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    Clinical Trial Results:
    Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP 2)

    Summary
    EudraCT number
    2010-020763-20
    Trial protocol
    IE   GB  
    Global end of trial date
    12 May 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Dec 2017
    First version publication date
    21 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    10072DMcA-CS
    Additional study identifiers
    ISRCTN number
    ISRCTN88244364
    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
    Christine McNally, Northern Ireland Clinical Trials Unit (NICTU), 02890 635794, christine.mcnally@nictu.hscni.net
    Scientific contact
    Prof Daniel McAuley, Queen's University of Belfast, 02890 972671, 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
    23 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To test the hypothesis that treatment with enteral simvastatin 80mg once daily for a maximum of 28 days would be of therapeutic value in patients with acute lung injury (ALI). Many patients admitted to ICU need a ventilator to help them breathe and ensure that enough oxygen gets into their blood. For reasons that are unclear, when people are critically ill their lungs often fail; termed acute lung injury. There are no specific drugs to treat patients with ALI. Some small studies that have taken place over the past few years have suggested that giving patients with ALI a drug called simvastatin (usually used to treat patients with high cholesterol), might help patients to recover more quickly. We aimed to determine how long patients needed assistance with a ventilator, how fast they recovered. We measured any residual effects of their illness on their lives after one year and took blood and urine samples to determine how ALI develops and how simvastatin might alleviate this
    Protection of trial subjects
    CK and liver function were closely monitored and an additional blood sample was added at day 21 to measure these. Study drug was stopped if the patient's CK or liver function was found to be out of range. To minimize the risk of causing distress to the relation of a patient who died after leaving the hospital, the Clinical Trials Unit contacted the patient's GP and the Health & Social Care Information Centre to ascertain the patient's survival status prior to sending out any follow up questionnaires. A Clinical Trials Monitor monitored study site compliance with study and CTU SOPs and provided feedback to the Trial Management Group on any actual or potential problems in relation to safeguarding patients safety and wellbeing. The HARP-2 DMEC was appointed comprising two clinicians with experience in undertaking clinical trials / caring for critically ill patients and a statistician who was independent of the trial. The DMEC met biannually and meetings were formally minuted. The DMEC’s responsibility was to safeguard the interests of the trial participants, in particular with regard to safety and assist and advise the TSC so as to protect the validity and credibility of the trial. The DMEC monitored recruitment, adverse events and outcome data. Patient experience whilst critically ill was taken into consideration when preparing patient information leaflets and consent forms. The Chairman of CritPaL (Barry Williams) represented the patient’s perspective on the TSC ensuring that the trial remained considerate of the needs of the patients and their families. Site PIs evaluated all AEs/SAES for expectedness, causality and severity. All AEs assessed by the PI as possibly or probably related to the study drug and all SAEs that occurred during this time were followed until they were resolved or were clearly determined to be due to a patient’s stable or chronic condition or intercurrent illness(es). All AEs and SAEs were reviewed by the CI
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    06 Dec 2010
    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: 510
    Country: Number of subjects enrolled
    Ireland: 29
    Worldwide total number of subjects
    539
    EEA total number of subjects
    539
    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)
    3
    Adults (18-64 years)
    386
    From 65 to 84 years
    147
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    Patients were recruited between 21st December 2010 and 13th March 2014. During the recruiting period to HARP-2 a total of 40 sites participated in the study: 5 in Ireland, 4 in Northern Ireland, 4 in Scotland and 27 in England. 1 site opened in 2010, 25 in 2011, 9 in 2012, 4 in 2013 and 1 in 2014.

    Pre-assignment
    Screening details
    Patients ≥ 16 years, intubated and mechanically ventilated with partial pressure of arterial oxygen to fractional inspired oxygen concentration ratio of 300 mmHg or less, with bilateral pulmonary infiltrates consistent with pulmonary oedema present on chest x-ray, and no evidence of left atrial hypertension. 5926 screened, 540 (9%) randomised.

    Pre-assignment period milestones
    Number of subjects started
    540 [1]
    Number of subjects completed
    539

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Consent withdrawn by subject: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One patient withdrew consent for use of their data. So although they were enrolled in the trial we have no data available. This affects the worldwide total when compared to the age categories, so the worldwide total has been amended to 539 for submission. Likewise this affects the baseline placebo arm as technically 281 started and 280 completed but as this does not tally with the worldwide total of 539 now I have amended to 280 starting and added the justification here.
    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
    Blinding implementation details
    Simvastatin 40mg or identical placebo (95% lactose) tablets were packaged identically and identified only by the unique trial identifier. A computer-generated randomisation sequence was used. Patients were randomised in a 1:1 ratio using an automated centralised 24-hour telephone or web-based randomisation service (Centre for Healthcare Randomised Trials, University of Aberdeen, UK). Randomisation was by permuted block stratified by site and by vasopressor requirement

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Intervention
    Arm description
    once daily simvastatin 80mg (as two 40mg tablets) administered enterally via a feeding tube or orally for up to 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    PL08215/0042
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Enteral use
    Dosage and administration details
    once daily simvastatin 80mg (as two 40mg tablets) administered enterally via a feeding tube or orally for up to 28 days.

    Arm title
    Placebo
    Arm description
    once daily 80mg placebo (as two 40mg tablets); identical to the Simvastatin, administered enterally via a feeding tube or orally for up to 28 days.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Enteral use
    Dosage and administration details
    once daily placebo 80mg, as two 40mg tablets administered enterally via a feeding tube or orally for up to 28 days.

    Number of subjects in period 1
    Intervention Placebo
    Started
    259
    280
    Completed
    259
    280

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention
    Reporting group description
    once daily simvastatin 80mg (as two 40mg tablets) administered enterally via a feeding tube or orally for up to 28 days.

    Reporting group title
    Placebo
    Reporting group description
    once daily 80mg placebo (as two 40mg tablets); identical to the Simvastatin, administered enterally via a feeding tube or orally for up to 28 days.

    Reporting group values
    Intervention Placebo Total
    Number of subjects
    259 280 539
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.2 ± 16.1 54.4 ± 16.7 -
    Gender categorical
    Units: Subjects
        Female
    122 110 232
        Male
    137 170 307
    Sepsis
    Units: Subjects
        sepsis
    189 218 407
        non-sepsis
    70 62 132
    vasopressor requirement
    Units: Subjects
        yes
    169 187 356
        no
    90 93 183
    aetiology of ARDS - smoke/toxin inhalation
    Units: Subjects
        yes
    1 2 3
        no
    258 278 536
    aetiology of ARDS - gastric content aspiration
    Units: Subjects
        yes
    21 29 50
        no
    238 251 489
    aetiology of ARDS - near drowning
    Units: Subjects
        yes
    0 0 0
        no
    259 280 539
    aetiology of ARDS - thoracic trauma
    Units: Subjects
        yes
    22 10 32
        no
    237 270 507
    aetiology of ARDS - pneumonia
    Units: Subjects
        yes
    161 154 315
        no
    98 126 224
    aetiology of ARDS - other direct
    Units: Subjects
        yes
    15 19 34
        no
    244 261 505
    aetiology of ARDS - sepsis
    Units: Subjects
        yes
    106 118 224
        no
    153 162 315
    aetiology of ARDS - cardiopulmonary bypass
    Units: Subjects
        yes
    1 0 1
        no
    258 280 538
    aetiology of ARDS - pancreatitis
    Units: Subjects
        yes
    5 17 22
        no
    254 263 517
    aetiology of ARDS - non-thoracic trauma
    Units: Subjects
        yes
    4 8 12
        no
    255 272 527
    aetiology of ARDS - other indirect
    Units: Subjects
        yes
    14 19 33
        no
    245 261 506
    plateau pressure
    Units: cmH2O
        arithmetic mean (standard deviation)
    23.6 ± 6.1 23.6 ± 6 -
    APACHE II
    Units: score
        arithmetic mean (standard deviation)
    19.4 ± 6.9 18.3 ± 6.2 -
    PaO2:FiO2 ratio
    Units: mmHg
        arithmetic mean (standard deviation)
    16.4 ± 7.3 17.6 ± 7.4 -
    tidal volume per ideal body weight
    Units: mls/kg
        arithmetic mean (standard deviation)
    8.1 ± 2.8 8.1 ± 2.6 -
    SOFA
    Units: score
        arithmetic mean (standard deviation)
    8.6 ± 3.2 9 ± 2.9 -
    oxygenation index
    Units: cm of water/mmHg
        arithmetic mean (standard deviation)
    112.8 ± 87.3 112 ± 89 -
    lowest mean arterial pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    65.4 ± 9.3 64.9 ± 8.4 -

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    once daily simvastatin 80mg (as two 40mg tablets) administered enterally via a feeding tube or orally for up to 28 days.

    Reporting group title
    Placebo
    Reporting group description
    once daily 80mg placebo (as two 40mg tablets); identical to the Simvastatin, administered enterally via a feeding tube or orally for up to 28 days.

    Primary: ventilator-free days

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    End point title
    ventilator-free days
    End point description
    VFDs to day 28 are defined as the number of days from the time of initiating unassisted breathing to day 28 after randomisation, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28. If a patient returns to assisted breathing and subsequently achieves unassisted breathing to day 28, VFDs will be counted from the end of the last period of assisted breathing to day 28. A period of assisted breathing lasting less than 24 hours and for the purpose of a surgical procedure will not count against the VFD calculation. If a patient was receiving assisted breathing at day 27 or dies prior to day 28, VFDs will be zero.
    End point type
    Primary
    End point timeframe
    up to 28 days post-randomisation
    End point values
    Intervention Placebo
    Number of subjects analysed
    258
    279
    Units: days
        arithmetic mean (standard deviation)
    12.6 ± 9.9
    11.5 ± 10.4
    Statistical analysis title
    VFD analysis
    Comparison groups
    Placebo v Intervention
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.21
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    2.8
    Statistical analysis title
    VFD analysis - bootstrapped
    Comparison groups
    Placebo v Intervention
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.22
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    2.8

    Secondary: non-pulmonary organ failure free days

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    End point title
    non-pulmonary organ failure free days
    End point description
    The number of days in the first 28 days after randomisation that the patient has none of: cardiovascular support, renal support, liver support or neurological support).
    End point type
    Secondary
    End point timeframe
    up to 28 days post-randomisation
    End point values
    Intervention Placebo
    Number of subjects analysed
    257
    279
    Units: days
        arithmetic mean (standard deviation)
    19.4 ± 11.1
    17.8 ± 11.7
    Statistical analysis title
    non-pulmonary OFFDs analysis
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    536
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.11
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    3.5
    Statistical analysis title
    non-pulmonary OFFDs - bootstrapped
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    536
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    3.5

    Secondary: change in oxygenation index from baseline to day 3

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    End point title
    change in oxygenation index from baseline to day 3
    End point description
    Change in oxygenation index from baseline to day 3
    End point type
    Secondary
    End point timeframe
    day 3
    End point values
    Intervention Placebo
    Number of subjects analysed
    167
    162
    Units: cm of water/mmHg
        arithmetic mean (standard deviation)
    -25.3 ± 59.7
    -8.5 ± 75.1
    Statistical analysis title
    OI day 3
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.02
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    -16.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -31.5
         upper limit
    -2.1

    Secondary: change in oxygenation index from baseline to day 7

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    End point title
    change in oxygenation index from baseline to day 7
    End point description
    Change in oxygenation index from baseline to day 7
    End point type
    Secondary
    End point timeframe
    day 7
    End point values
    Intervention Placebo
    Number of subjects analysed
    93
    111
    Units: cm of water/mmHg
        arithmetic mean (standard deviation)
    -33 ± 83.9
    -30.1 ± 78.5
    Statistical analysis title
    OI day 7
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -25.4
         upper limit
    19.5

    Secondary: change in oxygenation index from baseline to day 14

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    End point title
    change in oxygenation index from baseline to day 14
    End point description
    Change in oxygenation index from baseline to day 14
    End point type
    Secondary
    End point timeframe
    day 14
    End point values
    Intervention Placebo
    Number of subjects analysed
    43
    57
    Units: cm of water/mmHg
        arithmetic mean (standard deviation)
    -37.5 ± 111.3
    -24.6 ± 61.8
    Statistical analysis title
    OI day 14
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.46
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    -13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -47.7
         upper limit
    21.7

    Secondary: change in oxygenation index from baseline to day 28

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    End point title
    change in oxygenation index from baseline to day 28
    End point description
    Change in oxygenation index from baseline to day 28
    End point type
    Secondary
    End point timeframe
    day 28
    End point values
    Intervention Placebo
    Number of subjects analysed
    4
    15
    Units: cm of water/mmHg
        arithmetic mean (standard deviation)
    20.7 ± 125.4
    -54 ± 43.6
    Statistical analysis title
    OI day 28
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.06
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    74.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.5
         upper limit
    153

    Secondary: change in SOFA from baseline to day 3

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    End point title
    change in SOFA from baseline to day 3
    End point description
    Change in sequential organ failure assessment (SOFA) score from baselines to day 3
    End point type
    Secondary
    End point timeframe
    day 3
    End point values
    Intervention Placebo
    Number of subjects analysed
    205
    225
    Units: score
        arithmetic mean (standard deviation)
    -0.9 ± 2.2
    -0.8 ± 2.3
    Statistical analysis title
    SOFA day 3
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.67
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    0.3

    Secondary: change in SOFA from baseline to day 7

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    End point title
    change in SOFA from baseline to day 7
    End point description
    Change in sequential organ failure assessment (SOFA) score from baselines to day 7
    End point type
    Secondary
    End point timeframe
    day 7
    End point values
    Intervention Placebo
    Number of subjects analysed
    152
    155
    Units: score
        arithmetic mean (standard deviation)
    -2.5 ± 3
    -2.5 ± 2.7
    Statistical analysis title
    SOFA day 7
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.86
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    0.6

    Secondary: change in SOFA from baseline to day 14

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    End point title
    change in SOFA from baseline to day 14
    End point description
    Change in sequential organ failure assessment (SOFA) score from baselines to day 14
    End point type
    Secondary
    End point timeframe
    day 14
    End point values
    Intervention Placebo
    Number of subjects analysed
    70
    81
    Units: score
        arithmetic mean (standard deviation)
    -3.4 ± 3.3
    -2.4 ± 3.2
    Statistical analysis title
    SOFA day 14
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.047
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.1
         upper limit
    -0.01

    Secondary: change in SOFA from baseline to day 28

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    End point title
    change in SOFA from baseline to day 28
    End point description
    Change in sequential organ failure assessment (SOFA) score from baselines to day 28
    End point type
    Secondary
    End point timeframe
    day 28
    End point values
    Intervention Placebo
    Number of subjects analysed
    15
    23
    Units: score
        arithmetic mean (standard deviation)
    -4.1 ± 3.9
    -2.7 ± 4.3
    Statistical analysis title
    SOFA day 28
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.29
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.3
         upper limit
    1.3

    Secondary: all cause mortality 28 days post randomisation

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    End point title
    all cause mortality 28 days post randomisation
    End point description
    All cause mortality 28 days post randomisation
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    Intervention Placebo
    Number of subjects analysed
    259
    280
    Units: subjects
        Alive
    202
    205
        Dead
    57
    75
    Statistical analysis title
    28 day mortality
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.23
    Method
    Fisher exact
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1.1

    Secondary: death before discharge from critical care

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    End point title
    death before discharge from critical care
    End point description
    Patients who died before discharge from critical care environment
    End point type
    Secondary
    End point timeframe
    to discharge from critical care
    End point values
    Intervention Placebo
    Number of subjects analysed
    259
    280
    Units: subjects
        Alive
    203
    210
        Dead
    56
    70
    Statistical analysis title
    death before discharge from critical care
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.36
    Method
    Fisher exact
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1.2

    Secondary: death before discharge from hospital

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    End point title
    death before discharge from hospital
    End point description
    Participants who died prior to discharge from hospital
    End point type
    Secondary
    End point timeframe
    to discharge from hospital
    End point values
    Intervention Placebo
    Number of subjects analysed
    259
    280
    Units: subjects
        Alive
    192
    190
        Dead
    67
    90
    Statistical analysis title
    death before discharge from hospital
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.13
    Method
    Fisher exact
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1.1

    Secondary: Quality Adjusted Life Years

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    End point title
    Quality Adjusted Life Years
    End point description
    QALYs calculated used baseline, 6 and 12 month EQ5D utilities on patients with complete costs and QALY data.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    Intervention Placebo
    Number of subjects analysed
    139
    153
    Units: qalys
        arithmetic mean (standard deviation)
    0.136 ± 0.274
    0.072 ± 0.262
    Statistical analysis title
    QALY analysis
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.064
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.002
         upper limit
    0.127

    Secondary: Health Service Use Costs

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    End point title
    Health Service Use Costs
    End point description
    Total 12 month health service costs for patients with complete costs and QALY data
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    Intervention Placebo
    Number of subjects analysed
    139
    153
    Units: UK pounds
        arithmetic mean (standard deviation)
    24115.36 ± 17154.86
    27716.27 ± 23643.97
    Statistical analysis title
    Cost Analysis
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -3600.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8872.17
         upper limit
    722.79

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 30 days following the administration of the study drug
    Adverse event reporting additional description
    Due to small numbers a breakdown of term is not provided for serious or non-serious AEs. For non serious adverse events, investigations is broken down into the following terms: ALT>8 times the upper limit of normal and/or AST>8 times the upper limit of normal; CK>10 times the upper limit of normal and; Other.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Simvastatin
    Reporting group description
    Patients on Simvastatin who experienced an adverse event

    Reporting group title
    Placebo
    Reporting group description
    Patients receiving a placebo who experienced an adverse event

    Serious adverse events
    Simvastatin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 259 (4.25%)
    14 / 280 (5.00%)
         number of deaths (all causes)
    67
    90
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    injury, poisoning and procedural complications
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac disorder
         subjects affected / exposed
    3 / 259 (1.16%)
    5 / 280 (1.79%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    1 / 259 (0.39%)
    3 / 280 (1.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    nervous system disorders
         subjects affected / exposed
    1 / 259 (0.39%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    gastrointestinal disorders
         subjects affected / exposed
    3 / 259 (1.16%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal and urinary disorders
    renal and urinary disorders
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    hepatobiliary disorders
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    musculoskeletal and connective tissue disorders
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    infections and infestations
         subjects affected / exposed
    1 / 259 (0.39%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    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
    49 / 259 (18.92%)
    49 / 280 (17.50%)
    Injury, poisoning and procedural complications
    injury, poisoning and procedural complications
         subjects affected / exposed
    0 / 259 (0.00%)
    2 / 280 (0.71%)
         occurrences all number
    0
    2
    Investigations
    Elevated ALT/AST
         subjects affected / exposed
    26 / 259 (10.04%)
    20 / 280 (7.14%)
         occurrences all number
    32
    23
    Elevated CK
         subjects affected / exposed
    23 / 259 (8.88%)
    15 / 280 (5.36%)
         occurrences all number
    23
    15
    investigations other
         subjects affected / exposed
    2 / 259 (0.77%)
    2 / 280 (0.71%)
         occurrences all number
    2
    2
    Cardiac disorders
    cardiac disorders
         subjects affected / exposed
    1 / 259 (0.39%)
    2 / 280 (0.71%)
         occurrences all number
    2
    2
    Respiratory, thoracic and mediastinal disorders
    respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    2 / 259 (0.77%)
    1 / 280 (0.36%)
         occurrences all number
    2
    1
    Blood and lymphatic system disorders
    blood and lymphatic system disorders
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 280 (0.36%)
         occurrences all number
    1
    1
    Nervous system disorders
    nervous system disorders
         subjects affected / exposed
    1 / 259 (0.39%)
    1 / 280 (0.36%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    general disorders and administration site conditions
         subjects affected / exposed
    1 / 259 (0.39%)
    2 / 280 (0.71%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    gastrointestinal disorders
         subjects affected / exposed
    3 / 259 (1.16%)
    4 / 280 (1.43%)
         occurrences all number
    3
    4
    Renal and urinary disorders
    renal and urinary disorders
         subjects affected / exposed
    1 / 259 (0.39%)
    2 / 280 (0.71%)
         occurrences all number
    1
    2
    Skin and subcutaneous tissue disorders
    skin and subcutaneous tissue disorders
         subjects affected / exposed
    0 / 259 (0.00%)
    6 / 280 (2.14%)
         occurrences all number
    0
    6
    Infections and infestations
    infections and infestations
         subjects affected / exposed
    1 / 259 (0.39%)
    3 / 280 (1.07%)
         occurrences all number
    1
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Apr 2011
    Amendment 1 (main changes): Protocol v1.0_24.06.10 was submitted to ORECNI in the original application for Ethics approval. ORECNI requested some changes which necessitated amending the protocol to v2.0_01.09.10. The major changes included: • Amending the exclusion criteria to exclude non−english speaking patients or those who did not adequately understand verbal or written information unless an interpreter was available; • Amending the exclusion criteria to include the wording “currently” and “sustained” in relation to the use of listed concomitant medications. Amiodarone was added to the list of concomitant medications. • Clarification was given that the 80 mg dose was given as 2 x 40m tablets. • Sofa score was added to the schedule of assessments in day 14 and day 28.
    27 Jun 2011
    Protocol v2.0_01.09.10 was amended to v3.0_16.05.11. ORECNI and MHRA approved the following changes: • Change of address of the Chief Investigator (CI). • Non pulmonary organ failure free days added to secondary outcomes • An additional blood sample was added at day 21 to measure CK and liver function. • The exclusion criteria were amended to allow for patients receiving erythromycin as a prokinetic to be included in the study. • Change of address of study drug supplier. • Other changes: additional sites added.
    19 Sep 2011
    Amendment 3 (main changes): Protocol v3.0_16.05.11 was amended to v4.0_18.07.11 and was approved by ORECNI and MHRA to include the following changes: • The exclusion criteria were amended to remove clarithromycin and erythromycin. • Clarification was given that domiciliary ventilation used for sleep-disordered breathing would not be included as mechanical ventilation. • Scheduling for research samples submission was changed to allow that research samples due on bank holidays or weekends could be collected up to 2 days after the due date (with the exception of day 1).
    12 Mar 2012
    Amendment 5 (main changes): Protocol v4.0_18.07.11 was amended to v5.0_13.01.12. This amendment was approved by ORECNI and MHRA to include the following changes: • The exclusion criteria was amended to change the upper limit of normal for ALT and AST from > 5 times upper limit of normal to > 8 times upper limit of normal.

    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/25268516
    http://www.ncbi.nlm.nih.gov/pubmed/22985805
    http://www.ncbi.nlm.nih.gov/pubmed/28511660
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