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    Clinical Trial Results:
    Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in mechanically ventilated patients at high risk of delirium

    Summary
    EudraCT number
    		 2012-003114-13
    Trial protocol
    		 GB  
    Global end of trial date
    11 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Mar 2018
    First version publication date
    03 Mar 2018
    Other versions
    Summary report(s)
    		 MoDUS summary results

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RD2012-134
    Additional study identifiers
    ISRCTN number
    		 ISRCTN89079989
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    West Hertfordshire Hospitals NHS Trust
    Sponsor organisation address
    Vicarage Road, Watford, United Kingdom, WD18 0HB
    Public contact
    Intensive Care, West Hertfordshire Hospitals NHS Trust, +44 1923217610, valerie.page@whht.nhs.uk
    Scientific contact
    Intensive Care, West Hertfordshire Hospitals NHS Trust, +44 1923217610, valerie.page@whht.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
    15 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jan 2017
    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 will increase the number of delirium/coma free days in mechanically ventilated patients at high risk of delirium. The study has three distinct objectives: Objective 1: to conduct a prospective randomised double-blind, placebo-controlled phase II single-centre trial of Simvastatin for the prevention/treatment of delirium. Objective 2: to determine any improvement in related neurocognitive sequelae coupled with standard clinical outcomes. Objective 3: to study the biological effect of Simvastatin on systemic markers of inflammation and cholinergic activity as related to the number of delirium/coma free days and the potential of beta-amyloid as a predictor of the risk of long term cognitive impairment.
    Protection of trial subjects
    Consent to continue consent interview and follow up phone assessments provided opportunties for investigators to determine pain and distress so principal investigator was able to advise on referral or to recommend GP attendance.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    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: 142
    Worldwide total number of subjects
    142
    EEA total number of subjects
    142
    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)
    72
    From 65 to 84 years
    63
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited between Feb 1, 2013, and July 29, 2016 at a single site, Watford General Hospital.

    Pre-assignment
    Screening details
    		 Patients receiving invasive mechanical ventilation within the first 72 h of ICU admission were screened for inclusion in the study. 1164 screened, 142 (12.2%) randomised and included in the final analysis.

    Pre-assignment period milestones
    Number of subjects started
    		 142
    Number of subjects completed
    		 142

    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. The study statistician generated the randomisation schedule in advance using nQuery Advisor version 4.0, and randomisation was by variable block sizes of 2, 4, 6, and 8, without stratification.

    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
    		 Control
    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
    Placebo
    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 Control
    Started
    71
    71
    Completed
    71
    71

    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
    Control
    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 Control Total
    Number of subjects
    		 71 71 142
    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)
    		 61.9 ( 15.3 ) 62.1 ( 17.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 26 34 60
        Male
    		 45 37 82
    Diagnosis_ARDS
    Units: Subjects
        Yes
    		 23 18 41
        No
    		 48 53 101
    Diagnosis_Pneumonia
    Units: Subjects
        Yes
    		 33 30 63
        No
    		 38 41 79
    Diagnosis_MIorCCF
    Units: Subjects
        Yes
    		 2 3 5
        No
    		 69 68 137
    Diagnosis_RenalorHepFailure
    Units: Subjects
        Yes
    		 4 4 8
        No
    		 67 67 134
    Diagnosis_COPD
    Units: Subjects
        Yes
    		 7 3 10
        No
    		 64 68 132
    Diagnosis_Haemorrhage
    Units: Subjects
        Yes
    		 1 1 2
        No
    		 70 70 140
    Diagnosis_Drug Overdose
    Units: Subjects
        Yes
    		 3 6 9
        No
    		 68 65 133
    Diagnosis_Trauma
    Units: Subjects
        Yes
    		 0 0 0
        No
    		 71 71 142
    Diagnosis_Other
    Units: Subjects
        Yes
    		 19 17 36
        No
    		 52 54 106
    CAM-ICU Status
    Units: Subjects
        Positive
    		 56 56 112
        Negative
    		 0 4 4
        Unable to assess
    		 15 11 26
    Organ failure Free
    Units: Subjects
        Yes
    		 0 1 1
        No
    		 71 70 141
    Predeliric Diagnose Group
    Units: Subjects
        Surgical
    		 19 17 36
        Medical
    		 48 50 98
        Trauma
    		 0 1 1
        Neurology/Neurosurgical
    		 4 3 7
    Alcohol Abuse Present
    Units: Subjects
        Yes
    		 13 15 28
        No
    		 58 56 114
    IQCODE
    N=67 in Intervention arm and N=60 in Placebo arm only
    Units: Score
        arithmetic mean (standard deviation)
    		 3.2 ( 0.4 ) 3.1 ( 0.3 ) -
    Lowest RASS Score
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 -4 (-4 to -3) -4 (-4 to -3) -
    Highest RASS Score
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 1 (-1 to 2) 1 (-1 to 2) -
    Highest Creatinine
    Units: Umol/L
        arithmetic mean (standard deviation)
    		 111.6 ( 73.7 ) 118.5 ( 104.9 ) -
    Highest Bilirubin
    Units: Umol/L
        arithmetic mean (standard deviation)
    		 31.0 ( 68.6 ) 20.5 ( 25.6 ) -
    CRP
    Units: mg/L
        arithmetic mean (standard deviation)
    		 208.0 ( 169.0 ) 212.7 ( 155.6 ) -
    Fentanyl Total Dose
    Units: mgs
        arithmetic mean (standard deviation)
    		 0.6 ( 0.7 ) 0.6 ( 0.7 ) -
    Propofol Total Dose
    Units: mgs
        arithmetic mean (standard deviation)
    		 700.6 ( 778.8 ) 821.5 ( 936.9 ) -
    Apache II Score
    Units: Score
        arithmetic mean (standard deviation)
    		 17.2 ( 5.3 ) 16.7 ( 6.4 ) -
    Chance of delirium development
    Units: percent
        arithmetic mean (standard deviation)
    		 70.9 ( 26.9 ) 70.9 ( 24.5 ) -
    Total SOFA Score
    n=70 in Intervention and n=71 in Control arms
    Units: Score
        arithmetic mean (standard deviation)
    		 8.8 ( 3.7 ) 8.9 ( 3.1 ) -
    CK
    Units: U/L
        arithmetic mean (standard deviation)
    		 240.4 ( 294.7 ) 219.7 ( 250.0 ) -
    ALT
    Units: U/L
        arithmetic mean (standard deviation)
    		 65.0 ( 63.8 ) 62.6 ( 64.4 ) -

    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
    Control
    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: Delirium/Coma free at 14 days post randomisation

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    End point title
    		 Delirium/Coma free at 14 days post randomisation
    End point description
    The primary outcome is the number of days in the first 14 days following randomisation during which the patient is alive and free from delirium and coma where days are counted as calendar days i.e. from 00:00 to 23:59.
    End point type
    Primary
    End point timeframe
    Until 14 days post randomisation
    End point values
    		 Intervention Control
    Number of subjects analysed
    71
    71
    Units: Days
        arithmetic mean (standard deviation)
    5.7 ( 5.1 )
    6.1 ( 5.2 )
    Statistical analysis title
    		 DCF Days Analysis
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.66
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.33
         upper limit
    		 2.09
    Statistical analysis title
    		 DCF Analysis Bootstrapped
    Statistical analysis description
    Bootstrap t-test (bias corrected CI)
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.65
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.32
         upper limit
    		 2.02
    Statistical analysis title
    		 DCF Days Mann Whitney
    Statistical analysis description
    Two-sample Mann Whitney test
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.56
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 DCF Days Adjusted
    Statistical analysis description
    Adjusted for baseline SOFA and chance of delirium development
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.18
         upper limit
    		 2.02
    Statistical analysis title
    		 DCF Days Joint Modelling_Recurrences
    Statistical analysis description
    Joint modelling approach via the R statistical package frailty pack. This approach will combine two survival models: one for the repeated daily indicator of delirium and another for the terminating event of ICU discharge or death.
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 joint frailty modelling
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.23
    Statistical analysis title
    		 DCF Days Joint Modelling_Assignment(Simvastatin)
    Statistical analysis description
    Joint modelling approach via the R statistical package frailty pack. This approach will combine two survival models: one for the repeated daily indicator of delirium and another for the terminating event of ICU discharge or death.
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25
    Method
    		 joint frailty modelling
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 2.04
    Statistical analysis title
    		 DCF Days Joint Modelling_Type(Death)
    Statistical analysis description
    Joint modelling approach via the R statistical package frailty pack. This approach will combine two survival models: one for the repeated daily indicator of delirium and another for the terminating event of ICU discharge or death.
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 joint frailty modelling
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    3.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.12
         upper limit
    		 11.81
    Statistical analysis title
    		 DCF Days Joint Modelling_Assignment*Type
    Statistical analysis description
    Joint modelling approach via the R statistical package frailty pack. This approach will combine two survival models: one for the repeated daily indicator of delirium and another for the terminating event of ICU discharge or death.
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.69
    Method
    		 joint frailty modelling
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 3.29

    Secondary: Delirium/Coma free at 28 days post randomisation

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    End point title
    		 Delirium/Coma free at 28 days post randomisation
    End point description
    The number of days in the first 28 days following randomisation during which the patient is alive and free from delirium and coma where days are counted as calendar days i.e. from 00:00 to 23:59.
    End point type
    Secondary
    End point timeframe
    Until 28 days post randomisation
    End point values
    		 Intervention Control
    Number of subjects analysed
    71
    71
    Units: Days
        arithmetic mean (standard deviation)
    14.3 ( 11.2 )
    15.4 ( 10.9 )
    Statistical analysis title
    		 DCF 28 days t-test
    Statistical analysis description
    Two-sample t-test
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.56
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.59
         upper limit
    		 4.74
    Statistical analysis title
    		 DCF 28 days bootstrap t-test
    Statistical analysis description
    Bootstrap t-test (bias corrected CI)
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.56
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.04
         upper limit
    		 5.13
    Statistical analysis title
    		 DCF 28 days Mann-Whitney
    Statistical analysis description
    Two-sample Mann-Whitney test
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Incidence of Delirium

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    End point title
    		 Incidence of Delirium
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 28 days post randomisation
    End point values
    		 Intervention Control
    Number of subjects analysed
    71
    71
    Units: Subjects
    66
    67
    Statistical analysis title
    		 Test of Proportions
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.81
    Method
    		 two-sample test of proportions
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.07

    Secondary: Days in coma to 14 days

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    End point title
    		 Days in coma to 14 days
    End point description
    End point type
    Secondary
    End point timeframe
    up to 14 days
    End point values
    		 Intervention Control
    Number of subjects analysed
    71
    71
    Units: Days
        arithmetic mean (standard deviation)
    1.0 ( 1.4 )
    0.9 ( 1.5 )
    Statistical analysis title
    		 Days in coma 14
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.82
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 0.44

    Secondary: Days in coma to 28 days

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    End point title
    		 Days in coma to 28 days
    End point description
    End point type
    Secondary
    End point timeframe
    up to 28 days
    End point values
    		 Intervention Control
    Number of subjects analysed
    71
    71
    Units: days
        arithmetic mean (standard deviation)
    1.1 ( 1.7 )
    1.1 ( 1.8 )
    Statistical analysis title
    		 Days in coma 28
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.58
         upper limit
    		 0.58

    Secondary: Days in delirium to 14 days

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    End point title
    		 Days in delirium to 14 days
    End point description
    End point type
    Secondary
    End point timeframe
    up to 14 days
    End point values
    		 Intervention Control
    Number of subjects analysed
    71
    71
    Units: days
        arithmetic mean (standard deviation)
    5.6 ( 4.3 )
    5.5 ( 4.5 )
    Statistical analysis title
    		 Days in delirium 14
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.92
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.53
         upper limit
    		 1.39

    Secondary: Days in delirium to 28 days

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    End point title
    		 Days in delirium to 28 days
    End point description
    End point type
    Secondary
    End point timeframe
    up to 28 days
    End point values
    		 Intervention Control
    Number of subjects analysed
    71
    71
    Units: days
        arithmetic mean (standard deviation)
    6.4 ( 6.0 )
    6.8 ( 6.6 )
    Statistical analysis title
    		 Days in delirium 28
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.82
         upper limit
    		 2.35

    Secondary: VFDs to 28 days post randomisation

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    End point title
    		 VFDs to 28 days post randomisation
    End point description
    End point type
    Secondary
    End point timeframe
    up to 28 days
    End point values
    		 Intervention Control
    Number of subjects analysed
    71
    71
    Units: days
        arithmetic mean (standard deviation)
    13.7 ( 11.9 )
    15.5 ( 11.4 )
    Statistical analysis title
    		 VFDs t-test
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.36
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.07
         upper limit
    		 5.65
    Statistical analysis title
    		 VFDs bootstrap t-test
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.37
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.96
         upper limit
    		 5.32
    Notes
    [1] - Bootstrap t-test (bias corrected CI)
    Statistical analysis title
    		 VFDs Mann-whitney
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: OFFDs in first 28 days

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    End point title
    		 OFFDs in first 28 days
    End point description
    End point type
    Secondary
    End point timeframe
    up to 28 days
    End point values
    		 Intervention Control
    Number of subjects analysed
    71
    71
    Units: days
        arithmetic mean (standard deviation)
    14.3 ( 12.1 )
    15.7 ( 11.2 )
    Statistical analysis title
    		 OFFDs t-test
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.45
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.38
         upper limit
    		 5.34
    Statistical analysis title
    		 OFFDs bootstrap t-test
    Statistical analysis description
    Bootstrap t-test (bias corrected CI)
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.43
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.22
         upper limit
    		 5.03
    Statistical analysis title
    		 OFFDs Mann Whitney
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.65
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: All cause mortality at 6 months

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    End point title
    		 All cause mortality at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months post randomisation
    End point values
    		 Intervention Control
    Number of subjects analysed
    71
    71
    Units: subjects
    30
    22
    Statistical analysis title
    		 Mortality Risk Ratio
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.22
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 2.11
    Statistical analysis title
    		 Mortality Logrank
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2 [2]
    Method
    		 Logrank
    Confidence interval
    Notes
    [2] - Events expected from Logrank test were 25.45 in Intervention arm and 26.55 in Control arm.

    Secondary: Cognitive decline via IQCODE

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    End point title
    		 Cognitive decline via IQCODE
    End point description
    End point type
    Secondary
    End point timeframe
    at 6 months
    End point values
    		 Intervention Control
    Number of subjects analysed
    21
    27
    Units: score
        arithmetic mean (standard deviation)
    3.0 ( 0.5 )
    3.1 ( 0.7 )
    Statistical analysis title
    		 IQCODE ANCOVA
    Statistical analysis description
    ANCOVA adjusting for baseline IQCODE. n=21 in interventions arm and n=27 in the control arm
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.99
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.004
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 0.39

    Secondary: BTACT at 6 months

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    End point title
    		 BTACT at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    at 6 months
    End point values
    		 Intervention Control
    Number of subjects analysed
    18
    24
    Units: standardised scores
        arithmetic mean (standard deviation)
    -0.2 ( 0.5 )
    0.1 ( 0.5 )
    Statistical analysis title
    		 BTACT t-test
    Statistical analysis description
    BTACT composite is an average of the standardized scores and was calculated on the basis of no. of tasks completed.
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.08
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.6

    Secondary: Duration of hospital stay until death or discharge

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    End point title
    		 Duration of hospital stay until death or discharge
    End point description
    End point type
    Secondary
    End point timeframe
    randomisation until death or discharge
    End point values
    		 Intervention Control
    Number of subjects analysed
    71
    71
    Units: days
        arithmetic mean (standard deviation)
    20.3 ( 22.1 )
    20.4 ( 16.6 )
    Statistical analysis title
    		 hospital stay cox regression
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.45
    Statistical analysis title
    		 hospital stay t-test
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.96
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.31
         upper limit
    		 6.65
    Statistical analysis title
    		 hospital stay hodge-lehmann
    Statistical analysis description
    requested by Lancet reviewer. Median (IQR) for Intervention was 13(7,25) and for Control was 16(9,28). The median difference (IQR) was 2(-2,6)
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    142
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.3
    Method
    		 hodge-lehmann
    Confidence interval

    Secondary: Duration of hospital stay until discharge

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    End point title
    		 Duration of hospital stay until discharge
    End point description
    End point type
    Secondary
    End point timeframe
    randomisation until discharge
    End point values
    		 Intervention Control
    Number of subjects analysed
    47
    50
    Units: days
        arithmetic mean (standard deviation)
    23.3 ( 24.3 )
    23.1 ( 16.9 )
    Statistical analysis title
    		 hospital stay cox regression
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.925
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.53
    Statistical analysis title
    		 hospital stay t-test
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    97
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.97
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.56
         upper limit
    		 8.21
    Statistical analysis title
    		 hospital stay hodge-lehmann
    Statistical analysis description
    The median (IQR) for the Intervention arm was 16(9,26) and for the Control arm was 18(12,34). The median difference(IQR) was 2(-3,7).
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    97
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 hodge-lehmann
    Confidence interval

    Secondary: Quality Adjusted Life Years

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    End point title
    		 Quality Adjusted Life Years
    End point description
    QALYs calculated used baseline and 6 month EQ5D utilities on patients with complete costs and QALY data.
    End point type
    Secondary
    End point timeframe
    over 6 months
    End point values
    		 Intervention Control
    Number of subjects analysed
    48
    48
    Units: QALYs
        arithmetic mean (confidence interval 95%)
    0.078 (0.051 to 0.105)
    0.083 (0.055 to 0.110)
    Statistical analysis title
    		 QALY analysis
    Statistical analysis description
    95% CI based on 1000 bootstrapped replicates
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.005
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.03

    Secondary: Health service use costs

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    End point title
    		 Health service use costs
    End point description
    Total 6 month health service costs for patients with complete costs and QALY data
    End point type
    Secondary
    End point timeframe
    over 6 months
    End point values
    		 Intervention Control
    Number of subjects analysed
    48
    48
    Units: GBP
        arithmetic mean (confidence interval 95%)
    23792.37 (16109.92 to 31474.82)
    22433.41 (17558.32 to 27308.51)
    Statistical analysis title
    		 Cost analysis
    Statistical analysis description
    95% CI based on 1000 bootstrapped replicates
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1358.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7286.7
         upper limit
    		 10004.61

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    30 days following administration of study drug.
    Adverse event reporting additional description
    Events that were expected in this population (i.e. events that are in keeping with the patient’s underlying medical condition) were not reported as AEs. 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 ALT>8 times ULN and CK>10 times ULN.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 -

    Reporting group title
    Control
    Reporting group description
    		 -

    Serious adverse events
    		 Intervention Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 71 (12.68%)
    8 / 71 (11.27%)
         number of deaths (all causes)
    30
    22
         number of deaths resulting from adverse events
    1
    0
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    1 / 71 (1.41%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    7 / 71 (9.86%)
    7 / 71 (9.86%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Intervention Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 71 (16.90%)
    7 / 71 (9.86%)
    Investigations
    Elevated CK
         subjects affected / exposed
    8 / 71 (11.27%)
    3 / 71 (4.23%)
         occurrences all number
    8
    3
    Elevated ALT
         subjects affected / exposed
    4 / 71 (5.63%)
    4 / 71 (5.63%)
         occurrences all number
    4
    4
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    skin and subcutaneous tissue disorders
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (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
    22 Jul 2015
    3.3.2 Exclusion criteria 9. Patients with severe renal impairment (estimated creatinine clearance less than 15ml/minute) not receiving renal replacement therapy

    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/28734823
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