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    Clinical Trial Results:
    A Phase 3 Randomized, Open-Label Study Comparing Pexa-Vec (Vaccinia GM-CSF / Thymidine Kinase-Deactivated Virus) Followed by Sorafenib Versus Sorafenib in Patients with Advanced Hepatocellular Carcinoma (HCC) Without Prior Systemic Therapy

    Summary
    EudraCT number
    		 2014-001985-86
    Trial protocol
    		 DE   PT   PL   FR   IT  
    Global end of trial date
    14 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Aug 2020
    First version publication date
    15 Aug 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    JX594-HEP024
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02562755
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    SillaJen Inc.
    Sponsor organisation address
    475 Sansome St, Suite 740, San Francisco, United States, CA 94111
    Public contact
    Clinical Trial Information Desk, SillaJen Inc., 1 415 814 9862, clinicaltrialinfo@sillajen.com
    Scientific contact
    Clinical Trial Information Desk, SillaJen Inc., 1 415 814 9862, clinicaltrialinfo@sillajen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Jul 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jan 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine radiographic responses for patients treated with Pexa-Vec followed by sorafenib (Arm A) versus sorafenib alone (Arm B) based on central assessments using mRECIST for HCC for the following endpoints: time to progression (TTP), overall response rate (ORR), disease control rate (DCR), and time to tumor marker elevation (TTME).
    Protection of trial subjects
    Written consent was obtained from the patient before he/she could participate in the study. The content and process of obtaining informed consent was in accordance with all applicable regulatory requirements. Prior to the initiation of any procedures relating to the study, a patient’s consent was obtained using a consent form written in the patient’s native language that was approved by the IRB/IEC and that was signed and personally dated by the patient at the time of consent. The person who conducted the informed consent discussion signed and personally dated the consent form. A copy of the signed and dated informed consent was given to the patient. The Investigator kept each patient’s original, signed and dated consent form on file for inspection by a regulatory authority or authorized party at any time. Depending on national regulations, an authorized person other than the Investigator could inform the patient, sign and date the consent form. During the patient’s participation in the study, whenever important new information became available that was relevant to the patient’s consent, the consent form was updated accordingly for IRB/IEC approval. The patient was informed in a timely manner if new information became available that was relevant to the patient’s willingness to continue participation in the study. The communication of this information was documented. The approved revised consent form was signed and dated by the patient.
    Background therapy
    		 Any medications (as well as HCC medications) or significant non-drug therapies (such as prior radiation therapy, prior HCC surgery, prior HCC local-regional therapy) starting and ending before Day 1 was defined as prior medication. Any non-study medication or any therapeutic intervention (eg, surgery, blood transfusion) with a start date on or after Day 1 up to 28 days after the last dose of Pexa-Vec or sorafenib (eg, up to the safety follow-up visit), inclusive, or with a start date before Day 1 and an end date after Day 1 or ongoing, was considered concomitant medication. All anti-cancer therapies given after progressive disease (PD) were coded using the latest WHO Drug version. For patients who prematurely discontinued the study treatment (for another reason other than PD), all further antineoplastic therapies were collected and coded in the same way. Anti-cancer therapies received after the last dose of study treatment were recorded at follow-up visits after EOT, which also included concomitant treatment before the initiation of survival follow-up visits but after EOT date.
    Evidence for comparator
    		 N/A (Open-label study)
    Actual start date of recruitment
    30 Dec 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    China: 82
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    New Zealand: 54
    Country: Number of subjects enrolled
    Singapore: 11
    Country: Number of subjects enrolled
    Korea, Republic of: 129
    Country: Number of subjects enrolled
    Taiwan: 23
    Country: Number of subjects enrolled
    Thailand: 7
    Country: Number of subjects enrolled
    United States: 74
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Germany: 13
    Worldwide total number of subjects
    459
    EEA total number of subjects
    49
    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)
    281
    From 65 to 84 years
    178
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 459 patients were randomly assigned to one of the study treatment group (234 patients in the Pexa-Vec followed by sorafenib treatment group and 225 patients in the sorafenib only treatment group).

    Pre-assignment
    Screening details
    		 Screening assessments were performed for 756 subjects after the patient had signed the informed consent and a Patient Study Identification Number was generated. The patients could be screened within 21 days from Day 1 visit. 459 patients successfully completed the screening assessments and they were randomly assigned either in Arm A or Arm B.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Pexa-Vec followed by sorafenib treatment group. Study treatment was administered according to their treatment schedule as long as the patient clinically benefited from the treatment and at least until radiographic progression or until unacceptable toxicity occurred. After the treatment phase patients were included in survival follow-up phase consisting of patient and/or caregiver contact every 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pexa-Vec
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Pexa-Vec was administered at a dose of 1 × 109 plaque forming units (pfu) (equivalent to 9.0 Log pfu) as 3 bi-weekly IT injections on Day 1, Week 2, and Week 4.

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Control drug: Sorafenib was administered at dose of 400 mg oral, BID. In Arm A, treatment with sorafenib was initiated at the visit Week 6 or at least 2 weeks after last Pexa Vec IT injection, whichever was later. If not all 3 Pexa Vec IT were performed, sorafenib was started not earlier than Week 6.

    Arm title
    		 Arm B
    Arm description
    		 Sorafenib only treatment group. Study treatment was administered according to their treatment schedule as long as the patient clinically benefited from the treatment and at least until radiographic progression or until unacceptable toxicity occurred. After the treatment phase patients were included in survival follow-up phase consisting of patient and/or caregiver contact every 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib was administered at dose of 400 mg oral, BID daily from Day 1 onwards.

    Number of subjects in period 1
    		Arm A Arm B
    Started
    234
    225
    Completed
    161
    153
    Not completed
    73
    72
         Clinical progression
    7
    13
         Adverse event, serious fatal
    9
    5
         Consent withdrawn by subject
    11
    8
         Investigator judgement
    6
    2
         Adverse event, non-fatal
    2
    6
         Other
    -
    1
         Radiographic progression
    7
    7
         Lost to follow-up
    1
    -
         Missing
    2
    -
         Study closure
    28
    30

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Pexa-Vec followed by sorafenib treatment group. Study treatment was administered according to their treatment schedule as long as the patient clinically benefited from the treatment and at least until radiographic progression or until unacceptable toxicity occurred. After the treatment phase patients were included in survival follow-up phase consisting of patient and/or caregiver contact every 4 weeks.

    Reporting group title
    Arm B
    Reporting group description
    		 Sorafenib only treatment group. Study treatment was administered according to their treatment schedule as long as the patient clinically benefited from the treatment and at least until radiographic progression or until unacceptable toxicity occurred. After the treatment phase patients were included in survival follow-up phase consisting of patient and/or caregiver contact every 4 weeks.

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 234 225 459
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 133 148 281
        From 65-84 years
    		 101 77 178
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.3 ± 10.05 60.5 ± 11.06 -
    Gender categorical
    Units: Subjects
        Female
    		 30 43 73
        Male
    		 204 182 386
    Subject analysis sets

    Subject analysis set title
    Intent-to-treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomly assigned to IP. The ITT patients were analyzed according to the treatment and stratum they were assigned to at randomization. The ITT population was the primary population for efficacy analyses and for summaries of demographic and baseline variables. 459 patients were randomized.

    Subject analysis sets values
    		 Intent-to-treat (ITT) population
    Number of subjects
    459
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    281
        From 65-84 years
    178
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    60.9 ± 10.55
    Gender categorical
    Units: Subjects
        Female
    73
        Male
    386

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Pexa-Vec followed by sorafenib treatment group. Study treatment was administered according to their treatment schedule as long as the patient clinically benefited from the treatment and at least until radiographic progression or until unacceptable toxicity occurred. After the treatment phase patients were included in survival follow-up phase consisting of patient and/or caregiver contact every 4 weeks.

    Reporting group title
    Arm B
    Reporting group description
    		 Sorafenib only treatment group. Study treatment was administered according to their treatment schedule as long as the patient clinically benefited from the treatment and at least until radiographic progression or until unacceptable toxicity occurred. After the treatment phase patients were included in survival follow-up phase consisting of patient and/or caregiver contact every 4 weeks.

    Subject analysis set title
    Intent-to-treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomly assigned to IP. The ITT patients were analyzed according to the treatment and stratum they were assigned to at randomization. The ITT population was the primary population for efficacy analyses and for summaries of demographic and baseline variables. 459 patients were randomized.

    Primary: Time to Progression (TTP)

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    End point title
    		 Time to Progression (TTP)
    End point description
    The median TTP was 2.0 months (95% CI: 1.77, 2.96) in the Pexa Vec followed by sorafenib treatment group and 4.2 months (95% CI: 2.92, 4.63) in the sorafenib only treatment group. No statistically significant improvement in TTP was observed for Pexa Vec followed by sorafenib treatment over sorafenib only treatment group (P value=0.9270). The HR was 1.196 (95% CI: 0.932, 1.533).
    End point type
    Primary
    End point timeframe
    Time to progression was defined as the time from randomization to the date of first documented radiographic tumor progression.
    End point values
    		 Arm A Arm B Intent-to-treat (ITT) population
    Number of subjects analysed
    234
    225
    459
    Units: months
    median (confidence interval 95%)
        TTP quartiles (months) (95% CI)
    2 (1.77 to 2.96)
    4.2 (2.92 to 4.63)
    3.0 (2.73 to 3.25)
    Statistical analysis title
    		 Statistical analysis plan (SAP)
    Statistical analysis description
    Statistical analysis plan (SAP), dated 15 Jan 2020
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    459
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.927
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.196
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.932
         upper limit
    		 1.533
    Notes
    [1] - Time To Progression (TTP) was presented descriptively for each treatment arm separately using Kaplan-Meier curves. Summary statistics from the Kaplan-Meier distributions was determined, including median TTP and 25% and 75% quartiles with corresponding 95% confidence intervals (CIs). The proportions of patients remaining progression free at 3, 6, 9 and 12 months, along with 95% CIs was also provided by treatment arm.

    Primary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    The ORR was 19.2% (45 patients) in the Pexa-Vec followed by sorafenib treatment group and 20.9% (47 patients) in the sorafenib only treatment group for the ITT population. No statistically significant difference in ORR was observed for Pexa Vec followed by sorafenib treatment compared with the sorafenib only treatment group (difference of –1.7%, P value=0.6470).
    End point type
    Primary
    End point timeframe
    ORR was defined as the proportion of patients whose best overall response (BOR) during their participation in the study was either complete response (CR) or partial response (PR). The BOR was recorded from the randomization until tumor progression.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    234
    225
    Units: Overall Response Rate
    number (not applicable)
        Overall response rate (%)
    19.2
    20.9
    Statistical analysis title
    		 Statistical Analysis Plan
    Statistical analysis description
    Statistical Analysis Plan, 15 Jan 2020
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    459
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.647
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.13
         upper limit
    		 5.86
    Notes
    [2] - Overall Response Rate (ORR) was presented by treatment arm along with exact 95% CIs. Difference in ORR proportions (with 95% CI) was provided. A Cochran-Mantel-Haenszel test was performed to compare the 2 treatment arms with respect to the ORR at a 1-sided 2.5% level of significance. A re-randomization test stratified for region based on the Mantel-Haenszel Chi-square statistic was performed to obtain one-sided p-value.

    Primary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    The DCR was 50.0% (117 patients) in the Pexa-Vec followed by sorafenib treatment group and 57.3% (129 patients) in the sorafenib only treatment group for the ITT population. No statistically significant difference in DCR was observed for Pexa Vec followed by sorafenib treatment compared with the sorafenib only treatment group (difference of –7.3% [95% CI: –16.45, 1.95]; P-value=0.0690).
    End point type
    Primary
    End point timeframe
    DCR was defined as the proportion of patients whose BOR during their participation in the study was either CR, PR, or stable disease.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    234
    225
    Units: Subjects
    number (confidence interval 95%)
        Disease Control Rate (%)
    50.0 (43.42 to 56.58)
    57.3 (50.59 to 63.88)
    Statistical analysis title
    		 Statistical Analysis Plan
    Statistical analysis description
    Statistical Analysis Plan, 15 Jan 2020
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    459
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.069
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.45
         upper limit
    		 1.95
    Notes
    [3] - Disease Control Rate (DCR) was presented by treatment arm along with exact 95% CIs. Difference in proportions (with 95% CI) was also provided. A Cochran-Mantel-Haenszel test was performed to compare the 2 treatment arms with respect to the DCR at a 1-sided 2.5% level of significance. A re-randomization test stratified for region based on the Mantel-Haenszel Chi-square statistic was performed to obtain one-sided p-value.

    Primary: Time to Tumor Marker Elevation (TTME)

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    End point title
    		 Time to Tumor Marker Elevation (TTME)
    End point description
    If the patient was alive or had no tumor marker increase of >400 ng/mL at the cut-off date for analysis, TTME was censored at the date of last AFP recorded before the cut-off.
    End point type
    Primary
    End point timeframe
    TTME was defined as time from nadir AFP to AFP>400 ng/mL.
    End point values
    		 Arm A Arm B Intent-to-treat (ITT) population
    Number of subjects analysed
    234
    225
    459
    Units: months
    median (confidence interval 95%)
        TTME quartiles (months) (95% CI)
    3.3 (1.68 to 10.09)
    4.7 (2.0 to 17.28)
    4.2 (2.07 to 10.09)
    Statistical analysis title
    		 Statistical Analysis Plan
    Statistical analysis description
    Statistical Analysis Plan, 15 Jan 2020
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    459
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.9
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.124
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.823
         upper limit
    		 1.534
    Notes
    [4] - TTME was summarized by treatment arm. A Kaplan-Meier curve was constructed for each treatment arm. Median TTME and 25% and 75% quartiles was presented along with 95% CIs for each treatment arm. The Kaplan-Meier estimates with 95% CIs at 3, 6, 9 and 12 months was presented by treatment arm. Numbers of patients at risk was displayed at monthly intervals below the time axis for each of the two treatment groups and censored observations was marked by notches on the curves.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All TEAEs and serious TEAEs were collected after the initiation of study treatment and up to 28 days after the last dose of study treatment.
    Adverse event reporting additional description
    All safety data were listed and those collected later than 28 days after end date of study treatment were flagged in the listings.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Pexa-Vec followed by sorafenib treatment group. Study treatment was administered according to their treatment schedule as long as the patient clinically benefited from the treatment and at least until radiographic progression or until unacceptable toxicity occurred. After the treatment phase patients were included in survival follow-up phase consisting of patient and/or caregiver contact every 4 weeks.

    Reporting group title
    Arm B
    Reporting group description
    		 Sorafenib only treatment group. Study treatment was administered according to their treatment schedule as long as the patient clinically benefited from the treatment and at least until radiographic progression or until unacceptable toxicity occurred. After the treatment phase patients were included in survival follow-up phase consisting of patient and/or caregiver contact every 4 weeks.

    Serious adverse events
    		 Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    117 / 218 (53.67%)
    77 / 217 (35.48%)
         number of deaths (all causes)
    33
    25
         number of deaths resulting from adverse events
    33
    25
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
         subjects affected / exposed
    4 / 218 (1.83%)
    4 / 217 (1.84%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 3
    0 / 4
    Liver carcinoma ruptured
         subjects affected / exposed
    3 / 218 (1.38%)
    2 / 217 (0.92%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Tumour pain
         subjects affected / exposed
    2 / 218 (0.92%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Tumour rupture
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Metastases to spine
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         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
    Pyrexia
         subjects affected / exposed
    8 / 218 (3.67%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    11 / 13
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    3 / 218 (1.38%)
    5 / 217 (2.30%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    General physical health deterioration
         subjects affected / exposed
    2 / 218 (0.92%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 218 (0.92%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    3 / 218 (1.38%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 218 (0.92%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 218 (0.92%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory distress
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 218 (0.46%)
    4 / 217 (1.84%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         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
    Hepatic rupture
         subjects affected / exposed
    3 / 218 (1.38%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         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
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve disease
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (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
    1 / 218 (0.46%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hepatic encephalopathy
         subjects affected / exposed
    5 / 218 (2.29%)
    4 / 217 (1.84%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 217 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcoholic seizure
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (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 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 218 (1.83%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    7 / 218 (3.21%)
    3 / 217 (1.38%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    8 / 218 (3.67%)
    4 / 217 (1.84%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abdominal pain
         subjects affected / exposed
    4 / 218 (1.83%)
    5 / 217 (2.30%)
         occurrences causally related to treatment / all
    2 / 4
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 218 (1.38%)
    3 / 217 (1.38%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 218 (1.83%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 218 (1.83%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Constipation
         subjects affected / exposed
    2 / 218 (0.92%)
    2 / 217 (0.92%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    2 / 218 (0.92%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematemesis
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric varices haemorrhage
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (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 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric antral vascular ectasia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dieulafoy's vascular malformation
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    4 / 218 (1.83%)
    3 / 217 (1.38%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dental caries
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    11 / 218 (5.05%)
    8 / 217 (3.69%)
         occurrences causally related to treatment / all
    1 / 11
    0 / 8
         deaths causally related to treatment / all
    0 / 9
    0 / 7
    Hepatic function abnormal
         subjects affected / exposed
    3 / 218 (1.38%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    3 / 218 (1.38%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary dilatation
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute hepatic failure
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic pain
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 217 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity vasculitis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash pruritic
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis exfoliative generalised
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 218 (1.38%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis reactive
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 218 (1.38%)
    4 / 217 (1.84%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Sepsis
         subjects affected / exposed
    1 / 218 (0.46%)
    4 / 217 (1.84%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Peritonitis bacterial
         subjects affected / exposed
    4 / 218 (1.83%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia necrotising
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycobacterial infection
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis viral
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Decreased appetite
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    218 / 218 (100.00%)
    214 / 217 (98.62%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    44 / 218 (20.18%)
    39 / 217 (17.97%)
         occurrences all number
    44
    39
    Hypotension
         subjects affected / exposed
    35 / 218 (16.06%)
    2 / 217 (0.92%)
         occurrences all number
    35
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    184 / 218 (84.40%)
    28 / 217 (12.90%)
         occurrences all number
    184
    28
    Fatigue
         subjects affected / exposed
    65 / 218 (29.82%)
    64 / 217 (29.49%)
         occurrences all number
    65
    64
    Chills
         subjects affected / exposed
    71 / 218 (32.57%)
    4 / 217 (1.84%)
         occurrences all number
    71
    4
    Oedema peripheral
         subjects affected / exposed
    27 / 218 (12.39%)
    21 / 217 (9.68%)
         occurrences all number
    27
    21
    Asthenia
         subjects affected / exposed
    22 / 218 (10.09%)
    21 / 217 (9.68%)
         occurrences all number
    22
    21
    Influenza like illness
         subjects affected / exposed
    37 / 218 (16.97%)
    5 / 217 (2.30%)
         occurrences all number
    37
    5
    Injection site pain
         subjects affected / exposed
    27 / 218 (12.39%)
    0 / 217 (0.00%)
         occurrences all number
    27
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    31 / 218 (14.22%)
    25 / 217 (11.52%)
         occurrences all number
    31
    25
    Dyspnoea
         subjects affected / exposed
    18 / 218 (8.26%)
    11 / 217 (5.07%)
         occurrences all number
    18
    11
    Oropharyngeal pain
         subjects affected / exposed
    16 / 218 (7.34%)
    10 / 217 (4.61%)
         occurrences all number
    16
    10
    Dysphonia
         subjects affected / exposed
    10 / 218 (4.59%)
    12 / 217 (5.53%)
         occurrences all number
    10
    12
    Epistaxis
         subjects affected / exposed
    13 / 218 (5.96%)
    9 / 217 (4.15%)
         occurrences all number
    13
    9
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    16 / 218 (7.34%)
    20 / 217 (9.22%)
         occurrences all number
    16
    20
    Investigations
    Weight decreased
         subjects affected / exposed
    58 / 218 (26.61%)
    49 / 217 (22.58%)
         occurrences all number
    58
    49
    Aspartate aminotransferase increased
         subjects affected / exposed
    30 / 218 (13.76%)
    39 / 217 (17.97%)
         occurrences all number
    30
    39
    Blood bilirubin increased
         subjects affected / exposed
    22 / 218 (10.09%)
    33 / 217 (15.21%)
         occurrences all number
    22
    33
    Alanine aminotransferase increased
         subjects affected / exposed
    17 / 218 (7.80%)
    29 / 217 (13.36%)
         occurrences all number
    17
    29
    Platelet count decreased
         subjects affected / exposed
    15 / 218 (6.88%)
    15 / 217 (6.91%)
         occurrences all number
    15
    15
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    12 / 218 (5.50%)
    2 / 217 (0.92%)
         occurrences all number
    12
    2
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    13 / 218 (5.96%)
    3 / 217 (1.38%)
         occurrences all number
    13
    3
    Tachycardia
         subjects affected / exposed
    16 / 218 (7.34%)
    0 / 217 (0.00%)
         occurrences all number
    16
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    33 / 218 (15.14%)
    23 / 217 (10.60%)
         occurrences all number
    33
    23
    Dizziness
         subjects affected / exposed
    20 / 218 (9.17%)
    13 / 217 (5.99%)
         occurrences all number
    20
    13
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    33 / 218 (15.14%)
    23 / 217 (10.60%)
         occurrences all number
    33
    23
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    107 / 218 (49.08%)
    116 / 217 (53.46%)
         occurrences all number
    107
    116
    Nausea
         subjects affected / exposed
    74 / 218 (33.94%)
    63 / 217 (29.03%)
         occurrences all number
    74
    63
    Abdominal pain
         subjects affected / exposed
    62 / 218 (28.44%)
    60 / 217 (27.65%)
         occurrences all number
    62
    60
    Constipation
         subjects affected / exposed
    52 / 218 (23.85%)
    51 / 217 (23.50%)
         occurrences all number
    52
    51
    Vomiting
         subjects affected / exposed
    56 / 218 (25.69%)
    27 / 217 (12.44%)
         occurrences all number
    56
    27
    Ascites
         subjects affected / exposed
    46 / 218 (21.10%)
    36 / 217 (16.59%)
         occurrences all number
    46
    36
    Abdominal pain upper
         subjects affected / exposed
    43 / 218 (19.72%)
    30 / 217 (13.82%)
         occurrences all number
    43
    30
    Abdominal distension
         subjects affected / exposed
    26 / 218 (11.93%)
    26 / 217 (11.98%)
         occurrences all number
    26
    26
    Stomatitis
         subjects affected / exposed
    17 / 218 (7.80%)
    24 / 217 (11.06%)
         occurrences all number
    17
    24
    Dyspepsia
         subjects affected / exposed
    15 / 218 (6.88%)
    13 / 217 (5.99%)
         occurrences all number
    15
    13
    Skin and subcutaneous tissue disorders
    Palmar plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    73 / 218 (33.49%)
    99 / 217 (45.62%)
         occurrences all number
    73
    99
    Alopecia
         subjects affected / exposed
    32 / 218 (14.68%)
    46 / 217 (21.20%)
         occurrences all number
    32
    46
    Rash
         subjects affected / exposed
    23 / 218 (10.55%)
    28 / 217 (12.90%)
         occurrences all number
    23
    28
    Pruritus
         subjects affected / exposed
    16 / 218 (7.34%)
    17 / 217 (7.83%)
         occurrences all number
    16
    17
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    29 / 218 (13.30%)
    17 / 217 (7.83%)
         occurrences all number
    29
    17
    Arthralgia
         subjects affected / exposed
    20 / 218 (9.17%)
    15 / 217 (6.91%)
         occurrences all number
    20
    15
    Pain in extremity
         subjects affected / exposed
    19 / 218 (8.72%)
    12 / 217 (5.53%)
         occurrences all number
    19
    12
    Musculoskeletal pain
         subjects affected / exposed
    14 / 218 (6.42%)
    12 / 217 (5.53%)
         occurrences all number
    14
    12
    Muscle spasms
         subjects affected / exposed
    10 / 218 (4.59%)
    12 / 217 (5.53%)
         occurrences all number
    10
    12
    Myalgia
         subjects affected / exposed
    11 / 218 (5.05%)
    8 / 217 (3.69%)
         occurrences all number
    11
    8
    Infections and infestations
    Rash pustular
         subjects affected / exposed
    39 / 218 (17.89%)
    2 / 217 (0.92%)
         occurrences all number
    39
    2
    Upper respiratory tract infection
         subjects affected / exposed
    17 / 218 (7.80%)
    23 / 217 (10.60%)
         occurrences all number
    17
    23
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    85 / 218 (38.99%)
    64 / 217 (29.49%)
         occurrences all number
    85
    64
    Hypokalaemia
         subjects affected / exposed
    18 / 218 (8.26%)
    19 / 217 (8.76%)
         occurrences all number
    18
    19
    Hypoalbuminaemia
         subjects affected / exposed
    15 / 218 (6.88%)
    11 / 217 (5.07%)
         occurrences all number
    15
    11
    Hyponatraemia
         subjects affected / exposed
    16 / 218 (7.34%)
    10 / 217 (4.61%)
         occurrences all number
    16
    10
    Hyperkalaemia
         subjects affected / exposed
    14 / 218 (6.42%)
    4 / 217 (1.84%)
         occurrences all number
    14
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Oct 2017
    Protocol Amendment 1, dated 03 Oct 2017 - Added a section for “Notable Safety Findings” to include a brief description of rare but serious adverse events (SAEs) of myocardial infarction and/or cardiac ischemia and portal vein thrombosis, reported in this study (JX594-HEP024) following Pexa Vec treatment.
    26 Jun 2019
    Protocol Amendment 2, dated 26 Jun 2019 - was submitted to Food and Drug Administration (FDA). Exclusion criteria was updated to necessitate approval by a medical monitor for study participation of patients with adequately treated basal or squamous cell skin cancer, in situ cervical cancer, and adequately treated cancer from which the patient had been disease-free for at least 3 years. A window period of ±7 days was included in the survival follow-up phase. Once approved by Sponsor, the Screening window for a patient could be extended beyond 21 days. Screen failure patients were allowed to be re-screened for participation in the study if a prior Sponsor approval was granted etc. Due to the early termination of this study, based on IDMC recommendation, it was never submitted to the sites and implemented operationally. Therefore, the sections of this report describe the study conduct as amended in Protocol Amendment 1, dated 03 Oct 2017.

    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.
    IDMC identified no new safety concerns, however, recommended study discontinuation in view of the interim analysis suggesting that the original primary objective of improvement in overall survival will unlikely be met by the time of final analysis.
    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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