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    Clinical Trial Results:
    An Observer-Blinded, Randomized Study Comparing the Safety and Immunogenicity of HEPLISAV™ to Licensed Vaccine (Engerix-B®) among Adults (18 to 75 Years of Age) with Chronic Kidney Disease (CKD)

    Summary
    EudraCT number
    		 2009-015877-11
    Trial protocol
    		 DE  
    Global end of trial date
    09 Jan 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-17 synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    DV2-HBV-17
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00985426
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 US IND Number: BB-IND 12692, Canada File Number: 9427-D0897-21C
    Sponsors
    Sponsor organisation name
    Dynavax Technologies Corporation
    Sponsor organisation address
    2929 Seventh Street, Suite 100 Berkeley, Berkeley, California, United States, 94710
    Public contact
    Referat Klinische Prüfung, Paul-Ehrlich-Institut (PEI), 49 610377 1811, klinpruefung@pei.de
    Scientific contact
    Referat Klinische Prüfung, Paul-Ehrlich-Institut (PEI), 49 610377 1811, 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
    26 Jun 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jan 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jan 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the noninferiority of the immune response to a 3-dose regimen of HEPLISAV compared to the standard 4-dose regimen of Engerix-B in subjects with chronic kidney disease (CKD) at 4 weeks after the last injection (Week 28) as measured by the seroprotection rate defined as the percentage of subjects achieving an antibody level to hepatitis B surface antigen (anti-HBsAg) greater than or equal to 10 mIU/mL
    Protection of trial subjects
    Injection-site reactions were expected to subside spontaneously. 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 discouraged as it could interfere with the action of the study drug. IMP was not injected into a site if local pain, tenderness, swelling, or pruritus persisted from a previous injection or other cause. If a subject was stopped from receiving additional study injections, they were to continue to be followed through Week 52.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Sep 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Canada: 31
    Country: Number of subjects enrolled
    United States: 452
    Worldwide total number of subjects
    516
    EEA total number of subjects
    33
    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)
    280
    From 65 to 84 years
    236
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited at 59 sites: 47 in the US, 3 in Canada and 9 in Germany.

    Pre-assignment
    Screening details
    		 The screened population comprised 918 subjects who provided informed consent and began the screening process. Of these subjects, 521 (56.8%) were randomized and 397 (43.2%) were screen failures.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind [1]
    Roles blinded
    		 Subject, Monitor
    Blinding implementation details
    The subjects and the study personnel conducting clinical safety evaluations were blinded to treatment assignment. Study drug was not packaged in a blinded manner; therefore, designated study site personnel with no other study responsibilities were not blinded so they could prepare and/or administer the study injections. In addition, an unblinded study monitor with no other study responsibilities confirmed drug accountability.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 HEPLISAV arm
    Arm description
    		 3 single-dose regimen of HEPLISAV
    Arm type
    		 Experimental

    Investigational medicinal product name
    HBsAg-1018 ISS
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The test product (HEPLISAV) was 20 mcg recombinant HBsAg subtype adw with 3000 mcg 1018 immunostimulatory sequence (ISS) adjuvant. Subjects in the HEPLISAV group received a single IM injection (0.5 mL) in the right or left deltoid muscle at Weeks 0, 4, and 24 (placebo at Week 8). The reference therapy was Engerix-B (20 mcg recombinant HBsAg combined with 500 mcg alum adjuvant/mL) manufactured by GlaxoSmithKline Biologicals. Subjects in the Engerix-B group received 2 IM injections of 1.0 mL each (for a total dose of 40 mcg HBsAg and 1 mg alum) in the right or left deltoid muscle at Weeks 0, 4, 8, and 24. The treatment period was 24 weeks (Week 0 to Week 24), with study injections administered at Weeks 0, 4, 8, and 24. Follow-up for safety and immunogenicity was conducted from Week 24 through Week 52.

    Arm title
    		 Engerix-B arm
    Arm description
    		 4 double-dose regimen (total of 8 doses) of 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 pen
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The reference therapy was Engerix-B (20 mcg recombinant HBsAg combined with 500 mcg alum adjuvant/mL) manufactured by GlaxoSmithKline Biologicals. Subjects in the Engerix-B group received 2 IM injections of 1.0 mL each (for a total dose of 40 mcg HBsAg and 1 mg alum) in the right or left deltoid muscle at Weeks 0, 4, 8, and 24.

    Notes
    [1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
    Justification: This is an observer-blinded study but the subjects are also blinded.
    Number of subjects in period 1
    		HEPLISAV arm Engerix-B arm
    Started
    254
    262
    Completed
    215
    219
    Not completed
    39
    43
         Subject Non-Compliance
    3
    3
         Consent withdrawn by subject
    12
    16
         Adverse event, non-fatal
    -
    1
         Other
    7
    10
         Deaths
    7
    3
         Lost to follow-up
    8
    10
         Protocol deviation
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HEPLISAV arm
    Reporting group description
    		 3 single-dose regimen of HEPLISAV

    Reporting group title
    Engerix-B arm
    Reporting group description
    		 4 double-dose regimen (total of 8 doses) of Engerix-B

    Reporting group values
    		 HEPLISAV arm Engerix-B arm Total
    Number of subjects
    		 254 262 516
    Age categorical
    The effect of age on immunogenicity was evaluated in 3 age strata: Subjects 18 to 39 years of age (HEPLISAV: n = 2; Engerix-B: n = 11), subjects 40 to 55 years of age (HEPLISAV: n = 57; Engerix-B: n = 46), and subjects 56 to 75 years of age (HEPLISAV: n = 180; Engerix-B: n = 195). TO CONFIRM
    Units: Subjects
        Adults (18 - 64 years)
    		 137 143 280
        Adults (65 - 84 years)
    		 117 119 236
        Adults (> 84 years)
    		 0 0 0
    Age continuous
    Age mean (SD) by treatment group (HEPLISAV vs Engerix-B) Total age mean (SD) including both groups.
    Units: years
        arithmetic mean (standard deviation)
    		 61.4 ( 9.1 ) 61.3 ( 9.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 94 104 198
        Male
    		 160 158 318
    Subject analysis sets

    Subject analysis set title
    HEPLISAV mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The primary immunogenicity analysis was based on the mITT population. The mITT population for the immunogenicity analyses comprised all randomized subjects who received at least 1 study injection and had at least 1 post-injection immunogenicity evaluation excluding 16 subjects treated at Site 42 - subjects treated with HEPLISAV.

    Subject analysis set title
    Engerix-B mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The primary immunogenicity analysis was based on the mITT population. The mITT population for the immunogenicity analyses comprised all randomized subjects who received at least 1 study injection and had at least 1 post-injection immunogenicity evaluation excluding 16 subjects treated at Site 42 - subjects treated with Engerix-B.

    Subject analysis sets values
    		 HEPLISAV mITT Engerix-B mITT
    Number of subjects
    239
    252
    Age categorical
    The effect of age on immunogenicity was evaluated in 3 age strata: Subjects 18 to 39 years of age (HEPLISAV: n = 2; Engerix-B: n = 11), subjects 40 to 55 years of age (HEPLISAV: n = 57; Engerix-B: n = 46), and subjects 56 to 75 years of age (HEPLISAV: n = 180; Engerix-B: n = 195). TO CONFIRM
    Units: Subjects
        Adults (18 - 64 years)
        Adults (65 - 84 years)
        Adults (> 84 years)
    0
    0
    Age continuous
    Age mean (SD) by treatment group (HEPLISAV vs Engerix-B) Total age mean (SD) including both groups.
    Units: years
        arithmetic mean (standard deviation)
    61.4 ( 9.1 )
    61.5 ( 9.7 )
    Gender categorical
    Units: Subjects
        Female
    89
    101
        Male
    150
    151

    End points

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    End points reporting groups
    Reporting group title
    HEPLISAV arm
    Reporting group description
    		 3 single-dose regimen of HEPLISAV

    Reporting group title
    Engerix-B arm
    Reporting group description
    		 4 double-dose regimen (total of 8 doses) of Engerix-B

    Subject analysis set title
    HEPLISAV mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The primary immunogenicity analysis was based on the mITT population. The mITT population for the immunogenicity analyses comprised all randomized subjects who received at least 1 study injection and had at least 1 post-injection immunogenicity evaluation excluding 16 subjects treated at Site 42 - subjects treated with HEPLISAV.

    Subject analysis set title
    Engerix-B mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The primary immunogenicity analysis was based on the mITT population. The mITT population for the immunogenicity analyses comprised all randomized subjects who received at least 1 study injection and had at least 1 post-injection immunogenicity evaluation excluding 16 subjects treated at Site 42 - subjects treated with Engerix-B.

    Primary: Noninferiority of the immune response measured by SPR at Week 28

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    End point title
    		 Noninferiority of the immune response measured by SPR at Week 28 [1]
    End point description
    End point type
    Primary
    End point timeframe
    Week 28
    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: Descriptive Analysis
    End point values
    		 HEPLISAV mITT Engerix-B mITT
    Number of subjects analysed
    219
    235
    Units: Number of Subjects
        Week 28
    196
    191
    No statistical analyses for this end point

    Secondary: Superiority of the immune response measured by SPR at Week 28

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    End point title
    		 Superiority of the immune response measured by SPR at Week 28
    End point description
    To demonstrate the superiority of the immune response to a 3 single-dose regimen of HEPLISAV compared to the standard 4 double-dose regimen of Engerix-B in subjects with CKD at 4 weeks after the last dose of study treatment (Week 28) as measured by the SPR.
    End point type
    Secondary
    End point timeframe
    Week 28
    End point values
    		 HEPLISAV mITT Engerix-B mITT
    Number of subjects analysed
    219
    235
    Units: Percentage
        Week 28
    196
    191
    No statistical analyses for this end point

    Secondary: Evaluate the safety of HEPLISAV compared to Engerix-B

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    End point title
    		 Evaluate the safety of HEPLISAV compared to Engerix-B
    End point description
    Overall number of subjects who reported a local and/or systemic post-injection reaction
    End point type
    Secondary
    End point timeframe
    Overall trial period
    End point values
    		 HEPLISAV arm Engerix-B arm
    Number of subjects analysed
    254
    262
    Units: Number of Subjects
    117
    132
    No statistical analyses for this end point

    Secondary: Evaluate the immune response as measured by SPR of subjects with type 2 diabetes

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    End point title
    		 Evaluate the immune response as measured by SPR of subjects with type 2 diabetes
    End point description
    End point type
    Secondary
    End point timeframe
    Week 28
    End point values
    		 HEPLISAV mITT Engerix-B mITT
    Number of subjects analysed
    147
    145
    Units: Number of Subjects
    131
    110
    No statistical analyses for this end point

    Secondary: Compare the immunogenicity of HEPLISAV and Engerix-B measured by SPR

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    End point title
    		 Compare the immunogenicity of HEPLISAV and Engerix-B measured by SPR
    End point description
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 24, 28, 36, 44, 52
    End point values
    		 HEPLISAV mITT Engerix-B mITT
    Number of subjects analysed
    239
    250
    Units: percent
    number (confidence interval 95%)
        Week 4
    5.4 (2.9 to 9.1)
    6.0 (3.4 to 9.7)
        Week 8
    46.8 (40.2 to 53.4)
    20.0 (15.2 to 25.5)
        Week 12
    64.3 (57.8 to 70.5)
    49.8 (43.3 to 59.3)
        Week 24
    78 (72 to 83.2)
    61.5 (55.0 to 67.7)
        Week 28
    89.5 (84.7 to 93.2)
    81.3 (75.7 to 86.1)
        Week 36
    86.4 (81.1 to 90.7)
    79.7 (73.9 to 84.8)
        Week 44
    83.3 (77.6 to 88.1)
    78.0 (71.9 to 83.4)
        Week 52
    83.7 (78.0 to 88.5)
    76.6 (70.4 to 82.1)
    No statistical analyses for this end point

    Secondary: Compare the immunogenicity of HEPLISAV and Engerix-B as measured by the percentage of subjects with anti-HBsAg greater than or equal to 100 mIU/mL

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    End point title
    		 Compare the immunogenicity of HEPLISAV and Engerix-B as measured by the percentage of subjects with anti-HBsAg greater than or equal to 100 mIU/mL
    End point description
    Comparison of Percentage of Subjects With Anti-HBsAg Greater Than or Equal to 100 mIU/mL Between HEPLISAV and Engerix-B by Visit (mITT Population)
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 18, 24, 28, 36, 44 and 52
    End point values
    		 HEPLISAV mITT Engerix-B mITT
    Number of subjects analysed
    239
    250
    Units: percent
    number (confidence interval 95%)
        Week 4
    3.3 (1.5 to 6.5)
    2.4 (0.9 to 5.2)
        Week 8
    18.9 (14.1 to 24.5)
    7.2 (4.3 to 11.1)
        Week 12
    26.1 (20.5 to 32.3)
    21.6 (16.6 to 27.3)
        Week 18
    37.3 (31.0 to 43.9)
    24.9 (19.6 to 30.9)
        Week 24
    43.6 (37.1 to 50.3)
    28.0 (22.4 to 34.2)
        Week 28
    72.6 (66.2 to 78.4)
    62.1 (55.6 to 68.4)
        Week 36
    67.8 (61.0 to 74.0)
    57.7 (51.0 to 64.2)
        Week 44
    66.7 (59.9 to 73.0)
    53.3 (46.3 to 60.1)
        Week 52
    65.6 (58.7 to 72.0)
    47.7 (40.8 to 54.6)
    No statistical analyses for this end point

    Secondary: Evaluate the immunogenicity of HEPLISAV compared to Engerix-B as measured by serum anti-HBsAg GMC

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    End point title
    		 Evaluate the immunogenicity of HEPLISAV compared to Engerix-B as measured by serum anti-HBsAg GMC
    End point description
    Comparison of Geometric Mean Concentrations Between HEPLISAV and Engerix-B by Visit (mITT Population) (at Weeks 4, 8, 12, 18, 24, 28, 36, 44, and 52). The Ratio of GMCs HEPLISAV/Engerix-B (95% CI) is used to compare GMC (table 11-4 of CSR). To add Figure 11-2 of CSR in the 'chart' section in previous interface.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 18, 24, 28, 36, 44 and 52
    End point values
    		 HEPLISAV mITT Engerix-B mITT
    Number of subjects analysed
    239
    250
    Units: percent
    number (confidence interval 95%)
        Week4
    0.4 (0.3 to 0.5)
    0.2 (0.2 to 0.3)
        Week 8
    7.3 (5.1 to 10.5)
    0.9 (0.6 to 1.2)
        Week 12
    15.1 (10.7 to 21.5)
    6.8 (4.7 to 10.0)
        Week 18
    30.8 (21.7 to 43.7)
    11.6 (8.1 to 16.7)
        Week 24
    41.8 (29.5 to 59.2)
    14.5 (10.1 to 20.8)
        Week 28
    526.0 (344.6 to 802.9)
    143.4 (94.4 to 217.8)
        Week 36
    271.8 (179.1 to 412.4)
    96.3 (64.0 to 144.8)
        Week 44
    194.3 (130.8 to 288.8)
    66.5 (44.6 to 99.1)
        Week 52
    155.8 (106.1 to 228.8)
    47.5 (32.2 to 70.1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The reporting period for all nonserious AEs began at the time of first injection and extended through 4 weeks following the last injection (Week 28).
    Adverse event reporting additional description
    All AEs were monitored until resolution or until the subject completed the study. If an AE remained unresolved when the subject discontinued or completed the study, a clinical assessment was made by the investigator and the medical monitor to determine whether continued follow-up of the event was warranted.
    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
    		 3 single-dose regimen of HEPLISAV

    Reporting group title
    Engerix-B arm
    Reporting group description
    		 4 double-dose regimen (total of 8 doses) of Engerix-B

    Serious adverse events
    		 HEPLISAV arm Engerix-B arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    68 / 254 (26.77%)
    76 / 262 (29.01%)
         number of deaths (all causes)
    7
    3
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 254 (0.39%)
    4 / 262 (1.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant hypertension
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Steal syndrome
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Diarrhoea
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia obstructive
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-Organ failure
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 254 (0.79%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical Device Complication
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Victim of homicide
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    3 / 254 (1.18%)
    3 / 262 (1.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory depression
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Lipase increased
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft occlusion
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    3 / 254 (1.18%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 254 (0.00%)
    3 / 262 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    8 / 254 (3.15%)
    8 / 262 (3.05%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 254 (0.00%)
    5 / 262 (1.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery insufficiency
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 254 (1.18%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 254 (1.57%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enlarged uvula
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia, obstructive
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 254 (0.39%)
    3 / 262 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Azotaemia
         subjects affected / exposed
    0 / 254 (0.00%)
    3 / 262 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal artery stenosis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst ruptured
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal failure acute
         subjects affected / exposed
    5 / 254 (1.97%)
    7 / 262 (2.67%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal failure chronic
         subjects affected / exposed
    9 / 254 (3.54%)
    12 / 262 (4.58%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Gouty arthritis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial pyelonephritis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 254 (0.39%)
    3 / 262 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis staphylococcal
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic tonsillitis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal peritonitis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 254 (0.79%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal abscess
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal bacteraemia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 254 (1.97%)
    4 / 262 (1.53%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia escherichia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst infection
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    3 / 254 (1.18%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    2 / 254 (0.79%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 HEPLISAV arm Engerix-B arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    140 / 254 (55.12%)
    146 / 262 (55.73%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 254 (3.15%)
    18 / 262 (6.87%)
         occurrences all number
    8
    18
    Hypotension
         subjects affected / exposed
    6 / 254 (2.36%)
    7 / 262 (2.67%)
         occurrences all number
    6
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    16 / 254 (6.30%)
    13 / 262 (4.96%)
         occurrences all number
    16
    13
    Oedema peripheral
         subjects affected / exposed
    16 / 254 (6.30%)
    13 / 262 (4.96%)
         occurrences all number
    16
    13
    Non-cardiac chest pain
         subjects affected / exposed
    5 / 254 (1.97%)
    3 / 262 (1.15%)
         occurrences all number
    5
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 254 (4.33%)
    9 / 262 (3.44%)
         occurrences all number
    11
    9
    Dyspnoea
         subjects affected / exposed
    8 / 254 (3.15%)
    9 / 262 (3.44%)
         occurrences all number
    8
    9
    Oropharyngeal pain
         subjects affected / exposed
    4 / 254 (1.57%)
    6 / 262 (2.29%)
         occurrences all number
    4
    6
    Pulmonary oedema
         subjects affected / exposed
    6 / 254 (2.36%)
    3 / 262 (1.15%)
         occurrences all number
    6
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 254 (2.36%)
    1 / 262 (0.38%)
         occurrences all number
    6
    1
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    7 / 254 (2.76%)
    5 / 262 (1.91%)
         occurrences all number
    7
    5
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    12 / 254 (4.72%)
    10 / 262 (3.82%)
         occurrences all number
    12
    10
    Coronary artery disease
         subjects affected / exposed
    1 / 254 (0.39%)
    6 / 262 (2.29%)
         occurrences all number
    1
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 254 (1.57%)
    8 / 262 (3.05%)
         occurrences all number
    4
    8
    Headache
         subjects affected / exposed
    9 / 254 (3.54%)
    8 / 262 (3.05%)
         occurrences all number
    9
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 254 (3.54%)
    11 / 262 (4.20%)
         occurrences all number
    9
    11
    Eye disorders
    Cataract
         subjects affected / exposed
    7 / 254 (2.76%)
    3 / 262 (1.15%)
         occurrences all number
    7
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    11 / 254 (4.33%)
    11 / 262 (4.20%)
         occurrences all number
    11
    11
    Diarrhoea
         subjects affected / exposed
    11 / 254 (4.33%)
    10 / 262 (3.82%)
         occurrences all number
    11
    10
    Nausea
         subjects affected / exposed
    11 / 254 (4.33%)
    13 / 262 (4.96%)
         occurrences all number
    11
    13
    Vomiting
         subjects affected / exposed
    6 / 254 (2.36%)
    8 / 262 (3.05%)
         occurrences all number
    6
    8
    Abdominal pain
         subjects affected / exposed
    5 / 254 (1.97%)
    5 / 262 (1.91%)
         occurrences all number
    5
    5
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 254 (0.79%)
    8 / 262 (3.05%)
         occurrences all number
    2
    8
    Rash
         subjects affected / exposed
    5 / 254 (1.97%)
    2 / 262 (0.76%)
         occurrences all number
    5
    2
    Renal and urinary disorders
    renal failure chronic
         subjects affected / exposed
    11 / 254 (4.33%)
    13 / 262 (4.96%)
         occurrences all number
    11
    13
    Renal failure acute
         subjects affected / exposed
    8 / 254 (3.15%)
    9 / 262 (3.44%)
         occurrences all number
    8
    9
    Renal impairment
         subjects affected / exposed
    5 / 254 (1.97%)
    4 / 262 (1.53%)
         occurrences all number
    5
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 254 (5.91%)
    7 / 262 (2.67%)
         occurrences all number
    15
    7
    Back pain
         subjects affected / exposed
    3 / 254 (1.18%)
    12 / 262 (4.58%)
         occurrences all number
    3
    12
    Muscle spasms
         subjects affected / exposed
    5 / 254 (1.97%)
    10 / 262 (3.82%)
         occurrences all number
    5
    10
    Musculoskeletal pain
         subjects affected / exposed
    5 / 254 (1.97%)
    7 / 262 (2.67%)
         occurrences all number
    5
    7
    Myalgia
         subjects affected / exposed
    2 / 254 (0.79%)
    6 / 262 (2.29%)
         occurrences all number
    2
    6
    Pain in extremity
         subjects affected / exposed
    8 / 254 (3.15%)
    11 / 262 (4.20%)
         occurrences all number
    8
    11
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    9 / 254 (3.54%)
    8 / 262 (3.05%)
         occurrences all number
    9
    8
    Gastroenteritis
         subjects affected / exposed
    7 / 254 (2.76%)
    2 / 262 (0.76%)
         occurrences all number
    7
    2
    Nasopharyngitis
         subjects affected / exposed
    13 / 254 (5.12%)
    18 / 262 (6.87%)
         occurrences all number
    13
    18
    Sinusitis
         subjects affected / exposed
    7 / 254 (2.76%)
    7 / 262 (2.67%)
         occurrences all number
    7
    7
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 254 (4.33%)
    11 / 262 (4.20%)
         occurrences all number
    11
    11
    Urinary tract infection
         subjects affected / exposed
    12 / 254 (4.72%)
    7 / 262 (2.67%)
         occurrences all number
    12
    7
    Pneumonia
         subjects affected / exposed
    7 / 254 (2.76%)
    4 / 262 (1.53%)
         occurrences all number
    7
    4
    Cellulitis
         subjects affected / exposed
    6 / 254 (2.36%)
    3 / 262 (1.15%)
         occurrences all number
    6
    3
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    7 / 254 (2.76%)
    7 / 262 (2.67%)
         occurrences all number
    7
    7
    Hyperphosphataemia
         subjects affected / exposed
    4 / 254 (1.57%)
    8 / 262 (3.05%)
         occurrences all number
    4
    8
    Hypoglycaemia
         subjects affected / exposed
    6 / 254 (2.36%)
    6 / 262 (2.29%)
         occurrences all number
    6
    6
    Hypokalaemia
         subjects affected / exposed
    9 / 254 (3.54%)
    4 / 262 (1.53%)
         occurrences all number
    9
    4
    Metabolic acidosis
         subjects affected / exposed
    4 / 254 (1.57%)
    6 / 262 (2.29%)
         occurrences all number
    4
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Aug 2009
    Protocol Amendment 1 - first version of the protocol submitted to ethics committees and implemented at the site level.
    23 Nov 2009
    Protocol Amendment 2
    05 May 2010
    Protocol Amendment 3
    14 Jul 2011
    Protocol Amendment 4

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

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