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    Clinical Trial Results:
    A Multicenter Trial Comparing the Efficacy and Safety of Umeclidinium/Vilanterol 62.5/25 mcg Once Daily with Tiotropium 18 mcg Once Daily over 24 Weeks in Subjects with Chronic Obstructive Pulmonary Disease (COPD)

    Summary
    EudraCT number
    		 2012-003973-24
    Trial protocol
    		 HU   BG   ES  
    Global end of trial date
    24 Sep 2013

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ZEP117115
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01777334
    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 Nov 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Sep 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 of umeclidinium/vilanterol (UMEC/VI) Inhalation Powder (62.5/25 micrograms [mcg]) once-daily with tiotropium (18 mcg) once-daily over 24 weeks for the treatment of subjects with Chronic Obstructive Pulmonary Disease (COPD).
    Protection of trial subjects
    Several measures were taken to protect trial subjects: these included electrocardiogram (ECG) at screening, vital signs at all visits, adverse event monitoring throughout the study, frequent clinic visits (approximately every 4 weeks) to monitor subject status and safety, exclusion of subjects with clinically significant and uncontrolled medical conditions, and use of treatment arms where all subjects received pharmacologic treatment that was appropriate for their COPD. Umeclidinium/Vilanterol (experimental arm) combination has an acceptable safety profile for use as it is supported by the results of previously performed clinical studies. Tiotropium is a marketed product and was administered as an active control according to the local label. All subjects received active treatment with one of the two above mentioned medications during the treatment phase of the study.
    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
    Spain: 46
    Country: Number of subjects enrolled
    Bulgaria: 116
    Country: Number of subjects enrolled
    Germany: 171
    Country: Number of subjects enrolled
    Hungary: 136
    Country: Number of subjects enrolled
    Canada: 182
    Country: Number of subjects enrolled
    Romania: 121
    Country: Number of subjects enrolled
    Russian Federation: 107
    Country: Number of subjects enrolled
    United States: 292
    Country: Number of subjects enrolled
    Argentina: 20
    Worldwide total number of subjects
    1191
    EEA total number of subjects
    590
    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)
    697
    From 65 to 84 years
    488
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants (par.) who met the eligibility criteria at Screening (Visit 1) completed a 7- to 10-day Run-in Period and were then randomized to a 24-week Treatment Period. A total of 1191 par. were enrolled; 1053 par. were screened, and 905 par. were randomized and took at least one dose of randomized study medication.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind [1]
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    For further information on blinding reference the following publication: Maleki-Yazdi MR, Kaelin T, Richard N, Zvarich M, Church A. Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial.Respir Med. 2014 Dec;108(12):1752-60 http://www.ncbi.nlm.nih.gov/pubmed/25458157

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 UMEC/VI 62.5/25 µg
    Arm description
    		 Participants received umeclidinium bromide/vilanterol (UMEC/VI) 62.5/25 micrograms (µg) once daily (QD) each morning via a dry powder inhaler (DPI) and placebo QD each morning via a DPI for 24 weeks.
    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 µg once daily via a dry powered inhaler (DPI)

    Investigational medicinal product name
    Placebo (for matching Tiotropium)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Respiratory use
    Dosage and administration details
    Lactose with magnesium stearate administered once daily via a matching DPI

    Arm title
    		 TIO 18 µg
    Arm description
    		 Participants received tiotropium (TIO) 18 µg QD each morning via a DPI and placebo QD each morning via a DPI for 24 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Respiratory use
    Dosage and administration details
    1 8µg once daily via HandiHaler

    Investigational medicinal product name
    Placebo (for matching UMEC/VI)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Respiratory use
    Dosage and administration details
    Lactose administered once daily via matching HandiHaler

    Notes
    [1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
    Justification: For further information on blinding reference the following publication: Maleki-Yazdi MR, Kaelin T, Richard N, Zvarich M, Church A. Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial.Respir Med. 2014 Dec;108(12):1752-60 http://www.ncbi.nlm.nih.gov/pubmed/25458157
    Number of subjects in period 1 [2]
    		UMEC/VI 62.5/25 µg TIO 18 µg
    Started
    454
    451
    Completed
    401
    388
    Not completed
    53
    63
         Adverse event, serious fatal
    2
    5
         Consent withdrawn by subject
    14
    11
         Adverse event, non-fatal
    16
    9
         Lost to follow-up
    3
    2
         Lack of efficacy
    15
    29
         Protocol deviation
    3
    7
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The baseline period includes only those enrolled participants who were randomized and took at least one dose of randomized study medication (n=905).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    UMEC/VI 62.5/25 µg
    Reporting group description
    		 Participants received umeclidinium bromide/vilanterol (UMEC/VI) 62.5/25 micrograms (µg) once daily (QD) each morning via a dry powder inhaler (DPI) and placebo QD each morning via a DPI for 24 weeks.

    Reporting group title
    TIO 18 µg
    Reporting group description
    		 Participants received tiotropium (TIO) 18 µg QD each morning via a DPI and placebo QD each morning via a DPI for 24 weeks.

    Reporting group values
    		 UMEC/VI 62.5/25 µg TIO 18 µg Total
    Number of subjects
    		 454 451 905
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.9 ± 8.41 62.7 ± 8.5 -
    Gender categorical
    Units: Subjects
        Female
    		 144 148 292
        Male
    		 310 303 613
    Race, Customized
    Units: Subjects
        White/Caucasian/European Heritage
    		 438 442 880
        African American/African Heritage
    		 13 7 20
        American Indian or Alaska Native
    		 1 1 2
        White - Arabic/North African Heritage
    		 1 0 1
        Mixed Race
    		 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    UMEC/VI 62.5/25 µg
    Reporting group description
    		 Participants received umeclidinium bromide/vilanterol (UMEC/VI) 62.5/25 micrograms (µg) once daily (QD) each morning via a dry powder inhaler (DPI) and placebo QD each morning via a DPI for 24 weeks.

    Reporting group title
    TIO 18 µg
    Reporting group description
    		 Participants received tiotropium (TIO) 18 µg QD each morning via a DPI and placebo QD each morning via a DPI for 24 weeks.

    Primary: Change from Baseline (BL) in trough forced expiratory volume in one second (FEV1) on Day 169 (Week 24)

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    End point title
    		 Change from Baseline (BL) in trough forced expiratory volume in one second (FEV1) on Day 169 (Week 24)
    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 measurements were taken electronically by spirometry on Days 2, 28, 56, 84, 112, 140, 168, and 169. Baseline is defined as the mean of the assessments made 30 minutes (min) pre-dose and 5 min pre-dose on Treatment Day 1. Trough FEV1 is defined as the mean of the FEV1 values obtained at 23 and 24 hours (hr) after the previous morning's dosing (ie., trough FEV1 on Day 169 is the mean of the FEV1 values obtained 23 and 24 hr after the morning dosing on Day 168). Change from Baseline at a particular visit was calculated as the trough FEV1 value at that visit minus the Baseline value. Analysis was performed using a repeated measures model with covariates of treatment, Baseline (mean of the two assessmentsmade 30 min and 5 min pre-dose on Day 1), smoking status, center group, day, and day by Baseline and day by treatment interactions. ITT=Intent-to-Treat.
    End point type
    Primary
    End point timeframe
    Baseline and Day 169
    End point values
    		 UMEC/VI 62.5/25 µg TIO 18 µg
    Number of subjects analysed
    400 [1]
    388 [2]
    Units: Liters
        least squares mean (standard error)
    0.205 ± 0.0114
    0.093 ± 0.0115
    Notes
    [1] - ITT Population. Participants analyzed are those with data available at the presented time point.
    [2] - ITT Population. Participants analyzed are those with data available at the presented time point.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    UMEC/VI 62.5/25 µg v TIO 18 µg
    Number of subjects included in analysis
    788
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.001 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least squares mean difference
    Point estimate
    0.112
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.081
         upper limit
    		 0.144
    Notes
    [3] - Participants analyzed are those with data available at the presented time point; but, all participants without missing covariate information and with >=1 post-Baseline measurement were included in the analysis. Least squares mean difference=UMEC/VI 62.5/25 µg minus TIO 18 µg.
    [4] - Restricted maximum likelihood (REML)-based repeated measures approach (MMRM).

    Secondary: Change from Baseline (BL) in weighted mean (WM) 0-6 hour FEV1 obtained post-dose at Day 168

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    End point title
    		 Change from Baseline (BL) in weighted mean (WM) 0-6 hour FEV1 obtained post-dose at Day 168
    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 WM FEV1 was derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The WM was calculated at Days 1, 84, and 168 using the 0-6-hour post-dose FEV1 measurements collected on that day, which included pre-dose (Day 1: mean of 30 minutes [min] and 5 min prior to dosing; other serial visits: mean of 23 and 24 hours after the previous morning dose) and post-dose at 15 min, 30 min, 1 hour, 3 hours, and 6 hours. Change from BL at a particular visit was calculated as the WM value at that visit minus the BL value. Analysis was performed using a repeated measures model with covariates of treatment, BL (mean of two assessments made 30 min and 5 min pre-dose on Day 1), smoking status, center group, day, and day by BL and day by treatment interactions.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 168
    End point values
    		 UMEC/VI 62.5/25 µg TIO 18 µg
    Number of subjects analysed
    404 [5]
    387 [6]
    Units: Liters
        least squares mean (standard error)
    0.276 ± 0.0124
    0.17 ± 0.0126
    Notes
    [5] - ITT Population. Participants analyzed are those with data available at the presented time point.
    [6] - ITT Population. Participants analyzed are those with data available at the presented time point.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    UMEC/VI 62.5/25 µg v TIO 18 µg
    Number of subjects included in analysis
    791
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least squares mean difference
    Point estimate
    0.105
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.071
         upper limit
    		 0.14
    Notes
    [7] - Participants analyzed are those with data available at the presented time point; but, all participants without missing covariate information and with >=1 post-Baseline measurement were included in the analysis. Least squares mean difference=UMEC/VI 62.5/25 μg minus TIO 18 μg.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication until the end of treatment (up to 24 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 drug during the Treatment Period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    UMEC/VI 62.5/25 µg
    Reporting group description
    		 Participants received umeclidinium bromide/vilanterol (UMEC/VI) 62.5/25 micrograms (µg) once daily (QD) each morning via a dry powder inhaler (DPI) and placebo QD each morning via a DPI for 24 weeks.

    Reporting group title
    TIO 18 µg
    Reporting group description
    		 Participants received tiotropium (TIO) 18 µg QD each morning via a DPI and placebo QD each morning via a DPI for 24 weeks.

    Serious adverse events
    		 UMEC/VI 62.5/25 µg TIO 18 µg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 454 (3.52%)
    17 / 451 (3.77%)
         number of deaths (all causes)
    2
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 454 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 454 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rectal cancer
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 451 (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
    Arterial restenosis
         subjects affected / exposed
    0 / 454 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery restenosis
         subjects affected / exposed
    0 / 454 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 451 (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 / 454 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 454 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 454 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 454 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 454 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 454 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 454 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 454 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 454 (0.22%)
    1 / 451 (0.22%)
         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
    Haemoptysis
         subjects affected / exposed
    0 / 454 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 454 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 454 (0.44%)
    2 / 451 (0.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental disorder
         subjects affected / exposed
    0 / 454 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 454 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epiglottitis
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 454 (0.00%)
    2 / 451 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 UMEC/VI 62.5/25 µg TIO 18 µg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    71 / 454 (15.64%)
    72 / 451 (15.96%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    40 / 454 (8.81%)
    31 / 451 (6.87%)
         occurrences all number
    56
    43
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 454 (2.86%)
    15 / 451 (3.33%)
         occurrences all number
    15
    17
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    28 / 454 (6.17%)
    30 / 451 (6.65%)
         occurrences all number
    30
    34

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Oct 2012
    Edit list of abbreviations; edit time and event table footnotes; modified wording regarding randomization criteria; reference added; minor protocol corrections addressed

    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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