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    Clinical Trial Results:
    Reversal of steroid insensitivity in COPD by theophylline

    Summary
    EudraCT number
    		 2006-003561-13
    Trial protocol
    		 GB  
    Global end of trial date
    29 Aug 2007

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Dec 2019
    First version publication date
    02 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    cro488
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00241631
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    South Kensington, London, United Kingdom, SW7 2AZ
    Public contact
    Ian Adcock, Imperial College London, ian.adcock@imperial.ac.uk
    Scientific contact
    Ian Adcock, Imperial College London, ian.adcock@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
    01 Aug 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Aug 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Aug 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Does the addition of low dose theophylline restore the anti-inflammatory effects of steroids?
    Protection of trial subjects
    None
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Apr 2006
    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: 49
    Worldwide total number of subjects
    49
    EEA total number of subjects
    49
    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)
    24
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Forty-nine theophylline-naive (Global Initiative for Chronic Obstructive Lung Disease stage 2 or 3) patients with COPD were recruited, between April 2006 and August 2007.

    Pre-assignment
    Screening details
    		 Forty-nine theophylline-naive (Global Initiative for Chronic Obstructive Lung Disease stage 2 or 3) patients with COPD were recruited. Thirty completed the trial and were suitable for analysis.

    Period 1
    Period 1 title
    Run in (2 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All participants
    Arm description
    		 Run in period, no intervention
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		All participants
    Started
    49
    Completed
    43
    Not completed
    6
         Physician decision
    6
    Period 2
    Period 2 title
    Phase 1 (4 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 participants received placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Single dose for four weeks

    Investigational medicinal product name
    Theophylline Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Single dose for four weeks

    Arm title
    		 Steroid
    Arm description
    		 placebo theophylline capsules and inhaled fluticasone propionate (FP) (500 mg bid )
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone propionate (FP) (500 mg bid )
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    500 mg bid for four weeks

    Investigational medicinal product name
    Theophylline Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Single dose for four weeks

    Number of subjects in period 2
    		Placebo Steroid
    Started
    22
    21
    Completed
    14
    16
    Not completed
    8
    5
         Consent withdrawn by subject
    4
    4
         Sore throat
    1
    -
         Lost to follow-up
    3
    -
         Lack of efficacy
    -
    1
    Period 3
    Period 3 title
    Wash Out (2 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All participants
    Arm description
    		 wash out period, no intervention
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		All participants
    Started
    30
    Completed
    30
    Period 4
    Period 4 title
    Phase 2 (4 Weeks)
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Theophylline Active
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Single dose for four weeks

    Arm title
    		 Steroid
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Theophylline Active
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Single dose for four weeks

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The baseline characteristics are only for the participants who completed the study.
    Number of subjects in period 4 [2]
    		Placebo Steroid
    Started
    14
    16
    Completed
    14
    16
    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 characteristics are only for the participants who completed the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo

    Reporting group title
    Steroid
    Reporting group description
    		 -

    Reporting group values
    		 Placebo Steroid Total
    Number of subjects
    		 14 16 30
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 14 0 14
        From 65-84 years
    		 0 16 16
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 61 ( 2.2 ) 69 ( 1.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 2 5
        Male
    		 11 14 25

    End points

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    End points reporting groups
    Reporting group title
    All participants
    Reporting group description
    		 Run in period, no intervention
    Reporting group title
    Placebo
    Reporting group description
    		 participants received placebo

    Reporting group title
    Steroid
    Reporting group description
    		 placebo theophylline capsules and inhaled fluticasone propionate (FP) (500 mg bid )
    Reporting group title
    All participants
    Reporting group description
    		 wash out period, no intervention
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo

    Reporting group title
    Steroid
    Reporting group description
    		 -

    Primary: Sputum Inflammatory Cell Counts

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    End point title
    		 Sputum Inflammatory Cell Counts
    End point description
    End point type
    Primary
    End point timeframe
    10 weeks
    End point values
    		 Placebo Steroid
    Number of subjects analysed
    14
    16
    Units: millions cells/ ml
        geometric mean (confidence interval 95%)
    5.42 (3.56 to 8.2)
    3.89 (2.6 to 5.76)
    Statistical analysis title
    		 Sputum Inflammatory Cell Counts
    Comparison groups
    Placebo v Steroid
    Number of subjects included in analysis
    30
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.012
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Interleukin 8 (IL8)

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    End point title
    		 Interleukin 8 (IL8)
    End point description
    End point type
    Secondary
    End point timeframe
    10 weeks
    End point values
    		 Placebo Steroid
    Number of subjects analysed
    14
    16
    Units: ng/mL
        geometric mean (confidence interval 95%)
    33.3 (20 to 56)
    28.3 (19 to 42)
    Statistical analysis title
    		 Interleukin 8 (IL8)
    Comparison groups
    Placebo v Steroid
    Number of subjects included in analysis
    30
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Total Sputum Eosinophils

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    End point title
    		 Total Sputum Eosinophils
    End point description
    End point type
    Secondary
    End point timeframe
    10 weeks
    End point values
    		 Placebo Steroid
    Number of subjects analysed
    14
    16
    Units: millions cells/ml
        geometric mean (confidence interval 95%)
    0.132 (0.09 to 0.2)
    0.053 (0.03 to 0.1)
    Statistical analysis title
    		 Total Sputum Eosinophils
    Comparison groups
    Placebo v Steroid
    Number of subjects included in analysis
    30
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    10 weeks
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo

    Reporting group title
    Steroid
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo Steroid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 16 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Steroid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 14 (0.00%)
    4 / 16 (25.00%)
    Gastrointestinal disorders
    Nausea and upset stomach
         subjects affected / exposed
    0 / 14 (0.00%)
    4 / 16 (25.00%)
         occurrences all number
    0
    4

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/20299628
    http://www.ncbi.nlm.nih.gov/pubmed/15888697
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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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