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    Clinical Trial Results:
    A 3-Arm Phase 2 Double-Blind Randomized Study of Gemcitabine, Abraxane® plus Placebo versus Gemcitabine, Abraxane® plus 1 or 2 Truncated Courses of Demcizumab in Subjects with 1st-Line Metastatic Pancreatic Ductal Adenocarcinoma

    Summary
    EudraCT number
    		 2014-003355-56
    Trial protocol
    		 ES   GB   BE  
    Global end of trial date
    08 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Dec 2017
    First version publication date
    07 Dec 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    M18-006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    OncoMed Pharmaceuticals, Inc
    Sponsor organisation address
    800 Chesapeake Drive, Redwood City, CA, United States, 94063
    Public contact
    Robert Stagg, VP, Clinical Research, OncoMed Pharmaceuticals, Inc., +1 925 3239548, Robert.stagg@oncomed.com
    Scientific contact
    Robert Stagg, VP, Clinical Research, OncoMed Pharmaceuticals, Inc., +1 925 3239548, Robert.stagg@oncomed.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
    19 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    08 May 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the efficacy of placebo/placebo arm to the pooled demcizumab arm (i.e., placebo/placebo arm to demcizumab/placebo and demcizumab/demcizumab arms) in subjects with first-line metastatic pancreatic ductal adenocarcinoma.
    Protection of trial subjects
    Subjects experiencing a Grade 2 infusion reaction of dyspnea (asymptomatic bronchospasm) or generalized urticaria should be premedicated prior to subsequent infusions.Premedications may include medications such as corticosteroids, diphenhydramine, and/or bronchodialators as indicated. If an infusion reaction occurred, administration was stopped and appropriate medical care was administered. Once the infusion reaction was resolved, and at investigator discretion, the infusion was resumed at one-half of the initial rate of infusion. All subsequent infusions for that subject were then administered at the reduced rate of infusion.
    Background therapy
    		 Subjects who received adjuvant hormonal therapy, such as tamoxifen for a history of breast cancer, continued to receive this treatment. A deep venous thrombosis prophylaxis during a hospitalization according to institutional standards was permitted.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Dec 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 56
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    United States: 50
    Country: Number of subjects enrolled
    Spain: 71
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Belgium: 6
    Worldwide total number of subjects
    204
    EEA total number of subjects
    86
    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)
    100
    From 65 to 84 years
    103
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects aged ≥21 years with cytologically or histologically confirmed metastatic pancreatic ductal adenocarcinoma were included. Prior chemotherapy and/or radiotherapy either in the adjuvant or neoadjuvant setting or for metastatic disease was not allowed.

    Pre-assignment
    Screening details
    		 Prior to randomization, subjects underwent screening to determine study eligibility. Screening assessments were to include CT scans of the chest, abdomen, and pelvis, as well as MRI of the brain. CT scan of the neck or bone scan was performed if clinically indicated.

    Period 1
    Period 1 title
    Treatment Period 1 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject
    Blinding implementation details
    This was a Phase 2, randomized, double-blind controlled study. Placebo was a clear to slightly opalescent, colorless to slightly yellow liquid formulation of 50 mM histidine, 100 mM sodium chloride, 45 mM sucrose, and 0.01% (v/v) polysorbate-20, pH 6.0.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo/placebo arm
    Arm description
    		 Abraxane and gemcitabine plus placebo (3 cycles), Abraxane and gemcitabine (3 cycles), Abraxane and gemcitabine plus placebo (3 cycles), and then Abraxane and gemcitabine until disease progression.
    Arm type
    		 Placebo

    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 was a clear to slightly opalescent, colorless to slightly yellow liquid formulation of 50 mM histidine, 100 mM sodium chloride, 45 mM sucrose, and 0.01% (v/v) polysorbate-20, pH 6.0.

    Arm title
    		 Demcizumab/placebo
    Arm description
    		 Abraxane and gemcitabine plus demcizumab (3 cycles), Abraxane and gemcitabine (3 cycles), Abraxane and gemcitabine plus placebo (3 cycles), and then Abraxane and gemcitabine until disease progression.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Demcizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Demcizumab 3.5 mg/kg (or placebo) was administered once every 2 weeks for 6 doses (i.e., the last dose was given on Day 70). A second course of demcizumab 3.5 mg/kg or placebo was administered once every 2 weeks for 6 doses starting at Day 168 if the subject’s Day 168 BNP was ≤100 pg/mL, peak tricuspid velocity was ≤3.0 m/s, and LVEF was ≥50%, and the subject had not developed pulmonary hypertension or heart failure while on study. No dose reductions were allowed for required modifications of demcizumab/placebo dosing. Demcizumab was supplied at a concentration of 10 mg/mL in a 25-mL single-use glass vial filled to 20 mL to deliver a total of 200 mg per vial.

    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 was a clear to slightly opalescent, colorless to slightly yellow liquid formulation of 50 mM histidine, 100 mM sodium chloride, 45 mM sucrose, and 0.01% (v/v) polysorbate-20, pH 6.0.

    Arm title
    		 Demcizumab/demcizumab
    Arm description
    		 Abraxane and gemcitabine plus demcizumab (3 cycles), Abraxane and gemcitabine (3 cycles), Abraxane and gemcitabine plus demcizumab (3 cycles), and then Abraxane and gemcitabine until disease progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Demcizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Demcizumab 3.5 mg/kg (or placebo) was administered once every 2 weeks for 6 doses (i.e., the last dose was given on Day 70). A second course of demcizumab 3.5 mg/kg or placebo was administered once every 2 weeks for 6 doses starting at Day 168 if the subject’s Day 168 BNP was ≤100 pg/mL, peak tricuspid velocity was ≤3.0 m/s, and LVEF was ≥50%, and the subject had not developed pulmonary hypertension or heart failure while on study. No dose reductions were allowed for required modifications of demcizumab/placebo dosing. Demcizumab was supplied at a concentration of 10 mg/mL in a 25-mL single-use glass vial filled to 20 mL to deliver a total of 200 mg per vial.

    Number of subjects in period 1
    		Placebo/placebo arm Demcizumab/placebo Demcizumab/demcizumab
    Started
    68
    71
    65
    Completed
    16
    18
    9
    Not completed
    52
    53
    56
         Use of other anticancer therapy
    -
    -
    1
         Physician decision
    2
    5
    2
         Consent withdrawn by subject
    -
    4
    1
         Disease progression
    34
    28
    34
         Adverse event, non-fatal
    3
    5
    5
         Death
    5
    4
    3
         Other
    8
    7
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo/placebo arm
    Reporting group description
    		 Abraxane and gemcitabine plus placebo (3 cycles), Abraxane and gemcitabine (3 cycles), Abraxane and gemcitabine plus placebo (3 cycles), and then Abraxane and gemcitabine until disease progression.

    Reporting group title
    Demcizumab/placebo
    Reporting group description
    		 Abraxane and gemcitabine plus demcizumab (3 cycles), Abraxane and gemcitabine (3 cycles), Abraxane and gemcitabine plus placebo (3 cycles), and then Abraxane and gemcitabine until disease progression.

    Reporting group title
    Demcizumab/demcizumab
    Reporting group description
    		 Abraxane and gemcitabine plus demcizumab (3 cycles), Abraxane and gemcitabine (3 cycles), Abraxane and gemcitabine plus demcizumab (3 cycles), and then Abraxane and gemcitabine until disease progression.

    Reporting group values
    		 Placebo/placebo arm Demcizumab/placebo Demcizumab/demcizumab Total
    Number of subjects
    		 68 71 65 204
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 37 34 30 101
        From 65-84 years
    		 31 36 35 102
        85 years and over
    		 0 1 0 1
    Gender categorical
    Units: Subjects
        Female
    		 27 31 30 88
        Male
    		 41 40 35 116
    Subject analysis sets

    Subject analysis set title
    ITT analysis set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population comprised all subjects who received at least 1 partial or complete dose of demcizumab or placebo. All baseline characteristics and demographic, efficacy, immunogenicity, and biomarker data were analyzed using the ITT population.

    Subject analysis sets values
    		 ITT analysis set
    Number of subjects
    204
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units:
        
    ( )
    Gender categorical
    Units: Subjects
        Female
    88
        Male
    116

    End points

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    End points reporting groups
    Reporting group title
    Placebo/placebo arm
    Reporting group description
    		 Abraxane and gemcitabine plus placebo (3 cycles), Abraxane and gemcitabine (3 cycles), Abraxane and gemcitabine plus placebo (3 cycles), and then Abraxane and gemcitabine until disease progression.

    Reporting group title
    Demcizumab/placebo
    Reporting group description
    		 Abraxane and gemcitabine plus demcizumab (3 cycles), Abraxane and gemcitabine (3 cycles), Abraxane and gemcitabine plus placebo (3 cycles), and then Abraxane and gemcitabine until disease progression.

    Reporting group title
    Demcizumab/demcizumab
    Reporting group description
    		 Abraxane and gemcitabine plus demcizumab (3 cycles), Abraxane and gemcitabine (3 cycles), Abraxane and gemcitabine plus demcizumab (3 cycles), and then Abraxane and gemcitabine until disease progression.

    Subject analysis set title
    ITT analysis set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population comprised all subjects who received at least 1 partial or complete dose of demcizumab or placebo. All baseline characteristics and demographic, efficacy, immunogenicity, and biomarker data were analyzed using the ITT population.

    Primary: To compare the hazard of progression in the placebo/placebo arm and the pooled demcizumab arm

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    End point title
    		 To compare the hazard of progression in the placebo/placebo arm and the pooled demcizumab arm
    End point description
    The primary endpoint is to compare the hazard of progression using the investigator-assessed progression-free survival (PFS) time between subjects in the placebo/placebo arm and the pooled demcizumab arm (i.e., demcizumab/placebo arm + demcizumab/demcizumab arm) in first-line metastatic pancreatic ductal adenocarcinoma.
    End point type
    Primary
    End point timeframe
    Investigator-assessed progression-free survival (PFS) time.
    End point values
    		 Placebo/placebo arm Demcizumab/placebo Demcizumab/demcizumab
    Number of subjects analysed
    68
    71
    65
    Units: progression-free survival (PFS) time
        number (not applicable)
    68
    71
    65
    Statistical analysis title
    		 Statistical analysis plan dated 08 March 2017
    Statistical analysis description
    Efficacy was compared of placebo/placebo arm to the pooled demcizumab arm (i.e., placebo/placebo arm to demcizumab/placebo and demcizumab/demcizumab arms) in subjects with first-line metastatic pancreatic ductal adenocarcinoma.
    Comparison groups
    Demcizumab/placebo v Demcizumab/demcizumab v Placebo/placebo arm
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.7158
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hazard ratio (HR)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.81
         upper limit
    		 7.36
    Variability estimate
    Standard deviation
    Notes
    [1] - Gemcitabine was administered by intravenous (IV) infusion at a dose of 1000 mg/m2 on Days 1, 8, and 15 of each 28-day treatment cycle. Abraxane was administered by IV infusion at a dose of 125 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day treatment cycle. Demcizumab 3.5 mg/kg or placebo was administered by IV infusion (prior to the administration of Abraxane and gemcitabine) once every 2 weeks for either 1 or 2 70-day courses.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Investigators were required to follow their respective IRB or IEC requirements for the reporting of serious adverse events (SAEs)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo/placebo
    Reporting group description
    		 -

    Reporting group title
    Demcizumab/placebo
    Reporting group description
    		 -

    Reporting group title
    Demcizumab/Demcizumab
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo/placebo Demcizumab/placebo Demcizumab/Demcizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    40 / 68 (58.82%)
    49 / 71 (69.01%)
    34 / 65 (52.31%)
         number of deaths (all causes)
    5
    12
    3
         number of deaths resulting from adverse events
    5
    12
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic neoplasm
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Tumour rupture
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 68 (8.82%)
    3 / 71 (4.23%)
    6 / 65 (9.23%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 68 (2.94%)
    2 / 71 (2.82%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 71 (2.82%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Orthopnoea
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaesthetic complication
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 71 (2.82%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 71 (2.82%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peroneal nerve palsy
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    4 / 68 (5.88%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Anaemia
         subjects affected / exposed
    3 / 68 (4.41%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 71 (1.41%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 71 (2.82%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemolytic uraemic syndrome
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Papilloedema
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    5 / 68 (7.35%)
    4 / 71 (5.63%)
    5 / 65 (7.69%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 68 (1.47%)
    4 / 71 (5.63%)
    3 / 65 (4.62%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    4 / 68 (5.88%)
    0 / 71 (0.00%)
    3 / 65 (4.62%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 68 (5.88%)
    1 / 71 (1.41%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 71 (2.82%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    Ascites
         subjects affected / exposed
    1 / 68 (1.47%)
    2 / 71 (2.82%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 71 (2.82%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 71 (2.82%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colonic fistula
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal stenosis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic duct obstruction
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic insufficiency
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice cholestatic
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 71 (1.41%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic haematoma
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    3 / 65 (4.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertebral lesion
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    3 / 68 (4.41%)
    4 / 71 (5.63%)
    4 / 65 (6.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Liver abscess
         subjects affected / exposed
    2 / 68 (2.94%)
    2 / 71 (2.82%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 71 (1.41%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 68 (1.47%)
    2 / 71 (2.82%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 71 (2.82%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic infection
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tick-borne fever
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 71 (1.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 68 (2.94%)
    3 / 71 (4.23%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Food intolerance
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 71 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 71 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo/placebo Demcizumab/placebo Demcizumab/Demcizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    68 / 68 (100.00%)
    71 / 71 (100.00%)
    65 / 65 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    10 / 68 (14.71%)
    17 / 71 (23.94%)
    21 / 65 (32.31%)
         occurrences all number
    10
    17
    21
    Hypotension
         subjects affected / exposed
    11 / 68 (16.18%)
    6 / 71 (8.45%)
    5 / 65 (7.69%)
         occurrences all number
    11
    6
    5
    Deep vein thrombosis
         subjects affected / exposed
    7 / 68 (10.29%)
    4 / 71 (5.63%)
    9 / 65 (13.85%)
         occurrences all number
    7
    4
    9
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    34 / 68 (50.00%)
    31 / 71 (43.66%)
    37 / 65 (56.92%)
         occurrences all number
    34
    31
    37
    Oedema peripheral
         subjects affected / exposed
    29 / 68 (42.65%)
    39 / 71 (54.93%)
    34 / 65 (52.31%)
         occurrences all number
    29
    39
    34
    Pyrexia
         subjects affected / exposed
    24 / 68 (35.29%)
    30 / 71 (42.25%)
    23 / 65 (35.38%)
         occurrences all number
    24
    30
    23
    Asthenia
         subjects affected / exposed
    18 / 68 (26.47%)
    27 / 71 (38.03%)
    20 / 65 (30.77%)
         occurrences all number
    18
    27
    20
    Chills
         subjects affected / exposed
    6 / 68 (8.82%)
    3 / 71 (4.23%)
    8 / 65 (12.31%)
         occurrences all number
    6
    3
    8
    Headache
         subjects affected / exposed
    12 / 68 (17.65%)
    13 / 71 (18.31%)
    22 / 65 (33.85%)
         occurrences all number
    12
    13
    22
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    18 / 68 (26.47%)
    16 / 71 (22.54%)
    10 / 65 (15.38%)
         occurrences all number
    18
    16
    10
    Epistaxis
         subjects affected / exposed
    10 / 68 (14.71%)
    13 / 71 (18.31%)
    17 / 65 (26.15%)
         occurrences all number
    10
    13
    17
    Cough
         subjects affected / exposed
    10 / 68 (14.71%)
    12 / 71 (16.90%)
    11 / 65 (16.92%)
         occurrences all number
    10
    12
    11
    Dyspnoea exertional
         subjects affected / exposed
    3 / 68 (4.41%)
    4 / 71 (5.63%)
    8 / 65 (12.31%)
         occurrences all number
    3
    4
    8
    Pulmonary hypertension
         subjects affected / exposed
    1 / 68 (1.47%)
    7 / 71 (9.86%)
    7 / 65 (10.77%)
         occurrences all number
    1
    7
    7
    Rhinorrhoea
         subjects affected / exposed
    5 / 68 (7.35%)
    2 / 71 (2.82%)
    5 / 65 (7.69%)
         occurrences all number
    5
    2
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    9 / 68 (13.24%)
    8 / 71 (11.27%)
    9 / 65 (13.85%)
         occurrences all number
    9
    8
    9
    Anxiety
         subjects affected / exposed
    10 / 68 (14.71%)
    5 / 71 (7.04%)
    3 / 65 (4.62%)
         occurrences all number
    10
    5
    3
    Depression
         subjects affected / exposed
    6 / 68 (8.82%)
    3 / 71 (4.23%)
    7 / 65 (10.77%)
         occurrences all number
    6
    3
    7
    Investigations
    Platelet count decreased
         subjects affected / exposed
    16 / 68 (23.53%)
    20 / 71 (28.17%)
    13 / 65 (20.00%)
         occurrences all number
    16
    20
    13
    Alanine aminotransferase increased
         subjects affected / exposed
    16 / 68 (23.53%)
    15 / 71 (21.13%)
    15 / 65 (23.08%)
         occurrences all number
    16
    15
    15
    Neutrophil count decreased
         subjects affected / exposed
    16 / 68 (23.53%)
    12 / 71 (16.90%)
    12 / 65 (18.46%)
         occurrences all number
    16
    12
    12
    Aspartate aminotransferase increased
         subjects affected / exposed
    13 / 68 (19.12%)
    5 / 71 (7.04%)
    12 / 65 (18.46%)
         occurrences all number
    13
    5
    12
    Brain natriuretic peptide increased
         subjects affected / exposed
    5 / 68 (7.35%)
    11 / 71 (15.49%)
    14 / 65 (21.54%)
         occurrences all number
    5
    11
    14
    White blood cell count decreased
         subjects affected / exposed
    9 / 68 (13.24%)
    4 / 71 (5.63%)
    10 / 65 (15.38%)
         occurrences all number
    9
    4
    10
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 68 (7.35%)
    6 / 71 (8.45%)
    10 / 65 (15.38%)
         occurrences all number
    5
    6
    10
    Weight decreased
         subjects affected / exposed
    8 / 68 (11.76%)
    5 / 71 (7.04%)
    8 / 65 (12.31%)
         occurrences all number
    8
    5
    8
    Blood bilirubin increased
         subjects affected / exposed
    6 / 68 (8.82%)
    3 / 71 (4.23%)
    3 / 65 (4.62%)
         occurrences all number
    6
    3
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    5 / 68 (7.35%)
    2 / 71 (2.82%)
    5 / 65 (7.69%)
         occurrences all number
    5
    2
    5
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    18 / 68 (26.47%)
    16 / 71 (22.54%)
    17 / 65 (26.15%)
         occurrences all number
    18
    16
    17
    Peripheral sensory neuropathy
         subjects affected / exposed
    16 / 68 (23.53%)
    17 / 71 (23.94%)
    17 / 65 (26.15%)
         occurrences all number
    16
    17
    17
    Neuropathy peripheral
         subjects affected / exposed
    11 / 68 (16.18%)
    15 / 71 (21.13%)
    12 / 65 (18.46%)
         occurrences all number
    11
    15
    12
    Dizziness
         subjects affected / exposed
    10 / 68 (14.71%)
    5 / 71 (7.04%)
    7 / 65 (10.77%)
         occurrences all number
    10
    5
    7
    Neurotoxicity
         subjects affected / exposed
    2 / 68 (2.94%)
    11 / 71 (15.49%)
    4 / 65 (6.15%)
         occurrences all number
    2
    11
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    27 / 68 (39.71%)
    43 / 71 (60.56%)
    35 / 65 (53.85%)
         occurrences all number
    27
    43
    35
    Thrombocytopenia
         subjects affected / exposed
    15 / 68 (22.06%)
    14 / 71 (19.72%)
    16 / 65 (24.62%)
         occurrences all number
    15
    14
    16
    Neutropenia
         subjects affected / exposed
    21 / 68 (30.88%)
    24 / 71 (33.80%)
    25 / 65 (38.46%)
         occurrences all number
    21
    24
    25
    Eye disorders
    Vision blurred
         subjects affected / exposed
    3 / 68 (4.41%)
    3 / 71 (4.23%)
    5 / 65 (7.69%)
         occurrences all number
    3
    3
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    42 / 68 (61.76%)
    38 / 71 (53.52%)
    41 / 65 (63.08%)
         occurrences all number
    42
    38
    41
    Diarrhoea
         subjects affected / exposed
    34 / 68 (50.00%)
    41 / 71 (57.75%)
    45 / 65 (69.23%)
         occurrences all number
    34
    41
    45
    Vomiting
         subjects affected / exposed
    27 / 68 (39.71%)
    32 / 71 (45.07%)
    25 / 65 (38.46%)
         occurrences all number
    27
    32
    25
    Constipation
         subjects affected / exposed
    20 / 68 (29.41%)
    21 / 71 (29.58%)
    28 / 65 (43.08%)
         occurrences all number
    20
    21
    28
    Abdominal pain
         subjects affected / exposed
    24 / 68 (35.29%)
    16 / 71 (22.54%)
    27 / 65 (41.54%)
         occurrences all number
    24
    16
    27
    Stomatitis
         subjects affected / exposed
    13 / 68 (19.12%)
    12 / 71 (16.90%)
    15 / 65 (23.08%)
         occurrences all number
    13
    12
    15
    Abdominal pain upper
         subjects affected / exposed
    13 / 68 (19.12%)
    6 / 71 (8.45%)
    8 / 65 (12.31%)
         occurrences all number
    13
    6
    8
    Dry mouth
         subjects affected / exposed
    7 / 68 (10.29%)
    9 / 71 (12.68%)
    6 / 65 (9.23%)
         occurrences all number
    7
    9
    6
    Ascites
         subjects affected / exposed
    9 / 68 (13.24%)
    6 / 71 (8.45%)
    3 / 65 (4.62%)
         occurrences all number
    9
    6
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    6 / 68 (8.82%)
    7 / 71 (9.86%)
    5 / 65 (7.69%)
         occurrences all number
    6
    7
    5
    Abdominal distension
         subjects affected / exposed
    5 / 68 (7.35%)
    4 / 71 (5.63%)
    4 / 65 (6.15%)
         occurrences all number
    5
    4
    4
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    30 / 68 (44.12%)
    33 / 71 (46.48%)
    28 / 65 (43.08%)
         occurrences all number
    30
    33
    28
    Rash
         subjects affected / exposed
    18 / 68 (26.47%)
    14 / 71 (19.72%)
    17 / 65 (26.15%)
         occurrences all number
    18
    14
    17
    Dry skin
         subjects affected / exposed
    4 / 68 (5.88%)
    5 / 71 (7.04%)
    5 / 65 (7.69%)
         occurrences all number
    4
    5
    5
    Rash maculo-papular
         subjects affected / exposed
    6 / 68 (8.82%)
    3 / 71 (4.23%)
    5 / 65 (7.69%)
         occurrences all number
    6
    3
    5
    Erythema
         subjects affected / exposed
    3 / 68 (4.41%)
    7 / 71 (9.86%)
    3 / 65 (4.62%)
         occurrences all number
    3
    7
    3
    Hypokalaemia
         subjects affected / exposed
    7 / 68 (10.29%)
    7 / 71 (9.86%)
    6 / 65 (9.23%)
         occurrences all number
    7
    7
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    16 / 68 (23.53%)
    10 / 71 (14.08%)
    13 / 65 (20.00%)
         occurrences all number
    16
    10
    13
    Myalgia
         subjects affected / exposed
    6 / 68 (8.82%)
    10 / 71 (14.08%)
    15 / 65 (23.08%)
         occurrences all number
    6
    10
    15
    Arthralgia
         subjects affected / exposed
    8 / 68 (11.76%)
    9 / 71 (12.68%)
    10 / 65 (15.38%)
         occurrences all number
    8
    9
    10
    Pain in extremity
         subjects affected / exposed
    8 / 68 (11.76%)
    5 / 71 (7.04%)
    7 / 65 (10.77%)
         occurrences all number
    8
    5
    7
    Musculoskeletal pain
         subjects affected / exposed
    3 / 68 (4.41%)
    3 / 71 (4.23%)
    6 / 65 (9.23%)
         occurrences all number
    3
    3
    6
    Muscular weakness
         subjects affected / exposed
    5 / 68 (7.35%)
    2 / 71 (2.82%)
    4 / 65 (6.15%)
         occurrences all number
    5
    2
    4
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    7 / 68 (10.29%)
    5 / 71 (7.04%)
    7 / 65 (10.77%)
         occurrences all number
    7
    5
    7
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 68 (8.82%)
    6 / 71 (8.45%)
    6 / 65 (9.23%)
         occurrences all number
    6
    6
    6
    Oral candidiasis
         subjects affected / exposed
    8 / 68 (11.76%)
    2 / 71 (2.82%)
    4 / 65 (6.15%)
         occurrences all number
    8
    2
    4
    Cellulitis
         subjects affected / exposed
    6 / 68 (8.82%)
    5 / 71 (7.04%)
    1 / 65 (1.54%)
         occurrences all number
    6
    5
    1
    Sepsis
         subjects affected / exposed
    3 / 68 (4.41%)
    5 / 71 (7.04%)
    4 / 65 (6.15%)
         occurrences all number
    3
    5
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    19 / 68 (27.94%)
    30 / 71 (42.25%)
    27 / 65 (41.54%)
         occurrences all number
    19
    30
    27
    Hypoalbuminaemia
         subjects affected / exposed
    8 / 68 (11.76%)
    10 / 71 (14.08%)
    9 / 65 (13.85%)
         occurrences all number
    8
    10
    9
    Dehydration
         subjects affected / exposed
    6 / 68 (8.82%)
    10 / 71 (14.08%)
    6 / 65 (9.23%)
         occurrences all number
    6
    10
    6
    Hyperglycaemia
         subjects affected / exposed
    11 / 68 (16.18%)
    5 / 71 (7.04%)
    4 / 65 (6.15%)
         occurrences all number
    11
    5
    4
    Hyponatraemia
         subjects affected / exposed
    6 / 68 (8.82%)
    4 / 71 (5.63%)
    8 / 65 (12.31%)
         occurrences all number
    6
    4
    8
    Hypophosphataemia
         subjects affected / exposed
    5 / 68 (7.35%)
    5 / 71 (7.04%)
    6 / 65 (9.23%)
         occurrences all number
    5
    5
    6
    Hypocalcaemia
         subjects affected / exposed
    6 / 68 (8.82%)
    7 / 71 (9.86%)
    2 / 65 (3.08%)
         occurrences all number
    6
    7
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Nov 2014
    The following changes were made at the request of the USA Food and Drug Administration: the inclusion criteria for bilirubin was reduced to 1 × ULN, >Grade 2 pulmonary hypertension was added as a treatment termination criteria, a section was added regarding the role of the DSMB and clarifying the data that they would review and the sample informed consent was revised to clarify that subjects received 6 doses of demcizumab or placebo during each of the two 70-day truncated courses of therapy and that subjects might receive less intensive gemcitabine/Abraxane therapy than if they were not on the study due to demcizumab toxicity.
    10 Feb 2015
    The requirement for mandatory FFPE (either from archival tissue or from a fresh core biopsy) was removed and instead FFPE was only to be collected if available, i.e., subjects who did not have archival tissue were not undergo a core biopsy to obtain fresh tumor tissue. In addition, the requirement for subjects who had 2 BNP values > 100 pg/mL or 1 value> 200 pg/mL to be referred to a cardiologist changed to state that such subjects would referred to a cardiologist if appropriate. Definitions were added to the protocol for “women of child-bearing potential” and “adequate contraception”. Additional serum pregnancy tests were added every 56 days while on study, at the termination visit and at 56 and 112 days following the termination visit for women of child-bearing potential.
    28 May 2015
    The primary purpose of this amendment was to make the following modifications to the inclusion/exclusion criteria. Inclusion criterion #1 was modified to allow subjects with a cytologic diagnosis to be eligible. Exclusion criterion #6 was modified to provide a definition of clinically significant ascites. The previous exclusion criterion #7 was removed so that subjects with plastic biliary stents are eligible. The previous exclusion criterion #10 (now exclusion criterion #9) was modified to clarify that subjects with prior chest wall radiotherapy are excluded only if the radiation field involved the heart. The previous exclusion criterion #16 (now exclusion criterion #15) was modified to state that subjects on prophylactic doses of heparin, warfarin, factor Xa inhibitors, or other similar anticoagulates are eligible. In addition, Section 13 of the protocol was modified to clarify that the BNP measurement must be obtained on the Day of the demcizumab dosing and the result reviewed prior to dosing and the sample informed consent was modified to clarify the objectives of the study. In addition, modifications were made to clarify the appropriate radiologic assessments to be obtained.
    31 Mar 2016
    The primary purpose of this amendment was to change the method for analyzing the primary endpoint of PFS. The previous approach for the primary endpoint analysis involved comparing placebo/placebo arm to demcizumab/placebo arm and placebo/placebo arm to demcizumab/demcizumab arm, separately. This approach required that 80% of subject achieve the PFS endpoint (i.e., either progress or died). However, a blinded review of the data to date suggests that only about 69% of the subjects are having a PFS event. Thus, it appears that there may not be an adequate number of events at the end of the study to conduct the PFS analysis initially described in the protocol. Thus, the method for this analysis has been modified to compare the placebo/placebo arm to a pooled dataset of the demcizumab/placebo arm and demcizumab/demcizumab arm, which requires a lower percentage of subjects to achieve a PFS endpoint. In addition, the wording of the study objectives and endpoints were modified to account for this modification. A statement that standard of tests performed prior to the informed consent date may be used for screening purposes if they were done within 28 days of Day 0. Also, wording was added to allow the BNP to be drawn the day prior to dosing at a site if approved by the sponsor.
    19 Dec 2016
    The primary purpose of this amendment was to add 2 additional analyses of overall survival to be conducted on all deaths through 01 June 2017 and 01 November 2017, respectively. In addition, the protocol was modified to state that subjects in long-term follow-up would have their survival status updated every 3 months or sooner at the request of the Sponsor. In addition, changes were made to the Abraxane/gemcitabine dosage modification section to:  - Delete the statement that subjects having their gemcitabine/Abraxane therapy held for 21 days due to drug related toxicity should have their gemcitabine and Abraxane stopped  - To add a statement that subjects who had undergone 2 dose reductions of gemcitabine/Abraxane and still were unable to tolerate that treatment could receive gemcitabine/Abraxane on Days 1 and 15 (i.e., omit Day 8) of each 28-day cycle

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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