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    Clinical Trial Results:
    Study DB2116961, A Multicentre, Randomised, Blinded, Parallel Group Study to Compare UMEC/VI (Umeclidinium/Vilanterol) in a Fixed Dose Combination With Indacaterol Plus Tiotropium in Symptomatic Subjects With Moderate to Very Severe COPD

    Summary
    EudraCT number
    		 2013-001827-38
    Trial protocol
    		 DE   IT   RO   HU   SK   PL   EE  
    Global end of trial date
    04 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Apr 2016
    First version publication date
    06 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    116961
    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
    29 Jun 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to demonstrate that Umeclidinium/Vilanterol (UMEC/VI), when used in symptomatic moderate to very severe chronic obstructive pulmonary disorder (COPD) subjects, is non-inferior to the combination of indacaterol plus tiotropium, as measured by trough forced expiratory volume in 1 second (FEV1) on treatment day 85 (Visit 8).
    Protection of trial subjects
    To protect trial subjects only approved standard of care COPD medications were evaluated and subjects were not exposed to placebo-only treatment. Additionally, study subjects were provided with supplemental salbuterol as rescue medication and the use of inhaled corticosteroids was allowed as a concurrent 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. Frequent assessment of adverse events and COPD exacerbations was obtained during the study at clinic visits conducted 1 day following the first dose of study medication and every 2 to 4 weeks thereafter to ensure patient safety was closely monitored. Vital signs were monitored prior to study enrollment and at the study conclusion. 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 Oct 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
    Argentina: 109
    Country: Number of subjects enrolled
    Chile: 74
    Country: Number of subjects enrolled
    Estonia: 39
    Country: Number of subjects enrolled
    France: 54
    Country: Number of subjects enrolled
    Germany: 200
    Country: Number of subjects enrolled
    Hungary: 121
    Country: Number of subjects enrolled
    Italy: 43
    Country: Number of subjects enrolled
    Peru: 80
    Country: Number of subjects enrolled
    Poland: 100
    Country: Number of subjects enrolled
    Romania: 108
    Country: Number of subjects enrolled
    Russian Federation: 203
    Country: Number of subjects enrolled
    Slovakia: 59
    Worldwide total number of subjects
    1190
    EEA total number of subjects
    724
    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)
    606
    From 65 to 84 years
    580
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible participants (par) completed a 5-7 day run-in period, 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 run-in and up to Day 85.

    Pre-assignment
    Screening details
    		 A total of 1190 par were screened; 967 par randomized and 961 par comprised 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 each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg), BREEZHALER containing placebo, and HANDIHALER containing placebo. 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 mcg 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
    		 Indacaterol 150 µg + Tiotropium bromide 18 µg
    Arm description
    		 Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing placebo, BREEZHALER containing indacaterol 150 µg, and HANDIHALER containing tiotropium bromide 18 µg. The inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Indacaterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One dose of Indacaterol 150 mcg every morning for 12 weeks, via the BREEZHALER

    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 mcg every morning for 12 weeks, via the HANDIHALER

    Investigational medicinal product name
    Placebo matching Indacaterol
    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 BREEZHALER

    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 Indacaterol 150 µg + Tiotropium bromide 18 µg
    Started
    482
    479
    Completed
    460
    457
    Not completed
    22
    22
         Adverse event, serious fatal
    4
    1
         Consent withdrawn by subject
    4
    4
         Adverse event, non-fatal
    8
    7
         Lost to follow-up
    -
    1
         Lack of efficacy
    1
    2
         Protocol deviation
    5
    7
    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 1190 par were screened; 967 par randomized and 961 par comprised 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 each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg), BREEZHALER containing placebo, and HANDIHALER containing placebo. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.

    Reporting group title
    Indacaterol 150 µg + Tiotropium bromide 18 µg
    Reporting group description
    		 Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing placebo, BREEZHALER containing indacaterol 150 µg, and HANDIHALER containing tiotropium bromide 18 µg. The inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.

    Reporting group values
    		 Umeclidinium/Vilanterol 62.5/25 µg Indacaterol 150 µg + Tiotropium bromide 18 µg Total
    Number of subjects
    		 482 479 961
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.4 ( 7.75 ) 64 ( 8.44 ) -
    Gender categorical
    Units: Subjects
        Female
    		 127 138 265
        Male
    		 355 341 696
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 24 27 51
        Asian - Central/South Asian Heritage
    		 1 0 1
        Asian - East Asian Heritage
    		 0 1 1
        Asian - Japanese Heritage
    		 4 1 5
        White - Arabic/North African Heritage
    		 0 1 1
        White -White/Caucasian/European Heritage
    		 453 449 902

    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 each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg), BREEZHALER containing placebo, and HANDIHALER containing placebo. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.

    Reporting group title
    Indacaterol 150 µg + Tiotropium bromide 18 µg
    Reporting group description
    		 Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing placebo, BREEZHALER containing indacaterol 150 µg, and HANDIHALER containing tiotropium bromide 18 µg. The 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 Treatment Day 85 (Visit 8)

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    End point title
    		 Change from Baseline in trough forced expiratory volume in one second (FEV1) on Treatment 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 2 assessments made 30 and 5 minutes (min) pre-dose (PD) on Day 1. Trough FEV1 measurements were taken electronically by spirometry on Days 2, 28, 56, 84 and 85. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained at 23 and 24 hours (hr) after dosing on Day 84 (at Week 12 + 1 day). Analysis was performed using mixed model repeated measures (RM) with covariates of trt, BL FEV1 (mean of values measured at 30 and 5 min PD on Day 1), center group, day, day by BL interaction and day by trt interaction, where day was nominal. Per Protocol (PP) Pop: all ITT Pop par who were not full protocol deviators considered to impact efficacy. Only par with data available at the specified time points (TP) were analyzed but all par without (w/o) missing covariate information and with >= 1 post BL measurement 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 Indacaterol 150 µg + Tiotropium bromide 18 µg
    Number of subjects analysed
    392 [1]
    392 [2]
    Units: Liters
        least squares mean (standard error)
    0.172 ( 0.0107 )
    0.171 ( 0.0108 )
    Notes
    [1] - PP Population
    [2] - PP Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Umeclidinium/Vilanterol 62.5/25 µg v Indacaterol 150 µg + Tiotropium bromide 18 µg
    Number of subjects included in analysis
    784
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 = 0.964
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.001
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.029
         upper limit
    		 0.03
    Notes
    [3] - Alternate hypothesis:the difference between the trt means (umeclidinium/vilanterol minus indacaterol + tiotropium bromide) would be > -50 milliliters (mL). If the lower CI (2.5% 1-sided significance level) of the statistical test should fall above -50 mL, then umeclidinium/vilanterol may be deemed statistically non-inferior to indacaterol plus tiotropium. If the lower CI (2.5% 1-sided significance) of the statistical testing exceeded 0 then, statistical superiority would have been established.

    Secondary: Change from Baseline in weighted mean (WM) FEV1 over 0-6 hour post-dose at Day 84

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    End point title
    		 Change from Baseline in weighted mean (WM) FEV1 over 0-6 hour post-dose at Day 84
    End point description
    BL FEV1 was the mean of the 2 assessments made 30 and 5 min PD on Day 1. WM FEV1 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 and 84 using the 0-6 hr post-dose FEV1 measurements collected on that day, which included PD FEV1 (taken 30 and 5 min prior to dosing on Day 1 and the 30 and 5 min reading prior to dosing on Day 84) and post-dose FEV1 measurements at 1, 3 and 6 hr post-dose.WM change from BL was the WM at at the visit minus the BL value. Analysis was performed using a RM model with covariates of trt, BL FEV1 (mean of values measured at 30 and 5 min PD on Day 1) center group, day, day by BL and day by trt interaction, where day was nominal. Only par with data available at the specified TP were analyzed but all par w/o missing covariate information and with >=1 post-BL measurement 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 Indacaterol 150 µg + Tiotropium bromide 18 µg
    Number of subjects analysed
    455 [4]
    452 [5]
    Units: Liters
        least squares mean (standard error)
    0.235 ( 0.0111 )
    0.258 ( 0.0111 )
    Notes
    [4] - ITT Population
    [5] - ITT Population
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Umeclidinium/Vilanterol 62.5/25 µg v Indacaterol 150 µg + Tiotropium bromide 18 µg
    Number of subjects included in analysis
    907
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.145
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.023
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.054
         upper limit
    		 0.008

    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 96 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
    Reporting groups
    Reporting group title
    Indacaterol 150 µg + Tiotropium bromide 18 µg
    Reporting group description
    		 Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing placebo, BREEZHALER containing indacaterol 150 µg, and HANDIHALER containing tiotropium bromide 18 µg. The inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.

    Reporting group title
    Umeclidinium/Vilanterol 62.5/25 µg
    Reporting group description
    		 Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg), BREEZHALER containing placebo, and HANDIHALER containing placebo. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.

    Serious adverse events
    		 Indacaterol 150 µg + Tiotropium bromide 18 µg Umeclidinium/Vilanterol 62.5/25 µg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 479 (3.34%)
    21 / 482 (4.36%)
         number of deaths (all causes)
    4
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain neoplasm
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the oral cavity
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 482 (0.21%)
         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
    Alcohol poisoning
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
    alternative dictionary used: Angina pectoris Angina pe
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 482 (0.21%)
         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 / 479 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (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
    Chest pain
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Crohn's disease
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 479 (0.63%)
    6 / 482 (1.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 479 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 479 (0.42%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Laryngitis
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (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
    Hyperglycaemia
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 482 (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
    		 Indacaterol 150 µg + Tiotropium bromide 18 µg Umeclidinium/Vilanterol 62.5/25 µg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    65 / 479 (13.57%)
    76 / 482 (15.77%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    28 / 479 (5.85%)
    36 / 482 (7.47%)
         occurrences all number
    60
    56
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    17 / 479 (3.55%)
    16 / 482 (3.32%)
         occurrences all number
    18
    18
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    27 / 479 (5.64%)
    32 / 482 (6.64%)
         occurrences all number
    31
    34

    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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