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    Clinical Trial Results:
    An Open-Label, Randomized, Multi-Center Study Comparing the Safety and Immunogenicity of HEPLISAV™ to Engerix-B® and Fendrix® in Adults on Hemodialysis Who Have Previously Received Hepatitis B Vaccination and Are Not Seroprotected

    Summary
    EudraCT number
    		 2010-019633-10
    Trial protocol
    		 DE  
    Global end of trial date
    23 Apr 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Aug 2021
    First version publication date
    25 Aug 2021
    Other versions
    Summary report(s)
    		 study-report-dv2-hbv-18 synopsis

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    DV2-HBV-18
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01195246
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dynavax Technologies Corporation
    Sponsor organisation address
    2929 Seventh Street, Suite 100, Berkeley, California, United States, 94710
    Public contact
    Referat Klinische Prüfung, Paul-Ehrlich-Institut (PEI), +49 6103771811, klinpruefung@pei.de
    Scientific contact
    Referat Klinische Prüfung, Paul-Ehrlich-Institut (PEI), +49 6103771811, klinpruefung@pei.de
    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
    14 Mar 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Apr 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Apr 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the immune response of HEPLISAV with Engerix-B and Fendrix as measured by seroprotection rate (SPR) defined as the percentage of subjects with a serum antibody concentration to hepatitis B surface antigen (anti-HBs) ≥ 10 mIU/mL in subjects at 4 weeks after the booster injection
    Protection of trial subjects
    Injection site reactions were expected to spontaneously subside. Local pruritus and pain could be treated with oral medications. If significant symptoms of pain and induration persisted for more than 12 hours, an ice pack could be applied locally for 30 minutes every 2 hours, as needed. Use of an ice pack prior to 12 hours after the onset of symptoms was discourages as it could interfere with the action of the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Dec 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
    Germany: 155
    Worldwide total number of subjects
    155
    EEA total number of subjects
    155
    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)
    52
    From 65 to 84 years
    95
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 155 adult subjects (18 years of age or older with ESRD who were receiving hemodialysis and had previously received hepatitis B vaccinations, but were not seroprotected at enrollment) were enrolled at 20 sites in Germany and randomized as follows: HEPLISAV: n = 54; Engerix-B: n = 50; Fendrix: n = 51.

    Pre-assignment
    Screening details
    		 Approximately 150 subjects were planned and 155 subjects were enrolled. At visit 0 the subject was asked to sign an informed consent form, asked for a medical and medication history, given a physical exam with vital signs taken, hepatitis and HIV screen, serum and urine pregnancy test and Anti-HBsAg and stored serum aliquot.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This study is an open-label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 HEPLISAV arm
    Arm description
    		 Subjects received HEPLISAV.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Hepatitis B Surface Antigen (HBsAg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The test product (HEPLISAV) comprised 20 mcg recombinant HBsAg subtype adw with 3000 mcg 1018 ISS (immunostimulatory sequence) Adjuvant (0.5 mL) manufactured by Rentschler Biotechnologie GmbH (Germany). Subjects in the HEPLISAV group received a single intramuscular (IM) injection of HEPLISAV (0.5 mL) into the right or left deltoid muscle at Day 1 (Week 0). Subjects remained in the study for up to 16 weeks. The study had a screening period of up to 4 weeks prior to administration of study treatment and a follow-up period of 12 weeks after administration of study treatment.

    Arm title
    		 Engerix B
    Arm description
    		 Subjects received Engerix-B.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Hepatitis B (rDNA) vaccine (adsorbed) (HBV)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Each 1-mL adult Engerix-B dose contains 20 mcg of HBsAg adsorbed on 500 mcg aluminum as aluminum hydroxide. Engerix-B is manufactured by GlaxoSmithKline Biologicals. Subjects in the Engerix-B group received 2 IM injections of 1 mL each (a total injection volume of 2 mL) into the right or left deltoid muscle at Day 1 (Week 0). Subjects remained in the study for up to 16 weeks. The study had a screening period of up to 4 weeks prior to administration of study treatment and a follow-up period of 12 weeks after administration of study treatment.

    Arm title
    		 Fendrix
    Arm description
    		 Subjects received Fendrix.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Hepatitis B (rDNA) vaccine (adjuvanted, adsorbed).
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Each 0.5-mL adult Fendrix dose contains 20 mcg of HBsAg adsorbed on 500 mcg aluminum as aluminum phosphate and combined with 50 mcg monophosphoryl lipid A. Fendrix is manufactured by GlaxoSmithKline Biologicals. Subjects in the Fendrix group received a single IM injection (0.5 mL) into the right or left deltoid muscle at Day 1 (Week 0). Subjects remained in the study for up to 16 weeks. The study had a screening period of up to 4 weeks prior to administration of study treatment and a follow-up period of 12 weeks after administration of study treatment.

    Number of subjects in period 1
    		HEPLISAV arm Engerix B Fendrix
    Started
    54
    50
    51
    Completed
    52
    46
    51
    Not completed
    2
    4
    0
         Adverse event, serious fatal
    2
    4
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HEPLISAV arm
    Reporting group description
    		 Subjects received HEPLISAV.

    Reporting group title
    Engerix B
    Reporting group description
    		 Subjects received Engerix-B.

    Reporting group title
    Fendrix
    Reporting group description
    		 Subjects received Fendrix.

    Reporting group values
    		 HEPLISAV arm Engerix B Fendrix Total
    Number of subjects
    		 54 50 51 155
    Age categorical
    Units: Subjects
        Adults (18 - 64 years)
    		 22 12 18 52
        Adults (65 - 84 years)
    		 31 33 31 95
        Adults ( > 84 years)
    		 1 5 2 8
    Age continuous
    Age is calculated by comparing the date of informed consent signed to the date of birth. The prior nonresponder group (n = 117) mean age was 70.2 years (range, 36 to 91 years). The prior responder group (n = 38) mean age was 65.1 years (range, 23 to 85 years).
    Units: years
        arithmetic mean (standard deviation)
    		 66.9 ± 11.77 71.1 ± 11.90 69.0 ± 12.77 -
    Gender categorical
    Units: Subjects
        Female
    		 19 20 18 57
        Male
    		 35 30 33 98

    End points

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    End points reporting groups
    Reporting group title
    HEPLISAV arm
    Reporting group description
    		 Subjects received HEPLISAV.

    Reporting group title
    Engerix B
    Reporting group description
    		 Subjects received Engerix-B.

    Reporting group title
    Fendrix
    Reporting group description
    		 Subjects received Fendrix.

    Subject analysis set title
    Prior Nonresponders - HEPLISAV (mITT population)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Prior non-responder who was treated with HEPLISAV - mITT population

    Subject analysis set title
    Prior Responders - HEPLISAV (mITT population)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Prior responder who was treated with HEPLISAV - mITT population

    Subject analysis set title
    Prior Nonresponders - Engerix-B (mITT population)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Prior non-responder who was treated with Engerix-B - mITT population

    Subject analysis set title
    Prior Nonresponders - Fendrix (mITT population)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Prior non-responder who was treated with Fendrix - mITT population

    Subject analysis set title
    Prior Responders - Engerix-B (mITT population)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Prior responder who was treated with Engerix-B - mITT population

    Subject analysis set title
    Prior Responders - Fendrix (mITT population)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Prior responder who was treated with Fendrix - mITT population

    Primary: Primary Immunogenicity Analysis: Seroprotection Rate (SPR) at 4 Weeks After Study Injection (mITT Population)

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    End point title
    		 Primary Immunogenicity Analysis: Seroprotection Rate (SPR) at 4 Weeks After Study Injection (mITT Population)
    End point description
    End point type
    Primary
    End point timeframe
    4 weeks post study injection
    End point values
    		 Prior Nonresponders - HEPLISAV (mITT population) Prior Responders - HEPLISAV (mITT population) Prior Nonresponders - Engerix-B (mITT population) Prior Nonresponders - Fendrix (mITT population) Prior Responders - Engerix-B (mITT population) Prior Responders - Fendrix (mITT population)
    Number of subjects analysed
    38
    15
    37
    41
    11
    10
    Units: percent
        number (confidence interval 95%)
    42.1 (26.3 to 59.2)
    80.00 (51.9 to 95.7)
    18.9 (8.0 to 35.2)
    29.3 (16.1 to 45.5)
    90.9 (58.7 to 99.8)
    100 (69.2 to 100)
    Statistical analysis title
    		 HEPLISAV vs Engerix-B - prior nonresponders
    Statistical analysis description
    The difference in SPRs between the HEPLISAV and Engerix-B groups (HEPLISAV minus Engerix-B) at Week 4 and its two-sided 95% confidence intervals (CIs) were computed using the Wilson score method with continuity correction as described by Newcombe (Newcombe 1998). HEPLISAV was to be declared noninferior to Engerix-B with respect to SPR if the lower limit of the 95% CI from the above analysis was greater than -10% and declared superior if the lower limit of the 95% CI was greater than 0%.
    Comparison groups
    Prior Nonresponders - HEPLISAV (mITT population) v Prior Nonresponders - Engerix-B (mITT population)
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    23.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 43.1
    Variability estimate
    Standard deviation
    Notes
    [1] - Two-sided 95% confidence intervals (CIs) of the difference in seroprotection rates (SPR) between the HEPLISAV-B group and the Engerix-B group was computed using the Newcombe score method with continuity correction. All statistical tests were performed at the 2-sided 0.05 level of significance.
    Statistical analysis title
    		 HEPLISAV vs Fendrix - prior nonresponders
    Statistical analysis description
    The difference in SPRs between the HEPLISAV and Fendrix groups (HEPLISAV minus Fendrix) at Week 4 and its two-sided 95% confidence intervals (CIs) were computed using the Wilson score method with continuity correction as described by Newcombe (Newcombe 1998). HEPLISAV was to be declared noninferior to Fendrix with respect to SPR if the lower limit of the 95% CI from the above analysis was greater than -10% and declared superior if the lower limit of the 95% CI was greater than 0%.
    Comparison groups
    Prior Nonresponders - HEPLISAV (mITT population) v Prior Nonresponders - Fendrix (mITT population)
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    12.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.9
         upper limit
    		 34.1
    Variability estimate
    Standard deviation
    Notes
    [2] - Two-sided 95% confidence intervals (CIs) of the difference in seroprotection rates (SPR) between the HEPLISAV-B group and the Fendrix group was computed using the Newcombe score method with continuity correction. All statistical tests were performed at the 2-sided 0.05 level of significance.
    Statistical analysis title
    		 Engerix-B vs Fendrix - prior nonresponders
    Statistical analysis description
    The difference in SPRs between the Engerix-B and Fendrix groups (Engerix-B minus Fendrix) at Week 4 and its two-sided 95% confidence intervals (CIs) were computed using the Wilson score method with continuity correction as described by Newcombe (Newcombe 1998). Engerix-B was to be declared noninferior to Fendrix with respect to SPR if the lower limit of the 95% CI from the above analysis was greater than -10% and declared superior if the lower limit of the 95% CI was greater than 0%.
    Comparison groups
    Prior Nonresponders - Engerix-B (mITT population) v Prior Nonresponders - Fendrix (mITT population)
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -10.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.4
         upper limit
    		 9.4
    Variability estimate
    Standard deviation
    Notes
    [3] - Two-sided 95% confidence intervals (CIs) of the difference in seroprotection rates (SPR) between the Engerix-B group and the Fendrix group was computed using the Newcombe score method with continuity correction. All statistical tests were performed at the 2-sided 0.05 level of significance.
    Statistical analysis title
    		 HEPLISAV vs Engerix-B - prior responders
    Statistical analysis description
    The difference in SPRs between the HEPLISAV and Engerix-B groups (HEPLISAV minus Engerix-B) at Week 4 and its two-sided 95% confidence intervals (CIs) were computed using the Wilson score method with continuity correction as described by Newcombe (Newcombe 1998). HEPLISAV was to be declared noninferior to Engerix-B with respect to SPR if the lower limit of the 95% CI from the above analysis was greater than -10% and declared superior if the lower limit of the 95% CI was greater than 0%.
    Comparison groups
    Prior Responders - HEPLISAV (mITT population) v Prior Responders - Engerix-B (mITT population)
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -10.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.3
         upper limit
    		 23.5
    Variability estimate
    Standard deviation
    Notes
    [4] - Two-sided 95% confidence intervals (CIs) of the difference in seroprotection rates (SPR) between the HEPLISAV-B group and the Engerix-B group was computed using the Newcombe score method with continuity correction. All statistical tests were performed at the 2-sided 0.05 level of significance.
    Statistical analysis title
    		 HEPLISAV vs Fendrix - prior responders
    Statistical analysis description
    The difference in SPRs between the HEPLISAV and Fendrix groups (HEPLISAV minus Fendrix) at Week 4 and its two-sided 95% confidence intervals (CIs) were computed using the Wilson score method with continuity correction as described by Newcombe (Newcombe 1998). HEPLISAV was to be declared noninferior to Fendrix with respect to SPR if the lower limit of the 95% CI from the above analysis was greater than -10% and declared superior if the lower limit of the 95% CI was greater than 0%.
    Comparison groups
    Prior Responders - HEPLISAV (mITT population) v Prior Responders - Fendrix (mITT population)
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -20
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -48.6
         upper limit
    		 11.8
    Variability estimate
    Standard deviation
    Notes
    [5] - Two-sided 95% confidence intervals (CIs) of the difference in seroprotection rates (SPR) between the HEPLISAV-B group and the Fendrix group was computed using the Newcombe score method with continuity correction. All statistical tests were performed at the 2-sided 0.05 level of significance.
    Statistical analysis title
    		 Engerix-B vs Fendrix - prior responders
    Statistical analysis description
    The difference in SPRs between the Engerix-B and Fendrix groups (Engerix-B minus Fendrix) at Week 4 and its two-sided 95% confidence intervals (CIs) were computed using the Wilson score method with continuity correction as described by Newcombe (Newcombe 1998). Engerix-B was to be declared noninferior to Fendrix with respect to SPR if the lower limit of the 95% CI from the above analysis was greater than -10% and declared superior if the lower limit of the 95% CI was greater than 0%.
    Comparison groups
    Prior Responders - Engerix-B (mITT population) v Prior Responders - Fendrix (mITT population)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.3
         upper limit
    		 23.4
    Variability estimate
    Standard deviation
    Notes
    [6] - Two-sided 95% confidence intervals (CIs) of the difference in seroprotection rates (SPR) between the Engerix-B group and the Fendrix group was computed using the Newcombe score method with continuity correction. All statistical tests were performed at the 2-sided 0.05 level of significance.

    Secondary: Secondary Immunogenicity Analysis: Seroprotection Rate at 12 Weeks After Study Injection (mITT Population)

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    End point title
    		 Secondary Immunogenicity Analysis: Seroprotection Rate at 12 Weeks After Study Injection (mITT Population)
    End point description
    End point type
    Secondary
    End point timeframe
    At 12 weeks after the study injection.
    End point values
    		 Prior Nonresponders - HEPLISAV (mITT population) Prior Responders - HEPLISAV (mITT population) Prior Nonresponders - Engerix-B (mITT population) Prior Nonresponders - Fendrix (mITT population) Prior Responders - Engerix-B (mITT population) Prior Responders - Fendrix (mITT population)
    Number of subjects analysed
    37
    15
    36
    41
    10
    10
    Units: Percentage
        number (confidence interval 95%)
    24.3 (11.8 to 41.2)
    86.7 (59.5 to 98.3)
    13.9 (4.7 to 29.5)
    26.8 (14.2 to 42.9)
    50.0 (18.7 to 81.3)
    100 (69.2 to 100)
    No statistical analyses for this end point

    Secondary: Secondary Immunogenicity Analysis: Anti-HBsAg GMC at Week 4 After Study Injection (mITT Population)

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    End point title
    		 Secondary Immunogenicity Analysis: Anti-HBsAg GMC at Week 4 After Study Injection (mITT Population)
    End point description
    End point type
    Secondary
    End point timeframe
    Anti-HBsAg serum Geometric Mean Concentration (GMC) at Week 4
    End point values
    		 Prior Nonresponders - HEPLISAV (mITT population) Prior Responders - HEPLISAV (mITT population) Prior Nonresponders - Engerix-B (mITT population) Prior Nonresponders - Fendrix (mITT population) Prior Responders - Engerix-B (mITT population) Prior Responders - Fendrix (mITT population)
    Number of subjects analysed
    38
    15
    37
    41
    11
    10
    Units: mIU/mL
        geometric mean (confidence interval 95%)
    3.8 (1.6 to 9.2)
    99.6 (27.5 to 360.1)
    1.2 (0.5 to 2.9)
    1.9 (0.8 to 4.3)
    79.5 (17.7 to 357.7)
    278.1 (57.6 to 1343.0)
    Statistical analysis title
    		 Ratio HEPLISAV/Engerix-B (Week 4) - non responders
    Statistical analysis description
    Comparisons of the adjusted anti-HBsAg GMC at Week 4 and Week 12 by treatment group (mITT population).
    Comparison groups
    Prior Nonresponders - HEPLISAV (mITT population) v Prior Nonresponders - Engerix-B (mITT population)
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    Method
    Parameter type
    		 Ratio
    Point estimate
    3.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 10.88
    Notes
    [7] - Ratio of Anti-HBsAg Geometric Mean Concentrations ((95% CI) measured at Week 4 (mITT Population) for HEPLISAV/Engerix-B.

    Secondary: Secondary Immunogenicity Analyses: Percentage of Subjects With Anti-HBsAg Concentration Greater Than or Equal to 100 mIU/mL at Week 4 (mITT Population)

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    End point title
    		 Secondary Immunogenicity Analyses: Percentage of Subjects With Anti-HBsAg Concentration Greater Than or Equal to 100 mIU/mL at Week 4 (mITT Population)
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at Week 4
    End point values
    		 Prior Nonresponders - HEPLISAV (mITT population) Prior Responders - HEPLISAV (mITT population) Prior Nonresponders - Engerix-B (mITT population) Prior Nonresponders - Fendrix (mITT population) Prior Responders - Engerix-B (mITT population) Prior Responders - Fendrix (mITT population)
    Number of subjects analysed
    38
    15
    37
    41
    11
    10
    Units: Percentage
        number (confidence interval 95%)
    10.5 (2.9 to 24.8)
    66.7 (38.4 to 88.2)
    8.1 (1.7 to 21.9)
    14.6 (5.6 to 29.2)
    36.4 (10.9 to 69.2)
    70 (34.8 to 93.3)
    No statistical analyses for this end point

    Secondary: Post-Injection Reactions within 7 Days post-injection

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    End point title
    		 Post-Injection Reactions within 7 Days post-injection
    End point description
    End point type
    Secondary
    End point timeframe
    7-days post-injection
    End point values
    		 HEPLISAV arm Engerix B Fendrix
    Number of subjects analysed
    54
    49
    51
    Units: Number of Subjects
    13
    8
    20
    No statistical analyses for this end point

    Secondary: Secondary Immunogenicity Analysis: Anti-HBsAg GMC at Week 12 After Study Injection (mITT Population)

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    End point title
    		 Secondary Immunogenicity Analysis: Anti-HBsAg GMC at Week 12 After Study Injection (mITT Population)
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Prior Nonresponders - HEPLISAV (mITT population) Prior Responders - HEPLISAV (mITT population) Prior Nonresponders - Engerix-B (mITT population) Prior Nonresponders - Fendrix (mITT population) Prior Responders - Engerix-B (mITT population) Prior Responders - Fendrix (mITT population)
    Number of subjects analysed
    37
    15
    36
    41
    10
    10
    Units: mIU/mL
        geometric mean (confidence interval 95%)
    2.7 (1.3 to 5.8)
    73.2 (24.4 to 219.5)
    0.7 (0.3 to 1.4)
    1.4 (0.7 to 3.0)
    24.9 (6.5 to 95.4)
    105.5 (27.5 to 404.9)
    No statistical analyses for this end point

    Secondary: Incidence of AEs at Week 4

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    End point title
    		 Incidence of AEs at Week 4
    End point description
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 HEPLISAV arm Engerix B Fendrix
    Number of subjects analysed
    54
    50
    51
    Units: Number of Subjects
    24
    22
    22
    No statistical analyses for this end point

    Secondary: Incidence of AESIs at Week 12

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    End point title
    		 Incidence of AESIs at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 HEPLISAV arm Engerix B Fendrix
    Number of subjects analysed
    54
    50
    51
    Units: Number of Subjects
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were entered into CRFs from the time of first dose of study treatment at Day 1 (Week 0) through Week 4. AEs were recorded as medical history if they occurred before injection. AESIs and SAEs were recorded from the Screening Visit through Week 12.
    Adverse event reporting additional description
    The safety and tolerability assessments included monitoring and recording of local and systemic post-injection reactions (reactogenicity), AEs, AESIs, SAEs, and deaths. Post-injection reactions were entered into the CRFs for 6 days following the administration of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    HEPLISAV arm
    Reporting group description
    		 Subjects received 3 dose of HEPLISAV.

    Reporting group title
    Engerix B
    Reporting group description
    		 Subjects received Engerix-B.

    Reporting group title
    Fendrix
    Reporting group description
    		 Subjects received Fendrix.

    Serious adverse events
    		 HEPLISAV arm Engerix B Fendrix
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 54 (18.52%)
    9 / 50 (18.00%)
    7 / 51 (13.73%)
         number of deaths (all causes)
    2
    4
    0
         number of deaths resulting from adverse events
    2
    4
    0
    Injury, poisoning and procedural complications
    Shunt occlusion
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (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
    Post-operative thrombosis
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shunt thrombosis
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (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
    Shunt aneurysm
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (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
    Upper limb fracture
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (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
    Acetabulum fracture
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Extremity necrosis
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (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
    Femoral artery occlusion
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (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
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 50 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (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
    Atrioventricular block complete
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (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
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebellar infarction
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (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
    Cerebral ischaemia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (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
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (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
    Impaired healing
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 50 (4.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 50 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (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
    Gastrointestinal disorders
    Cholecystitis infective
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (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
    Intestinal ischaemia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (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
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (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
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (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
    Renal and urinary disorders
    Azotaemia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (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
    Bladder neck sclerosis
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (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
    Septic shock
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (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
    Endocarditis staphylococcal
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (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
    Gastroenteritis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (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
    Pneumonia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (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
    Endocarditis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (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
    Localised infection
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (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
    Bronchitis
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (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
    Hypovolaemia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (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
    Hyperkalaemia
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 HEPLISAV arm Engerix B Fendrix
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 54 (25.93%)
    13 / 50 (26.00%)
    15 / 51 (29.41%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm skin
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Extremity necrosis
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Femoral artery occlusion
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Haematoma
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    1
    Hypotension
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    1
    0
    2
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 50 (4.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Fatigue
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    General physical health deterioration
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Impaired healing
         subjects affected / exposed
    0 / 54 (0.00%)
    3 / 50 (6.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    3
    1
    Injection site erythema
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Injection site haematoma
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Injection site pain
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Injection site reaction
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Malaise
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    2
    0
    1
    Multi-organ failure
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 50 (4.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Dysphonia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Hiccups
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Pleural effusion
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Pneumothorax
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Productive cough
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Acetabulum fracture
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Femoral neck fracture
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Haemodialysis-induced symptom
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Laceration
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Postoperative thrombosis
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    0
    Procedural hypertension
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Procedural hypotension
         subjects affected / exposed
    4 / 54 (7.41%)
    1 / 50 (2.00%)
    2 / 51 (3.92%)
         occurrences all number
    4
    1
    2
    Procedural vomiting
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Rib fracture
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Shunt aneurysm
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Shunt occlusion
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Shunt stenosis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Shunt thrombosis
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Tooth fracture
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Upper limb fracture
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Carotid artery occlusion
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Cerebellar infarction
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    0
    2
    Grand mal convulsion
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Headache
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    1
    2
    Hypoaesthesia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Syncope
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Nephrogenic anaemia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Vertigo positional
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis contact
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Azotaemia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Bladder neck sclerosis
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Bone pain
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 50 (4.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    Muscle spasms
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    3 / 54 (5.56%)
    2 / 50 (4.00%)
    0 / 51 (0.00%)
         occurrences all number
    3
    2
    0
    Tendon pain
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Tendonitis
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    0
    3
    Cholecystitis infective
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Cystitis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Endocarditis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Endocarditis staphylococcal
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    1
    Erysipelas
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Localised infection
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 50 (4.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    2
    1
    Pneumonia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Septic shock
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Hypovolaemia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Dec 2011
    Protocol Amendment 1 - included changes that occurred since the study began. Number of sites increased from 15 to 20 in order to reach the enrollment goal of approx. 150 subjects

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

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