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    Clinical Trial Results:
    A MULTICENTRE, PHASE II, OPEN LABEL, RANDOMISED CONTROLLED TRIAL OF REPEATED AUTOLOGOUS INFUSIONS OF G-CSF MOBILISED CD133+ BONE MARROW STEM CELLS IN PATIENTS WITH CIRRHOSIS

    Summary
    EudraCT number
    2009-010335-41
    Trial protocol
    GB  
    Global end of trial date
    18 May 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    04 May 2019
    First version publication date
    04 May 2019
    Other versions
    Summary report(s)
    Study Protocol
    Public summary of Results: REALISTIC

    Trial information

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    Trial identification
    Sponsor protocol code
    RG_09-151
    Additional study identifiers
    ISRCTN number
    ISRCTN91288089
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Birmingham
    Sponsor organisation address
    Room 119, Aston Webb Building,Edgbaston,, Birmingham, United Kingdom, B15 2TT
    Public contact
    Mr Darren Barton, D3B Trial Management Team Leader CRUK Clinical Trials Unit Birmingham United Kingdom, 44 1213718027, d.barton@bham.ac.uk
    Scientific contact
    Prof Philip Newsome, Director of Centre for Liver research University of Birmingham Birmingham United Kingdom, 44 1214145614, p.n.newsome@bham.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    18 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary aim of the trial is to examine whether administering either G-CSF alone or G-CSF followed by repeated infusions of stem cells is better than standard supportive care in improving severity of liver disease over 3 months.
    Protection of trial subjects
    All adverse events and serious adverse events experienced by participants in the clinical trial were collected by the study team. Data analyses will be supplied in confidence to an independent Data Monitoring Committee (DMC), which will be asked to give advice on whether the accumulated data from the trial, together with the results from other relevant research, justifies the continuing recruitment of further patients. The DMC will operate in accordance with a trial specific charter based upon the template created by the Damocles Group. Additional meetings may be called if recruitment is much faster than anticipated and the DMC may, at their discretion, request to meet more frequently or to continue to meet following completion of recruitment. An emergency meeting may also be convened if a safety issue is identified. The DMC will report directly to the Trial Management Group who will convey the findings of the DMC to the Study Sponsor, the MHRA and Ethics Committee. The DMC may consider discontinuing the trial if the recruitment rate or data quality are unacceptable or if any issues are identified which may compromise participant safety.
    Background therapy
    see attached protocol
    Evidence for comparator
    see attached protocol
    Actual start date of recruitment
    18 May 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 81
    Worldwide total number of subjects
    81
    EEA total number of subjects
    81
    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)
    70
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients were recruited from 3 NHS participating hospitals in the united kingdom. The Recruitment was between 18th May 2010 - 26th Feb 2015. A total of 81 patients were recruited across 3 different treatment groups

    Pre-assignment
    Screening details
    All screening procedures were performed a maximum of 7 days prior to randomisation and with 14 days of start of treatment

    Period 1
    Period 1 title
    Recruitment Period + Follow-up (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1: Control group: standard conservative management
    Arm description
    Standard conservative management only
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Group 2: Treatment: GCSF Alone
    Arm description
    Standard conservative management + GCSF
    Arm type
    Experimental

    Investigational medicinal product name
    Lenograstim
    Investigational medicinal product code
    Other name
    Granocyte
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dosage to be used in this study will be 15μg/kg/day. This is higher than the standard dose and has been shown to be safe and more effective in patients with cirrhosis

    Arm title
    Group 3: GSCF + CD133+ cell infusion (x3)
    Arm description
    GCSF followed by Leukapheresis, CD133+ cell isolation and repeated infusions on days 5/6, 30, 60 via peripheral vein
    Arm type
    Experimental

    Investigational medicinal product name
    Lenograstim
    Investigational medicinal product code
    Other name
    Granocyte
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dosage to be used in this study will be 15μg/kg/day. This is higher than the standard dose and has been shown to be safe and more effective in patients with cirrhosis

    Number of subjects in period 1
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3)
    Started
    27
    26
    28
    Completed
    27
    26
    26
    Not completed
    0
    0
    2
         Patient died before treatment
    -
    -
    1
         Patient did not receive any cell infusions
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1: Control group: standard conservative management
    Reporting group description
    Standard conservative management only

    Reporting group title
    Group 2: Treatment: GCSF Alone
    Reporting group description
    Standard conservative management + GCSF

    Reporting group title
    Group 3: GSCF + CD133+ cell infusion (x3)
    Reporting group description
    GCSF followed by Leukapheresis, CD133+ cell isolation and repeated infusions on days 5/6, 30, 60 via peripheral vein

    Reporting group values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) Total
    Number of subjects
    27 26 28 81
    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
        median (inter-quartile range (Q1-Q3))
    52.0 (47.0 to 60.0) 54.0 (49.0 to 61.0) 56.5 (47.5 to 62.5) -
    Gender categorical
    Units: Subjects
        Female
    14 8 6 28
        Male
    13 18 22 53
    Aetiology
    Units: Subjects
        Alcohol related liver disease
    12 12 13 37
        Hepatitis C
    4 3 3 10
        Other
    11 11 12 34
    Centre
    Units: Subjects
        Queen's Medical Centre, Nottingham
    1 1 2 4
        The Queen Elizabeth Hospital
    20 19 19 58
        Royal Infirmary of Edinburgh
    6 6 7 19
    Alcohol related
    Units: Subjects
        No
    15 14 13 42
        Yes
    12 12 15 39
    Hep C
    Units: Subjects
        No
    23 23 24 70
        Yes
    4 3 4 11
    Hep B
    Units: Subjects
        No
    26 26 28 80
        Yes
    1 0 0 1
    Primary biliary cirrhosis
    Units: Subjects
        No
    22 19 25 66
        Yes
    5 7 3 15
    Haemochromatosis
    Units: Subjects
        No
    27 26 28 81
    Cryptogenic cirrhosis
    Units: Subjects
        No
    27 25 26 78
        Yes
    0 1 2 3
    NAFLD
    Units: Subjects
        No
    21 23 20 64
        Yes
    6 3 8 17
    Ascites
    Units: Subjects
        No
    14 16 14 44
        Yes
    13 10 14 37
    Variceal Bleeding
    Units: Subjects
        No
    20 15 17 52
        Yes
    7 11 11 29
    Encephalopathy
    Units: Subjects
        No
    24 23 21 68
        Yes
    3 3 7 13
    Age (years)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    52.00 (47.00 to 60.00) 54.00 (49.00 to 61.00) 56.50 (47.50 to 62.50) -
    Creatinine (mu mol/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    62.00 (52.00 to 74.00) 63.00 (56.00 to 75.00) 71.00 (64.00 to 90.00) -
    INR
    Units: see title
        median (inter-quartile range (Q1-Q3))
    1.40 (1.20 to 1.40) 1.20 (1.20 to 1.40) 1.30 (1.20 to 1.40) -
    MELD
    Units: see title
        median (inter-quartile range (Q1-Q3))
    13.12 (12.41 to 13.76) 12.69 (11.98 to 13.09) 13.15 (12.09 to 13.87) -
    UKELD
    Units: see title
        median (inter-quartile range (Q1-Q3))
    51.50 (49.84 to 54.21) 51.14 (49.96 to 52.51) 51.97 (50.89 to 53.46) -
    Haemoglobin (g/dL)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    12.90 (11.80 to 13.80) 13.10 (11.60 to 14.30) 12.95 (12.05 to 14.30) -
    Platelets (*10^9/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    77.00 (57.00 to 92.00) 90.50 (54.00 to 116.00) 78.50 (57.00 to 106.50) -
    WBC (*10^9/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    4.20 (3.30 to 5.40) 4.30 (3.40 to 5.20) 4.25 (3.30 to 5.35) -
    Bilirubin (mu mol/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    38.00 (30.00 to 53.00) 44.00 (34.00 to 53.00) 41.50 (33.00 to 51.00) -
    Urea (mmol/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    3.70 (2.70 to 4.20) 3.75 (2.90 to 4.80) 4.75 (3.70 to 5.35) -
    Potassium (mmol/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    3.90 (3.70 to 4.40) 3.95 (3.70 to 4.20) 4.10 (3.95 to 4.20) -
    Sodium(mmol/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    140.00 (137.00 to 142.00) 140.00 (137.00 to 142.00) 139.00 (137.00 to 140.00) -
    Calcium (U/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    2.23 (2.15 to 2.37) 2.19 (2.13 to 2.30) 2.25 (2.13 to 2.30) -
    Magnesium (mmol/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.73 (0.69 to 0.81) 0.75 (0.70 to 0.79) 0.74 (0.70 to 0.78) -
    AST (U/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    44.00 (35.00 to 62.00) 50.50 (37.00 to 82.00) 48.00 (37.00 to 62.00) -
    ALT (U/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    28.00 (20.00 to 39.00) 31.50 (21.00 to 54.00) 31.00 (21.50 to 45.00) -
    ALP (U/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    160.00 (108.00 to 255.00) 142.50 (118.00 to 282.00) 138.50 (97.50 to 244.00) -
    Bilirubin (mu mol/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    38.00 (30.00 to 53.00) 44.00 (34.00 to 53.00) 41.50 (33.00 to 51.00) -
    Albumin (g/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    33.00 (30.00 to 37.00) 36.00 (30.00 to 39.00) 35.50 (33.50 to 39.00) -
    GGT(g/dL)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    68.00 (49.00 to 110.00) 86.00 (57.00 to 198.00) 73.00 (41.00 to 188.50) -
    AFP (KU/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    3.00 (2.00 to 6.00) 3.00 (2.00 to 5.00) 3.00 (2.00 to 5.00) -
    Subject analysis sets

    Subject analysis set title
    primary population (mITT)
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    The mITT population included all participants who received at least one day of treatment (one day of G-CSF at 15 μg/kg bodyweight in the treatment groups, plus one infusion of at least 0·17 × 106 cells per kg for the G-CSF plus stem-cell infusion group), with patients retained in their randomly assigned treatment groups, including those who violated the protocol or were ineligible.

    Subject analysis set title
    trial cohort
    Subject analysis set type
    Full analysis
    Subject analysis set description
    all patient randomised

    Subject analysis set title
    Per-protocol
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The per-protocol population was defined as any patients who received 5 days of G-CSF at an average daily dose of at least 12 μg/kg and any patients who received 5 days of G-CSF plus three infusions at a minimum of 0·17 × 106 cells per kg each. All patients in the control group were included in the mITT and per-protocol populations.

    Subject analysis sets values
    primary population (mITT) trial cohort Per-protocol
    Number of subjects
    79
    81
    74
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    54 (48 to 61)
    Gender categorical
    Units: Subjects
        Female
        Male
    Aetiology
    Units: Subjects
        Alcohol related liver disease
    37
        Hepatitis C
    10
        Other
    34
    Centre
    Units: Subjects
        Queen's Medical Centre, Nottingham
    4
        The Queen Elizabeth Hospital
    58
        Royal Infirmary of Edinburgh
    19
    Alcohol related
    Units: Subjects
        No
    42
        Yes
    39
    Hep C
    Units: Subjects
        No
    70
        Yes
    11
    Hep B
    Units: Subjects
        No
    80
        Yes
    1
    Primary biliary cirrhosis
    Units: Subjects
        No
    66
        Yes
    15
    Haemochromatosis
    Units: Subjects
        No
    81
    Cryptogenic cirrhosis
    Units: Subjects
        No
    78
        Yes
    3
    NAFLD
    Units: Subjects
        No
    64
        Yes
    17
    Ascites
    Units: Subjects
        No
    44
        Yes
    37
    Variceal Bleeding
    Units: Subjects
        No
    52
        Yes
    29
    Encephalopathy
    Units: Subjects
        No
    68
        Yes
    13
    Age (years)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    54.00 (48.00 to 61.00)
    54.00 (48.00 to 61.00)
    Creatinine (mu mol/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    54.00 (48.00 to 61.00)
    66.00 (58.00 to 77.00)
    66.00 (58.00 to 77.00)
    INR
    Units: see title
        median (inter-quartile range (Q1-Q3))
    66.00 (58.00 to 77.00)
    1.30 (1.20 to 1.40)
    1.30 (1.20 to 1.40)
    MELD
    Units: see title
        median (inter-quartile range (Q1-Q3))
    1.30 (1.20 to 1.40)
    12.85 (12.20 to 13.66)
    12.85 (12.20 to 13.66)
    UKELD
    Units: see title
        median (inter-quartile range (Q1-Q3))
    12.85 (12.20 to 13.66)
    51.52 (50.50 to 53.29)
    51.52 (50.50 to 53.29)
    Haemoglobin (g/dL)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    51.52 (50.50 to 53.29)
    12.90 (11.80 to 14.20)
    12.90 (11.80 to 14.20)
    Platelets (*10^9/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    12.90 (11.80 to 14.20)
    81.00 (57.00 to 106.00)
    81.00 (57.00 to 106.00)
    WBC (*10^9/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    81.00 (57.00 to 106.00)
    4.20 (3.30 to 5.30)
    4.20 (3.30 to 5.30)
    Bilirubin (mu mol/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    4.20 (3.30 to 5.30)
    42.00 (33.00 to 53.00)
    42.00 (33.00 to 53.00)
    Urea (mmol/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    42.00 (33.00 to 53.00)
    4.00 (2.90 to 4.90)
    4.00 (2.90 to 4.90)
    Potassium (mmol/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    4.00 (2.90 to 4.90)
    4.00 (3.80 to 4.20)
    4.00 (3.80 to 4.20)
    Sodium(mmol/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    4.00 (3.80 to 4.20)
    140.00 (137.00 to 141.00)
    140.00 (137.00 to 141.00)
    Calcium (U/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    140.00 (137.00 to 141.00)
    2.23 (2.14 to 2.31)
    2.23 (2.14 to 2.31)
    Magnesium (mmol/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    2.23 (2.14 to 2.31)
    0.75 (0.70 to 0.79)
    0.75 (0.70 to 0.79)
    AST (U/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.75 (0.70 to 0.79)
    48.00 (37.00 to 62.00)
    48.00 (37.00 to 62.00)
    ALT (U/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    48.00 (37.00 to 62.00)
    30.00 (21.00 to 43.00)
    30.00 (21.00 to 43.00)
    ALP (U/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    30.00 (21.00 to 43.00)
    147.00 (108.00 to 255.00)
    147.00 (108.00 to 255.00)
    Bilirubin (mu mol/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    147.00 (108.00 to 255.00)
    42.00 (33.00 to 53.00)
    42.00 (33.00 to 53.00)
    Albumin (g/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    42.00 (33.00 to 53.00)
    35.00 (30.00 to 39.00)
    35.00 (30.00 to 39.00)
    GGT(g/dL)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    35.00 (30.00 to 39.00)
    79.00 (49.00 to 152.00)
    79.00 (49.00 to 152.00)
    AFP (KU/L)
    Units: see title
        median (inter-quartile range (Q1-Q3))
    79.00 (49.00 to 152.00)
    3.00 (2.00 to 5.00)
    3.00 (2.00 to 5.00)

    End points

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    End points reporting groups
    Reporting group title
    Group 1: Control group: standard conservative management
    Reporting group description
    Standard conservative management only

    Reporting group title
    Group 2: Treatment: GCSF Alone
    Reporting group description
    Standard conservative management + GCSF

    Reporting group title
    Group 3: GSCF + CD133+ cell infusion (x3)
    Reporting group description
    GCSF followed by Leukapheresis, CD133+ cell isolation and repeated infusions on days 5/6, 30, 60 via peripheral vein

    Subject analysis set title
    primary population (mITT)
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    The mITT population included all participants who received at least one day of treatment (one day of G-CSF at 15 μg/kg bodyweight in the treatment groups, plus one infusion of at least 0·17 × 106 cells per kg for the G-CSF plus stem-cell infusion group), with patients retained in their randomly assigned treatment groups, including those who violated the protocol or were ineligible.

    Subject analysis set title
    trial cohort
    Subject analysis set type
    Full analysis
    Subject analysis set description
    all patient randomised

    Subject analysis set title
    Per-protocol
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The per-protocol population was defined as any patients who received 5 days of G-CSF at an average daily dose of at least 12 μg/kg and any patients who received 5 days of G-CSF plus three infusions at a minimum of 0·17 × 106 cells per kg each. All patients in the control group were included in the mITT and per-protocol populations.

    Primary: Change from baseline to day 90 (mITT) MELD

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    End point title
    Change from baseline to day 90 (mITT) MELD
    End point description
    Non parametric comparison of distributions
    End point type
    Primary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    26
    26
    79
    Units: see title
        median (inter-quartile range (Q1-Q3))
    -0.483 (-1.480 to 1.055)
    -0.522 (-1.727 to 0.479)
    -0.453 (-1.290 to 1.001)
    -0.483 (-1.480 to 0.712)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.718
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.904
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    change point model (group 2 vs 1) mitt
    Statistical analysis description
    A model incorporating splines was constructed to assess fit. Model selection was then performed beginning with a mixed-model including just treatment arm (factor) and time (continuous) covariates, and then by iteratively increasing flexibility as required to find the most parsimonious model resulting in approximately optimum fit; polynomial, interaction, and change-point terms were all explored in doing so.
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.31 [2]
    Method
    non standard method
    Confidence interval
    Notes
    [1] - The continuous time-scale, representing timing of measurement, was split at 4.3 weeks (30 days) allowing differing trends to be explored both prior to and after this point, hereafter referred to as period 1 and 2 respectively. Splits at 8.6 weeks, and +/- 5 days either side of the particular change-point were also explored but found to fit the data less well. The model also incorporates interactions between time period and group, to allow for the rate of change to differ between groups.
    [2] - period 1, group 2 interaction estimates of 0.14 (p=0. 28), hence no evidence differed from group 1. No evidence of non-zero slope in period 2, with group 2 interaction coefficient -0.066 (p=0.31).
    Statistical analysis title
    change point model (group 3 vs 1) mitt
    Statistical analysis description
    A model incorporating splines was constructed to assess fit. Model selection was then performed beginning with a mixed-model including just treatment arm (factor) and time (continuous) covariates, and then by iteratively increasing flexibility as required to find the most parsimonious model resulting in approximately optimum fit; polynomial, interaction, and change-point terms were all explored in doing so.
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0.94 [4]
    Method
    non-standard method
    Confidence interval
    Notes
    [3] - The continuous time-scale, representing timing of measurement, was split at 4.3 weeks (30 days) allowing differing trends to be explored both prior to and after this point, hereafter referred to as period 1 and 2 respectively. Splits at 8.6 weeks, and +/- 5 days either side of the particular change-point were also explored but found to fit the data less well. The model also incorporates interactions between time period and group, to allow for the rate of change to differ between groups.
    [4] - period 1, group 3 interaction estimates of 0.022 (p=0. 87), hence no evidence differed from group 1. No evidence of non-zero slope in period 2, with group 3 interaction coefficient -0.005 (p=0. 94).

    Secondary: Change from baseline to day 90 (mITT) UKELD

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    End point title
    Change from baseline to day 90 (mITT) UKELD
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    26
    26
    Units: see title
        median (inter-quartile range (Q1-Q3))
    -0.060 (-3.217 to 1.679)
    0.538 (-1.044 to 1.393)
    -0.459 (-1.186 to 0.518)
    -0.181 (-1.346 to 1.143)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.346
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.689
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) Haemoglobin (g/dL)

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    End point title
    Change from baseline to day 90 (mITT) Haemoglobin (g/dL)
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    22
    26
    26
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.250 (-0.600 to 0.500)
    -0.300 (-0.600 to 0.500)
    -0.350 (-1.000 to 0.400)
    -0.300 (-0.800 to 0.500)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.449
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.175
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) WBC (*10^9/L)

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    End point title
    Change from baseline to day 90 (mITT) WBC (*10^9/L)
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    22
    26
    26
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.300 (-0.200 to 0.600)
    -0.050 (-0.800 to 0.600)
    -0.150 (-1.100 to 0.500)
    0.000 (-0.800 to 0.600)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.238
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.102
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) Platelets (*10^9/L)

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    End point title
    Change from baseline to day 90 (mITT) Platelets (*10^9/L)
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    22
    26
    26
    Units: see title
        median (inter-quartile range (Q1-Q3))
    -0.500 (-8.000 to 9.000)
    0.000 (-8.000 to 7.000)
    1.000 (-3.000 to 5.000)
    0.000 (-7.000 to 7.000)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.983
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.548
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) INR

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    End point title
    Change from baseline to day 90 (mITT) INR
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    26
    26
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.000 (-0.100 to 0.100)
    0.000 (-0.100 to 0.100)
    0.000 (0.000 to 0.000)
    0.000 (-0.100 to 0.100)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.859
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.983
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) Sodium(mmol/L)

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    End point title
    Change from baseline to day 90 (mITT) Sodium(mmol/L)
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    26
    26
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.000 (-2.000 to 3.000)
    -1.000 (-2.000 to 1.000)
    0.000 (-1.000 to 3.000)
    0.000 (-1.000 to 2.000)
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.431
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.231
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) Potassium (mmol/L)

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    End point title
    Change from baseline to day 90 (mITT) Potassium (mmol/L)
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    22
    26
    26
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.075 (-0.100 to 0.300)
    0.150 (-0.200 to 0.500)
    -0.050 (-0.300 to 0.300)
    0.000 (-0.300 to 0.300)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.64
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.323
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) Urea (mmol/L)

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    End point title
    Change from baseline to day 90 (mITT) Urea (mmol/L)
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    26
    26
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.100 (-0.400 to 1.000)
    0.150 (-0.600 to 0.900)
    -0.050 (-1.000 to 0.400)
    0.100 (-0.600 to 0.900)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.508
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.261
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) Creatinine (mu mol/L)

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    End point title
    Change from baseline to day 90 (mITT) Creatinine (mu mol/L)
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    26
    26
    Units: see title
        median (inter-quartile range (Q1-Q3))
    1.000 (-2.000 to 10.000)
    2.500 (-1.000 to 10.000)
    1.500 (-4.000 to 9.000)
    2.000 (-3.000 to 10.000)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.857
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.711
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) Bilirubin (mu mol/L)

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    End point title
    Change from baseline to day 90 (mITT) Bilirubin (mu mol/L)
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    26
    26
    Units: see title
        median (inter-quartile range (Q1-Q3))
    -5.000 (-12.000 to 3.000)
    -6.000 (-12.000 to -1.000)
    -2.000 (-9.000 to 7.000)
    -5.000 (-10.000 to 5.000)
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.372
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.771
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) Albumin (g/L)

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    End point title
    Change from baseline to day 90 (mITT) Albumin (g/L)
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    25
    26
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.000 (-3.000 to 1.000)
    -2.000 (-3.000 to 0.000)
    -1.000 (-4.000 to 2.000)
    -1.000 (-3.000 to 1.000)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.309
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.848
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) AST (U/L)

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    End point title
    Change from baseline to day 90 (mITT) AST (U/L)
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    21
    24
    23
    Units: see title
        median (inter-quartile range (Q1-Q3))
    -2.000 (-6.000 to 4.000)
    -4.000 (-13.500 to 4.000)
    -2.000 (-9.000 to 1.000)
    -2.000 (-9.000 to 4.000)
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.306
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.406
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) ALT (U/L)

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    End point title
    Change from baseline to day 90 (mITT) ALT (U/L)
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    26
    26
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.000 (-4.000 to 4.000)
    -2.000 (-9.000 to 4.000)
    -4.500 (-8.000 to 0.000)
    -2.000 (-9.000 to 2.000)
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.652
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) ALP (U/L)

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    End point title
    Change from baseline to day 90 (mITT) ALP (U/L)
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    26
    26
    Units: see title
        median (inter-quartile range (Q1-Q3))
    -4.000 (-20.000 to 11.000)
    -5.000 (-16.000 to 7.000)
    1.500 (-10.000 to 24.000)
    -3.000 (-17.000 to 16.000)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.912
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.346
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) GGT(g/dL)

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    End point title
    Change from baseline to day 90 (mITT) GGT(g/dL)
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    24
    25
    Units: see title
        median (inter-quartile range (Q1-Q3))
    -1.000 (-10.000 to 9.000)
    -10.000 (-42.500 to 0.500)
    -3.000 (-18.000 to 1.000)
    -3.000 (-19.500 to 3.500)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.099
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.363
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) AFP (KU/L)

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    End point title
    Change from baseline to day 90 (mITT) AFP (KU/L)
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    19
    21
    18
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.000 (-1.000 to 1.000)
    0.000 (-1.000 to 0.000)
    0.000 (-1.000 to 0.000)
    0.000 (-1.000 to 0.000)
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.31
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) Overall QoL

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    End point title
    Change from baseline to day 90 (mITT) Overall QoL
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    26
    25
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.183 (-0.137 to 0.603)
    -0.076 (-0.354 to 0.275)
    0.029 (-0.192 to 0.231)
    0.035 (-0.229 to 0.443)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.144
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.489
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) QoL: Abdominal symptoms

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    End point title
    Change from baseline to day 90 (mITT) QoL: Abdominal symptoms
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    25
    24
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.000 (-0.667 to 0.000)
    0.000 (-1.000 to 0.667)
    0.000 (0.000 to 0.500)
    0.000 (-0.667 to 0.333)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 1
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.178
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) QoL: Fatigue

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    End point title
    Change from baseline to day 90 (mITT) QoL: Fatigue
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    25
    25
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.400 (-0.600 to 0.800)
    0.000 (-0.800 to 0.400)
    0.200 (-0.400 to 0.600)
    0.200 (-0.400 to 0.600)
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.451
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.193
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) QoL: Systemic

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    End point title
    Change from baseline to day 90 (mITT) QoL: Systemic
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    26
    25
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.400 (-0.200 to 0.800)
    0.000 (-0.400 to 0.400)
    0.000 (-0.400 to 0.400)
    0.000 (-0.400 to 0.400)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.324
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.263
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) QoL: Activity

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    End point title
    Change from baseline to day 90 (mITT) QoL: Activity
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    25
    24
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.333 (0.000 to 0.667)
    0.000 (-0.333 to 0.667)
    -0.167 (-0.667 to 0.667)
    0.000 (-0.333 to 0.667)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.266
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.117
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) QoL: Emotional function

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    End point title
    Change from baseline to day 90 (mITT) QoL: Emotional function
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    24
    25
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.125 (-0.125 to 0.375)
    -0.063 (-0.438 to 0.313)
    0.125 (-0.250 to 0.500)
    0.125 (-0.250 to 0.375)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.392
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.648
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (mITT) QoL: Worry

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    End point title
    Change from baseline to day 90 (mITT) QoL: Worry
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) primary population (mITT)
    Number of subjects analysed
    23
    26
    25
    Units: see title
        median (inter-quartile range (Q1-Q3))
    0.200 (0.000 to 1.000)
    0.000 (-0.400 to 0.600)
    0.200 (-0.400 to 0.800)
    0.200 (-0.400 to 0.800)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.151
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.584
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (PP) MELD

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    End point title
    Change from baseline to day 90 (PP) MELD
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) Per-protocol
    Number of subjects analysed
    23
    26
    21
    Units: see title
        median (inter-quartile range (Q1-Q3))
    -0.483 (-1.480 to 1.055)
    -0.522 (-1.727 to 0.479)
    -0.708 (-1.054 to 0.734)
    -0.508 (-1.357 to 0.602)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.718
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.897
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline to day 90 (PP) UKELD

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    End point title
    Change from baseline to day 90 (PP) UKELD
    End point description
    Non parametric comparison of distributions
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    Group 1: Control group: standard conservative management Group 2: Treatment: GCSF Alone Group 3: GSCF + CD133+ cell infusion (x3) Per-protocol
    Number of subjects analysed
    23
    26
    21
    Units: see title
        median (inter-quartile range (Q1-Q3))
    -0.060 (-3.217 to 1.679)
    0.538 (-1.044 to 1.393)
    -0.181 (-0.907 to 0.518)
    -0.140 (-1.316 to 1.203)
    Statistical analysis title
    Standard Care vs G-CSF
    Comparison groups
    Group 1: Control group: standard conservative management v Group 2: Treatment: GCSF Alone
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.346
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Standard Care vs G-CSF + Cells
    Comparison groups
    Group 1: Control group: standard conservative management v Group 3: GSCF + CD133+ cell infusion (x3)
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.916
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Date of consent - Day 360
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Standard Care
    Reporting group description
    safety reporting period is up to 1 year after randomisation

    Reporting group title
    G-CSF + CD133 + cell infusion
    Reporting group description
    safety reporting period is up to 1 year after randomisation

    Reporting group title
    G-CSF only
    Reporting group description
    safety reporting period is up to 1 year after randomisation

    Serious adverse events
    Standard Care G-CSF + CD133 + cell infusion G-CSF only
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 28 (7.14%)
    8 / 26 (30.77%)
    3 / 27 (11.11%)
         number of deaths (all causes)
    1
    2
    0
         number of deaths resulting from adverse events
    1
    0
    0
    Vascular disorders
    Esophageal hemorrhage
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Heart failure
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 26 (11.54%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Ascites
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Edema limbs
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycemia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Standard Care G-CSF + CD133 + cell infusion G-CSF only
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 28 (96.43%)
    26 / 26 (100.00%)
    27 / 27 (100.00%)
    Vascular disorders
    Esophageal varices hemorrhage
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Oral hemorrhage
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Dizziness
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Epistaxis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    0
    2
    Skin ulceration
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Hematoma
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 26 (11.54%)
    0 / 27 (0.00%)
         occurrences all number
    0
    3
    0
    Hypotension
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Immune system disorders
    Allergic rhinitis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Edema trunk
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Fatigue
         subjects affected / exposed
    13 / 28 (46.43%)
    9 / 26 (34.62%)
    10 / 27 (37.04%)
         occurrences all number
    13
    10
    13
    Fever
         subjects affected / exposed
    2 / 28 (7.14%)
    3 / 26 (11.54%)
    1 / 27 (3.70%)
         occurrences all number
    2
    3
    1
    Flu like symptoms
         subjects affected / exposed
    1 / 28 (3.57%)
    14 / 26 (53.85%)
    7 / 27 (25.93%)
         occurrences all number
    1
    16
    8
    Malaise
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    2 / 27 (7.41%)
         occurrences all number
    0
    1
    3
    Pain
         subjects affected / exposed
    6 / 28 (21.43%)
    1 / 26 (3.85%)
    3 / 27 (11.11%)
         occurrences all number
    6
    1
    3
    Lethargy
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    1
    Psychiatric disorders
    Somnolence
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Confusion
         subjects affected / exposed
    3 / 28 (10.71%)
    4 / 26 (15.38%)
    2 / 27 (7.41%)
         occurrences all number
    4
    4
    4
    Depression
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 26 (3.85%)
    2 / 27 (7.41%)
         occurrences all number
    1
    1
    2
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 26 (7.69%)
    1 / 27 (3.70%)
         occurrences all number
    0
    2
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Fracture
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    4 / 28 (14.29%)
    8 / 26 (30.77%)
    10 / 27 (37.04%)
         occurrences all number
    7
    8
    14
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 28 (25.00%)
    9 / 26 (34.62%)
    13 / 27 (48.15%)
         occurrences all number
    11
    12
    22
    Alkaline phosphatase increased
         subjects affected / exposed
    15 / 28 (53.57%)
    15 / 26 (57.69%)
    21 / 27 (77.78%)
         occurrences all number
    16
    17
    30
    Aspartate aminotransferase increased
         subjects affected / exposed
    15 / 28 (53.57%)
    15 / 26 (57.69%)
    18 / 27 (66.67%)
         occurrences all number
    16
    24
    30
    Blood bilirubin increased
         subjects affected / exposed
    24 / 28 (85.71%)
    23 / 26 (88.46%)
    25 / 27 (92.59%)
         occurrences all number
    44
    44
    68
    Cardiac troponin I increased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Creatinine increased
         subjects affected / exposed
    3 / 28 (10.71%)
    6 / 26 (23.08%)
    2 / 27 (7.41%)
         occurrences all number
    3
    7
    2
    GGT increased
         subjects affected / exposed
    17 / 28 (60.71%)
    16 / 26 (61.54%)
    21 / 27 (77.78%)
         occurrences all number
    24
    21
    32
    Haptoglobin decreased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Hemoglobin increased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    INR increased
         subjects affected / exposed
    10 / 28 (35.71%)
    10 / 26 (38.46%)
    12 / 27 (44.44%)
         occurrences all number
    12
    14
    16
    Lymphocyte count decreased
         subjects affected / exposed
    9 / 28 (32.14%)
    8 / 26 (30.77%)
    8 / 27 (29.63%)
         occurrences all number
    15
    16
    27
    Lymphocyte count increased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    3 / 27 (11.11%)
         occurrences all number
    0
    1
    3
    Neutrophil count decreased
         subjects affected / exposed
    11 / 28 (39.29%)
    12 / 26 (46.15%)
    17 / 27 (62.96%)
         occurrences all number
    16
    22
    29
    Platelet count decreased
         subjects affected / exposed
    22 / 28 (78.57%)
    22 / 26 (84.62%)
    24 / 27 (88.89%)
         occurrences all number
    32
    41
    41
    Weight loss
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    White blood cell decreased
         subjects affected / exposed
    16 / 28 (57.14%)
    16 / 26 (61.54%)
    15 / 27 (55.56%)
         occurrences all number
    27
    31
    48
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Heart failure
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Palpitations
         subjects affected / exposed
    3 / 28 (10.71%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
         occurrences all number
    3
    1
    1
    Presyncope
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    12 / 28 (42.86%)
    15 / 26 (57.69%)
    15 / 27 (55.56%)
         occurrences all number
    17
    21
    28
    Leukocytosis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchial infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Lung infection
         subjects affected / exposed
    2 / 28 (7.14%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
         occurrences all number
    2
    2
    0
    Upper respiratory infection
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Dyspnea
         subjects affected / exposed
    4 / 28 (14.29%)
    2 / 26 (7.69%)
    4 / 27 (14.81%)
         occurrences all number
    4
    2
    5
    Cough
         subjects affected / exposed
    1 / 28 (3.57%)
    4 / 26 (15.38%)
    3 / 27 (11.11%)
         occurrences all number
    1
    4
    4
    Hypoxia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Pleural effusion
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Pleuritic pain
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Sore throat
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Fecal incontinence
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Gait disturbance
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    1
    Generalized muscle weakness
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    1
    Akathisia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Amnesia
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    Concentration impairment
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Encephalopathy
         subjects affected / exposed
    2 / 28 (7.14%)
    4 / 26 (15.38%)
    2 / 27 (7.41%)
         occurrences all number
    2
    8
    2
    Headache
         subjects affected / exposed
    0 / 28 (0.00%)
    11 / 26 (42.31%)
    13 / 27 (48.15%)
         occurrences all number
    0
    14
    13
    Memory impairment
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 26 (7.69%)
    3 / 27 (11.11%)
         occurrences all number
    0
    3
    3
    Paresthesia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    2
    1
    0
    Seizure
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Tremor
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Trigeminal nerve disorder
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Insomnia
         subjects affected / exposed
    3 / 28 (10.71%)
    1 / 26 (3.85%)
    5 / 27 (18.52%)
         occurrences all number
    3
    1
    5
    Urinary incontinence
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    8 / 28 (28.57%)
    8 / 26 (30.77%)
    12 / 27 (44.44%)
         occurrences all number
    9
    9
    13
    Bloating
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    0
    2
    Constipation
         subjects affected / exposed
    3 / 28 (10.71%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    3
    1
    0
    Diarrhea
         subjects affected / exposed
    2 / 28 (7.14%)
    4 / 26 (15.38%)
    3 / 27 (11.11%)
         occurrences all number
    2
    4
    3
    Dry mouth
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    3 / 28 (10.71%)
    3 / 26 (11.54%)
    0 / 27 (0.00%)
         occurrences all number
    3
    3
    0
    Gastritis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Nausea
         subjects affected / exposed
    1 / 28 (3.57%)
    10 / 26 (38.46%)
    6 / 27 (22.22%)
         occurrences all number
    1
    10
    6
    Oral pain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Rectal hemorrhage
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Toothache
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Stomach pain
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    2 / 28 (7.14%)
    4 / 26 (15.38%)
    3 / 27 (11.11%)
         occurrences all number
    2
    5
    3
    Gum infection
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatobiliary disorders
    Gallbladder obstruction
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Ascites
         subjects affected / exposed
    1 / 28 (3.57%)
    8 / 26 (30.77%)
    4 / 27 (14.81%)
         occurrences all number
    1
    11
    8
    Renal and urinary disorders
    Cystitis noninfective
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Hematuria
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Renal calculi
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary retention
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Urinary tract pain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 28 (10.71%)
    4 / 26 (15.38%)
    4 / 27 (14.81%)
         occurrences all number
    4
    6
    4
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 28 (10.71%)
    3 / 26 (11.54%)
    2 / 27 (7.41%)
         occurrences all number
    3
    3
    2
    Arthritis
         subjects affected / exposed
    3 / 28 (10.71%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
         occurrences all number
    3
    1
    1
    Back pain
         subjects affected / exposed
    3 / 28 (10.71%)
    2 / 26 (7.69%)
    4 / 27 (14.81%)
         occurrences all number
    3
    2
    6
    Bone pain
         subjects affected / exposed
    0 / 28 (0.00%)
    14 / 26 (53.85%)
    15 / 27 (55.56%)
         occurrences all number
    0
    15
    15
    Musculoskeletal deformity
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    1
    Pain in extremity
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    5 / 27 (18.52%)
         occurrences all number
    0
    1
    5
    Endocrine disorders
    Hypercalcemia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Gynecomastia
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 26 (7.69%)
    1 / 27 (3.70%)
         occurrences all number
    1
    2
    1
    Metabolism and nutrition disorders
    Edema limbs
         subjects affected / exposed
    9 / 28 (32.14%)
    12 / 26 (46.15%)
    5 / 27 (18.52%)
         occurrences all number
    9
    15
    5
    Anorexia
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 26 (7.69%)
    2 / 27 (7.41%)
         occurrences all number
    1
    2
    3
    Dehydration
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperglycemia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Hyperkalemia
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 26 (3.85%)
    2 / 27 (7.41%)
         occurrences all number
    1
    2
    3
    Hypermagnesemia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Hypernatremia
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    Hyperuricemia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoalbuminemia
         subjects affected / exposed
    13 / 28 (46.43%)
    14 / 26 (53.85%)
    15 / 27 (55.56%)
         occurrences all number
    19
    19
    33
    Hypocalcemia
         subjects affected / exposed
    9 / 28 (32.14%)
    7 / 26 (26.92%)
    13 / 27 (48.15%)
         occurrences all number
    11
    9
    26
    Hypoglycemia
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    3
    0
    3
    Hypokalemia
         subjects affected / exposed
    5 / 28 (17.86%)
    5 / 26 (19.23%)
    4 / 27 (14.81%)
         occurrences all number
    7
    5
    9
    Hypomagnesemia
         subjects affected / exposed
    11 / 28 (39.29%)
    8 / 26 (30.77%)
    9 / 27 (33.33%)
         occurrences all number
    16
    13
    14
    Hyponatremia
         subjects affected / exposed
    2 / 28 (7.14%)
    6 / 26 (23.08%)
    4 / 27 (14.81%)
         occurrences all number
    3
    9
    8
    Hypophosphatemia
         subjects affected / exposed
    5 / 28 (17.86%)
    1 / 26 (3.85%)
    8 / 27 (29.63%)
         occurrences all number
    6
    1
    12
    Osteoporosis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Lip infection
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Mucosal infection
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    4 / 28 (14.29%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    4
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 May 2009
    Protocol version 2.0 : substantial amendment: a) Section 3.2 - Further Exclusion Criteria added b) Section 7.4, 7.5 - Addition of Treatment Day 4 Blood Test c) Section 7.9 - Lenograstim Discontinuation Criteria added
    05 Nov 2009
    Protocol V3.0 Substantial Amendment a) Section 3.2 - Further detail added to Exclusion Criteria. b) Section 7.1 – Change to study administration (all drug will be administered by suitable qualified medical staff only). c) Section 7.2 – Dose modification and toxicity management recommendations (new section). d) Section 8.0 – Additional information added to adverse event reporting section, clarification of SAE reporting period and procedures. e) Section 13.0 Additional information added to power calculations, Interim and final analysis sections f) Section 14.1 Change in sponsor details : single sponsor to Co-sponsorship g) Appendix 2 – change to questionnaire layout. A number of minor amendments have been made throughout the protocol. Which include change in study personnel, Use of μg to replace mcg
    06 Jul 2011
    Protocol version 4.0 Substantial Amendment a) Section 3.1 amended inclusion MELD range b) Section 4 changed wording to say multi centre c) Section 5.3, 7.4, 7.5, 7.6: Increased ELF testing frequency A number of minor changes have been made through the protocol, which includes change in study personnel.
    22 Feb 2012
    Protocol v5.0 Substantial Amendment a) Changes to inclusion criteria and addition of new inclusion criteria • Alpha-1 Antitrypsin Deficiency • Changes to some diagnostic requirements relating to aetiology of the liver disease. b) Change to wording of exclusion criteria • The requirement (time scales) for Ascites, Portal hypertensive bleeding and Encephalopathy (requiring treatment or hospitalisation) free period prior to randomisation has been reduced from 6 months to 3 months. A number of minor changes have been made throughout the protocol, which includes change in study personnel.
    24 May 2012
    Protocol V6.0 Substantial Amendment a) Change of sponsor details from co-sponsor to single sponsor b) Change to IMP label c) update to UKELD information
    07 Nov 2012
    Protocol V7.0 Substantial Amendment a) Change to inclusion criteria (MELD range) b) Change to inclusion criteria (Age range) A number of minor changes have been made throughout the protocol, which includes change in study personnel and information on eRDC.
    05 Mar 2015
    Protocol v8.0 Substantial Amendment A number of minor changes to the protocol. Section 11 : Statistical Considerations Changes to the primary statistical analysis to include MELD measurements at baseline, 30, 60 and 90 days.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/25795699
    http://www.ncbi.nlm.nih.gov/pubmed/29127060
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