEV1 measurements at Day 84, which included pre-dose, and post-dose at 15 min, 30 min, 1 hour, 3 hours, and 6 hours. Baseline FEV1 is the mean of the two assessments made at -30 and -5 min pre-dose on Treatment Day 1. Change from Baseline was calculated as the Day 84 value minus the Baseline value. Analysis was performed using a repeated measures model with covariates of treatment, Baseline (mean of the two assessments made at -30and -5 min pre-dose on Treatment Day 1), smoking status, day, day by Baseline, and day by treatment interactions.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 84
    End point values
    		 Placebo QD + FSC 250/50 µg BID UMEC 62.5 µg QD + FSC 250/50 µg BID UMEC 125 µg QD + FSC 250/50 µg BID
    Number of subjects analysed
    200 [4]
    203 [5]
    202 [6]
    Units: Liters
        least squares mean (standard error)
    0.052 ( 0.0137 )
    0.196 ( 0.0135 )
    0.217 ( 0.0133 )
    Notes
    [4] - Analysis included all subjects with at least one post-baseline non-missing 0-6 h weighted mean value
    [5] - Analysis included all subjects with at least one post-baseline non-missing 0-6 h weighted mean value
    [6] - Analysis included all subjects with at least one post-baseline non-missing 0-6 h weighted mean value
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    UMEC 62.5 µg QD + FSC 250/50 µg BID v Placebo QD + FSC 250/50 µg BID
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least squares mean
    Point estimate
    0.144
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.107
         upper limit
    		 0.182
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    UMEC 125 µg QD + FSC 250/50 µg BID v Placebo QD + FSC 250/50 µg BID
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least squares mean
    Point estimate
    0.165
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.128
         upper limit
    		 0.203

    Secondary: Change from Baseline in the percentage of rescue-free days over Weeks 1-12

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    End point title
    		 Change from Baseline in the percentage of rescue-free days over Weeks 1-12
    End point description
    A rescue-free day is defined as a day on which no rescue medication was taken. Baseline calculations include a period of the later of 27 days before Visit 2 and the day after Visit 1, up to and including Day 1. The Weeks 1-12 calculations include a period from Study Day 2 up to the earlier of Study Day 85 and the day before Visit 7. Change from Baseline was calculated as the Weeks 1-12 value minus the Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1-12
    End point values
    		 Placebo QD + FSC 250/50 µg BID UMEC 62.5 µg QD + FSC 250/50 µg BID UMEC 125 µg QD + FSC 250/50 µg BID
    Number of subjects analysed
    174 [7]
    191 [8]
    187 [9]
    Units: Percentage of days
        arithmetic mean (standard deviation)
    1.9 ( 27.38 )
    8.4 ( 30.23 )
    15.2 ( 28.25 )
    Notes
    [7] - Only those participants with data available over Weeks 1-12 were summarized.
    [8] - Only those participants with data available over Weeks 1-12 were summarized.
    [9] - Only those participants with data available over Weeks 1-12 were summarized.
    No statistical analyses for this end point

    Secondary: Change from Baseline in the mean number of puffs per day of rescue albuterol/salbutamol over Weeks 1-12

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    End point title
    		 Change from Baseline in the mean number of puffs per day of rescue albuterol/salbutamol over Weeks 1-12
    End point description
    The number of puffs and nebules per day of rescue albuterol/salbutamol at Baseline and on-treatment was recorded. The total puffs and nebules of rescue albuterol/salbutamol for each day was calculated as: (number of puffs + [2 * number of nebules]). Baseline calculations include a period of the later of 27 days before Visit 2 and the day after Visit 1, up to and including Day 1. The Weeks 1-12 calculations include a period from Study Day 2 up to the earlier of Study Day 85 and the day before Visit 7. Change from Baseline was calculated as the Weeks 1-12 value minus the Baseline value. Analysis was performed using an analysis of covariance (ANCOVA) model with covariates of treatment, Baseline (mean during the 4 weeks prior to Day 1), and smoking status.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1-12
    End point values
    		 Placebo QD + FSC 250/50 µg BID UMEC 62.5 µg QD + FSC 250/50 µg BID UMEC 125 µg QD + FSC 250/50 µg BID
    Number of subjects analysed
    174 [10]
    191 [11]
    187 [12]
    Units: Puffs
        least squares mean (standard error)
    -0.2 ( 0.1 )
    -0.4 ( 0.1 )
    -0.7 ( 0.1 )
    Notes
    [10] - Only those participants with data available over Weeks 1-12 were analyzed.
    [11] - Only those participants with data available over Weeks 1-12 were analyzed.
    [12] - Only those participants with data available over Weeks 1-12 were analyzed.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Placebo QD + FSC 250/50 µg BID v UMEC 62.5 µg QD + FSC 250/50 µg BID
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.085
    Method
    		 ANCOVA
    Parameter type
    		 least squares mean
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 0
    Statistical analysis title
    		 Copy of Statistical Analysis 4
    Comparison groups
    Placebo QD + FSC 250/50 µg BID v UMEC 125 µg QD + FSC 250/50 µg BID
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 least squares mean
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 -0.3

    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) are defined as those events occurring while participants were on treatment or those events with an onset during the follow-up period (up to 13 weeks).
    Adverse event reporting additional description
    SAEs and non-serious AEs are reported for members of the ITT Population, comprised of all participants randomized to treatment who received at least one dose of randomized study medication in the Treatment Period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo QD + FSC 250/50 µg BID
    Reporting group description
    		 Participants received placebo once daily (QD) each morning via a dry powder inhaler (DPI) and FSC 250/50 µg twice daily (BID) (one inhalation each morning and one inhalation each evening) via a DPI for 12 weeks.

    Reporting group title
    UMEC 62.5 µg QD + FSC 250/50 µg BID
    Reporting group description
    		 Participants received umeclidinium bromide (UMEC) 62.5 µg QD each morning via a DPI and FSC 250/50 µg BID (one inhalation each morning and one inhalation each evening) via a DPI for 12 weeks.

    Reporting group title
    UMEC 125 µg QD + FSC 250/50 µg BID
    Reporting group description
    		 Participants received UMEC 125 µg QD each morning via a DPI and FSC 250/50 µg BID (one inhalation each morning and one inhalation each evening) via a DPI for 12 weeks.

    Serious adverse events
    		 Placebo QD + FSC 250/50 µg BID UMEC 62.5 µg QD + FSC 250/50 µg BID UMEC 125 µg QD + FSC 250/50 µg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 201 (7.46%)
    6 / 203 (2.96%)
    6 / 202 (2.97%)
         number of deaths (all causes)
    2
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 203 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 203 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    8 / 201 (3.98%)
    3 / 203 (1.48%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure chronic
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Dupuytren’s contracture
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 203 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    2 / 201 (1.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 201 (1.99%)
    3 / 203 (1.48%)
    3 / 202 (1.49%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Placebo QD + FSC 250/50 µg BID UMEC 62.5 µg QD + FSC 250/50 µg BID UMEC 125 µg QD + FSC 250/50 µg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 201 (8.96%)
    13 / 203 (6.40%)
    16 / 202 (7.92%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 201 (4.48%)
    9 / 203 (4.43%)
    6 / 202 (2.97%)
         occurrences all number
    32
    15
    12
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 201 (4.48%)
    6 / 203 (2.96%)
    10 / 202 (4.95%)
         occurrences all number
    13
    6
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Feb 2013
    The main revisions to the protocol were to clarify the time period for detection of adverse events and serious adverse events, and clarifications to the study procedures and prohibited medications.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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