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    Clinical Trial Results:
    Investigation of the anti-inflammatory effects of simvastatin in a model of acute lung injury after inhalation of lipopolysaccharide by healthy volunteers

    Summary
    EudraCT number
    		 2006-004396-35
    Trial protocol
    		 GB  
    Global end of trial date
    10 Nov 2013

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

    Trial information

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    Trial identification
    Sponsor protocol code
    06078SE-A
    Additional study identifiers
    ISRCTN number
    		 ISRCTN21056528
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Belfast Health & Social Care Trust (BHSCT)
    Sponsor organisation address
    King Edward Building, Royal Hospitals, Grosvenor Road, Belfast, United Kingdom, BT12 6BA
    Public contact
    Prof Daniel McAuley, Queen's University of Belfast, 02890 976385, d.f.mcauley@qub.ac.uk
    Scientific contact
    Prof Daniel McAuley, Queen's University of Belfast, 02890 976385, d.f.mcauley@qub.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
    22 Oct 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Oct 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The hypothesis of the study is that treatment with simvastatin for 4 days will reduce pulmonary inflammation induced by LPS inhalation in humans. The primary outcome measure will be a reduction in bronchoalveolar lavage (BAL) CXCL8 concentration between the simvastatin and placebo treated groups.
    Protection of trial subjects
    A DMEC was appointed which was independent of the study team and comprised of two clinicians with experience in undertaking clinical trials, and a statistician. The DMEC met to agree conduct and remit which included an early termination process. The DMEC met after the first 2 participants have been enrolled into the study and met after every 10 participants thereafter. An interim analysis of efficacy was not planned. The DMEC functioned primarily as a check for safety, reviewing adverse events. The DMEC reported to the Sponsor via the principal investigator.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    11 Jan 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    30
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Healthy subjects were recruited by advertising.

    Pre-assignment
    Screening details
    		 Screening consisting of a questionnaire, physical examination, routine blood investigation, ECG, and measurement of lung function with spirometry (FEV1 and FVC) was performed.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Blinding of the simvastatin tablets and placebo was achieved by encapsulation with a gelatin capsule. The simvastatin capsule contained the simvastatin tablet with lactose powder. The placebo capsule contained lactose powder only. Both the simvastatin and placebo study drugs had an identical appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Simvastatin
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    Other name
    Simvastatin
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Simvastatin 40 mg and 80mg for 4 days

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 days

    Number of subjects in period 1
    		Simvastatin Placebo
    Started
    20
    10
    Completed
    20
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Simvastatin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Simvastatin Placebo Total
    Number of subjects
    		 20 10 30
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 20 10 30
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 25.8 ± 6.01 25.8 ± 4.49 -
    Gender categorical
    Units: Subjects
        Female
    		 11 5 16
        Male
    		 9 5 14
    height
    Units: metres
        arithmetic mean (standard deviation)
    		 1.69 ± 0.08 1.68 ± 0.08 -
    weight
    Units: kg
        arithmetic mean (standard deviation)
    		 68.13 ± 10.58 74.17 ± 9.58 -
    FEV1
    Units: litres
        arithmetic mean (standard deviation)
    		 3.60 ± 0.67 3.88 ± 0.73 -
    FVC
    Units: litres
        arithmetic mean (standard deviation)
    		 4.27 ± 0.81 4.58 ± 0.92 -

    End points

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    End points reporting groups
    Reporting group title
    Simvastatin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: IL-8

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    End point title
    		 IL-8
    End point description
    End point type
    Primary
    End point timeframe
    6 hours after inhalation of LPS
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    20
    10
    Units: units
        median (inter-quartile range (Q1-Q3))
    315.3 (190.1 to 497.4)
    381.8 (317.1 to 463.7)
    Statistical analysis title
    		 comparison of 2 groups
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: total cells

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    End point title
    		 total cells
    End point description
    End point type
    Secondary
    End point timeframe
    6 hours after inhalation of LPS
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    20
    10
    Units: 10*5/ml
        median (inter-quartile range (Q1-Q3))
    10.7 (4.6 to 17.4)
    15.2 (10.3 to 49.8)
    Statistical analysis title
    		 total cells comparison of 2 groups
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: neutrophils

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    End point title
    		 neutrophils
    End point description
    End point type
    Secondary
    End point timeframe
    6 hours after inhalation of LPS
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    20
    10
    Units: units
        median (inter-quartile range (Q1-Q3))
    3.0 (1.8 to 8.1)
    8.5 (4.4 to 16.2)
    Statistical analysis title
    		 neutrophils comparison of 2 groups
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: macrophages

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    End point title
    		 macrophages
    End point description
    End point type
    Secondary
    End point timeframe
    6 hours after inhalation of LPS
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    20
    10
    Units: units
        median (inter-quartile range (Q1-Q3))
    5.1 (2.1 to 13.0)
    7.0 (3.1 to 19.1)
    Statistical analysis title
    		 macrophages comparison of 2 groups
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.48
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: lymphocytes

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    End point title
    		 lymphocytes
    End point description
    End point type
    Secondary
    End point timeframe
    6 hours after inhalation of LPS
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    20
    10
    Units: units
        median (inter-quartile range (Q1-Q3))
    0.9 (0.2 to 1.6)
    1.1 (0.6 to 3.2)
    Statistical analysis title
    		 lymphocytes comparison of 2 groups
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to 24 hrs after LPS inhalational
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Simvastatin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Simvastatin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Simvastatin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 20 (35.00%)
    5 / 10 (50.00%)
    Investigations
    Asymptomatic elevated CK
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Fall in FEV1
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Nervous system disorders
    Migraine 3 days after starting study medication and took NSAIDS. Did not have LPS inhalation or BAL
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Chest pain and fall in FEV1 (unable to take deep breath)
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    URTI 2 days after starting study medication. Family had similar symptoms. Did not have LPS inhalatio
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    URTI 3 days after starting study medication. Did not have LPS inhalation or BAL
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jun 2007
    To increase the duration of the study by 2 years
    22 Apr 2009
    To request an extension for sample analysis only
    30 Dec 2009
    Amendment to protocol: measurement of plasma and BAL serine protase and anti-protease activity and mRNA analysis for additional proteases and other proteins modulating the inflammatory response

    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/19324974
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