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    Clinical Trial Results:
    A Randomised, Double Blind, Double Dummy, Parallel Group Study Comparing UMEC/VI (A Fixed Combination Of Umeclidinium and Vilanterol) With Tiotropium In COPD Subjects Who Continue To Have Symptoms on Tiotropium.

    Summary
    EudraCT number
    		 2012-005007-41
    Trial protocol
    		 SE   CZ   EE   NL   ES   GR  
    Global end of trial date
    22 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Mar 2016
    First version publication date
    03 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DB2116960
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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
    30 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to compare the efficacy of UMEC/VI Inhalation Powder (62.5/25 µg) once-daily with tiotropium (18 µg) once-daily over 12 weeks for the treatment of subjects with COPD who have received tiotropium and continue to have symptoms while on tiotropium.
    Protection of trial subjects
    To protect trial subjects only approved standard of care Chronic Obstructive Pulmonary Disease (COPD) medications were evaluated and subjects were not exposed to placebo-only treatment. Additionally study subjects, were provided with supplemental salbuterol as rescue medication. Subjects enrolled into the study had stable disease with no hospitalization for COPD within at least 12 weeks of screening and no use of systemic corticosteroids or antibiotics for a lower respiratory tract infection for at least 6 weeks prior to screening. Additionally, subjects with severe disease requiring long-term oxygen therapy (LTOT) are excluded from participation. Frequent safety assessments including evaluations of adverse events and vital signs were conducted to ensure patient safety was closely monitored. Subjects were allowed to withdraw from the study at any point without giving a reason, and without affecting their continued medical care.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Sep 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
    Norway: 31
    Country: Number of subjects enrolled
    Sweden: 91
    Country: Number of subjects enrolled
    Estonia: 59
    Country: Number of subjects enrolled
    Germany: 152
    Country: Number of subjects enrolled
    Argentina: 122
    Country: Number of subjects enrolled
    Russian Federation: 94
    Country: Number of subjects enrolled
    South Africa: 48
    Country: Number of subjects enrolled
    Ukraine: 118
    Country: Number of subjects enrolled
    United States: 24
    Worldwide total number of subjects
    739
    EEA total number of subjects
    333
    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)
    351
    From 65 to 84 years
    384
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible participants (par) completed a 4-week open label tiotropium run-in phase, and were randomized to blinded study medication for 12 weeks. Supplemental albuterol/salbutamol was provided to all par, to be used on an as-needed basis during the run-in phase and up to Day 85.

    Pre-assignment
    Screening details
    		 A total of 739 par were enrolled; 496 par randomized and 494 par were included in the Intent-to-Treat (ITT) Population (Pop), comprised of all par randomized to treatment (trt) who received at least 1 dose of randomized study medication in the trt 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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Umeclidinium/Vilanterol 62.5/25 µg
    Arm description
    		 Participants self-administered one dose of umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg) once daily via an ELLIPTA dry powder inhaler and placebo once daily via a HANDIHALER each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Umeclidinium/Vilanterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One dose of Umeclidinium/Vilanterol 62.5/25 µg every morning for 12 weeks, via the ELLIPTA dry powder inhaler

    Investigational medicinal product name
    Placebo matching Umeclidinium/Vilanterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of placebo (lactose blended with magnesium stearate) every morning for 12 weeks, via the ELLIPTA dry powder inhaler

    Arm title
    		 Tiotropium bromide 18 µg
    Arm description
    		 Participants self-administered one dose of tiotropium bromide 18 µg once daily via a HANDIHALER and placebo once daily via an ELLIPTA dry powder inhaler each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tiotropium bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One dose of Tiotropium bromide 18 µg every morning for 12 weeks, via the HANDIHALER

    Investigational medicinal product name
    Placebo matching Tiotropium bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of placebo (lactose) every morning for 12 weeks, via the HANDIHALER

    Number of subjects in period 1 [1]
    		Umeclidinium/Vilanterol 62.5/25 µg Tiotropium bromide 18 µg
    Started
    247
    247
    Completed
    230
    231
    Not completed
    17
    16
         Consent withdrawn by subject
    9
    5
         Adverse event, non-fatal
    5
    4
         Lack of efficacy
    1
    5
         Protocol deviation
    2
    2
    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: A total of 739 par were enrolled; 496 par randomized and 494 par were included in the Intent-to-Treat (ITT) Population (Pop), comprised of all par randomized to treatment (trt) who received at least 1 dose of randomized study medication in the trt period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Umeclidinium/Vilanterol 62.5/25 µg
    Reporting group description
    		 Participants self-administered one dose of umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg) once daily via an ELLIPTA dry powder inhaler and placebo once daily via a HANDIHALER each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.

    Reporting group title
    Tiotropium bromide 18 µg
    Reporting group description
    		 Participants self-administered one dose of tiotropium bromide 18 µg once daily via a HANDIHALER and placebo once daily via an ELLIPTA dry powder inhaler each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.

    Reporting group values
    		 Umeclidinium/Vilanterol 62.5/25 µg Tiotropium bromide 18 µg Total
    Number of subjects
    		 247 247 494
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.5 ( 8.71 ) 64.3 ( 8.74 ) -
    Gender categorical
    Units: Subjects
        Female
    		 84 87 171
        Male
    		 163 160 323
    Race, Customized
    Units: Subjects
        African American/African Heritage
    		 2 4 6
        Asian - Central/South Asian Heritage
    		 1 1 2
        White - Arabic/North African Heritage
    		 4 4 8
        White - White/Caucasian/European Heritage
    		 239 237 476
        White - Mixed Race
    		 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Umeclidinium/Vilanterol 62.5/25 µg
    Reporting group description
    		 Participants self-administered one dose of umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg) once daily via an ELLIPTA dry powder inhaler and placebo once daily via a HANDIHALER each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.

    Reporting group title
    Tiotropium bromide 18 µg
    Reporting group description
    		 Participants self-administered one dose of tiotropium bromide 18 µg once daily via a HANDIHALER and placebo once daily via an ELLIPTA dry powder inhaler each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.

    Primary: Change from Baseline in trough forced expiratory volume in one second (FEV1) on Day 85 (Visit 8)

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    End point title
    		 Change from Baseline in trough forced expiratory volume in one second (FEV1) on Day 85 (Visit 8)
    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 1 second. BL was the mean of the values measured 23 hour and 24 hour after dosing prior to Day 1 (ie. after the last open label [OL] tiotropium dosing and prior to the randomized dose). Change from BL is defined as the post-BL value minus the BL value. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained at 23 and 24 hours after dosing on Day 84 (at Week 12 + 1 day). Analysis performed using a mixed repeated measures model (MMRM) with covariates of treatment, BL, center group, 24 hour subset flag, Day, Day by BL and Day by treatment interactions. ITT Population is defined as participants who received at least one dose of randomized study medication in the treatment period. Only those participants with data available at the specified time point were included in the analysis.
    End point type
    Primary
    End point timeframe
    Baseline (BL) and Day 85
    End point values
    		 Umeclidinium/Vilanterol 62.5/25 µg Tiotropium bromide 18 µg
    Number of subjects analysed
    224 [1]
    225 [2]
    Units: Liters
        least squares mean (standard error)
    0.074 ( 0.0155 )
    -0.014 ( 0.0155 )
    Notes
    [1] - ITT Population
    [2] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Umeclidinium/Vilanterol 62.5/25 µg v Tiotropium bromide 18 µg
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.088
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.045
         upper limit
    		 0.131

    Secondary: Change from BL in FEV1 at 3 hours postdose on Day 84

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    End point title
    		 Change from BL in FEV1 at 3 hours postdose on 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 1 second. FEV1 assessments taken on 0 to 3 hour on Day 84 (pre-dose, 5 minutes (min), 15 min, 30 min, 1 hour, and 3 hour post-dose). Pre-dose was the reading obtained at 24 hours after the previous day’s dose (Day 83 dose). BL is defined as mean of the values measured 23 hour and 24 hour after dosing prior to Day 1 (ie. after the last OL tiotropium dosing and prior to the randomized dose). Change from BL is defined as the post-BL value minus the BL value. Analysis performed using mixed model repeated measures with covariates of treatment, BL FEV1, center group, 24 hour subset flag, time, time by treatment interaction and time by BL interaction. Only those participants with data available at the specified time point were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 84
    End point values
    		 Umeclidinium/Vilanterol 62.5/25 µg Tiotropium bromide 18 µg
    Number of subjects analysed
    225 [3]
    228 [4]
    Units: Liters
        least squares mean (standard error)
    0.164 ( 0.0178 )
    0.091 ( 0.0177 )
    Notes
    [3] - ITT Population
    [4] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Umeclidinium/Vilanterol 62.5/25 µg v Tiotropium bromide 18 µg
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.073
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.024
         upper limit
    		 0.122

    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 over a period of a maximum of 94 days starting from Day 1 of treatment until the follow-up contact.
    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 medication in the treatment period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Umeclidinium/Vilanterol 62.5/25 µg
    Reporting group description
    		 Participants self-administered one dose of umeclidinium/vilanterol inhalation powder 62.5/25 µg once daily via an ELLIPTA dry powder inhaler and placebo once daily via a HANDIHALER each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.

    Reporting group title
    Tiotropium bromide 18 µg
    Reporting group description
    		 Participants self-administered one dose of tiotropium bromide 18 µg once daily via a HANDIHALER and placebo once daily via an ELLIPTA dry powder inhaler each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.

    Serious adverse events
    		 Umeclidinium/Vilanterol 62.5/25 µg Tiotropium bromide 18 µg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 247 (2.83%)
    6 / 247 (2.43%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 247 (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
    1 / 247 (0.40%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 247 (0.00%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 247 (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
    1 / 247 (0.40%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 247 (0.40%)
         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: 3%
    Non-serious adverse events
    		 Umeclidinium/Vilanterol 62.5/25 µg Tiotropium bromide 18 µg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 247 (13.77%)
    34 / 247 (13.77%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 247 (6.48%)
    18 / 247 (7.29%)
         occurrences all number
    20
    30
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    18 / 247 (7.29%)
    17 / 247 (6.88%)
         occurrences all number
    19
    18

    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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    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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