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    Clinical Trial Results:
    A Phase 2 Pilot, Multicenter, Single Arm Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of GSK1070806 plus Standard of Care for the Prevention of Delayed Graft Function in Adult Subjects After Renal Transplantation

    Summary
    EudraCT number
    		 2015-002812-33
    Trial protocol
    		 GB   ES  
    Global end of trial date
    06 Mar 2018

    Results information
    Results version number
    		 v4(current)
    This version publication date
    03 Jul 2019
    First version publication date
    15 Apr 2018
    Other versions
    		 v1 , v2 , v3
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    204824
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    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
    16 Aug 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Mar 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the frequency of delayed graft function (DGF) in donation after circulatory death (DCD) renal transplant recipients treated with GSK1070806
    Protection of trial subjects
    This study uses standard of care (SoC) aligning study tasks with SoC tasks and visit schedule to mitigate participant study-burden. Additionally, participants are required to use additional anti-infective protocols due to the potential of GSK1070806 to increase immunosuppression.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Aug 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 6
    Worldwide total number of subjects
    7
    EEA total number of subjects
    7
    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)
    5
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a single arm study to evaluate the efficacy, safety, tolerability, and pharmacokinetics (PK) of GSK1070806 plus standard of care (SOC) for the prevention of delayed graft function in adult participants after renal transplantation.

    Pre-assignment
    Screening details
    		 A total of 10 participants were screened for the study, and 7 of them received study treatment. The study enrolled participants in 4 centers across 2 countries (Spain and United Kingdom).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 GSK1070806 3 mg/kg IV
    Arm description
    		 Participants received a single dose of 3 milligram per kilogram (mg/kg) intravenous (IV) infusion of GSK1070806 administered prior to kidney allograft reperfusion. Participants also received a combination immunosuppression comprised of basiliximab; mycophenolate mofetil (MMF) or aziothioprine; tacrolimus; and corticosteroids based on the clinical judgment of the investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GSK1070806
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received a single dose of 3 milligram per kilogram (mg/kg) intravenous (IV) infusion of GSK1070806 administered prior to kidney allograft reperfusion.

    Number of subjects in period 1
    		GSK1070806 3 mg/kg IV
    Started
    7
    Completed
    6
    Not completed
    1
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GSK1070806 3 mg/kg IV
    Reporting group description
    		 Participants received a single dose of 3 milligram per kilogram (mg/kg) intravenous (IV) infusion of GSK1070806 administered prior to kidney allograft reperfusion. Participants also received a combination immunosuppression comprised of basiliximab; mycophenolate mofetil (MMF) or aziothioprine; tacrolimus; and corticosteroids based on the clinical judgment of the investigator.

    Reporting group values
    		 GSK1070806 3 mg/kg IV Total
    Number of subjects
    		 7 7
    Age categorical
    Units: Subjects
        All Participants
    		 7 7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.7 ± 13.46 -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 7 7
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 7 7

    End points

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    End points reporting groups
    Reporting group title
    GSK1070806 3 mg/kg IV
    Reporting group description
    		 Participants received a single dose of 3 milligram per kilogram (mg/kg) intravenous (IV) infusion of GSK1070806 administered prior to kidney allograft reperfusion. Participants also received a combination immunosuppression comprised of basiliximab; mycophenolate mofetil (MMF) or aziothioprine; tacrolimus; and corticosteroids based on the clinical judgment of the investigator.

    Primary: Number of participants requiring dialysis during the first 7 days post transplant

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    End point title
    		 Number of participants requiring dialysis during the first 7 days post transplant [1]
    End point description
    The requirement of dialysis (except as needed for hyperkalemia during the first 24 hours [hrs]) were used to assess the frequency of delayed graft function (DGF) in donation after circulatory death (DCD) renal transplant recipients treated with GSK1070806. The ‘Analysis Population’ (AP) is defined as participants in the ‘All Subjects’ Population who have been declared to have DGF or have reached 7 days. Statistical analysis was carried out using Bayesian methodology. The proportion of participants with DGF was 0.57, highest Posterior Density (HPD) 95% Credible interval (CI) (0.25,0.90). The posterior probability for the proportion of participants with DGF <30% was 0.07 (HPD 95% CI [0.00,1.00]). The posterior probability for the proportion of participants with DGF <50% was 0.34 (HPD 95% CI [0.00,1.00]).
    End point type
    Primary
    End point timeframe
    Up to Day 7
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical details are presented in outcome measure description for this single arm endpoint.
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    7 [2]
    Units: Participants
        Participants
    4
    Notes
    [2] - AP Population
    No statistical analyses for this end point

    Secondary: Serum creatinine at Baseline and Change from Baseline over time post transplant

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    End point title
    		 Serum creatinine at Baseline and Change from Baseline over time post transplant
    End point description
    Blood samples were collected to measure serum creatinine at the indicated timepoints to assess graft function in DCD renal transplant recipients treated with GSK1070806. Baseline value was the latest pre-dose assessment value. Change from Baseline was post Baseline value minus Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). 99999 indicates data is not available as standard deviation could not be calculated due to n=1. The AP Population is defined as participants having Baseline and at least one post-Baseline assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 12 months
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    7 [3]
    Units: Micromoles per liter
    arithmetic mean (standard deviation)
        Screening, n=7
    679.0 ± 175.14
        Day 0, n=7
    -39.3 ± 160.09
        Day 1, n=7
    -44.7 ± 214.06
        Day 2, n=7
    -99.0 ± 304.29
        Day 3, n=7
    -36.7 ± 378.28
        Day 4, n=7
    -104.6 ± 378.79
        Day 5, n=6
    -57.2 ± 334.19
        Day 6, n=6
    -75.7 ± 308.22
        Day 7, n=6
    -43.5 ± 321.91
        Day 8, n=5
    -150.8 ± 293.48
        Day 9, n=3
    -24.0 ± 297.82
        Day 10, n=3
    -53.0 ± 395.94
        Day 11, n=3
    -97.0 ± 462.46
        Day 12, n=2
    110.0 ± 257.39
        Day 13, n=2
    38.0 ± 209.30
        Day 14, n=2
    4.0 ± 190.92
        Day 15, n=2
    -51.0 ± 172.53
        Day 16, n=2
    -61.5 ± 173.24
        Day 17, n=2
    -107.5 ± 143.54
        Day 18, n=2
    -145.0 ± 123.04
        Day 19, n=2
    -173.5 ± 95.46
        Day 20, n=2
    -183.5 ± 81.32
        Day 21, n=1
    -117.0 ± 99999
        Day 22, n=1
    -91.0 ± 99999
        Day 23, n=1
    -95.0 ± 99999
        Day 24, n=1
    -115.0 ± 99999
        Day 25, n=1
    -152.0 ± 99999
        Day 26, n=1
    -155.0 ± 99999
        Day 27, n=1
    -175.0 ± 99999
        Day 28, n=1
    -191.0 ± 99999
        Day 30, n=7
    -478.3 ± 225.47
        Day 90, n=7
    -489.9 ± 214.06
        6 months, n=7
    -467.4 ± 232.49
        12 months, n=6
    -490.5 ± 224.32
    Notes
    [3] - AP Population
    No statistical analyses for this end point

    Secondary: Urine volume at Baseline and change from Baseline over time post transplant

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    End point title
    		 Urine volume at Baseline and change from Baseline over time post transplant
    End point description
    Urine volume at Baseline and over time post transplant was measured to assess graft function in DCD renal transplant recipients treated with GSK1070806. Baseline value was the latest pre-dose assessment value. Change from Baseline was post Baseline value minus Baseline value. All Subjects Population comprised of participants who received the dose of study medication. 99999 indicates data is not available as standard deviation could not be calculated due to n=1. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Pre-operative) and up to Day 28
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    7 [4]
    Units: Liter
    arithmetic mean (standard deviation)
        Day 0, n=4
    -0.5150 ± 0.59533
        Day 1, n=5
    0.5862 ± 1.56917
        Day 2, n=5
    1.2820 ± 2.62989
        Day 3, n=5
    0.8840 ± 1.04040
        Day 4, n=5
    1.1480 ± 1.00442
        Day 5, n=4
    0.8270 ± 1.02297
        Day 6, n=4
    1.1168 ± 1.30252
        Day 7, n=4
    1.2985 ± 1.37212
        Day 8, n=3
    1.2090 ± 1.20354
        Day 9, n=2
    1.2135 ± 1.46866
        Day 10, n=2
    0.8585 ± 0.62720
        Day 11, n=2
    0.4985 ± 0.22840
        Day 12, n=1
    1.4000 ± 99999
        Day 13, n=1
    1.6900 ± 99999
        Day 14, n=1
    1.1800 ± 99999
        Day 15, n=1
    1.5500 ± 99999
        Day 16, n=1
    1.8500 ± 99999
        Day 17, n=1
    1.5000 ± 99999
        Day 18, n=1
    1.9000 ± 99999
        Day 19, n=1
    1.6000 ± 99999
        Day 20, n=1
    1.2500 ± 99999
        Day 21, n=1
    0.7500 ± 99999
        Day 22, n=1
    1.0500 ± 99999
        Day 23, n=1
    1.1500 ± 99999
        Day 24, n=1
    1.4500 ± 99999
        Day 25, n=1
    2.0500 ± 99999
        Day 26, n=1
    2.0000 ± 99999
        Day 27, n=1
    1.5500 ± 99999
        Day 28, n=1
    1.4600 ± 99999
        Pre-operative, n=5
    0.6700 ± 0.60581
    Notes
    [4] - All Subjects Population
    No statistical analyses for this end point

    Secondary: Number of participants in the first 7 days with: primary non function, functional DGF, intermediate graft function, immediate graft function

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    End point title
    		 Number of participants in the first 7 days with: primary non function, functional DGF, intermediate graft function, immediate graft function
    End point description
    Number of participants in the first 7 days with primary non function, functional DGF, intermediate graft function and immediate graft function were evaluated to access graft function in DCD renal transplant recipients treated with GSK1070806.
    End point type
    Secondary
    End point timeframe
    Up to Day 7
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    7 [5]
    Units: Participants
        Primary Non Function
    1
        3 day Functional DGF
    3
        7 day Functional DGF
    5
        3 day Intermediate Graft Function
    0
        7 day Intermediate Graft Function
    1
        3 day Immediate Graft Function
    1
        7 day Immediate Graft Function
    0
    Notes
    [5] - All Subjects Population
    No statistical analyses for this end point

    Secondary: Number of participants with episodes of biopsy-proven acute rejection

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    End point title
    		 Number of participants with episodes of biopsy-proven acute rejection
    End point description
    Number of participants with episodes of biopsy-proven acute rejection were evaluated to assess the effect of GSK1070806 on acute rejection risk, and rejection/ Pharmacodynamics (PD) biomarkers. Only those participants with data available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    2 [6]
    Units: Participants
    1
    Notes
    [6] - AP Population
    No statistical analyses for this end point

    Secondary: Serum Interferon gamma-induced Protein 10 (IP-10) and Serum Monokine Induced Gamma interferon (Mig) levels at Baseline and Change from Baseline over time post transplant

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    End point title
    		 Serum Interferon gamma-induced Protein 10 (IP-10) and Serum Monokine Induced Gamma interferon (Mig) levels at Baseline and Change from Baseline over time post transplant
    End point description
    The interferon-gamma -inducible chemokine IP10 and the interferon-gamma -inducible chemokine Mig have been identified as an early predictive marker of antibody-mediated kidney graft rejection. Baseline value was the latest pre-dose assessment value. Change from Baseline was calculated as post Baseline value minus Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline and at 0.75 hours, 4-8 hours, Day 1, Day 2, Day 30, Day 90, 6 months and 12 months post reperfusion
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    7 [7]
    Units: Picograms per Liter
    arithmetic mean (standard deviation)
        IP-10, Baseline, n=7
    518.83817 ± 269.010355
        IP-10, Day 0, 0.75 hour, n=6
    -48.36607 ± 178.371827
        IP-10, Day 0, 4-8 hour, n=6
    -262.30099 ± 176.415675
        IP-10, Day 1, n=6
    -214.27224 ± 198.587957
        IP-10, Day 2, n=5
    -91.07498 ± 397.795706
        IP-10, Day 30, n=6
    -215.96831 ± 350.419207
        IP-10, Day 90, n=7
    221.97286 ± 617.906913
        IP-10, 6 months, n=7
    145.05039 ± 846.080946
        IP-10, 12 months, n=5
    241.29317 ± 564.374462
        Mig, Baseline, n=7
    175.76865 ± 194.372235
        Mig, Day 0, 0.75 hour, n=6
    -14.02145 ± 32.535124
        Mig, Day 0, 4-8 hour, n=6
    -49.28436 ± 54.067623
        Mig, Day 1, n=6
    -67.61716 ± 61.009544
        Mig, Day 2, n=5
    -133.99600 ± 165.972042
        Mig, Day 30, n=6
    -159.17646 ± 207.921389
        Mig, Day 90, n=7
    -78.69081 ± 227.901113
        Mig, 6 months, n=7
    -43.68148 ± 325.518838
        Mig, 12 months, n=5
    -30.52711 ± 75.218188
    Notes
    [7] - All Subjects Population
    No statistical analyses for this end point

    Secondary: Number of participants with dialysis events in the first 30 days post-transplant

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    End point title
    		 Number of participants with dialysis events in the first 30 days post-transplant
    End point description
    Number of participants with dialysis events in the first 30 days post transplant was evaluated to assess the effect of GSK1070806 on dialysis dependency and graft survival. The AP Population is defined as participants having Baseline and at least one post-Baseline assessment.
    End point type
    Secondary
    End point timeframe
    Up to 30 days
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    7 [8]
    Units: Participants
        Participants
    5
    Notes
    [8] - AP Population
    No statistical analyses for this end point

    Secondary: Number of participants who are dialysis independent at visits up to 12 months post-transplant

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    End point title
    		 Number of participants who are dialysis independent at visits up to 12 months post-transplant
    End point description
    Number of participants who are dialysis independent at visits up to 12 months post transplant was evaluated to assess the effect of GSK1070806 on dialysis dependency and graft survival.
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    7 [9]
    Units: Participants
    2
    Notes
    [9] - All Subjects Population
    No statistical analyses for this end point

    Secondary: Number of participants with adverse event (AE) and serious adverse event (SAE)

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    End point title
    		 Number of participants with adverse event (AE) and serious adverse event (SAE)
    End point description
    AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment were categorized as SAE.
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    7 [10]
    Units: Participants
        Any AE
    7
        Any SAE
    6
    Notes
    [10] - AP Population
    No statistical analyses for this end point

    Secondary: Number of participants having any abnormality in hematology results of Potential Clinical Importance

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    End point title
    		 Number of participants having any abnormality in hematology results of Potential Clinical Importance
    End point description
    Blood samples were collected to evaluate hematology parameters. Number of participants with abnormality in any hematology parameter results of potential clinical importance (high or low) observed at any time post Baseline are presented. PCI (high or low) was considered if hematocrit (high:>0.54;low:change from baseline [CFB] 0.075 decrease), hemoglobin (high:180; low: CFB 25 decrease), lymphocytes (low: 0.8), neutrophil count (low: 1.5), platelet count (low: 100; high: 550), White blood cells (low: 3; high:20).
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    7 [11]
    Units: Participants
        Lymphocytes, Low
    7
        Hematocrit, High
    1
        White Blood Cells, High
    1
        White Blood Cells, Low
    1
        Platelet Count, Low
    1
        Total neutrophils, Low
    1
    Notes
    [11] - All Subjects Population
    No statistical analyses for this end point

    Secondary: Number of participants having any abnormal clinical chemistry results of Potential Clinical Importance

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    End point title
    		 Number of participants having any abnormal clinical chemistry results of Potential Clinical Importance
    End point description
    Blood samples were collected to evaluate clinical chemistry parameters. Number of participants with abnormal chemistry results of potential clinical importance (high or low) in any of these parameters at any time post Baseline visit have been presented. PCI (high or low) was considered if albumin (low<30), calcium (low<2, high>2.75), creatinine (high: CHB>44.2 increase), glucose (low<3, high>9), magnesium (low<0.5, high>1.23), phosphorus (low<0.8, high>1.6), potassium (low<3, high>5.5), sodium (low: 130, high>150), Total carbon dioxide (CO2) (low:18, high>32), Alanine aminotransferase (ALT) (high>=2*upper limit of normal [ULN]), Aspartate aminotransferase (AST) (high: >=2*ULN), Alkaline phosphatase (ALP) (high:>=2*ULN), Total bilirubin (high: >2*ULN), Total bilirubin+ALT (high: 1.5*ULN total bilirubin with >=2*ULN ALT).
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    7 [12]
    Units: Participants
        Albumin, Low
    6
        Calcium, Low
    7
        Glucose, High
    5
        Potassium, Low
    1
        Potassium, High
    3
        Total Bilirubin, High
    1
        Sodium, Low
    2
        ALT, High
    1
        ALP, High
    1
        AST, High
    1
    Notes
    [12] - All Subjects Population
    No statistical analyses for this end point

    Secondary: Number of participants having any abnormality of Potential Clinical Importance of vital signs results

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    End point title
    		 Number of participants having any abnormality of Potential Clinical Importance of vital signs results
    End point description
    Vital signs parameters included analysis of systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) and body temperature. Number of participants with any abnormality of potential clinical importance (high or low) in any of these vitals signs at any time post Baseline visit have been presented. PCI (high or low) was considered if SBP (low: <85, high:>160), DBP (low: <45, high>100), HR (low: <40, high: >110) and temperature (low: <35.5, high: >37.5).
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    7 [13]
    Units: Participants
        SBP, High
    5
        SBP, Low
    1
        DBP, High
    2
        DBP, Low
    1
        HR, High
    1
        Temperature, High
    1
        Temperature, Low
    2
    Notes
    [13] - All Subjects Population
    No statistical analyses for this end point

    Secondary: Serum concentrations of GSK1070806

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    End point title
    		 Serum concentrations of GSK1070806
    End point description
    Serial blood samples were collected to evaluate PK of GSK1070806 at Pre-operative, 0.75 hours, 4-8 hours, 24 hours, 168 hours, Day 30, Day 90, 6 months and 12 months after kidney reperfusion. PK Population included participants in the ‘All Subjects’ Population for whom a serum PK sample is obtained and analyzed for GSK1070806. 99999 indicates data was not available as standard deviation is not calculated as most of the values at these time points were imputed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Pre-operative, 0.75 hours, 4-8 hours, 24 hours, 168 hours, Day 30, Day 90, 6 months and 12 months after kidney reperfusion
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    7 [14]
    Units: Nanograms per milliliter
    arithmetic mean (standard deviation)
        Pre-operative, n=7
    0.0 ± 99999
        0.75 hours, n=6
    58783.3 ± 11287.77
        4-8 hours, n=6
    60033.3 ± 13577.43
        24 hours, n=6
    50933.3 ± 12681.11
        168 hours, n=5
    28260.0 ± 9643.29
        Day 30, n=6
    17366.7 ± 6809.60
        Day 90, n=7
    5047.0 ± 2914.37
        6 months, n=7
    1083.4 ± 720.18
        12 months, n=6
    19.2 ± 99999
    Notes
    [14] - PK Population
    No statistical analyses for this end point

    Secondary: Number of participants having infections

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    End point title
    		 Number of participants having infections
    End point description
    Number of participants having infections were summarized.
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    7 [15]
    Units: Participants
    5
    Notes
    [15] - All Subjects Population
    No statistical analyses for this end point

    Secondary: Maximum plasma concentration (Cmax) of GSK1070806

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    End point title
    		 Maximum plasma concentration (Cmax) of GSK1070806
    End point description
    Serial blood samples were collected to evaluate PK of GSK1070806 at Pre-operative, 0.75 hours, 4-8 hours, 24 hours, 168 hours, Day 30, Day 90, 6 months and 12 months after kidney reperfusion. Log-transformed geometric mean and 95% confidence interval have been presented.
    End point type
    Secondary
    End point timeframe
    Pre-operative, 0.75 hours, 4-8 hours, 24 hours, 168 hours, Day 30, Day 90, 6 months and 12 months after kidney reperfusion
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    7 [16]
    Units: Log (nanograms per milliliter)
        geometric mean (confidence interval 95%)
    36315.1 (10237.6 to 128818.4)
    Notes
    [16] - PK Population
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration time curve (AUC) from time 0 to the last measurable concentration (AUC[0-t]) and AUC from time 0 to infinite time (AUC[0-inf]) of GSK1070806

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    End point title
    		 Area under the plasma concentration time curve (AUC) from time 0 to the last measurable concentration (AUC[0-t]) and AUC from time 0 to infinite time (AUC[0-inf]) of GSK1070806
    End point description
    Blood samples were to be collected to evaluate PK of GSK1070806 at Pre-operative, 0.75 hours, 4-8 hours, 24 hours, 168 hours, Day 30, Day 90, 6 months and 12 months after kidney reperfusion. Log-transformed geometric mean and 95% confidence interval have been presented.
    End point type
    Secondary
    End point timeframe
    Pre-operative, 0.75 hours, 4-8 hours, 24 hours, 168 hours, Day 30, Day 90, 6 months and 12 months after kidney reperfusion
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    7 [17]
    Units: Log (Hour*nanograms per milliliter)
    geometric mean (confidence interval 95%)
        AUC (0-t), n=7
    26131338.2 (8927844.0 to 76485076.9)
        AUC (0-inf), n=6
    41032450.7 (28127219.0 to 59858815.6)
    Notes
    [17] - PK Population
    No statistical analyses for this end point

    Secondary: Serum levels of free, total, and GSK1070806 bound Interleukin 18 (IL-18) at Baseline and change from Baseline over time post-transplant

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    End point title
    		 Serum levels of free, total, and GSK1070806 bound Interleukin 18 (IL-18) at Baseline and change from Baseline over time post-transplant
    End point description
    IL-18 is itself rapidly secreted from intracellular stores following inflammasome mediated-activation. The appearance of IL-18 marks the initiation of the inflammatory response leading to further injury. Blood samples were collected at indicated time points to assess serum levels of free, total, and GSK1070806 bound IL-18. Baseline value was the latest pre-dose assessment value. Change from Baseline was post Baseline value minus Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). 99999 indicates data was not available due to n=0.
    End point type
    Secondary
    End point timeframe
    Baseline and at 0.75 hours, 4-8 hours, Day 1, Day 2, Day 30, Day 90, 6 months and 12 months post reperfusion
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    7 [18]
    Units: Picograms per milliliter
    arithmetic mean (standard deviation)
        Serum Free IL-18, Baseline (preoperative), n=5
    26.840 ± 37.0569
        Serum Free IL-18, Day 0, 0.75 hour, n=5
    -22.620 ± 37.1672
        Serum Free IL-18, Day 0, 4-8 hour, n=5
    -22.540 ± 34.1535
        Serum Free IL-18, Day 1, n=5
    -23.890 ± 37.0569
        Serum Free IL-18, Day 2, n=4
    -5.263 ± 14.4846
        Serum Free IL-18, Day 30, n=4
    -27.925 ± 41.5019
        Serum Free IL-18, Day 90, n=2
    -2.250 ± 3.1820
        Serum Free IL-18, 6 months, n=0
    99999 ± 99999
        Serum Free IL-18, 12 months, n=0
    99999 ± 99999
        Serum Bound IL-18, Baseline (preoperative), n=5
    21.156 ± 7.5139
        Serum Bound IL-18, Day 0, 0.75 hour, n=5
    362.084 ± 220.2164
        Serum Bound IL-18, Day 0, 4-8 hour, n=5
    314.864 ± 139.1919
        Serum Bound IL-18, Day 1, n=5
    472.204 ± 193.0366
        Serum Bound IL-18, Day 2, n=4
    485.740 ± 252.2876
        Serum Bound IL-18, Day 30, n=4
    617.543 ± 282.9679
        Serum Bound IL-18, Day 90, n=2
    946.020 ± 21.3971
        Serum Bound IL-18, 6 months, n=0
    99999 ± 99999
        Serum Bound IL-18, 12 months, n=0
    99999 ± 99999
        Serum Total IL-18, Baseline (preoperative), n=7
    130.6857 ± 71.37029
        Serum Total IL-18, Day 0, 0.75 hour, n=6
    572.3333 ± 368.68620
        Serum Total IL-18, Day 0, 4-8 hour, n=6
    576.3667 ± 273.88543
        Serum Total IL-18, Day 1, n=6
    636.5667 ± 208.88294
        Serum Total IL-18, Day 2, n=5
    660.6600 ± 297.32305
        Serum Total IL-18, Day 30, n=6
    1175.5000 ± 710.48323
        Serum Total IL-18, Day 90, n=7
    1423.5429 ± 685.42012
        Serum Total IL-18, 6 months, n=7
    1303.7143 ± 1006.89585
        Serum Total IL-18, 12 months, n=6
    1091.0833 ± 1102.78861
    Notes
    [18] - All Subjects Population
    No statistical analyses for this end point

    Secondary: Number of participants with positive result in anti-GSK1070806 antibodies (ADAs)

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    End point title
    		 Number of participants with positive result in anti-GSK1070806 antibodies (ADAs)
    End point description
    Serum samples were to be collected to test for the presence of antibodies against GSK1070806 at indicated time points. The presence of anti-GSK1070806 binding antibodies were to be assessed using a validated electrochemiluminescent (ECL) immunoassay. Data was not collected as the immunogenicity samples were not collected for this terminated indication since healthy volunteers showed low titers and Type 2 Diabetics showed no titers per Investigator's Brochure.
    End point type
    Secondary
    End point timeframe
    0.75 hour and 4-8 hour on Day 0, Day 1, Day 2, Day 30, Day 90, 6 months and 12 months post reperfusion
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    0 [19]
    Units: Participants
    Notes
    [19] - All Subjects Population
    No statistical analyses for this end point

    Secondary: ADA titer before and after GSK1070806 administration

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    End point title
    		 ADA titer before and after GSK1070806 administration
    End point description
    Serum samples were to be collected to test for the presence of antibodies against GSK1070806 at indicated time points. The presence of ADA titer was to be assessed using a validated ECL immunoassay. Data was not collected as the immunogenicity samples were not collected for this terminated indication since healthy volunteers showed low titers and Type 2 Diabetics showed no titers per Investigator's Brochure.
    End point type
    Secondary
    End point timeframe
    0.75 hour and 4-8 hour on Day 0, Day 1, Day 2, Day 30, Day 90, 6 months and 12 months post reperfusion
    End point values
    		 GSK1070806 3 mg/kg IV
    Number of subjects analysed
    0 [20]
    Units: Picograms per milliliter
        arithmetic mean (standard deviation)
    ±
    Notes
    [20] - All Subjects Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment serious adverse events (SAEs) and non-serious AEs were defined as events occurring from the first dose until 12 months.
    Adverse event reporting additional description
    SAEs and Non-serious AEs were collected for All Subjects Population, comprised of participants who received the dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    2.0
    Reporting groups
    Reporting group title
    GSK1070806 3 mg/kg IV
    Reporting group description
    		 Participants received a single dose of 3 milligram per kilogram (mg/kg) intravenous (IV) infusion of GSK1070806 administered prior to kidney allograft reperfusion. Participants also received a combination immunosuppression comprised of basiliximab; mycophenolate mofetil (MMF) or aziothioprine; tacrolimus; and corticosteroids based on the clinical judgment of the investigator.

    Serious adverse events
    		 GSK1070806 3 mg/kg IV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 7 (85.71%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Transplant dysfunction
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Ventricular fibrillation
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Ureteral stent removal
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Hernia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Kidney transplant rejection
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Prostatomegaly
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory arrest
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Ureteric obstruction
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    End stage renal disease
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Visceral leishmaniasis
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 GSK1070806 3 mg/kg IV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    2
    General disorders and administration site conditions
    Catheter site haemorrhage
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Immune system disorders
    Kidney transplant rejection
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Transplant rejection
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Wheezing
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Product issues
    Product contamination
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Investigations
    Blood creatine increased
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Blood potassium decreased
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Blood sodium decreased
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Candida test positive
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Haemoglobin increased
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Body temperature decreased
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Blood glucose increased
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Cytomegalovirus test positive
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Weight increased
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Wound evisceration
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Wound dehiscence
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Arteriovenous fistula site complication
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Post procedural discharge
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Nervous system disorders
    Tremor
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Anaemia
         subjects affected / exposed
    5 / 7 (71.43%)
         occurrences all number
    5
    Neutropenia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Thrombocytopenia
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    2
    Constipation
         subjects affected / exposed
    4 / 7 (57.14%)
         occurrences all number
    4
    Abdominal pain
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    3 / 7 (42.86%)
         occurrences all number
    3
    Inguinal hernia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Frequent bowel movements
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Lip swelling
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Decubitus ulcer
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Urticaria
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    4
    Renal disorder
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Ureteric stenosis
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Renal impairment
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    4
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    2
    Postoperative wound infection
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Pyelonephritis acute
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Bacterial disease carrier
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Nail infection
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Purulent discharge
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Urinary tract infection enterococcal
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Acidosis
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    2
    Fluid overload
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    2
    Hypomagnesaemia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Feb 2016
    Amendment 01: Updates to clarify select safety criteria; completion of abbreviations table.
    09 Aug 2016
    Amendment 02: Eligibility Criteria: Allowance of second kidney transplant recipients for enrollment, removal of upper age limits, addition of definition for ‘surgical damage’ related to transplant organ retrieval; and clarifications to interim analysis and DCD categorization type.
    22 Mar 2017
    Amendment 03: Dose escalation: clarifications based on data from patients receiving 3 mg/kg dose to escalate to higher dose.
    04 May 2017
    Amendment 04: Eligibility Criteria: Additional exclusion criteria have been added to reduce the chance of enrolling participants with high cardiac risk profiles. Dose escalation: Based on emergent efficacy and pharmacokinetic-pharmacodynamics (PKPD) data, the number of participants required to be treated prior to a decision to escalate dose has been reduced, and stopping criteria following dose escalation have been amended.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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