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    Clinical Trial Results:
    EFFICACY AND SAFETY OF NIULIVA FOR THE PREVENTION OF HEPATITIS B VIRUS RECURRENCE IN NEWLY ORTHOTOPIC LIVER TRANSPLANT RECIPIENTS

    Summary
    EudraCT number
    		 2010-020931-37
    Trial protocol
    		 IT  
    Global end of trial date
    16 Jun 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Dec 2016
    First version publication date
    31 Dec 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    IG0907
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01131065
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Instituto Grifols S.A.
    Sponsor organisation address
    C/ Can Guasch 2, Parets del Vallés, Spain, 08150
    Public contact
    Michael K. Woodward, Grifols Therapeutics Inc., michael.woodward@grifols.com
    Scientific contact
    Michael K. Woodward, Grifols Therapeutics Inc., michael.woodward@grifols.com
    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
    10 Nov 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Jun 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the percentage of patients that present HBV recurrence, after the administration of Niuliva in newly liver transplanted patients due to HBV induced liver disease, during the first six months after transplantation
    Protection of trial subjects
    Trial subjects were informed of the advantages, risk and constraints of the study before signing the informed consent form. Precautions were taken in case any patient had presented an episode of infection associated with fever, chills or nausea at the time of the infusion, the infusion would have been interrupted until the infection was under control. Precautions were also taken in case intolerance problems had occurred, the admininstration rate would have been reduced or even temporarily stopped. Suspicion of allergic or anaphylactic type reactions would have required immediate discontinuation of the infusion. In the case of shock, the current medical treatment protocols must have been followed. The dose administration frequency established for each subject could be modified according to clinical criteria and should have been justified in the case report form.
    Background therapy
    		 -
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    26 Jul 2010
    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
    Italy: 15
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    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)
    14
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Fifteen subjects (newly liver transplanted due to HBV induced liver disease) were screened in the study in a total of four centers in Italy. First subject enrolled - 26 July 2010 Last subject completed - 16 June 2014

    Pre-assignment
    Screening details
    		 Subjects participating in this study were selected among subjects that were to undergo orthotopic liver transplantation due to HBV infection-related disease. Baseline visit (screening visit) will be performed within 3 months (maximum) prior to transplanstation

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Day 3
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 10,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 10,000 IU

    Arm title
    		 Day 4
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 10,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 10,000 IU

    Arm title
    		 Day 5
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 10,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 10,000 IU

    Arm title
    		 Day 6
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 10,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 10,000 IU

    Arm title
    		 Day 7
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 10,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 10,000 IU

    Arm title
    		 Week 2
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 5,000 IU

    Arm title
    		 Week 3
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 5,000 IU

    Arm title
    		 Week 4
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 5,000 IU

    Arm title
    		 Month 2
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 5,000 IU

    Arm title
    		 Month 3
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 5,000 IU

    Arm title
    		 Month 4
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 5,000 IU

    Arm title
    		 Month 5
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 5,000 IU

    Arm title
    		 Month 6
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 5,000 IU

    Arm title
    		 Month 7
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 5,000 IU

    Arm title
    		 Month 8
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 5,000 IU

    Arm title
    		 Month 9
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 5,000 IU

    Arm title
    		 Month 10
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 5,000 IU

    Arm title
    		 Month 11
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 5,000 IU

    Arm title
    		 Month 12
    Arm description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niuliva
    Investigational medicinal product code
    Other name
    Hepatitis B immune globulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Hepatitis B immune globulin intravenously dose of 5,000 IU

    Number of subjects in period 1
    		Day 3 Day 4 Day 5 Day 6 Day 7 Week 2 Week 3 Week 4 Month 2 Month 3 Month 4 Month 5 Month 6 Month 7 Month 8 Month 9 Month 10 Month 11 Month 12
    Started
    15
    15
    15
    15
    15
    15
    15
    15
    15
    15
    15
    15
    15
    3
    3
    3
    3
    3
    3
    Completed
    15
    15
    15
    15
    15
    15
    15
    15
    15
    15
    15
    15
    15
    3
    3
    3
    3
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall study
    Reporting group description
    		 -

    Reporting group values
    		 Overall study Total
    Number of subjects
    		 15 15
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 14 14
        From 65-84 years
    		 1 1
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.27 ± 10.51 -
    Gender categorical
    Units: Subjects
        Female
    		 3 3
        Male
    		 12 12
    Race
    Units: Subjects
        white
    		 15 15
        black
    		 0 0
        asian
    		 0 0
        other
    		 0 0
    Alcohol consumption
    Units: Subjects
        Abstemious
    		 15 15
        Currently uses
    		 0 0
        History of alcohol abuse (Exclusion criteria)
    		 0 0
    Hepatitis History
    Units: Subjects
        chronic HBV
    		 15 15
        fulminant HBV
    		 0 0
    Adequate Birth control
    Units: Subjects
        Yes
    		 1 1
        No
    		 1 1
        Not applicable
    		 13 13
    Pregnancy test
    Units: Subjects
        negative
    		 1 1
        Not applicable
    		 14 14
    E-Antigen (HBeAg)
    Units: Subjects
        negative
    		 14 14
        positive
    		 1 1
    HBV-DNA
    Units: Subjects
        negative
    		 14 14
        positive
    		 1 1
    Height
    Units: centimeters
        arithmetic mean (standard deviation)
    		 170.33 ± 8.08 -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 73.73 ± 12.05 -
    Subject analysis sets

    Subject analysis set title
    ITT set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects enrolled in the clinical trial and treated with at least 1 administration of the investigational drug

    Subject analysis sets values
    		 ITT set
    Number of subjects
    15
    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)
    14
        From 65-84 years
    1
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.27 ± 10.51
    Gender categorical
    Units: Subjects
        Female
    3
        Male
    12
    Race
    Units: Subjects
        white
    15
        black
    0
        asian
    0
        other
    0
    Alcohol consumption
    Units: Subjects
        Abstemious
    15
        Currently uses
    0
        History of alcohol abuse (Exclusion criteria)
    0
    Hepatitis History
    Units: Subjects
        chronic HBV
    15
        fulminant HBV
    0
    Adequate Birth control
    Units: Subjects
        Yes
    1
        No
    1
        Not applicable
    13
    Pregnancy test
    Units: Subjects
        negative
    1
        Not applicable
    14
    E-Antigen (HBeAg)
    Units: Subjects
        negative
    14
        positive
    1
    HBV-DNA
    Units: Subjects
        negative
    14
        positive
    1
    Height
    Units: centimeters
        arithmetic mean (standard deviation)
    170.33 ± 8.08
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    73.73 ± 12.05

    End points

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    End points reporting groups
    Reporting group title
    Day 3
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 10,000 IU

    Reporting group title
    Day 4
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 10,000 IU

    Reporting group title
    Day 5
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 10,000 IU

    Reporting group title
    Day 6
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 10,000 IU

    Reporting group title
    Day 7
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 10,000 IU

    Reporting group title
    Week 2
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU

    Reporting group title
    Week 3
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU

    Reporting group title
    Week 4
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU

    Reporting group title
    Month 2
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU

    Reporting group title
    Month 3
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU

    Reporting group title
    Month 4
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU

    Reporting group title
    Month 5
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU

    Reporting group title
    Month 6
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU

    Reporting group title
    Month 7
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU

    Reporting group title
    Month 8
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU

    Reporting group title
    Month 9
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU

    Reporting group title
    Month 10
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU

    Reporting group title
    Month 11
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU

    Reporting group title
    Month 12
    Reporting group description
    		 Hepatitis B immune globulin intravenously dose of 5,000 IU

    Subject analysis set title
    ITT set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects enrolled in the clinical trial and treated with at least 1 administration of the investigational drug

    Primary: HBV recurrence at six months

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    End point title
    		 HBV recurrence at six months [1]
    End point description
    HBV recurrence is measured by seroconversion or reappearance of HBsAg and HBV DNA positivity
    End point type
    Primary
    End point timeframe
    First six months after liver transplantation
    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: HBV recurrence at six months after liver transplantation was descriptively evaluated by proportion of subjects estimated together with its confidence interval calculated by means of the Clopper-Pearson method, which inverts the equal-tailed test based on the binomial distribution. There is no comparison statistical analysis for this primary endpoint.
    End point values
    		 ITT set
    Number of subjects analysed
    15
    Units: subjects
        Month 6
    0
    No statistical analyses for this end point

    Primary: HBV recurrence at twelve months

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    End point title
    		 HBV recurrence at twelve months [2]
    End point description
    HBV recurrence is measured by seroconversion or reappearance of HBsAg and HBV DNA positivity
    End point type
    Primary
    End point timeframe
    First twelve months after liver transplantation
    Notes
    [2] - 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: HBV recurrence at twelve months after liver transplantation was descriptively evaluated by proportion of subjects estimated together with its confidence interval calculated by means of the Clopper-Pearson method, which inverts the equal-tailed test based on the binomial distribution. There is no comparison statistical analysis for this primary endpoint.
    End point values
    		 ITT set
    Number of subjects analysed
    3
    Units: subjects
    0
    No statistical analyses for this end point

    Primary: HBsAg pre-infusion levels

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    End point title
    		 HBsAg pre-infusion levels [3]
    End point description
    Trough levels before each Niuliva administration
    End point type
    Primary
    End point timeframe
    Days 3 to 7, Weeks 2 to 4, Months 2 to 6, Months 7 to 12
    Notes
    [3] - 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: HBsAb titer (i.e. immediately pre-infusion) was descriptively evaluated at relevant visits by mean, standard deviation (SD), median, minimum and maximum values and 95% Confidence Interval (CI) of the mean computed using a t-distribution. There is no comparison statistical analysis for this primary endpoint
    End point values
    		 Day 3 Day 4 Day 5 Day 6 Day 7 Week 2 Week 3 Week 4 Month 2 Month 3 Month 4 Month 5 Month 6 Month 7 Month 8 Month 9 Month 10 Month 11 Month 12
    Number of subjects analysed
    10
    10
    10
    12
    12
    11
    13
    14
    14
    14
    15
    15
    14
    3
    3
    3
    3
    3
    3
    Units: IU/L
        arithmetic mean (standard deviation)
    764.7 ± 375.91
    910.7 ± 282.39
    969.6 ± 96.13
    1000 ± 0
    1000 ± 0
    1073.6 ± 244.21
    945.2 ± 250.38
    1029.2 ± 175.21
    592.5 ± 260.14
    439.2 ± 218.22
    398.1 ± 272.68
    351.9 ± 179.01
    369 ± 182.75
    277.7 ± 89.14
    304.3 ± 50.24
    266 ± 34.7
    301 ± 61.99
    273.3 ± 117.93
    284.3 ± 137.47
    No statistical analyses for this end point

    Secondary: Safety and Tolerance

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    End point title
    		 Safety and Tolerance
    End point description
    Safety and tolerance to the product administration will be measured by the detection of adverse events or clinically relevant changes in vital signs
    End point type
    Secondary
    End point timeframe
    During and after each product administration (up to 12 month of treatment period)
    End point values
    		 ITT set
    Number of subjects analysed
    15
    Units: subjects
        Well-tolerared
    15
        Very slight discomfort
    0
        Discomfort
    0
        Early cessation of infusion
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events data was collected up to 12 month following orthotopic liver transplant
    Adverse event reporting additional description
    The duration of treatment was 6 months after which subjects were offered the option to be treated for an additional 6 months (12 months total)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.1
    Reporting groups
    Reporting group title
    Safety
    Reporting group description
    		 -

    Serious adverse events
    		 Safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 15 (20.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Liver function test abnormal
    Additional description: Liver function test abnormal was also associated with hepatic artery thrombosis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
    Additional description: Pyrexia event was also associated with possible cholangitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Liver transplant rejection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Biliary fistula
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 15 (93.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Immune system disorders
    Transplant rejection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Blood glucose increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Cardiac murmur
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Kell blood group positive
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pharyngeal culture positive
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Weight decreased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Nervous system disorders
    Aphonia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hypokinesia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Hemorrhagic anemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Leukopenia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pancytopenia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Aphthous stomatitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Localized intraabdominal fluid collection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pancreatitis acute
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Biliary fistula
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hepatic function abnormal
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Portal vein thrombosis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Renal failure acute
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Renal impairment
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Infections and infestations
    Biliary tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Herpes virus infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Postoperative wound infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 15 (6.67%)
         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
    04 Nov 2011
    There were no important modifications of the study protocol that could potentially alter the interpretation of the study. The modifications made to the study protocol were administrative to reflect the change of the Coordinating Investigator of the study (Pisa).
    23 Apr 2012
    Amendment No. 2 was classified as relevant as one of the Exclusion criteria #6 (i.e. Evidence of hepatocellular carcinoma in the transplanted liver, or metastatic disease, at time of inclusion in the clinical trial) was removed from the protocol. The latter criteria was originally placed to reduce bias and inter-subject variability as the presence of hepatocellular carcinoma was a well-known risk factor for postoperative HBV recurrence. However, the participating Investigators indicated that this criteria was an important barrier to subject enrollment as approximately 80% of their current liver transplantations were performed on subjects presenting with concomitant hepatocellular carcinoma. On the other hand, subjects with simple HBV-related cirrhosis were progressively being managed with new and more effective antiviral drugs which in most cases avoided the need for transplantation. This modification potentially could have had a negative effect on the primary efficacy and safety variables due to an elevated risk of HBV reinfection in these subjects. However, all participating subjects with hepatocellular carcinoma successfully completed the study and did not present a higher reinfection rate as no subjects presented HBV recurrence at the end of the study.
    19 Oct 2012
    Amendment No. 3 was also classified as relevant as modifications were made to the previous treatment regimen and follow-up period duration. Specifically, the monthly maintenance dose of 5,000 IU of Niuliva was optionally extended from 6 to 12 months and the final follow-up phone call visit was scheduled at month 13 post-OLT. Accordingly, the primary efficacy and safety variables were to be determined at both month 6 and 12 in order to provide a better insight of the Niuliva’s long-term efficacy.
    25 Oct 2013
    There were no important modifications of the study protocol that could potentially alter the interpretation of the study. The modifications made to the study protocol were administrative to reflect changes in the CRO contact numbers and a change of the Principal Investigator at one investigational site (Modena).

    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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