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    Clinical Trial Results:
    A study of the effects of Simvastatin on neutrophil function in elderly subjects

    Summary
    EudraCT number
    		 2011-002082-38
    Trial protocol
    		 GB  
    Global end of trial date
    01 Sep 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Nov 2019
    First version publication date
    27 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RG_11-123
    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, B15 2TT
    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
    Sponsor organisation name
    University of Birmingham
    Sponsor organisation address
    Edgbaston, Birmingham, United Kingdom, B15 2TH
    Public contact
    Dr Elizabeth Sapey, University of Birmingham,, 44 1212462000, e.sapey@bham.ac.uk
    Scientific contact
    Dr Elizabeth Sapey, University of Birmingham,, 44 1212462000, e.sapey@bham.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
    09 Jan 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Hypothesis. The age-related loss of neutrophil function contributes to delayed resolution of infection and inflammation. These changes in neutrophil function with advanced age are a result of alterations in signal transduction pathways due to altered membrane cholesterol levels and can be corrected using simvastatin. In vitro studies have confirmed that neutrophils isolated from elderly subjects respond differently to those from young donors in terms of migration, phagocytosis and superoxide production when pre-treated with physiological concentrations of Simvastatin. Question: Is this clinically relevant in vivo? Does a course of treatment with simvastatin improve migratory dynamics, phagocytosis and superoxide generation of neutrophils isolated from the peripheral blood of older subjects and is this associated with altered membrane cholesterol levels?
    Protection of trial subjects
    As per EU and UK law with monitoring and safety checks as per the protocol
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Dec 2011
    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: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    24
    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)
    3
    From 65 to 84 years
    12
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    		 24 participants were recruited but only 21 had the CTIMP or placebo, and 20 completed the full cross-over period. 20 were included in the analysis

    Pre-assignment
    Screening details
    		 Healthy old (OH) subjects, identified from among the Birmingham 1000 Elders cohort, had never smoked, had no evidence of acute or chronic disease, had normal spirometry, were medication free, and had no previous episodes of hospitalized sepsis.

    Pre-assignment period milestones
    Number of subjects started
    		 24
    Number of subjects completed
    		 24

    Period 1
    Period 1 title
    Period 1 in cross over
    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
    Study drugs (simvastatin or placebo) were prepared, randomised, and packaged identically by Bilcare Ltd (Powys, UK). Computer-based block randomisation was performed in a 1:1 ratio by a centralised service (Bilcare Ltd, UK) ready for period 2

    Arms
    Arm title
    		 CTIMP
    Arm description
    		 Simvastatin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    MA-PL0075/017
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    80mg once daily for 2 weeks

    Number of subjects in period 1
    		CTIMP
    Started
    24
    Completed
    20
    Not completed
    4
         Consent withdrawn by subject
    4
    Period 2
    Period 2 title
    Placebo cross over period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Study drugs (simvastatin or placebo) were prepared, randomised, and packaged identically by Bilcare Ltd (Powys, UK). Computer-based block randomisation was performed in a 1:1 ratio by a centralised service (Bilcare Ltd, UK)

    Arms
    Arm title
    		 Placebo
    Arm description
    		 Placebo in cross over
    Arm type
    		 Placebo

    Investigational medicinal product name
    DBAAe capsule shells filled with Microcrystalline cellulose.
    Investigational medicinal product code
    MA-10284
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily for 2 weeks

    Number of subjects in period 2
    		Placebo
    Started
    20
    Completed
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Period 1 in cross over
    Reporting group description
    		 -

    Reporting group values
    		 Period 1 in cross over Total
    Number of subjects
    		 24 24
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 3 3
        From 65-84 years
    		 12 12
        85 years and over
    		 9 9
    Gender categorical
    Units: Subjects
        Female
    		 15 15
        Male
    		 9 9
    Subject analysis sets

    Subject analysis set title
    Baseline characteristics
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    As this was a comparison of a change in neutrophil function, only those who completed the study were include din the analysis

    Subject analysis set title
    CTIMP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    As this was a comparison of changes in neutrophil function, only those who completed the study were included

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    As this was a comparison of changes in neutrophil function, only those who completed the study were included

    Subject analysis sets values
    		 Baseline characteristics CTIMP Placebo
    Number of subjects
    20
    20
    20
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    2
    2
    2
        From 65-84 years
    10
    10
    10
        85 years and over
    8
    8
    8
    Age continuous
    Units:
        
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    11
    11
    11
        Male
    9
    9
    9

    End points

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    End points reporting groups
    Reporting group title
    CTIMP
    Reporting group description
    		 Simvastatin
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo in cross over

    Subject analysis set title
    Baseline characteristics
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    As this was a comparison of a change in neutrophil function, only those who completed the study were include din the analysis

    Subject analysis set title
    CTIMP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    As this was a comparison of changes in neutrophil function, only those who completed the study were included

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    As this was a comparison of changes in neutrophil function, only those who completed the study were included

    Primary: Median change in neutrophil migration to fMLP

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    End point title
    		 Median change in neutrophil migration to fMLP
    End point description
    End point type
    Primary
    End point timeframe
    After 2 weeks of CTIMP therapy
    End point values
    		 CTIMP Placebo
    Number of subjects analysed
    20
    20
    Units: um/min
        median (inter-quartile range (Q1-Q3))
    0.34 (0.05 to 0.72)
    -0.05 (-0.38 to 0.08)
    Statistical analysis title
    		 Change in chemotaxis from baseline values
    Comparison groups
    CTIMP v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change in chemotaxis towards CXCL8

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    End point title
    		 Change in chemotaxis towards CXCL8
    End point description
    End point type
    Secondary
    End point timeframe
    Compared to baseline after 2 weeks of therapy in cross over trial
    End point values
    		 CTIMP Placebo
    Number of subjects analysed
    20
    20
    Units: um/min
        median (inter-quartile range (Q1-Q3))
    0.26 (0.01 to 0.61)
    0.03 (-0.73 to 0.34)
    Statistical analysis title
    		 Change from baseline chemotaxis
    Comparison groups
    CTIMP v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.042
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change in phagocytosis E Coli

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    End point title
    		 Change in phagocytosis E Coli
    End point description
    End point type
    Secondary
    End point timeframe
    After two weeks of CTIMP or placebo in cross over trial
    End point values
    		 CTIMP Placebo
    Number of subjects analysed
    20
    20
    Units: arbitrary units
        median (inter-quartile range (Q1-Q3))
    580 (-22.0 to 1347)
    690 (-79.0 to 1207)
    Statistical analysis title
    		 Change in phagocytosis E Coli
    Comparison groups
    CTIMP v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.404
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change in phagocytosis staph aureus

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    End point title
    		 Change in phagocytosis staph aureus
    End point description
    End point type
    Secondary
    End point timeframe
    After 2 weeks of CTIMP or placebo in cross over trial
    End point values
    		 CTIMP Placebo
    Number of subjects analysed
    20
    20
    Units: arbitrary units
        median (inter-quartile range (Q1-Q3))
    257 (-616.7 to 1951)
    1217 (-588.7 to 2048)
    Statistical analysis title
    		 Change in phagocytic index
    Comparison groups
    CTIMP v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.196
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: NETosis PMA

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    End point title
    		 NETosis PMA
    End point description
    End point type
    Secondary
    End point timeframe
    Two weeks of CTIMP or placebo in cross over study
    End point values
    		 CTIMP Placebo
    Number of subjects analysed
    20
    20
    Units: Arbitrary Units
        median (inter-quartile range (Q1-Q3))
    5985 (-24415 to 30189)
    6964 (-17992 to 22048)
    Statistical analysis title
    		 Change in PMA induced NETs
    Comparison groups
    CTIMP v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 729
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: NETosis to fMLP

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    End point title
    		 NETosis to fMLP
    End point description
    End point type
    Secondary
    End point timeframe
    After two weeks of CTIMP or Placebo
    End point values
    		 CTIMP Placebo
    Number of subjects analysed
    20
    20
    Units: Arbitrary Units
        median (inter-quartile range (Q1-Q3))
    1355 (-2133 to 6518)
    1099 (-2818 to 2719)
    Statistical analysis title
    		 Change in ketosis to fMLP
    Comparison groups
    CTIMP v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.216
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Netosis to LPS

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    End point title
    		 Netosis to LPS
    End point description
    End point type
    Secondary
    End point timeframe
    After 2 weeks of CTIMP or placebo in cross over trial
    End point values
    		 CTIMP Placebo
    Number of subjects analysed
    20
    20
    Units: Arbitrary Units
        median (inter-quartile range (Q1-Q3))
    7115 (-839 to 9851)
    4048 (2833 to 6279)
    Statistical analysis title
    		 Change in Netosis to LPS
    Comparison groups
    CTIMP v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.596
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For up to two weeks after completion of study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 ICD
    Dictionary version
    10
    Reporting groups
    Reporting group title
    All subjects
    Reporting group description
    		 -

    Serious adverse events
    		 All subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 21 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 All subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 21 (4.76%)
    Musculoskeletal and connective tissue disorders
    Muscle ache
    Additional description: Muscle ache in one subject with no change in blood tests and able to complete study
         subjects affected / exposed
    1 / 21 (4.76%)
         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
    04 May 2012
    Justification in protocol for giving 80mg Simvastatin, as requested by MHRA

    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/28657793
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