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    Clinical Trial Results:
    DB2114930: A randomized, multi-center, double-blind, doubledummy, parallel group study to evaluate the efficacy and safety of umeclidinium/vilanterol compared with fluticasone propionate/salmeterol over 12 weeks in subjects with COPD.

    Summary
    EudraCT number
    2012-000525-45
    Trial protocol
    GR  
    Global end of trial date
    25 Oct 2013

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

    Trial information

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    Trial identification
    Sponsor protocol code
    DB2114930
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01817764
    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
    14 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare the efficacy and safety of UMEC/VI Inhalation Powder (62.5/25mcg oncedaily) with fluticasone propionate/salmeterol (250/50mcg twice-daily) over 12 weeks in subjects with COPD who have a history of infrequent COPD exacerbations
    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. Fluticasone propionate/salmeterol combination inhalation powder is a marketed product and was administered according to the local label. Fluticasone propionate/salmeterol has an acceptable safety profile for use. This conclusion is supported by the results of previously performed clinical studies and post-marketing experience (see local label). All patients were on active treatment.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Mar 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
    Argentina: 126
    Country: Number of subjects enrolled
    Chile: 124
    Country: Number of subjects enrolled
    Greece: 69
    Country: Number of subjects enrolled
    Peru: 16
    Country: Number of subjects enrolled
    Romania: 192
    Country: Number of subjects enrolled
    Ukraine: 210
    Country: Number of subjects enrolled
    United States: 184
    Worldwide total number of subjects
    921
    EEA total number of subjects
    261
    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)
    531
    From 65 to 84 years
    385
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 707 participants, representing the enrolled participants, were randomized to study treatment. Of these, 706 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
    Umeclidinium bromide/vilanterol 62.5/25 mcg
    Arm description
    Participants were randomized to umeclidinium bromide/vilanterol (UMEC/VI) 62.5/25 micrograms (µg) once-daily (QD) treatment in the morning via a dry powder inhaler (DPI) and placebo in the morning and evening via a separate DPI.
    Arm type
    Experimental

    Investigational medicinal product name
    Umeclidinium bromide/ vilanterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Respiratory use
    Dosage and administration details
    62.5/25 mcg once-daily via dry powder inhaler

    Arm title
    Fluticasone propionate/salmeterol 250/50 mcg
    Arm description
    Participants were randomized to fluticasone propionate/salmeterol (FSC) 250/50 µg twice-daily (BID) treatment in the morning and evening via a DPI and placebo in the morning via a separate DPI.
    Arm type
    Active comparator

    Investigational medicinal product name
    fluticasone propionate/salmeterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Respiratory use
    Dosage and administration details
    250/50 mcg twice-daily via dry powder inhaler

    Number of subjects in period 1 [1]
    Umeclidinium bromide/vilanterol 62.5/25 mcg Fluticasone propionate/salmeterol 250/50 mcg
    Started
    353
    353
    Completed
    319
    315
    Not completed
    34
    38
         Protocol deviation
    7
    5
         Lack of efficacy
    9
    7
         Adverse event, non-fatal
    7
    10
         Consent withdrawn by subject
    10
    12
         Lost to follow-up
    1
    4
    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 921 participants were enrolled in the trial worldwide, only 707 were randomized to treatment. Of these, 706 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
    Umeclidinium bromide/vilanterol 62.5/25 mcg
    Reporting group description
    Participants were randomized to umeclidinium bromide/vilanterol (UMEC/VI) 62.5/25 micrograms (µg) once-daily (QD) treatment in the morning via a dry powder inhaler (DPI) and placebo in the morning and evening via a separate DPI.

    Reporting group title
    Fluticasone propionate/salmeterol 250/50 mcg
    Reporting group description
    Participants were randomized to fluticasone propionate/salmeterol (FSC) 250/50 µg twice-daily (BID) treatment in the morning and evening via a DPI and placebo in the morning via a separate DPI.

    Reporting group values
    Umeclidinium bromide/vilanterol 62.5/25 mcg Fluticasone propionate/salmeterol 250/50 mcg Total
    Number of subjects
    353 353 706
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    62.5 ± 9.05 63 ± 8.91 -
    Gender categorical
    Units: Subjects
        Female
    100 109 209
        Male
    253 244 497
    Race
    Units: Subjects
        African American/African Heritage
    4 3 7
        American Indian or Alaska Native
    5 5 10
        Asian - East Asian Heritage
    1 1 2
        Asian - Japanese Heritage
    2 1 3
        White - Arabic/North African Heritage
    0 1 1
        White - White/Caucasian/European
    341 342 683

    End points

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    End points reporting groups
    Reporting group title
    Umeclidinium bromide/vilanterol 62.5/25 mcg
    Reporting group description
    Participants were randomized to umeclidinium bromide/vilanterol (UMEC/VI) 62.5/25 micrograms (µg) once-daily (QD) treatment in the morning via a dry powder inhaler (DPI) and placebo in the morning and evening via a separate DPI.

    Reporting group title
    Fluticasone propionate/salmeterol 250/50 mcg
    Reporting group description
    Participants were randomized to fluticasone propionate/salmeterol (FSC) 250/50 µg twice-daily (BID) treatment in the morning and evening via a DPI and placebo in the morning via a separate DPI.

    Primary: Change from Baseline in 24-hour weighted-mean serial FEV1 on Treatment Day 84

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    End point title
    Change from Baseline in 24-hour weighted-mean serial FEV1 on Treatment 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. Weighted mean is calculated from the pre-dose FEV1 and post-dose FEV1 measurements at 5 and 15 minutes and 1, 3, 6, 9, 12 (pre-evening dose), 13, 15, 18, 23, and 24 hours after the morning dose. Change from Baseline was calculated as the value at Day 84 minus the value at Baseline. Analysis was performed using an analysis of covariance of treatment, Baseline (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), and smoking status. par.=participants.
    End point type
    Primary
    End point timeframe
    Baseline and Day 84
    End point values
    Umeclidinium bromide/vilanterol 62.5/25 mcg Fluticasone propionate/salmeterol 250/50 mcg
    Number of subjects analysed
    315 [1]
    310 [2]
    Units: Liters
        least squares mean (standard error)
    0.165 ± 0.013
    0.091 ± 0.0131
    Notes
    [1] - Intent-to-Treat (ITT) Population
    [2] - Intent-to-Treat (ITT) Population
    Statistical analysis title
    Analysis 1
    Comparison groups
    Umeclidinium bromide/vilanterol 62.5/25 mcg v Fluticasone propionate/salmeterol 250/50 mcg
    Number of subjects included in analysis
    625
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0.074
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.038
         upper limit
    0.11

    Secondary: Change from Baseline in trough FEV1 on Day 85

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    End point title
    Change from Baseline in trough 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. BL is defined as the mean of the assessments made 30 and 5 min pre-dose on treatment (trt) Day 1. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained 23 and 24 hours after morning dosing on Day 84. Analysis was performed using a repeated measures model with covariates of trt, BL (mean of the 2 assessments made 30 and 5 min pre-dose on Day 1), smoking status, day, day by BL and day by trt interactions. The model used all available trough FEV1 values recorded on Days 28, 56, 84, and 85. Missing data were not directly imputed in this analysis; however, all non-missing data for a par. were used to estimate the trt effect for trough FEV1 at Day 85. Change from BL=value at Day 84 minus value at BL. Par. analyzed were those with data available at the time point; but, all par. without missing covariate information were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 85
    End point values
    Umeclidinium bromide/vilanterol 62.5/25 mcg Fluticasone propionate/salmeterol 250/50 mcg
    Number of subjects analysed
    317 [3]
    312 [4]
    Units: Liters
        least squares mean (standard error)
    0.154 ± 0.0133
    0.072 ± 0.0134
    Notes
    [3] - Intent-to-Treat (ITT) Population
    [4] - Intent-to-Treat (ITT) Population
    Statistical analysis title
    Analysis 2
    Comparison groups
    Umeclidinium bromide/vilanterol 62.5/25 mcg v Fluticasone propionate/salmeterol 250/50 mcg
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Repeated measures
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.045
         upper limit
    0.119

    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 study medication until the follow-up contact (up to 13 weeks).
    Adverse event reporting additional description
    On-treatment SAEs and non-serious AEs were reported for members of the ITT Population, comprised of all participants randomized to treatment who received at least one dose of randomized study drug in the treatment period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Umeclidinium bromide/vilanterol 62.5/25 mcg
    Reporting group description
    Participants were randomized to umeclidinium bromide/vilanterol (UMEC/VI) 62.5/25 micrograms (µg) once-daily (QD) treatment in the morning via a dry powder inhaler (DPI) and placebo in the morning and evening via a separate DPI.

    Reporting group title
    Fluticasone propionate/salmeterol 250/50 mcg
    Reporting group description
    Participants were randomized to fluticasone propionate/salmeterol (FSC) 250/50 µg twice-daily (BID) treatment in the morning and evening via a DPI and placebo in the morning via a separate DPI.

    Serious adverse events
    Umeclidinium bromide/vilanterol 62.5/25 mcg Fluticasone propionate/salmeterol 250/50 mcg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 353 (1.70%)
    10 / 353 (2.83%)
         number of deaths (all causes)
    0
    3
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 353 (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
    0 / 353 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Obstructive airways disorder
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 353 (0.28%)
    3 / 353 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 353 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 353 (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
    Bronchitis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burn infection
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 353 (0.00%)
    3 / 353 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    Umeclidinium bromide/vilanterol 62.5/25 mcg Fluticasone propionate/salmeterol 250/50 mcg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 353 (10.76%)
    25 / 353 (7.08%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    23 / 353 (6.52%)
    17 / 353 (4.82%)
         occurrences all number
    36
    29
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    16 / 353 (4.53%)
    8 / 353 (2.27%)
         occurrences all number
    18
    9

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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