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    Clinical Trial Results:
    Simvastatin as adjuvant therapy to correct neutrophil dysfunction in older pneumonia patients - a randomised double blind placebo controlled trial

    Summary
    EudraCT number
    		 2012-003343-29
    Trial protocol
    		 GB  
    Global end of trial date
    30 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Nov 2019
    First version publication date
    27 Nov 2019
    Other versions
    Summary report(s)
    		 Abridged protocol

    Trial information

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    Trial identification
    Sponsor protocol code
    RG_12-179
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Birmingham
    Sponsor organisation address
    Edgbaston, Birmingham, United Kingdom, B152TT
    Public contact
    Clinical Trials Coordinator, Queen Elizabeth Hospital Birmingham NHS Trust, 44 01214721311, anita.pye@uhb.nhs.uk
    Scientific contact
    Clinical Trials Coordinator, Queen Elizabeth Hospital Birmingham NHS Trust, 44 01214721311, anita.pye@uhb.nhs.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
    06 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Pneumonia (severe lung infection) is one of the commonest causes of death and the death rate has not fallen for many years. Elderly patients are at greater risk of pneumonia and its complications such as sepsis. Usually the immune system works cooperatively to clear infection and prevent organ damage. Neutrophils are cells of the immune system that are critical in clearing bacteria. These cells are the foot soldiers of the immune system and move from the blood into infected tissues/organs to locate and kill the invading bacteria using an arsenal of toxic products. Sepsis occurs when the bodies normally helpful reaction to infection becomes harmful. As part of this process, neutrophils stop working properly, they become less able to clear bacteria and release their toxic products indiscriminately, causing organ damage. Defects in the efficiency of these cells is associated with a poor outcome from pneumonia and sepsis. We have undertaken a pilot study in patients, which
    Protection of trial subjects
    As per EU CTIMP law and under MHRA guidance. Daily review by research team and safety bloods taken for creatine kinase, liver function tests and renal function, as stipulated in the protocol.
    Background therapy
    		 Patients were treated as per British Thoracic Society Community acquired pneumonia with the patients physician directing care. Contraindicated drugs were stipulated in protocol inclusion and exclusion criteria.
    Evidence for comparator
    		 This was an additional therapy
    Actual start date of recruitment
    07 Jan 2013
    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: 62
    Worldwide total number of subjects
    62
    EEA total number of subjects
    62
    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)
    8
    From 65 to 84 years
    33
    85 years and over
    21

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from a secondary care hospital. They were eligible if they met The British Thoracic Society guidelines for community acquired pneumonia, and the 2012 Surviving Sepsis Campaign Guidelines

    Pre-assignment
    Screening details
    		 Chest radiograph review, bloods and observations.

    Period 1
    Period 1 title
    Within 48 hours of admission (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The randomization sequence was pre-determined by Sharp Clinical Services, designed to provide a 1:1 randomization pattern.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Statin treatment
    Arm description
    		 Simvastatin 80mg OD PO
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    MA - PL0075/0017
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    80mg orally once daily

    Arm title
    		 Placebo
    Arm description
    		 Placebo tablet
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    MA10284
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    DBAAe capsule shells filled with Microcrystalline cellulose taken once a day

    Number of subjects in period 1
    		Statin treatment Placebo
    Started
    32
    30
    Completed
    28
    25
    Not completed
    4
    5
         Consent withdrawn by subject
    1
    2
         Lost to follow-up
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Statin treatment
    Reporting group description
    		 Simvastatin 80mg OD PO

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablet

    Reporting group values
    		 Statin treatment Placebo Total
    Number of subjects
    		 32 30 62
    Age categorical
    Adults aged over 50 years of age
    Units: Subjects
        Adults (18-64 years)
    		 4 4 8
        From 65-84 years
    		 19 14 33
        85 years and over
    		 9 12 21
    Age continuous
    Study was for people aged 50 and over
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 78.1 (70 to 88) 83.8 (68 to 90) -
    Gender categorical
    Units: Subjects
        Female
    		 13 14 27
        Male
    		 19 16 35
    Subject analysis sets

    Subject analysis set title
    All randomised subjects
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subject data analysed on intention to treat basis

    Subject analysis set title
    Simvastatin Day 4 - Day 0
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All analysis on intention to treat basis

    Subject analysis set title
    Placebo Day 4 - Day 0
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All analysis on intention to treat basis

    Subject analysis sets values
    		 All randomised subjects Simvastatin Day 4 - Day 0 Placebo Day 4 - Day 0
    Number of subjects
    62
    32
    30
    Age categorical
    Adults aged over 50 years of age
    Units: Subjects
        Adults (18-64 years)
    8
    4
    4
        From 65-84 years
    33
    19
    14
        85 years and over
    21
    9
    12
    Age continuous
    Study was for people aged 50 and over
    Units: years
        median (inter-quartile range (Q1-Q3))
    79.4 (70.2 to 87.0)
    78.1 (70 to 88)
    83.8 (68 to 90)
    Gender categorical
    Units: Subjects
        Female
    27
    13
    14
        Male
    35
    19
    16

    End points

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    End points reporting groups
    Reporting group title
    Statin treatment
    Reporting group description
    		 Simvastatin 80mg OD PO

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablet

    Subject analysis set title
    All randomised subjects
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subject data analysed on intention to treat basis

    Subject analysis set title
    Simvastatin Day 4 - Day 0
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All analysis on intention to treat basis

    Subject analysis set title
    Placebo Day 4 - Day 0
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All analysis on intention to treat basis

    Primary: Change in fMLP induced NETosis

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    End point title
    		 Change in fMLP induced NETosis
    End point description
    Neutrophil extracellular traps
    End point type
    Primary
    End point timeframe
    Change from Day 0 to day 4
    End point values
    		 Statin treatment Placebo Simvastatin Day 4 - Day 0 Placebo Day 4 - Day 0
    Number of subjects analysed
    32
    30
    32
    30
    Units: Arbitrary units
        median (inter-quartile range (Q1-Q3))
    -230.0 (-1187.0 to 53.7)
    46.2 (-430.8 to 679.8)
    -230.0 (-1187 to 53.7)
    46.2 (-430.8 to 679.8)
    Attachments
    		 Change in NETosis
    Statistical analysis title
    		 Change in netosis
    Statistical analysis description
    Day 4 - Day 0 results
    Comparison groups
    Simvastatin Day 4 - Day 0 v Placebo Day 4 - Day 0
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.034
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Change in neutrophil migration

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    End point title
    		 Change in neutrophil migration
    End point description
    End point type
    Secondary
    End point timeframe
    Day 4 - Day 0
    End point values
    		 Simvastatin Day 4 - Day 0 Placebo Day 4 - Day 0
    Number of subjects analysed
    32
    30
    Units: um/min
        median (inter-quartile range (Q1-Q3))
    0.36 (-0.43 to 0.86)
    -0.04 (-0.74 to 0.32)
    Statistical analysis title
    		 Change in chemotaxis
    Comparison groups
    Simvastatin Day 4 - Day 0 v Placebo Day 4 - Day 0
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.033
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Systemic neutrophil elastase activity

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    End point title
    		 Systemic neutrophil elastase activity
    End point description
    End point type
    Secondary
    End point timeframe
    Day 4 - Day 0
    End point values
    		 Simvastatin Day 4 - Day 0 Placebo Day 4 - Day 0
    Number of subjects analysed
    21
    20
    Units: nM
        median (inter-quartile range (Q1-Q3))
    -2.55 (-5.23 to -1.15)
    0.25 (-2.13 to 1.92)
    Statistical analysis title
    		 Change in neutrophil elastase activity
    Comparison groups
    Simvastatin Day 4 - Day 0 v Placebo Day 4 - Day 0
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change in SOFA score

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    End point title
    		 Change in SOFA score
    End point description
    End point type
    Secondary
    End point timeframe
    Day 4 - Day 0
    End point values
    		 Simvastatin Day 4 - Day 0 Placebo Day 4 - Day 0
    Number of subjects analysed
    32
    30
    Units: Score
        median (inter-quartile range (Q1-Q3))
    -2 (-3 to -1)
    -1 (-2 to 0)
    Statistical analysis title
    		 Change in SOFA score from day 0 to day 4
    Comparison groups
    Simvastatin Day 4 - Day 0 v Placebo Day 4 - Day 0
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Post-hoc: Hospitalisation free survival

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    End point title
    		 Hospitalisation free survival
    End point description
    End point type
    Post-hoc
    End point timeframe
    Analysis of readmission and survival as a composite endpoint at 180-days
    End point values
    		 All randomised subjects Simvastatin Day 4 - Day 0 Placebo Day 4 - Day 0
    Number of subjects analysed
    62
    32
    30
    Units: Odds ratio
        number (not applicable)
    62
    32
    30
    Statistical analysis title
    		 Odds ratio
    Comparison groups
    Placebo Day 4 - Day 0 v Simvastatin Day 4 - Day 0 v All randomised subjects
    Number of subjects included in analysis
    124
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.03
    Method
    		 Odds ratio
    Confidence interval
    Notes
    [1] - Analysis of readmission and survival as a composite endpoint demonstrated a significant increase in hospitalization free survival at both 180-days Odds ratio: 0.45; 95% CI 0.22 to 0.93

    Post-hoc: Hospitalisation free survival 365 days

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    End point title
    		 Hospitalisation free survival 365 days
    End point description
    End point type
    Post-hoc
    End point timeframe
    Analysis of readmission and survival as a composite endpoint at 365-days
    End point values
    		 All randomised subjects Simvastatin Day 4 - Day 0 Placebo Day 4 - Day 0
    Number of subjects analysed
    62
    32
    30
    Units: Odds ratio
        number (not applicable)
    62
    32
    30
    Statistical analysis title
    		 Odds ratio for hospitalisation free survival
    Statistical analysis description
    Comparing those on CTIMP to placebo
    Comparison groups
    Simvastatin Day 4 - Day 0 v Placebo Day 4 - Day 0
    Number of subjects included in analysis
    62
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.03
    Method
    		 odds ratio
    Confidence interval
    Notes
    [2] - Odds ratio: 0.45, 95% CI 0.22 to 0.90

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All SAEs irrespective of the causal relationship with the trial medications will be reported to the Sponsor within 24 hours of awareness by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 ICD
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Only 1 Adverse event reported
    Reporting group description
    		 One adverse event- myalgia in the simvastatin arm

    Serious adverse events
    		 Only 1 Adverse event reported
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 32 (0.00%)
         number of deaths (all causes)
    20
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Only 1 Adverse event reported
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 32 (3.13%)
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Dec 2014
    5 amendments in total. 2 prior to study start (1 of these stipulated by MHRA to add more contraindicated medications). Last amendment 2014.

    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/31206313
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