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    Clinical Trial Results:
    Investigation of the protective effects of keratinocyte growth factor (KGF) in a human lipopolysaccharide induced model of acute lung injury

    Summary
    EudraCT number
    		 2008-000441-58
    Trial protocol
    		 GB  
    Global end of trial date
    09 Apr 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Feb 2020
    First version publication date
    08 Feb 2020
    Other versions
    Summary report(s)
    		 Figures from publication
    Figures from supplementary section of publication
    Am J Respir Crit Care Med publication

    Trial information

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    Trial identification
    Sponsor protocol code
    08005DM-A
    Additional study identifiers
    ISRCTN number
    		 ISRCTN98813895
    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 Nov 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Nov 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The hypothesis of the study is that treatment with a clinically relevant dose of KGF reduces pulmonary and systemic inflammation induced by LPS inhalation in humans. The primary endpoint of this study is to evaluate the ability of KGF to reduce alveolar epithelial injury, as measured by BAL RAGE concentration, between the KGF and placebo treated groups. All outcomes are BAL.
    Protection of trial subjects
    A DMEC was appointed which was independent of the study team. The DMEC met to agree conduct and remit which included an early termination process. The DMEC functioned primarily as a check for safety, reviewing adverse events. The DMEC reported to the Sponsor via the principal investigator.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    08 Aug 2008
    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: 39
    Worldwide total number of subjects
    39
    EEA total number of subjects
    39
    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)
    39
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Healthy subjects were recruited by advertising.

    Pre-assignment
    Screening details
    		 Screening consisting of a questionnaire, physical examination, routine blood investigation, ECG, and measurement of lung function with spirometry (FEV1 and FVC) was performed.

    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
    When an eligible subject was recruited, the clinical trials pharmacist was contacted with the subject details. The medication was prepared by the pharmacist according to guidance in a covered syringe thereby maintaining blinding. Both the active and placebo treatment had an identical appearance.

    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 injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    60 μg/kg per day for 3 days

    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
    3 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
    3 days

    Number of subjects in period 1
    		Keratinocyte growth factor (KGF) Placebo
    Started
    19
    20
    Completed
    16
    20
    Not completed
    3
    0
         Adverse event, non-fatal
    3
    -

    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
    		 19 20 39
    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)
    		 19 20 39
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 23.6 ( 5.2 ) 26.1 ( 5.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 11 21
        Male
    		 9 9 18
    height
    Units: cm
        arithmetic mean (standard deviation)
    		 171 ( 10.4 ) 170 ( 9.0 ) -
    weight
    Units: kg
        arithmetic mean (standard deviation)
    		 68 ( 9 ) 71 ( 11 ) -
    FEV1
    Units: litres
        arithmetic mean (standard deviation)
    		 3.8 ( 0.8 ) 3.8 ( 0.7 ) -

    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: RAGE

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    End point title
    		 RAGE
    End point description
    End point type
    Primary
    End point timeframe
    24 hours after LPS inhalation
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    16
    20
    Units: ng/ml
        arithmetic mean (standard deviation)
    4.2 ( 1.0 )
    3.5 ( 1.5 )
    Statistical analysis title
    		 RAGE comparison of groups
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.11
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: WBC count

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    End point title
    		 WBC count
    End point description
    white blood count
    End point type
    Secondary
    End point timeframe
    24 hours after LPS inhalation
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    16
    20
    Units: 10*5/ml
        median (inter-quartile range (Q1-Q3))
    5.5 (3.6 to 8.4)
    5.3 (4.0 to 7.6)
    Statistical analysis title
    		 WBC count comparison of groups
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: albumin

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    End point title
    		 albumin
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours after LPS inhalation
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    16
    20
    Units: mg/l
        median (inter-quartile range (Q1-Q3))
    64.6 (49.2 to 111.6)
    58.7 (44.4 to 84.5)
    Statistical analysis title
    		 albumin comparison of groups
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: IL-1Ra

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    End point title
    		 IL-1Ra
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours after LPS inhalation
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    16
    20
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    5.02 (3.78 to 9.50)
    3.41 (1.73 to 5.42)
    Statistical analysis title
    		 IL-1Ra comparison of groups
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: IL-1b/IL-1Ra ratio

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    End point title
    		 IL-1b/IL-1Ra ratio
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours after LPS inhalation
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    16
    20
    Units: ratio
        median (inter-quartile range (Q1-Q3))
    0.004 (0.003 to 0.007)
    0.009 (0.005 to 0.014)
    Statistical analysis title
    		 IL-1b/IL-1Ra ratio comparison of groups
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: IL-1b

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    End point title
    		 IL-1b
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours after LPS inhalation
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    16
    20
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    25.7 (15.1 to 48.6)
    29.0 (13.9 to 41.7)
    Statistical analysis title
    		 IL-1b comparison of groups
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: TNF-a

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    End point title
    		 TNF-a
    End point description
    tumor necrosis factor
    End point type
    Secondary
    End point timeframe
    24 hours after LPS inhalation
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    16
    20
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    63.5 (40.0 to 96.0)
    46.0 (20.9 to 65.6)
    Statistical analysis title
    		 TNF-a comparison of groups
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: IL-6

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    End point title
    		 IL-6
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours after inhalation
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    16
    20
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    527 (228 to 1154)
    350 (175 to 512)
    Statistical analysis title
    		 IL-6 comparison of groups
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: IL-8

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    End point title
    		 IL-8
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours after LPS inhalation
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    16
    20
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    336 (290 to 436)
    289 (197 to 457)
    Statistical analysis title
    		 IL-8 comparison of groups
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: VEGF

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    End point title
    		 VEGF
    End point description
    vascular endothelial growth factor
    End point type
    Secondary
    End point timeframe
    24 hours after LPS inhalation
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    16
    20
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    140 (110 to 193)
    122 (93.5 to 213)
    Statistical analysis title
    		 VEGF comparison of groups
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: MCP-1

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    End point title
    		 MCP-1
    End point description
    monocyte chemoattractant protein
    End point type
    Secondary
    End point timeframe
    24 hours after inhalation
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    16
    20
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    520 (366 to 684)
    347 (210 to 532)
    Statistical analysis title
    		 MCP-1 comparison of groups
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: HMGB1

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    End point title
    		 HMGB1
    End point description
    high-mobility group box 1
    End point type
    Secondary
    End point timeframe
    24 hours after LPS inhalation
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    16
    20
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    21.8 (13.2 to 30.7)
    16.7 (9.9 to 34.8)
    Statistical analysis title
    		 HMGB1 comparison of groups
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Calgranulin C

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    End point title
    		 Calgranulin C
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours after LPS inhalation
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    16
    20
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    34.7 (18.5 to 49.5)
    28.6 (13.3 to 56.4)
    Statistical analysis title
    		 Calgranulin C comparison of groups
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: CRP

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    End point title
    		 CRP
    End point description
    C-reactive protein
    End point type
    Secondary
    End point timeframe
    24 hours after LPS inhalation
    End point values
    		 Keratinocyte growth factor (KGF) Placebo
    Number of subjects analysed
    16
    20
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    491 (296 to 968)
    161 (62 to 392)
    Statistical analysis title
    		 CRP comparison of groups
    Comparison groups
    Keratinocyte growth factor (KGF) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 hours after LPS inhalation
    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
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Keratinocyte growth factor (KGF) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    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
    18 / 19 (94.74%)
    6 / 20 (30.00%)
    Investigations
    Liver function
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Nervous system disorders
    Altered taste
         subjects affected / exposed
    5 / 19 (26.32%)
    3 / 20 (15.00%)
         occurrences all number
    5
    3
    Tingling in toes
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Oral tingling
         subjects affected / exposed
    5 / 19 (26.32%)
    0 / 20 (0.00%)
         occurrences all number
    5
    0
    Tongue swelling
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Tongue disorder
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Tongue Discolouration
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Lip disorder
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    8 / 19 (42.11%)
    1 / 20 (5.00%)
         occurrences all number
    8
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Dec 2008
    To source the study medication from Biovitrum
    22 Jan 2009
    To increase the number of volunteers undergoing bronchoscopy and BAL from 5 to 10; to recruit 5 volunteers who undergo bronchoscopy and BAL after pre treatment with 3 days for KGF at a dose of 60 microgram/kg; to isolate alveolar macrophages from BAL and study them in vitro
    30 Dec 2009
    To measure the serine protease and anti protease activity in plasma samples

    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. An additional 15 control subjects were enrolled. In keeping with the study protocol these subjects were not randomised to receive IMP. In addition to the Endpoints section, other outcomes are presented graphically in the attachments.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/24716610
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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