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    Clinical Trial Results:
    Keratinocyte growth factor in Acute lung injury to REduce pulmonary dysfunction – a randomised placebo controlled trial (KARE)

    Summary
    EudraCT number
    		 2010-021186-70
    Trial protocol
    		 GB  
    Global end of trial date
    17 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 May 2019
    First version publication date
    24 May 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    10089DMCA-CS
    Additional study identifiers
    ISRCTN number
    		 ISRCTN95690673
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Belfast Health & Social Care Trust (BHSCT)
    Sponsor organisation address
    King Edward Building, Royal Hospitals, Grosvenor Road, Belfast, United Kingdom, BT12 6BA
    Public contact
    Prof Daniel McAuley, Queen's University of Belfast, 02890 976385, d.f.mcauley@qub.ac.uk
    Scientific contact
    Prof Daniel McAuley, Queen's University of Belfast, 02890 976385, d.f.mcauley@qub.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Aug 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this study is to test the hypothesis that palifermin will be effective in the treatment of patients with acute lung injury (ALI). The trial objective is to undertaken a randomised double blind placebo controlled (i.e. dummy medication) clinical trial to study whether palifermin improves important surrogate markers of clinical outcome and is safe in adult patients with ALI in intensive care.
    Protection of trial subjects
    Patients were closely monitored for AEs. A Clinical Trials Monitor monitored study site compliance with study and sponsor SOPs and provided feedback to the Trial Management Group on any actual or potential problems in relation to safeguarding patients safety and wellbeing. The DMEC was appointed comprising two clinicians with experience in undertaking clinical trials / caring for critically ill patients. The DMEC met regularly and meetings were formally minuted. The DMEC’s responsibility was to safeguard patient safety. The DMEC monitored recruitment and adverse event data. All AEs/SAEs were assessed for expectedness, causality and severity. All AEs were assessed as possibly, probably or definitely related to the study drug. We originally intended that any events that are normally expected in this population would not be recorded as serious adverse events; however, the approved protocol stated that all serious adverse events that occurred would be reported, regardless of the underlying association to the underlying clinical condition. Subsequently all serious adverse events were reported and the association to underlying clinical condition was recorded. All of the serious adverse events were assessed by the chief investigator and an independent intensive care unit physician as being due to the patient’s underlying medical condition and unrelated to the study drug.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    23 Feb 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: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    60
    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)
    35
    From 65 to 84 years
    23
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between Feb 23, 2011, and Feb 26, 2014, 368 patients were assessed for eligibility and 60 patients recruited in UK.

    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. 368 screened, 60 randomised.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Patients and investigators were both masked to treatment. The study drug was stored in a masked container in a locked fridge. A trained member of the intensive care unit nursing staff who was not involved in the clinical trial removed the study drug container from the fridge and brought it to the bedside, where the study drug was reconstituted and administered intravenously to the unconscious patient, before returning the masked study drug container to the fridge.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Keratinocyte growth factor (KGF)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Keratinocyte growth factor
    Investigational medicinal product code
    Other name
    palifermin
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    60 μg/kg per day for 6 days

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    0·9% sodium chloride solution for 6 days

    Number of subjects in period 1
    		Keratinocyte growth factor (KGF) Placebo
    Started
    29
    31
    Completed
    29
    31

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Keratinocyte growth factor (KGF)
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Keratinocyte growth factor (KGF) Placebo Total
    Number of subjects
    		 29 31 60
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 18 17 35
        From 65-84 years
    		 11 12 23
        85 years and over
    		 0 2 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.6 ± 17.5 61 ± 15.4 -
    Gender categorical
    Units: Subjects
        Female
    		 12 11 23
        Male
    		 17 20 37
    Sepsis requiring vasopressors
    Units: Subjects
        sepsis
    		 14 15 29
        non-sepsis
    		 15 16 31
    Cause of ARDS - Smoke or toxin inhalation
    Units: Subjects
        yes
    		 1 0 1
        no
    		 28 31 59
    Cause of ARDS - Aspiration
    Units: Subjects
        yes
    		 10 7 17
        no
    		 19 24 43
    Cause of ARDS - Thoracic trauma
    Units: Subjects
        yes
    		 1 2 3
        no
    		 28 29 57
    Cause of ARDS - Pneumonia
    Units: Subjects
        yes
    		 10 18 28
        no
    		 19 13 32
    Cause of ARDS - Sepsis
    Units: Subjects
        yes
    		 11 16 27
        no
    		 18 15 33
    Cause of ARDS - Pancreatitis
    Units: Subjects
        yes
    		 0 2 2
        no
    		 29 29 58
    Cause of ARDS - Non-thoracic trauma
    Units: Subjects
        yes
    		 5 1 6
        no
    		 24 30 54
    Cause of ARDS - Other
    Units: Subjects
        yes
    		 3 2 5
        no
    		 26 29 55
    APACHE II
    Units: score
        arithmetic mean (standard deviation)
    		 18.8 ± 9.0 22.7 ± 6.5 -
    LIS
    Units: score
        arithmetic mean (standard deviation)
    		 2 ± 0.6 2.2 ± 0.6 -
    Mean arterial pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 63.5 ± 11.2 64.5 ± 10.3 -
    Tidal Volume at randomisation
    Units: ml/kg PBW
        arithmetic mean (standard deviation)
    		 7.9 ± 2.6 8.3 ± 2.1 -
    PEEP
    Units: cm H2O
        arithmetic mean (standard deviation)
    		 7.3 ± 2.2 8.5 ± 2.4 -
    Plateau pressure
    Units: cm H2O
        arithmetic mean (standard deviation)
    		 23.3 ± 4.7 24 ± 3.3 -
    Oxygenation index
    Units: kPa
        arithmetic mean (standard deviation)
    		 72.3 ± 51.6 103.2 ± 60.2 -
    PaO2/FiO2 ratio
    Units: kPa
        arithmetic mean (standard deviation)
    		 21.4 ± 8.6 15.8 ± 5.7 -
    Compliance
    Units: ml/cm H2O
        arithmetic mean (standard deviation)
    		 40.1 ± 16.3 43.9 ± 15.8 -
    SOFA
    Units: score
        arithmetic mean (standard deviation)
    		 9.5 ± 4.0 8.9 ± 3.1 -
    airway pressure
    Units: cm H20
        arithmetic mean (standard deviation)
    		 12.2 ± 4.2 13.9 ± 4.1 -

    End points

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    End points reporting groups
    Reporting group title
    Keratinocyte growth factor (KGF)
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Oxygenation index (last available) day 7

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    End point title
    		 Oxygenation index (last available) day 7
    End point description
    End point type
    Primary
    End point timeframe
    day 7
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    29
    31
    Units: kPa
        arithmetic mean (standard deviation)
    62.3 ± 57.8
    43.1 ± 33.5
    Statistical analysis title
    		 OI day 7
    Comparison groups
    Placebo v Keratinocyte growth factor (KGF)
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    19.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.6
         upper limit
    		 44

    Secondary: Oxygenation index (last available) day 3

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    End point title
    		 Oxygenation index (last available) day 3
    End point description
    End point type
    Secondary
    End point timeframe
    day 3
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    29
    31
    Units: kPa
        arithmetic mean (standard deviation)
    66.9 ± 55.0
    60.1 ± 45.4
    Statistical analysis title
    		 OI day 3
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.2
         upper limit
    		 32.8

    Secondary: Oxygenation index (last available) day 14

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    End point title
    		 Oxygenation index (last available) day 14
    End point description
    End point type
    Secondary
    End point timeframe
    day 14
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    29
    31
    Units: kPa
        arithmetic mean (standard deviation)
    59.4 ± 58.4
    30.1 ± 24.2
    Statistical analysis title
    		 OI day 14
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    29.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.6
         upper limit
    		 53

    Secondary: Oxygenation index (measured) day 3

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    End point title
    		 Oxygenation index (measured) day 3
    End point description
    End point type
    Secondary
    End point timeframe
    day 3
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    26
    30
    Units: kPa
        arithmetic mean (standard deviation)
    62.8 ± 50.1
    60.9 ± 45.9
    Statistical analysis title
    		 OI day 3
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.89
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.9
         upper limit
    		 27.6

    Secondary: Oxygenation index (measured) day 7

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    End point title
    		 Oxygenation index (measured) day 7
    End point description
    End point type
    Secondary
    End point timeframe
    day 7
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    23
    21
    Units: kPa
        arithmetic mean (standard deviation)
    45.4 ± 32.1
    48.6 ± 38.6
    Statistical analysis title
    		 OI day 7
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.76
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.8
         upper limit
    		 18.3

    Secondary: Oxygenation index (measured) day 14

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    End point title
    		 Oxygenation index (measured) day 14
    End point description
    End point type
    Secondary
    End point timeframe
    day 14
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    11
    5
    Units: kPa
        arithmetic mean (standard deviation)
    52.9 ± 35.2
    43.3 ± 37.2
    Statistical analysis title
    		 OI day 14
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.63
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.8
         upper limit
    		 51

    Secondary: Respiratory compliance day 3

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    End point title
    		 Respiratory compliance day 3
    End point description
    End point type
    Secondary
    End point timeframe
    day 3
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    16
    20
    Units: mL/cm H2O
        arithmetic mean (standard deviation)
    48.6 ± 16.4
    53.5 ± 28.8
    Statistical analysis title
    		 Respiratory compliance day 3
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.3
         upper limit
    		 11.6

    Secondary: Respiratory compliance day 7

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    End point title
    		 Respiratory compliance day 7
    End point description
    End point type
    Secondary
    End point timeframe
    day 7
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    14
    7
    Units: mL/cm H2O
        arithmetic mean (standard deviation)
    51.1 ± 25.2
    65.1 ± 15.4
    Statistical analysis title
    		 Respiratory compliance day 7
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -35.9
         upper limit
    		 7.9

    Secondary: Respiratory compliance day 14

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    End point title
    		 Respiratory compliance day 14
    End point description
    End point type
    Secondary
    End point timeframe
    day 14
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    6
    1
    Units: mL/cm H2O
        arithmetic mean (standard deviation)
    45.0 ± 10.4
    77.5 ± 0
    No statistical analyses for this end point

    Secondary: PaO2/FiO2 ratio day 3

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    End point title
    		 PaO2/FiO2 ratio day 3
    End point description
    End point type
    Secondary
    End point timeframe
    day 3
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    26
    31
    Units: kPa
        arithmetic mean (standard deviation)
    23.1 ± 9.1
    20.3 ± 6.0
    Statistical analysis title
    		 PaO2/FiO2 ratio day 3
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 7.1

    Secondary: PaO2/FiO2 ratio day 7

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    End point title
    		 PaO2/FiO2 ratio day 7
    End point description
    End point type
    Secondary
    End point timeframe
    day 7
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    23
    21
    Units: kPa
        arithmetic mean (standard deviation)
    27.6 ± 10.4
    24.6 ± 7.6
    Statistical analysis title
    		 PaO2/FiO2 ratio day 7
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.29
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 8.6

    Secondary: PaO2/FiO2 ratio day 14

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    End point title
    		 PaO2/FiO2 ratio day 14
    End point description
    End point type
    Secondary
    End point timeframe
    day 14
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    11
    7
    Units: kPa
        arithmetic mean (standard deviation)
    27.2 ± 12.0
    21.3 ± 9.0
    Statistical analysis title
    		 PaO2/FiO2 ratio day 14
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.28
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.3
         upper limit
    		 17.2

    Secondary: SOFA day 3

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    End point title
    		 SOFA day 3
    End point description
    End point type
    Secondary
    End point timeframe
    day 3
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    22
    29
    Units: score
        arithmetic mean (standard deviation)
    7.6 ± 3.6
    7.8 ± 4.0
    Statistical analysis title
    		 SOFA day 3
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.83
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.4
         upper limit
    		 2

    Secondary: SOFA day 7

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    End point title
    		 SOFA day 7
    End point description
    End point type
    Secondary
    End point timeframe
    day 7
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    15
    17
    Units: score
        arithmetic mean (standard deviation)
    6.7 ± 3.0
    7.9 ± 4.1
    Statistical analysis title
    		 SOFA day 7
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8
         upper limit
    		 1.5

    Secondary: SOFA day 14

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    End point title
    		 SOFA day 14
    End point description
    End point type
    Secondary
    End point timeframe
    day 14
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    10
    7
    Units: score
        arithmetic mean (standard deviation)
    6.9 ± 2.0
    5.9 ± 2.8
    Statistical analysis title
    		 SOFA day 14
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.39
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 3.5

    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
    End point type
    Secondary
    End point timeframe
    day 3
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    21
    29
    Units: score
        arithmetic mean (standard deviation)
    -1.4 ± 1.9
    -1.2 ± 2.3
    Statistical analysis title
    		 Change in SOFA from baseline to day 3
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.68
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 1

    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
    End point type
    Secondary
    End point timeframe
    day 7
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    14
    17
    Units: score
        arithmetic mean (standard deviation)
    -2.9 ± 2.7
    -2.0 ± 3.0
    Statistical analysis title
    		 Change in SOFA from baseline to day 7
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 1.3

    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
    End point type
    Secondary
    End point timeframe
    day 14
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    9
    7
    Units: score
        arithmetic mean (standard deviation)
    -2.3 ± 1.7
    -3.9 ± 3.8
    Statistical analysis title
    		 Change in SOFA from baseline to day 14
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.31
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 4.6

    Secondary: Ventilator-free days to day 28

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    End point title
    		 Ventilator-free days to day 28
    End point description
    End point type
    Secondary
    End point timeframe
    up to 28 days
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    29
    31
    Units: days
        median (inter-quartile range (Q1-Q3))
    1 (0 to 17)
    20 (13 to 22)
    Statistical analysis title
    		 Ventilator-free days to day 28
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17
         upper limit
    		 -2

    Secondary: Duration of ventilation

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    End point title
    		 Duration of ventilation
    End point description
    End point type
    Secondary
    End point timeframe
    Duration of ventilation
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    29
    31
    Units: days
        median (inter-quartile range (Q1-Q3))
    16 (13 to 30)
    11 (8 to 16)
    Statistical analysis title
    		 Duration of ventilation
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2
         upper limit
    		 14

    Secondary: ICU stay

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    End point title
    		 ICU stay
    End point description
    End point type
    Secondary
    End point timeframe
    ICU stay
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    29
    31
    Units: days
        median (inter-quartile range (Q1-Q3))
    22 (14 to 32)
    12 (10 to 19)
    Statistical analysis title
    		 ICU stay
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3
         upper limit
    		 17

    Secondary: Hospital length of stay

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    End point title
    		 Hospital length of stay
    End point description
    End point type
    Secondary
    End point timeframe
    Hospital stay
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    29
    31
    Units: days
        median (inter-quartile range (Q1-Q3))
    39 (30 to 67)
    23 (18 to 33)
    Statistical analysis title
    		 Hospital length of stay
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7
         upper limit
    		 33

    Secondary: 28-day mortality

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    End point title
    		 28-day mortality
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    29
    31
    Units: subjects
    9
    3
    Statistical analysis title
    		 28-day mortality
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.054
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 10.7

    Secondary: 90-day mortality

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    End point title
    		 90-day mortality
    End point description
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    29
    31
    Units: subjects
    13
    5
    Statistical analysis title
    		 90-day mortality
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 6.8

    Secondary: ICU mortality

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    End point title
    		 ICU mortality
    End point description
    End point type
    Secondary
    End point timeframe
    ICU stay
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    29
    31
    Units: subjects
    12
    2
    Statistical analysis title
    		 ICU mortality
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    6.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.6
         upper limit
    		 26.2

    Secondary: Hospital mortality

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    End point title
    		 Hospital mortality
    End point description
    End point type
    Secondary
    End point timeframe
    Hospital stay
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    29
    31
    Units: subjects
    14
    4
    Statistical analysis title
    		 Hospital mortality
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 10.1

    Secondary: 1-year mortality

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    End point title
    		 1-year mortality
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    29
    31
    Units: subjects
    15
    8
    Statistical analysis title
    		 1-year mortality
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 4

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events that occur between trial entry and up to 28 days after completion of the study drug will be reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Keratinocyte growth factor (KGF)
    Reporting group description
    		 Patients on KGF who experienced an adverse event

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

    Serious adverse events
    		 Keratinocyte growth factor (KGF) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 29 (41.38%)
    4 / 31 (12.90%)
         number of deaths (all causes)
    11
    4
         number of deaths resulting from adverse events
    11
    4
    Cardiac disorders
    Cardiac Arrest
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction and ruptured aortic aneurysm and metastatic pancreatic cancer
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Severe hypoxic brain injury
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral haematoma and midline shift and intraventricular subdural haemorrhage
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Variceal bleed multi-organ failure chronic liver failure hepatitis C
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ruptured aortic aneurysm with subsequent multi-organ failure
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Multi-organ failure gram negative sepsis chronic liver disease
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Multi-organ failure, pulmonary haemorrhage, PCJ pneumonia and alcohol related liver disease.
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Multi-organ failure due to sepsis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis and ongoing pancreatitis and multi-organ failure
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Multi organ failure and sepsis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Pancreatitis contributing to prolonged hospitalisation
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Alcohol liver disease
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    COPD and type 2 respiratory failure
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infections and infestations
    Obstructive hydrocephalus gram negative sepsis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Systemic fungal infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Keratinocyte growth factor (KGF) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 31 (3.23%)
    General disorders and administration site conditions
    Hyperthermia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Maculopapular Rash
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Aug 2013
    Changes to inclusion/exclusion criteria – extend to 72 hours post onset of acute lung injury; inclusion of patients with haematological malignancies; removal of exclusion criteria in relationship to patients with pancreatitis; recruitment window extended to 72 hours post development of acute lung injury; definition change of site to include other intensive care units.

    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/23419093
    http://www.ncbi.nlm.nih.gov/pubmed/28494790
    http://www.ncbi.nlm.nih.gov/pubmed/28526233
    For support, Contact us.
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