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    Clinical Trial Results:
    A Randomized, Open-Label, 8-Week Cross-Over Study to Compare Umeclidinium/Vilanterol with Tiotropium/Olodaterol Once-Daily in Subjects with Chronic Obstructive Pulmonary Disease (COPD)

    Summary
    EudraCT number
    		 2016-000585-36
    Trial protocol
    		 DE   ES  
    Global end of trial date
    27 Apr 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    21 Jun 2018
    First version publication date
    19 Apr 2018
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    204990
    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
    04 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of UMEC/VI 62.5/25 mcg with TIO/OLO 5/5mcg once daily on lung function in subjects with moderate COPD over 8 weeks of treatment
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Jul 2016
    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
    Germany: 91
    Country: Number of subjects enrolled
    Spain: 66
    Country: Number of subjects enrolled
    United Kingdom: 67
    Country: Number of subjects enrolled
    United States: 219
    Worldwide total number of subjects
    443
    EEA total number of subjects
    224
    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)
    209
    From 65 to 84 years
    231
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 This is a multicenter, randomized, open label, 2 period crossover complete block design study. Participants (par.) with Chronic Obstructive Pulmonary Disease (COPD) were enrolled across 4 countries: Germany, Spain, the United Kingdom and the United States.

    Pre-assignment
    Screening details
    		 Study consisted of a run-in period of approximately 2 weeks followed by two 8-week treatment periods with a washout of approximately 3 weeks. The total duration of the study was approximately 22 weeks including follow-up. A total of 443 par. were screened, of which 236 par. were randomized (207 par. were pre-screen, screen and run-in failures).

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Treatment Period 1
    Arm description
    		 In this 2-way crossover study, eligible participants were randomized to receive UMEC/VI inhalation powder 62.5/25 mcg QD administered as 1 inhalation via the ELLIPTA® Inhaler and TIO/OLO 5/5 mcg inhalation spray administered as 2 inhalations via the RESPIMAT® inhaler in 8-week TP1 and TP2 per randomization. This was separated by a 3-week washout period. Albuterol/salbutamol was supplied as an inhalation spray via metered dose inhaler throughout the study for use as-needed
    Arm type
    		 Experimental

    Investigational medicinal product name
    Umeclidinium/Vilanterol 62.5/25 mcg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    UMEC/VI was delivered via ELLIPTA. ELLIPTA dry powder inhaler (DPI) contained a total of 30 doses. Each DPI comprised of two double-foil, laminate blister strips. Each blister of one strip consisted of 62.5 mcg of UMEC blended with lactose and magnesium stearate while each blister of other strip consisted of 25 mcg of VI blended with lactose and magnesium stearate. Each actuation of the DPI delivered the contents of one blister from each strip simultaneously

    Investigational medicinal product name
    Tiotropium/Olodaterol 5/5 mcg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    TIO/OLO inhalation spray was supplied as an inhalation spray and was delivered using a RESPIMAT inhaler. Each actuation from the RESPIMAT inhaler delivered 3.124 mcg tiotropium bromide monohydrate (equivalent to 2.5 mcg tiotropium) and 2.736 mcg olodaterol hydrochloride (equivalent to 2.5 mcg olodaterol)

    Arm title
    		 Washout Period (3 weeks)
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Treatment Period 2
    Arm description
    		 In this 2-way crossover study, eligible participants were randomized to receive UMEC/VI inhalation powder 62.5/25 mcg QD administered as 1 inhalation via the ELLIPTA® Inhaler and TIO/OLO 5/5 mcg inhalation spray administered as 2 inhalations via the RESPIMAT® inhaler in 8-week TP1 and TP2 per randomization. This was separated by a 3-week washout period. Albuterol/salbutamol was supplied as an inhalation spray via metered dose inhaler throughout the study for use as-needed
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium/Olodaterol 5/5 mcg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    TIO/OLO inhalation spray was supplied as an inhalation spray and was delivered using a RESPIMAT inhaler. Each actuation from the RESPIMAT inhaler delivered 3.124 mcg tiotropium bromide monohydrate (equivalent to 2.5 mcg tiotropium) and 2.736 mcg olodaterol hydrochloride (equivalent to 2.5 mcg olodaterol)

    Investigational medicinal product name
    Umeclidinium/Vilanterol 62.5/25 mcg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    UMEC/VI was delivered via ELLIPTA. ELLIPTA dry powder inhaler (DPI) contained a total of 30 doses. Each DPI comprised of two double-foil, laminate blister strips. Each blister of one strip consisted of 62.5 mcg of UMEC blended with lactose and magnesium stearate while each blister of other strip consisted of 25 mcg of VI blended with lactose and magnesium stearate. Each actuation of the DPI delivered the contents of one blister from each strip simultaneously

    Number of subjects in period 1
    		Treatment Period 1 Washout Period (3 weeks) Treatment Period 2
    Started
    236
    229
    229
    Completed
    229
    229
    225
    Not completed
    7
    0
    4
         Consent withdrawn by subject
    5
    -
    1
         Adverse event, non-fatal
    -
    -
    1
         Lost to follow-up
    2
    -
    1
         Par. reached protocol stopping criteria
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Overall Study
    Reporting group description
    		 Overall Study

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 443 participants were enrolled of which 236 were randomized.
    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 236
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.4 ± 8.47 -
    Gender categorical
    Units: Subjects
        Female
    		 94 94
        Male
    		 142 142
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage
    		 13 13
        White - White/Caucasian/European Heritage
    		 223 223

    End points

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    End points reporting groups
    Reporting group title
    Treatment Period 1
    Reporting group description
    		 In this 2-way crossover study, eligible participants were randomized to receive UMEC/VI inhalation powder 62.5/25 mcg QD administered as 1 inhalation via the ELLIPTA® Inhaler and TIO/OLO 5/5 mcg inhalation spray administered as 2 inhalations via the RESPIMAT® inhaler in 8-week TP1 and TP2 per randomization. This was separated by a 3-week washout period. Albuterol/salbutamol was supplied as an inhalation spray via metered dose inhaler throughout the study for use as-needed

    Reporting group title
    Washout Period (3 weeks)
    Reporting group description
    		 -

    Reporting group title
    Treatment Period 2
    Reporting group description
    		 In this 2-way crossover study, eligible participants were randomized to receive UMEC/VI inhalation powder 62.5/25 mcg QD administered as 1 inhalation via the ELLIPTA® Inhaler and TIO/OLO 5/5 mcg inhalation spray administered as 2 inhalations via the RESPIMAT® inhaler in 8-week TP1 and TP2 per randomization. This was separated by a 3-week washout period. Albuterol/salbutamol was supplied as an inhalation spray via metered dose inhaler throughout the study for use as-needed

    Subject analysis set title
    Umeclidinium/Vilanterol 62.5/25 mcg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Eligible par. were administered Umeclidinium/Vilanterol (UMEC/VI) 62.5/25 mcg (as one inhalation) once-daily (QD) via the ELLIPTA Inhaler for 8 weeks followed by a washout period of 3 weeks in period-1 or 2 as per randomization. Albuterol/salbutamol was supplied as an inhalation spray via metered dose inhaler throughout the study for use as-needed

    Subject analysis set title
    Tiotropium/Olodaterol 5/5 mcg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Eligible par. were administered Tiotropium/Olodaterol (TIO/OLO) 5/5 mcg inhalation spray as 2 inhalations of 2.5/2.5 mcg each via the RESPIMAT® inhaler for 8 weeks followed by a washout period of 3 weeks in period-1 or 2 as per randomization. Albuterol/salbutamol was supplied as an inhalation spray via metered dose inhaler throughout the study for use as-needed

    Primary: Trough forced expiratory volume in one second (FEV1) at Week 8

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    End point title
    		 Trough forced expiratory volume in one second (FEV1) at Week 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 one second. Trough FEV1 was defined as 23 and 24 hour post-dose FEV1 measurements. All par. in the Intent To Treat (ITT) Population who were not identified as full protocol deviators were included in Per-Protocol (PP) Population. ITT Population, comprised of all randomized subjects, who received at least one dose of study medication.
    End point type
    Primary
    End point timeframe
    Week 8
    End point values
    		 Umeclidinium/Vilanterol 62.5/25 mcg Tiotropium/Olodaterol 5/5 mcg
    Number of subjects analysed
    202 [1]
    192
    Units: Liters
    least squares mean (standard error)
        Liters
    1.745 ± 0.0131
    1.692 ± 0.0135
    Notes
    [1] - Per Protocol Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The correct Number of Subjects Included in Analysis is 236. Due to a system limitation, the value 394 is incorrectly auto-populated.
    Comparison groups
    Tiotropium/Olodaterol 5/5 mcg v Umeclidinium/Vilanterol 62.5/25 mcg
    Number of subjects included in analysis
    394
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.053
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.026
         upper limit
    		 0.08
    Notes
    [2] - If the lower bound of the two-sided 95% confidence interval around the (UMEC/VI 62.5/25 mcg versus TIO/OLO 5/5 mcg) treatment difference is above -50 milliliter then UMEC/VI 62.5/25 mcg was to be considered non-inferior to TIO/OLO 5/5 mcg.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-therapy Serious Adverse Events (SAEs) and non-SAEs were collected from the start of study treatment and until follow up visit (Week 22).
    Adverse event reporting additional description
    On-therapy SAEs and non-SAEs are reported for ITT Population, comprised of all randomized participants, who received at least one dose of study medication
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Umeclidinium/Vilanterol 62.5/25 mcg
    Reporting group description
    		 Eligible par. were administered Umeclidinium/Vilanterol (UMEC/VI) 62.5/25 mcg (as one inhalation) once-daily (QD) via the ELLIPTA Inhaler for 8 weeks followed by a washout period of 3 weeks in period-1 or 2 as per randomization. Albuterol/salbutamol was supplied as an inhalation spray via metered dose inhaler throughout the study for use as-needed

    Reporting group title
    Tiotropium/Olodaterol 5/5 mcg
    Reporting group description
    		 Eligible par. were administered Tiotropium/Olodaterol (TIO/OLO) 5/5 mcg inhalation spray as 2 inhalations of 2.5/2.5 mcg each via the RESPIMAT® inhaler for 8 weeks followed by a washout period of 3 weeks in period-1 or 2 as per randomization. Albuterol/salbutamol was supplied as an inhalation spray via metered dose inhaler throughout the study for use as-needed

    Serious adverse events
    		 Umeclidinium/Vilanterol 62.5/25 mcg Tiotropium/Olodaterol 5/5 mcg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 235 (1.28%)
    2 / 230 (0.87%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 230 (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
    Rib fracture
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 230 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 230 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site haemorrhage
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 230 (0.43%)
         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 mcg Tiotropium/Olodaterol 5/5 mcg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 235 (8.09%)
    21 / 230 (9.13%)
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 235 (3.40%)
    7 / 230 (3.04%)
         occurrences all number
    8
    7
    Viral upper respiratory tract infection
         subjects affected / exposed
    11 / 235 (4.68%)
    14 / 230 (6.09%)
         occurrences all number
    11
    15

    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
    For support, Contact us.
    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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