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    Clinical Trial Results:
    A Phase 2 Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate the Efficacy and Safety of GS-6624 Combined with Gemcitabine as First Line Treatment for Metastatic Pancreatic Adenocarcinoma

    Summary
    EudraCT number
    		 2011-003753-26
    Trial protocol
    		 DE   PL  
    Global end of trial date
    28 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Aug 2016
    First version publication date
    14 Aug 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-324-0101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01472198
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.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
    28 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the additive efficacy of simtuzumab (SIM; GS-6624) versus placebo combined with gemcitabine as measured by improvement in progression-free survival (PFS) in adults with metastatic pancreatic adenocarcinoma.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 All participants received gemcitabine as background therapy.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Nov 2011
    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
    Russian Federation: 83
    Country: Number of subjects enrolled
    United States: 167
    Worldwide total number of subjects
    250
    EEA total number of subjects
    0
    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)
    141
    From 65 to 84 years
    106
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in the United States and Russia. The first participant was screened on 22 November 2011. The last study visit occurred on 28 January 2015.

    Pre-assignment
    Screening details
    		 343 participants were screened.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Part A: open-label and non-randomized; Part B: double-blind and randomized.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SIM (Part A)
    Arm description
    		 Simtuzumab (SIM) 700 mg on Days 1 and 15 followed by gemcitabine on Days 1, 8, and 15 for one 28-day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simtuzumab
    Investigational medicinal product code
    Other name
    GS-6624
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Simtuzumab 700 mg prepared by reconstituting vials of simtuzumab in sterile 0.9% sodium chloride USP solution

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine administered at a dose of 1000 mg/m^2 over approximately 30 minutes

    Arm title
    		 SIM 200 mg (Part B)
    Arm description
    		 SIM 200 mg on Days 1 and 15 followed by gemcitabine on Days 1, 8, and 15 of each 28-day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simtuzumab
    Investigational medicinal product code
    Other name
    GS-6624
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Simtuzumab 200 mg prepared by reconstituting vials of simtuzumab and placebo in sterile 0.9% sodium chloride USP solution

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine administered at a dose of 1000 mg/m^2 over approximately 30 minutes

    Arm title
    		 SIM 700 mg (Part B)
    Arm description
    		 SIM 700 mg on Days 1 and 15 followed by gemcitabine on Days 1, 8, and 15 of each 28-day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simtuzumab
    Investigational medicinal product code
    Other name
    GS-6624
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Simtuzumab 700 mg prepared by reconstituting vials of simtuzumab in sterile 0.9% sodium chloride USP solution

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine administered at a dose of 1000 mg/m^2 over approximately 30 minutes

    Arm title
    		 Placebo (Part B)
    Arm description
    		 Placebo on Days 1 and 15 followed by gemcitabine on Days 1, 8, and 15 of each 28-day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo prepared by reconstituting vials of simtuzumab placebo in sterile 0.9% sodium chloride USP solution

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine administered at a dose of 1000 mg/m^2 over approximately 30 minutes

    Number of subjects in period 1 [1]
    		SIM (Part A) SIM 200 mg (Part B) SIM 700 mg (Part B) Placebo (Part B)
    Started
    10
    76
    79
    81
    Completed Follow-up
    10
    76
    79
    81
    Completed
    0
    0
    0
    0
    Not completed
    10
    76
    79
    81
         Adverse event, serious fatal
    1
    3
    4
    4
         Subject Withdrew Consent
    1
    5
    9
    7
         Adverse event, non-fatal
    -
    4
    3
    6
         Death
    -
    -
    1
    -
         Investigator's Discretion
    -
    3
    2
    4
         Study Discontinued by Sponsor
    -
    -
    1
    6
         Lost to follow-up
    -
    -
    1
    -
         Disease Progression
    8
    61
    58
    54
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 4 participants who were randomized but not treated (2 withdrew consent, 1 discontinued due to physician decision, and 1 discontinued due to progressive disease) are not included in the subject disposition table.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SIM (Part A)
    Reporting group description
    		 Simtuzumab (SIM) 700 mg on Days 1 and 15 followed by gemcitabine on Days 1, 8, and 15 for one 28-day cycle

    Reporting group title
    SIM 200 mg (Part B)
    Reporting group description
    		 SIM 200 mg on Days 1 and 15 followed by gemcitabine on Days 1, 8, and 15 of each 28-day cycle

    Reporting group title
    SIM 700 mg (Part B)
    Reporting group description
    		 SIM 700 mg on Days 1 and 15 followed by gemcitabine on Days 1, 8, and 15 of each 28-day cycle

    Reporting group title
    Placebo (Part B)
    Reporting group description
    		 Placebo on Days 1 and 15 followed by gemcitabine on Days 1, 8, and 15 of each 28-day cycle

    Reporting group values
    		 SIM (Part A) SIM 200 mg (Part B) SIM 700 mg (Part B) Placebo (Part B) Total
    Number of subjects
    		 10 76 79 81 246
    Age categorical
    Units: Subjects
        ≥ 65 years
    		 4 36 33 34 107
        < 65 years
    		 6 40 46 47 139
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.2 ( 7.71 ) 63 ( 10.11 ) 63.1 ( 11.04 ) 64.6 ( 9.53 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 34 30 34 104
        Male
    		 4 42 49 47 142
    Race
    Units: Subjects
        White
    		 9 68 66 78 221
        Black or African Heritage
    		 0 5 11 2 18
        Asian
    		 0 2 1 1 4
        Native Hawaiian or Pacific Islander
    		 0 1 0 0 1
        Not Permitted
    		 0 0 1 0 1
        Other
    		 1 0 0 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 3 2 4 2 11
        Not Hispanic or Latino
    		 7 70 74 77 228
        Not Permitted
    		 0 4 1 2 7

    End points

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    End points reporting groups
    Reporting group title
    SIM (Part A)
    Reporting group description
    		 Simtuzumab (SIM) 700 mg on Days 1 and 15 followed by gemcitabine on Days 1, 8, and 15 for one 28-day cycle

    Reporting group title
    SIM 200 mg (Part B)
    Reporting group description
    		 SIM 200 mg on Days 1 and 15 followed by gemcitabine on Days 1, 8, and 15 of each 28-day cycle

    Reporting group title
    SIM 700 mg (Part B)
    Reporting group description
    		 SIM 700 mg on Days 1 and 15 followed by gemcitabine on Days 1, 8, and 15 of each 28-day cycle

    Reporting group title
    Placebo (Part B)
    Reporting group description
    		 Placebo on Days 1 and 15 followed by gemcitabine on Days 1, 8, and 15 of each 28-day cycle

    Primary: Progression-Free Survival

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    End point title
    		 Progression-Free Survival
    End point description
    Progression-free survival (PFS) was defined as the time from the date of randomization to the earliest event time of a) death regardless of cause, or b) first indication of disease progression. PFS was analyzed using Kaplan-Meier (KM) estimates. Full Analysis Set (participants who were randomized and received at least 1 dose of any study drug (SIM or placebo)) with available data were analyzed.
    End point type
    Primary
    End point timeframe
    Up to 15 months
    End point values
    		 SIM (Part A) SIM 200 mg (Part B) SIM 700 mg (Part B) Placebo (Part B)
    Number of subjects analysed
    10
    76
    79
    81
    Units: Months
        median (confidence interval 95%)
    4.3 (2.4 to 5.4)
    3.5 (1.9 to 5.3)
    3.7 (3.4 to 5.4)
    3.7 (3.3 to 4.2)
    Statistical analysis title
    		 PFS - SIM 200 mg vs Placebo
    Statistical analysis description
    The difference in PFS among the treatment groups was assessed using Kaplan-Meier methods and the stratified log-rank test, adjusted for the stratification factors.
    Comparison groups
    SIM 200 mg (Part B) v Placebo (Part B)
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6148 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.66
    Notes
    [1] - P-value was based on a two-sided log-rank test stratified based on the ECOG performance status and prior therapy of the pancreatic primary tumor at randomization.
    Statistical analysis title
    		 PFS - SIM 700 mg vs Placebo
    Statistical analysis description
    The difference in PFS among the treatment groups was assessed using Kaplan-Meier methods and the stratified log-rank test, adjusted for the stratification factors.
    Comparison groups
    SIM 700 mg (Part B) v Placebo (Part B)
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7312 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.61
    Notes
    [2] - P-value was based on a two-sided log-rank test stratified based on the ECOG performance status and prior therapy of the pancreatic primary tumor at randomization.

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survivial (OS) was defined as the time from the date of randomization to death regardless of cause. Participants in the Full Analysis Set with available data were analyzed. 999 = NA; not reached.
    End point type
    Secondary
    End point timeframe
    Up to 18 months
    End point values
    		 SIM (Part A) SIM 200 mg (Part B) SIM 700 mg (Part B) Placebo (Part B)
    Number of subjects analysed
    10
    76
    79
    81
    Units: months
        median (confidence interval 95%)
    4.3 (2.4 to 999)
    5.9 (4.6 to 7.3)
    7.6 (6 to 9)
    5.7 (4.1 to 7.3)
    No statistical analyses for this end point

    Secondary: Objective Response Rate

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    End point title
    		 Objective Response Rate
    End point description
    Objective response was assessed by the RECIST criteria (ver. 1.1) as Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD). Objective response rate (ORR) was defined as the proportion of participants who achieve a CR or PR. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 15 months
    End point values
    		 SIM (Part A) SIM 200 mg (Part B) SIM 700 mg (Part B) Placebo (Part B)
    Number of subjects analysed
    10
    76
    79
    81
    Units: percentage of participants
        number (confidence interval 95%)
    20 (2.5 to 55.6)
    14.5 (7.5 to 24.4)
    13.9 (7.2 to 23.5)
    23.5 (14.8 to 34.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 18 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    SIM (Part A)
    Reporting group description
    		 Simtuzumab (SIM) 700 mg on Days 1 and 15 followed by gemcitabine on Days 1, 8, and 15 for one 28-day cycle

    Reporting group title
    SIM 200 mg (Part B)
    Reporting group description
    		 SIM 200 mg on Days 1 and 15 followed by gemcitabine on Days 1, 8, and 15 of each 28-day cycle

    Reporting group title
    SIM 700 mg (Part B)
    Reporting group description
    		 SIM 700 mg on Days 1 and 15 followed by gemcitabine on Days 1, 8, and 15 of each 28-day cycle

    Reporting group title
    Placebo (Part B)
    Reporting group description
    		 Placebo on Days 1 and 15 followed by gemcitabine on Days 1, 8, and 15 of each 28-day cycle

    Serious adverse events
    		 SIM (Part A) SIM 200 mg (Part B) SIM 700 mg (Part B) Placebo (Part B)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 10 (80.00%)
    27 / 76 (35.53%)
    24 / 79 (30.38%)
    35 / 81 (43.21%)
         number of deaths (all causes)
    1
    3
    4
    3
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatobiliary cancer
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 76 (3.95%)
    2 / 79 (2.53%)
    3 / 81 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 76 (3.95%)
    2 / 79 (2.53%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 76 (1.32%)
    1 / 79 (1.27%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 76 (2.63%)
    1 / 79 (1.27%)
    5 / 81 (6.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 76 (2.63%)
    1 / 79 (1.27%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 76 (1.32%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    2 / 79 (2.53%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Febrile nonhaemolytic transfusion reaction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative stitch sinus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    2 / 79 (2.53%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tricuspid valve incompetence
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    6 / 76 (7.89%)
    1 / 79 (1.27%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 7
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    3 / 81 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 76 (3.95%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 76 (2.63%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bandaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Heparin-induced thrombocytopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic vein occlusion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 76 (2.63%)
    2 / 79 (2.53%)
    4 / 81 (4.94%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    3 / 81 (3.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    1 / 79 (1.27%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    1 / 79 (1.27%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids thrombosed
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic cyst rupture
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute hepatic failure
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 76 (2.63%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 76 (3.95%)
    3 / 79 (3.80%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 76 (2.63%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 76 (1.32%)
    2 / 79 (2.53%)
    7 / 81 (8.64%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    2 / 79 (2.53%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SIM (Part A) SIM 200 mg (Part B) SIM 700 mg (Part B) Placebo (Part B)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    71 / 76 (93.42%)
    72 / 79 (91.14%)
    77 / 81 (95.06%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 10 (0.00%)
    7 / 76 (9.21%)
    2 / 79 (2.53%)
    7 / 81 (8.64%)
         occurrences all number
    0
    7
    3
    7
    Deep vein thrombosis
         subjects affected / exposed
    0 / 10 (0.00%)
    5 / 76 (6.58%)
    1 / 79 (1.27%)
    6 / 81 (7.41%)
         occurrences all number
    0
    5
    1
    6
    Hot flush
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 76 (5.26%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    0
    4
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 10 (50.00%)
    35 / 76 (46.05%)
    33 / 79 (41.77%)
    38 / 81 (46.91%)
         occurrences all number
    7
    41
    39
    43
    Oedema peripheral
         subjects affected / exposed
    1 / 10 (10.00%)
    20 / 76 (26.32%)
    18 / 79 (22.78%)
    22 / 81 (27.16%)
         occurrences all number
    1
    26
    25
    24
    Pyrexia
         subjects affected / exposed
    5 / 10 (50.00%)
    13 / 76 (17.11%)
    21 / 79 (26.58%)
    12 / 81 (14.81%)
         occurrences all number
    9
    23
    35
    19
    Asthenia
         subjects affected / exposed
    2 / 10 (20.00%)
    10 / 76 (13.16%)
    5 / 79 (6.33%)
    5 / 81 (6.17%)
         occurrences all number
    2
    10
    17
    10
    Chills
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 76 (5.26%)
    6 / 79 (7.59%)
    7 / 81 (8.64%)
         occurrences all number
    0
    4
    7
    10
    Malaise
         subjects affected / exposed
    3 / 10 (30.00%)
    3 / 76 (3.95%)
    2 / 79 (2.53%)
    2 / 81 (2.47%)
         occurrences all number
    3
    3
    2
    2
    Peripheral swelling
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 76 (2.63%)
    6 / 79 (7.59%)
    1 / 81 (1.23%)
         occurrences all number
    2
    2
    7
    1
    Influenza like illness
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    6 / 79 (7.59%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    7
    1
    Pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 76 (1.32%)
    1 / 79 (1.27%)
    3 / 81 (3.70%)
         occurrences all number
    2
    1
    1
    4
    Thrombosis in device
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Reproductive system and breast disorders
    Scrotal swelling
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 10 (30.00%)
    15 / 76 (19.74%)
    9 / 79 (11.39%)
    15 / 81 (18.52%)
         occurrences all number
    5
    16
    12
    17
    Pleural effusion
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 76 (1.32%)
    2 / 79 (2.53%)
    5 / 81 (6.17%)
         occurrences all number
    1
    1
    2
    5
    Cough
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 76 (5.26%)
    6 / 79 (7.59%)
    8 / 81 (9.88%)
         occurrences all number
    0
    4
    6
    9
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 10 (10.00%)
    8 / 76 (10.53%)
    6 / 79 (7.59%)
    6 / 81 (7.41%)
         occurrences all number
    1
    8
    6
    6
    Anxiety
         subjects affected / exposed
    1 / 10 (10.00%)
    5 / 76 (6.58%)
    6 / 79 (7.59%)
    5 / 81 (6.17%)
         occurrences all number
    1
    5
    6
    5
    Depression
         subjects affected / exposed
    0 / 10 (0.00%)
    5 / 76 (6.58%)
    4 / 79 (5.06%)
    6 / 81 (7.41%)
         occurrences all number
    0
    5
    4
    6
    Agitation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    14 / 76 (18.42%)
    9 / 79 (11.39%)
    14 / 81 (17.28%)
         occurrences all number
    2
    27
    24
    36
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    16 / 76 (21.05%)
    12 / 79 (15.19%)
    8 / 81 (9.88%)
         occurrences all number
    1
    23
    15
    13
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    15 / 76 (19.74%)
    11 / 79 (13.92%)
    9 / 81 (11.11%)
         occurrences all number
    1
    19
    13
    15
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    10 / 76 (13.16%)
    10 / 79 (12.66%)
    7 / 81 (8.64%)
         occurrences all number
    1
    11
    14
    8
    Weight decreased
         subjects affected / exposed
    4 / 10 (40.00%)
    5 / 76 (6.58%)
    7 / 79 (8.86%)
    5 / 81 (6.17%)
         occurrences all number
    4
    6
    7
    5
    Neutrophil count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    8 / 76 (10.53%)
    5 / 79 (6.33%)
    4 / 81 (4.94%)
         occurrences all number
    0
    11
    6
    6
    Blood bilirubin increased
         subjects affected / exposed
    1 / 10 (10.00%)
    5 / 76 (6.58%)
    4 / 79 (5.06%)
    4 / 81 (4.94%)
         occurrences all number
    1
    6
    6
    4
    White blood cell count decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    5 / 76 (6.58%)
    3 / 79 (3.80%)
    3 / 81 (3.70%)
         occurrences all number
    1
    13
    3
    6
    Blood creatinine increased
         subjects affected / exposed
    0 / 10 (0.00%)
    8 / 76 (10.53%)
    2 / 79 (2.53%)
    1 / 81 (1.23%)
         occurrences all number
    0
    9
    2
    1
    Blood urine present
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 76 (5.26%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 10 (0.00%)
    8 / 76 (10.53%)
    6 / 79 (7.59%)
    5 / 81 (6.17%)
         occurrences all number
    0
    8
    7
    5
    Dysgeusia
         subjects affected / exposed
    1 / 10 (10.00%)
    5 / 76 (6.58%)
    6 / 79 (7.59%)
    6 / 81 (7.41%)
         occurrences all number
    1
    5
    7
    6
    Dizziness
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 76 (5.26%)
    6 / 79 (7.59%)
    7 / 81 (8.64%)
         occurrences all number
    0
    6
    6
    7
    Hypoaesthesia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 76 (1.32%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 10 (60.00%)
    25 / 76 (32.89%)
    28 / 79 (35.44%)
    30 / 81 (37.04%)
         occurrences all number
    6
    43
    37
    50
    Thrombocytopenia
         subjects affected / exposed
    4 / 10 (40.00%)
    29 / 76 (38.16%)
    22 / 79 (27.85%)
    27 / 81 (33.33%)
         occurrences all number
    11
    73
    43
    48
    Neutropenia
         subjects affected / exposed
    3 / 10 (30.00%)
    18 / 76 (23.68%)
    27 / 79 (34.18%)
    22 / 81 (27.16%)
         occurrences all number
    4
    52
    62
    59
    Leukopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    7 / 76 (9.21%)
    11 / 79 (13.92%)
    12 / 81 (14.81%)
         occurrences all number
    0
    12
    21
    29
    Leukocytosis
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 76 (2.63%)
    6 / 79 (7.59%)
    3 / 81 (3.70%)
         occurrences all number
    0
    2
    7
    3
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 76 (0.00%)
    4 / 79 (5.06%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    4
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    6 / 10 (60.00%)
    31 / 76 (40.79%)
    33 / 79 (41.77%)
    31 / 81 (38.27%)
         occurrences all number
    10
    39
    63
    49
    Vomiting
         subjects affected / exposed
    4 / 10 (40.00%)
    17 / 76 (22.37%)
    14 / 79 (17.72%)
    17 / 81 (20.99%)
         occurrences all number
    5
    28
    20
    23
    Constipation
         subjects affected / exposed
    3 / 10 (30.00%)
    18 / 76 (23.68%)
    8 / 79 (10.13%)
    22 / 81 (27.16%)
         occurrences all number
    3
    23
    9
    22
    Diarrhoea
         subjects affected / exposed
    3 / 10 (30.00%)
    13 / 76 (17.11%)
    15 / 79 (18.99%)
    17 / 81 (20.99%)
         occurrences all number
    3
    14
    17
    20
    Abdominal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    17 / 76 (22.37%)
    11 / 79 (13.92%)
    13 / 81 (16.05%)
         occurrences all number
    3
    19
    11
    16
    Ascites
         subjects affected / exposed
    1 / 10 (10.00%)
    6 / 76 (7.89%)
    6 / 79 (7.59%)
    6 / 81 (7.41%)
         occurrences all number
    1
    6
    7
    6
    Dyspepsia
         subjects affected / exposed
    2 / 10 (20.00%)
    6 / 76 (7.89%)
    8 / 79 (10.13%)
    3 / 81 (3.70%)
         occurrences all number
    6
    6
    8
    5
    Abdominal pain upper
         subjects affected / exposed
    0 / 10 (0.00%)
    5 / 76 (6.58%)
    4 / 79 (5.06%)
    9 / 81 (11.11%)
         occurrences all number
    0
    6
    4
    9
    Abdominal distension
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 76 (5.26%)
    1 / 79 (1.27%)
    5 / 81 (6.17%)
         occurrences all number
    2
    4
    1
    6
    Dry mouth
         subjects affected / exposed
    1 / 10 (10.00%)
    4 / 76 (5.26%)
    1 / 79 (1.27%)
    3 / 81 (3.70%)
         occurrences all number
    1
    4
    1
    3
    Flatulence
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 76 (2.63%)
    4 / 79 (5.06%)
    3 / 81 (3.70%)
         occurrences all number
    0
    2
    5
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 10 (0.00%)
    5 / 76 (6.58%)
    0 / 79 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    0
    5
    0
    2
    Retching
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    1
    1
    0
    1
    Haematochezia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 10 (10.00%)
    7 / 76 (9.21%)
    3 / 79 (3.80%)
    7 / 81 (8.64%)
         occurrences all number
    1
    8
    3
    9
    Pruritus
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 76 (2.63%)
    2 / 79 (2.53%)
    5 / 81 (6.17%)
         occurrences all number
    1
    2
    2
    5
    Alopecia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 76 (1.32%)
    4 / 79 (5.06%)
    2 / 81 (2.47%)
         occurrences all number
    0
    1
    4
    2
    Ecchymosis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 76 (1.32%)
    1 / 79 (1.27%)
    1 / 81 (1.23%)
         occurrences all number
    1
    1
    1
    1
    Skin haemorrhage
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 76 (3.95%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    1
    3
    0
    1
    Polyuria
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 10 (10.00%)
    5 / 76 (6.58%)
    6 / 79 (7.59%)
    7 / 81 (8.64%)
         occurrences all number
    1
    6
    6
    8
    Back pain
         subjects affected / exposed
    0 / 10 (0.00%)
    5 / 76 (6.58%)
    5 / 79 (6.33%)
    6 / 81 (7.41%)
         occurrences all number
    0
    5
    5
    8
    Muscular weakness
         subjects affected / exposed
    1 / 10 (10.00%)
    4 / 76 (5.26%)
    2 / 79 (2.53%)
    5 / 81 (6.17%)
         occurrences all number
    1
    5
    2
    5
    Musculoskeletal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    6 / 76 (7.89%)
    0 / 79 (0.00%)
    3 / 81 (3.70%)
         occurrences all number
    1
    6
    0
    3
    Arthralgia
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 76 (2.63%)
    1 / 79 (1.27%)
    2 / 81 (2.47%)
         occurrences all number
    1
    2
    1
    2
    Joint swelling
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 76 (1.32%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 76 (3.95%)
    5 / 79 (6.33%)
    8 / 81 (9.88%)
         occurrences all number
    1
    3
    6
    8
    Influenza
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    1
    1
    0
    3
    Cystitis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Localised infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 10 (30.00%)
    28 / 76 (36.84%)
    16 / 79 (20.25%)
    18 / 81 (22.22%)
         occurrences all number
    3
    31
    17
    21
    Hypokalaemia
         subjects affected / exposed
    3 / 10 (30.00%)
    5 / 76 (6.58%)
    3 / 79 (3.80%)
    12 / 81 (14.81%)
         occurrences all number
    4
    12
    5
    16
    Dehydration
         subjects affected / exposed
    2 / 10 (20.00%)
    7 / 76 (9.21%)
    6 / 79 (7.59%)
    7 / 81 (8.64%)
         occurrences all number
    2
    8
    7
    9
    Hyperglycaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    8 / 76 (10.53%)
    4 / 79 (5.06%)
    4 / 81 (4.94%)
         occurrences all number
    1
    9
    4
    4
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    6 / 76 (7.89%)
    7 / 79 (8.86%)
    4 / 81 (4.94%)
         occurrences all number
    0
    6
    8
    5
    Hyponatraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 76 (2.63%)
    2 / 79 (2.53%)
    5 / 81 (6.17%)
         occurrences all number
    0
    3
    2
    6
    Hypoglycaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 76 (2.63%)
    2 / 79 (2.53%)
    3 / 81 (3.70%)
         occurrences all number
    1
    2
    2
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Nov 2011
    ● Clarify monthly follow-up assessment was to be performed to determine overall survival ● Define safety and tumor response could be followed every 8 weeks if study medication was discontinued but the subject continued on study
    13 Mar 2012
    ● Exclusion criteria were added for subjects with planned combination treatment with erlotinib and gemcitabine and for subjects with uncontrolled hypertension at screening ● Urinalysis was performed at screening and at the beginning of each cycle
    10 Sep 2012
    ● Added inclusion of systemic biomarker sample analysis
    12 Mar 2013
    ● Removal of the interim analysis ● Clarification to the contraception section
    07 Mar 2014
    ● Added text regarding treatment of subjects randomized to either 200 mg simtuzumab or 700 mg simtuzumab in Part B who continue on study after the determination of trial closure has been made by Gilead.

    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.
    There were no limitations affecting the analysis or results.
    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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