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    Clinical Trial Results:
    Improving Inhaler Treatment and Small Airways Assessment in Chronic Obstructive Pulmonary Disease

    Summary
    EudraCT number
    		 2011-005544-10
    Trial protocol
    		 GB  
    Global end of trial date
    27 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Oct 2019
    First version publication date
    19 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NIHRCDF
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01721291
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperila College London
    Sponsor organisation address
    South Kensington Campus, London, United Kingdom, SW7 2AZ
    Public contact
    Dr Omar Usmani, National Heart & Lung Institute, +44 20 7351 8051, o.usmani@imperial.ac.uk
    Scientific contact
    Dr Omar Usmani, National Heart & Lung Institute, +44 20 7351 8051, o.usmani@imperial.ac.uk
    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
    27 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Nov 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    What is the lung deposition behaviour of inhaled bronchodilator (salbutamol)aerosols of different particle size within the airways of patients with chronic obstructive pulmonary disease (COPD)? How does this distribution compare to that observed in healthy subjects with no lung disease?
    Protection of trial subjects
    no protection
    Background therapy
    		 no background therapy
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2012
    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
    United Kingdom: 65
    Worldwide total number of subjects
    65
    EEA total number of subjects
    65
    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)
    34
    From 65 to 84 years
    31
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited at Royal Brompton Hospital, London between 01.10.2012 and 27.11.2017

    Pre-assignment
    Screening details
    		 A total numbers of 70 participants were screened for eligibility, of whom were 65 randomized, the remaining 5 participant were excluded due to not meeting inclusion criteria. The study had two term, first was the deposition study with healthy and COPD patients, second part was the lung physiology study with COPD and Asthmatic patients.

    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, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 COPD 1.
    Arm description
    		 COPD patients
    Arm type
    		 Experimental

    Investigational medicinal product name
    Salbutamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Visit1 - 1.5um particle 30ug slow, Visit2 - 1.5um particle 30ug fast, Visit3 - 3um particle 30ug slow, Visit4 - 3um particle 30ug fast, Visit5 - 6um particle 30ug slow, Visit6 - 6um particle 30ug fast, Visit7 - pMDI 200ug slow.

    Arm title
    		 Healthy
    Arm description
    		 Healthy participant
    Arm type
    		 Placebo

    Investigational medicinal product name
    Salbutamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Visit1 - 1.5um particle 30ug slow, Visit2 - 1.5um particle 30ug fast, Visit3 - 3um particle 30ug slow, Visit4 - 3um particle 30ug fast, Visit5 - 6um particle 30ug slow, Visit6 - 6um particle 30ug fast, Visit7 - pMDI 200ug slow.

    Arm title
    		 COPD 2.
    Arm description
    		 COPD patients
    Arm type
    		 Experimental

    Investigational medicinal product name
    Salbutamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Visit1 - 1.5um particle 15ug, Visit2 - 1.5um particle 30ug, Visit3 - 3um particle 15ug, Visit4 - 3um particle 30ug , Visit5 - 6um particle 15ug, Visit6 - 6um particle 30ug, Visit7 - pMDI 200ug.

    Arm title
    		 Asthmatic
    Arm description
    		 Asthmatic
    Arm type
    		 Experimental

    Investigational medicinal product name
    Salbutamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Visit1 - 1.5um particle 15ug, Visit2 - 1.5um particle 30ug, Visit3 - 3um particle 15ug, Visit4 - 3um particle 30ug , Visit5 - 6um particle 15ug, Visit6 - 6um particle 30ug, Visit7 - pMDI 200ug.

    Number of subjects in period 1
    		COPD 1. Healthy COPD 2. Asthmatic
    Started
    14
    12
    26
    13
    Completed
    12
    12
    26
    12
    Not completed
    2
    0
    0
    1
         Consent withdrawn by subject
    1
    -
    -
    1
         did not like the treatment
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    COPD 1.
    Reporting group description
    		 COPD patients

    Reporting group title
    Healthy
    Reporting group description
    		 Healthy participant

    Reporting group title
    COPD 2.
    Reporting group description
    		 COPD patients

    Reporting group title
    Asthmatic
    Reporting group description
    		 Asthmatic

    Reporting group values
    		 COPD 1. Healthy COPD 2. Asthmatic Total
    Number of subjects
    		 14 12 26 13 65
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 5 5 12 12 34
        From 65-84 years
    		 9 7 14 1 31
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 66.08 (56 to 77) 64.08 (50 to 76) 64.5 (58 to 79) 40.4 (19 to 66) -
    Gender categorical
    Units: Subjects
        Female
    		 8 5 17 8 38
        Male
    		 6 7 9 5 27
    Force experation in 1s (FEV1 )
    Units: litre(s)
        arithmetic mean (full range (min-max))
    		 1.63 (0.97 to 2.24) 2.55 (1.55 to 3.76) 1.46 (0.71 to 2.13) 2.85 (2.03 to 3.9) -

    End points

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    End points reporting groups
    Reporting group title
    COPD 1.
    Reporting group description
    		 COPD patients

    Reporting group title
    Healthy
    Reporting group description
    		 Healthy participant

    Reporting group title
    COPD 2.
    Reporting group description
    		 COPD patients

    Reporting group title
    Asthmatic
    Reporting group description
    		 Asthmatic

    Subject analysis set title
    Healthy_1.5 um slow
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Healthy participants with treatment of 1.5 um Salbutamol

    Subject analysis set title
    Healthy_1.5 um fast
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Healthy participants with treatment of 1.5 um Salbutamol fast

    Subject analysis set title
    COPD_1.5 um slow
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    COPD participants with treatment of 1.5 um Salbutamol

    Subject analysis set title
    COPD_1.5 um fast
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    COPD participants with treatment of 1.5 um Salbutamol fast

    Subject analysis set title
    Healthy_3 um slow
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Healthy participants with treatment of 3 um Salbutamol slow

    Subject analysis set title
    Healthy_3 um fast
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Healthy participants with treatment of 3 um Salbutamol fast

    Subject analysis set title
    COPD_3 um slow
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    COPD with treatment of 3 um Salbutamol slow

    Subject analysis set title
    COPD_3 um fast
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    COPD participants with treatment of 3 um Salbutamol fast

    Subject analysis set title
    Healthy_6 um slow
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Healthy participants with treatment of 6 um Salbutamol slow

    Subject analysis set title
    COPD_6 um fast
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Healthy participants with treatment of 6 um Salbutamol fast

    Subject analysis set title
    COPD_6 um slow
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    COPD participants with treatment of 6 um Salbutamol slow

    Subject analysis set title
    Healthy_6 um fast
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Healthy participants with treatment of 6 um Salbutamol fast

    Subject analysis set title
    COPD_1.5um, 15ug
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    COPD participants with treatment of 15 ug Salbutamol

    Subject analysis set title
    COPD_1.5um, 30ug
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    COPD participants with treatment of 1.5um, 30 ug Salbutamol

    Subject analysis set title
    COPD_3um, 15 ug
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    COPD participants with treatment of 3um, 15 ug Salbutamol

    Subject analysis set title
    COPD_3um, 30 ug
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    COPD participants with treatment of 3um, 30 ug Salbutamol

    Subject analysis set title
    COPD_6um, 15 ug
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    COPD participants with treatment of 6um, 15 ug Salbutamol

    Subject analysis set title
    COPD_6um,30 ug
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    COPD participants with treatment of 6um, 30 ug Salbutamol

    Subject analysis set title
    COPD_pMDI
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participant treatment with pMDI and Salbutamol

    Subject analysis set title
    Asthmatics_1.5um, 15ug
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Asthmatics participants with treatment of 1.5um, 15 ug Salbutamol

    Subject analysis set title
    Asthmatics_1.5um, 30ug
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Asthmatics participants with treatment of 1.5um, 30 ug Salbutamol

    Subject analysis set title
    Asthmatics_3um, 15ug
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Asthmatics participants with treatment of 3um, 15 ug Salbutamol

    Subject analysis set title
    Asthmatics_3um, 30ug
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Asthmatics participants with treatment of 3um, 30 ug Salbutamol

    Subject analysis set title
    Asthmatics_6um, 15ug
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Asthmatics participants with treatment of 6um, 15 ug Salbutamol

    Subject analysis set title
    Asthmatics_6um, 30ug
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Asthmatics participants with treatment of 6um, 15 ug Salbutamol

    Subject analysis set title
    Asthmatics_pMDI
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Asthmatics participants with treatment of pMDI and Salbutamol

    Primary: Penetration index

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    End point title
    		 Penetration index
    End point description
    End point type
    Primary
    End point timeframe
    5min
    End point values
    		 Healthy_1.5 um slow Healthy_1.5 um fast COPD_1.5 um slow COPD_1.5 um fast Healthy_3 um slow Healthy_3 um fast COPD_3 um slow COPD_3 um fast Healthy_6 um slow COPD_6 um fast COPD_6 um slow Healthy_6 um fast
    Number of subjects analysed
    12
    12
    12
    12
    12
    12
    12
    12
    12
    12
    12
    12
    Units: ratio
        arithmetic mean (standard deviation)
    0.8 ( 0.08 )
    0.72 ( 0.12 )
    0.69 ( 0.13 )
    0.58 ( 0.14 )
    0.75 ( 0.11 )
    0.63 ( 0.15 )
    0.65 ( 0.18 )
    0.48 ( 0.16 )
    0.51 ( 0.1 )
    0.46 ( 0.04 )
    0.37 ( 0.12 )
    0.32 ( 0.08 )
    Statistical analysis title
    		 Compaisons of Penetraion Index for COPD
    Comparison groups
    COPD_1.5 um slow v COPD_1.5 um fast v COPD_3 um slow v COPD_3 um fast v COPD_6 um fast v COPD_6 um slow
    Number of subjects included in analysis
    72
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -0.0489
         upper limit
    		 0.2739
    Variability estimate
    Standard deviation

    Primary: Multi-breath nitrgen washout (MBNW) indices of conducting airways (Scond)

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    End point title
    		 Multi-breath nitrgen washout (MBNW) indices of conducting airways (Scond) [1]
    End point description
    End point type
    Primary
    End point timeframe
    120min
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis has been performed on this endpoint.
    End point values
    		 COPD_1.5 um slow COPD_1.5 um fast COPD_3 um slow COPD_3 um fast COPD_6 um fast COPD_6 um slow
    Number of subjects analysed
    12
    12
    12
    12
    12
    12
    Units: litre(s) -1
        arithmetic mean (full range (min-max))
    0.047 (0 to 0.089)
    0.04 (0.011 to 0.089)
    0.047 (0.022 to 0.069)
    0.044 (0.011 to 0.078)
    0.047 (0.011 to 0.089)
    0.045 (0.022 to 0.078)
    No statistical analyses for this end point

    Secondary: Multi-breath nitrgen washout (MBNW) indices of acinar airways (Sacin)

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    End point title
    		 Multi-breath nitrgen washout (MBNW) indices of acinar airways (Sacin)
    End point description
    End point type
    Secondary
    End point timeframe
    120min
    End point values
    		 COPD_1.5 um slow COPD_1.5 um fast COPD_3 um slow COPD_3 um fast COPD_6 um fast COPD_6 um slow Healthy_6 um fast
    Number of subjects analysed
    12
    12
    12
    12
    12
    12
    12
    Units: litre(s) -1
        arithmetic mean (full range (min-max))
    0.462 (0.229 to 1.27)
    0.508 (0.179 to 0.734)
    0.471 (0.158 to 1.534)
    0.437 (0.198 to 1.090)
    0.487 (0.163 to 1.365)
    0.426 (0.170 to 0.949)
    0 (0 to 0)
    Statistical analysis title
    		 Multi-breath nitrgen washout indices (Sacin)
    Comparison groups
    COPD_1.5 um slow v COPD_1.5 um fast v COPD_3 um slow v COPD_3 um fast v COPD_6 um fast v COPD_6 um slow v Healthy_6 um fast
    Number of subjects included in analysis
    84
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.05 [3]
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [2] - 2-way ANOVA
    [3] - No significance was found between any of the parameters

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    6 months
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SNOMED CT
    Dictionary version
    10
    Reporting groups
    Reporting group title
    COPD 1.
    Reporting group description
    		 COPD patients

    Reporting group title
    Healthy
    Reporting group description
    		 Healthy participant

    Reporting group title
    COPD 2.
    Reporting group description
    		 COPD patients

    Reporting group title
    Asthmatic
    Reporting group description
    		 Asthmatic

    Serious adverse events
    		 COPD 1. Healthy COPD 2. Asthmatic
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 COPD 1. Healthy COPD 2. Asthmatic
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 12 (50.00%)
    0 / 12 (0.00%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
    Surgical and medical procedures
    Hernia operation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cataract operation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac disorders
    Hypertension
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Pulled muscle
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infections and infestations
    Chest infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sore throat
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 May 2013
    AMENDMENTS made to Protocol (Flow chart), PIS and Consent form
    07 Aug 2015
    Amendments to GP letter, Protocol Flow chart) PIS and Consent form
    11 Apr 2016
    The request relates to an extension to the current ethics approval to be extended to 31st March 2017.

    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
    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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