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    Clinical Trial Results:
    Phase III Double-blinded, Placebo Controlled Study of Xilonix for Improving Survival in Metastatic Colorectal Cancer

    Summary
    EudraCT number
    		 2012-005287-10
    Trial protocol
    		 HU   PL   BE   CZ   ES   AT   DE   NL   GB   IT  
    Global end of trial date
    09 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Apr 2021
    First version publication date
    09 Apr 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2012-PT023
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01767857
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route 202, Raritan, United States, NJ 08869
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.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
    09 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jun 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to assess the overall survival (OS) which was measured from the date of randomization until death or last follow-up.
    Protection of trial subjects
    The study was performed in accordance with the current version of the declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013). The trial was conducted in compliance with the International Conference on Harmonization (ICH) guidelines on Good Clinical Practice (GCP). The safety data was monitored every 6 months or after every 200 subjects of accrual.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Apr 2015
    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
    Australia: 25
    Country: Number of subjects enrolled
    Austria: 15
    Country: Number of subjects enrolled
    Belgium: 76
    Country: Number of subjects enrolled
    Czechia: 11
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Poland: 48
    Country: Number of subjects enrolled
    Spain: 173
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    United States: 199
    Worldwide total number of subjects
    611
    EEA total number of subjects
    364
    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)
    351
    From 65 to 84 years
    258
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 611 subjects were randomized (modified intent to treat population [mITT] population) and analyzed for efficacy and safety.

    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
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Xilonix
    Arm description
    		 Subjects received 7.5 milligram per kilogram (mg/kg) Xilonix (MABp1) via intravenous (IV) injection once every 2 weeks until evidence of radiographic or clinical progression along with best supportive care (BSC) (up to 18 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Xilonix
    Investigational medicinal product code
    Other name
    MABp1
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Xilonix was administered as IV injection of 7.5 mg/kg once every 2 weeks (one cycle) until evidence of radiographic or clinical progression.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo via IV injection once every 2 weeks until evidence of radiographic or clinical progression plus BSC (up to 18 months).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was administered as IV injection until evidence of radiographic or clinical progression.

    Number of subjects in period 1
    		Xilonix Placebo
    Started
    411
    200
    Completed
    0
    0
    Not completed
    411
    200
         Adverse event, serious fatal
    35
    16
         Consent withdrawn by subject
    38
    18
         Physician decision
    17
    10
         Adverse event, non-fatal
    20
    4
         Lost to follow-up
    1
    1
         Protocol terminated
    1
    -
         Lack of efficacy
    299
    151

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Xilonix
    Reporting group description
    		 Subjects received 7.5 milligram per kilogram (mg/kg) Xilonix (MABp1) via intravenous (IV) injection once every 2 weeks until evidence of radiographic or clinical progression along with best supportive care (BSC) (up to 18 months).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo via IV injection once every 2 weeks until evidence of radiographic or clinical progression plus BSC (up to 18 months).

    Reporting group values
    		 Xilonix Placebo Total
    Number of subjects
    		 411 200 611
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 229 122 351
        From 65 to 84 years
    		 181 77 258
        85 years and over
    		 1 1 2
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.9 ( 10.14 ) 61.1 ( 9.98 ) -
    Title for Gender
    Units: subjects
        Female
    		 159 94 253
        Male
    		 252 106 358

    End points

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    End points reporting groups
    Reporting group title
    Xilonix
    Reporting group description
    		 Subjects received 7.5 milligram per kilogram (mg/kg) Xilonix (MABp1) via intravenous (IV) injection once every 2 weeks until evidence of radiographic or clinical progression along with best supportive care (BSC) (up to 18 months).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo via IV injection once every 2 weeks until evidence of radiographic or clinical progression plus BSC (up to 18 months).

    Primary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    Overall survival time was defined as the duration from the date of randomization until death or last follow-up. OS was summarized by Kaplan-Meier method and compared between the treatment groups using un-adjusted log-rank test. The modified intent-to-treat (mITT) population consisted of subjects who were randomized and received at least one infusion of study drug.
    End point type
    Primary
    End point timeframe
    Up to 18 months
    End point values
    		 Xilonix Placebo
    Number of subjects analysed
    411
    200
    Units: Months
        median (confidence interval 95%)
    5.6 (4.9 to 6.2)
    5.4 (4.6 to 6.2)
    Statistical analysis title
    		 Statistical Analaysis
    Comparison groups
    Xilonix v Placebo
    Number of subjects included in analysis
    611
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.613
    Method
    		 Logrank
    Confidence interval

    Secondary: Change from Baseline in Lean Body Mass (LBM) Measured by Dual-energy X-ray Absorptiometry (DEXA) Scans

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    End point title
    		 Change from Baseline in Lean Body Mass (LBM) Measured by Dual-energy X-ray Absorptiometry (DEXA) Scans
    End point description
    Change from baseline in LBM as measured by Dexa scans was reported. DEXA is an X-ray imaging modality used to determine the mass of one material in the presence of another material, using the knowledge of their unique X-ray attenuation at different energies. The per protocol (PP) population was defined as subjects that had baseline and follow up values for both the DEXA assessment and the European Organization for Research and Treatment of Cancer (EORTC) questionnaire.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 8
    End point values
    		 Xilonix Placebo
    Number of subjects analysed
    202
    94
    Units: kilogram (Kg)
        least squares mean (standard error)
    0.51 ( 0.158 )
    -0.21 ( 0.231 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Xilonix v Placebo
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from Baseline in Symptom Scale and Global Health Status/Quality of Life (QoL) Assessed Through the Cancer-specific European Organization for Research and Treatment of Cancer – Quality of Life Questionnaire (EORTC QLQ-C30)

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    End point title
    		 Change from Baseline in Symptom Scale and Global Health Status/Quality of Life (QoL) Assessed Through the Cancer-specific European Organization for Research and Treatment of Cancer – Quality of Life Questionnaire (EORTC QLQ-C30)
    End point description
    The EORTC QLQ-C30 questionnaire incorporates nine multi-item scales: 5 functional scales (physical, cognitive, role, emotional, and social); 3 symptom scales (pain, fatigue, and appetite loss) and a Global Health Status/QoL scale. Each item, except Global Health Status, is answered on a four-point scale (0-4): 1-not at all, 2-a little, 3-quite a bit, 4-very much. Response to Global Health Status is measured on a 1 to 7 scale. “1” being very poor and “7” being excellent. As planned, the data for symptom scales (pain, fatigue, appetite loss) and a Global Health Status/QoL scale was evaluated and reported. The PP population was defined as subjects that had baseline and follow up values for both the DEXA assessment and the EORTC questionnaire.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 8
    End point values
    		 Xilonix Placebo
    Number of subjects analysed
    202
    94
    Units: Units on a scale
    least squares mean (standard error)
        Global Health Status/Qol
    -6.64 ( 1.392 )
    -8.16 ( 2.041 )
        Pain
    8.50 ( 1.707 )
    10.27 ( 2.503 )
        Fatigue
    7.42 ( 1.516 )
    8.82 ( 2.223 )
        Appetite Loss
    9.34 ( 2.010 )
    11.84 ( 2.947 )
    Statistical analysis title
    		 Statistical Analysis for Global Health Status/Qol
    Comparison groups
    Xilonix v Placebo
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.541
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis for Pain
    Comparison groups
    Xilonix v Placebo
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.56
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis for Fatigue
    Comparison groups
    Xilonix v Placebo
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.603
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis for Appetite Loss
    Comparison groups
    Xilonix v Placebo
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.485
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from Baseline in Platelet Counts

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    End point title
    		 Change from Baseline in Platelet Counts
    End point description
    Change from baseline in platelet counts up to Week 8 was evaluated. The PP population was defined as subjects that had baseline and follow up values for both the DEXA assessment and the EORTC questionnaire.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 8
    End point values
    		 Xilonix Placebo
    Number of subjects analysed
    202
    94
    Units: 1000 cells/cubic millimeter
        least squares mean (standard error)
    5.50 ( 4.721 )
    16.19 ( 7.082 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Xilonix v Placebo
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Percentage of Subjects with Objective Response (OR)

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    End point title
    		 Percentage of Subjects with Objective Response (OR)
    End point description
    The percentage of OR was estimated by dividing the total number of confirmed complete response (CR) and partial response (PR) by the total number of subjects randomized where CR was complete disappearance of all lesions (whether measurable or not, and no new lesions); confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented and PR was decrease in tumor burden greater than or equal to (>=) 50 percent (%) relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. The mITT population consisted of subjects who were randomized and received at least one infusion of study drug.
    End point type
    Secondary
    End point timeframe
    Up to 18 months
    End point values
    		 Xilonix Placebo
    Number of subjects analysed
    411
    200
    Units: Percentage of subjects
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Disease Control

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    End point title
    		 Percentage of Subjects with Disease Control
    End point description
    Percentage of subjects who achieved disease control was estimated by dividing total number of confirmed CRs, PRs and stable disease (SD) by total number of subjects randomized. CR was complete disappearance of all lesions (whether measurable or not, and no new lesions); confirmed by repeat, consecutive assessment no less than (<) 4 weeks from date first documented, PR was decrease in tumor burden >= 50% relative to baseline confirmed by consecutive assessment at least 4 weeks after first documentation. SD defined as not meeting criteria for CR and PR, in absence of Progressive Disease (increase in tumor burden >= 25 % relative to nadir [minimum recorded tumor burden] confirmed by repeat, consecutive assessment no < 4 weeks from date first documented). The subjects with baseline and follow up radiographic assessments were included in this analysis.
    End point type
    Secondary
    End point timeframe
    Up to 18 months
    End point values
    		 Xilonix Placebo
    Number of subjects analysed
    296
    154
    Units: Percentage of Subjects
        number (not applicable)
    25
    27.3
    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
    Adverse event reporting additional description
    Safety analysis included the safety population, defined as enrolled subjects who received at least one dose of study drug.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo via IV injection once every 2 weeks until evidence of radiographic or clinical progression plus best supportive care (BSC) (up to 18 months).

    Reporting group title
    Xilonix
    Reporting group description
    		 Subjects received 7.5 milligram per kilogram (mg/kg) Xilonix (MABp1) via intravenous (IV) injection once every 2 weeks until evidence of radiographic or clinical progression along with best supportive care (BSC) (up to 18 months).

    Serious adverse events
    		 Placebo Xilonix
    Total subjects affected by serious adverse events
         subjects affected / exposed
    84 / 200 (42.00%)
    169 / 411 (41.12%)
         number of deaths (all causes)
    41
    78
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bone Neoplasm
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer Pain
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon Cancer
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal Cancer
         subjects affected / exposed
    5 / 200 (2.50%)
    8 / 411 (1.95%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    Colorectal Cancer Metastatic
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant Neoplasm Progression
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant Pleural Effusion
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to Central Nervous System
         subjects affected / exposed
    4 / 200 (2.00%)
    3 / 411 (0.73%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm Progression
         subjects affected / exposed
    2 / 200 (1.00%)
    3 / 411 (0.73%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic Neoplasm
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory Collapse
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Pain Management
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteral Stent Removal
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse Drug Reaction
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 200 (1.00%)
    3 / 411 (0.73%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chest Pain
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 200 (0.50%)
    3 / 411 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Disease Progression
         subjects affected / exposed
    14 / 200 (7.00%)
    21 / 411 (5.11%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 21
         deaths causally related to treatment / all
    0 / 5
    0 / 7
    Fatigue
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    5 / 200 (2.50%)
    8 / 411 (1.95%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Localised Oedema
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    0 / 200 (0.00%)
    3 / 411 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 200 (0.00%)
    5 / 411 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance Status Decreased
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 200 (0.50%)
    6 / 411 (1.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Distress Syndrome
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Respiratory Failure
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    0 / 200 (0.00%)
    3 / 411 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    9 / 200 (4.50%)
    12 / 411 (2.92%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    2 / 200 (1.00%)
    5 / 411 (1.22%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    0 / 200 (0.00%)
    3 / 411 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed Suicide
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional State
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Bilirubin Increased
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Culture Positive
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Stoma Complication
         subjects affected / exposed
    2 / 200 (1.00%)
    3 / 411 (0.73%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion Related Reaction
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma Site Haemorrhage
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic Vertebral Fracture
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to Various Agents
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Stoma Complication
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urostomy Complication
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial Effusion
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Balance Disorder
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain Oedema
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of Consciousness
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 200 (2.50%)
    3 / 411 (0.73%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    6 / 200 (3.00%)
    9 / 411 (2.19%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal Stenosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 200 (0.00%)
    7 / 411 (1.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric Haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Perforation
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large Intestinal Obstruction
         subjects affected / exposed
    0 / 200 (0.00%)
    3 / 411 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large Intestine Perforation
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant Bowel Obstruction
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 200 (1.50%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal Haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal Varices Haemorrhage
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Stenosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    1 / 200 (0.50%)
    6 / 411 (1.46%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile Duct Obstruction
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile Duct Stenosis
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Failure
         subjects affected / exposed
    3 / 200 (1.50%)
    11 / 411 (2.68%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice Cholestatic
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver Disorder
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 200 (0.50%)
    8 / 411 (1.95%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 200 (0.00%)
    3 / 411 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Incontinence
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in Extremity
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Pain
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal Abscess
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter Site Abscess
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter Site Infection
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney Infection
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 200 (1.00%)
    5 / 411 (1.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Staphylococcal
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 200 (2.00%)
    3 / 411 (0.73%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Infection
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis Septic
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 411 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 411 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to Thrive
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 411 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Xilonix
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    167 / 200 (83.50%)
    324 / 411 (78.83%)
    Investigations
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    6 / 200 (3.00%)
    23 / 411 (5.60%)
         occurrences all number
    6
    29
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    13 / 200 (6.50%)
    20 / 411 (4.87%)
         occurrences all number
    14
    24
    Blood Bilirubin Increased
         subjects affected / exposed
    7 / 200 (3.50%)
    25 / 411 (6.08%)
         occurrences all number
    9
    31
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 200 (7.50%)
    25 / 411 (6.08%)
         occurrences all number
    16
    34
    Cardiac disorders
    Sinus Tachycardia
         subjects affected / exposed
    10 / 200 (5.00%)
    11 / 411 (2.68%)
         occurrences all number
    13
    14
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 200 (6.50%)
    21 / 411 (5.11%)
         occurrences all number
    18
    24
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    20 / 200 (10.00%)
    42 / 411 (10.22%)
         occurrences all number
    26
    62
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    35 / 200 (17.50%)
    63 / 411 (15.33%)
         occurrences all number
    58
    91
    Fatigue
         subjects affected / exposed
    60 / 200 (30.00%)
    109 / 411 (26.52%)
         occurrences all number
    75
    139
    Oedema Peripheral
         subjects affected / exposed
    23 / 200 (11.50%)
    39 / 411 (9.49%)
         occurrences all number
    23
    49
    Pyrexia
         subjects affected / exposed
    27 / 200 (13.50%)
    38 / 411 (9.25%)
         occurrences all number
    39
    47
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    41 / 200 (20.50%)
    78 / 411 (18.98%)
         occurrences all number
    55
    95
    Constipation
         subjects affected / exposed
    31 / 200 (15.50%)
    51 / 411 (12.41%)
         occurrences all number
    34
    63
    Diarrhoea
         subjects affected / exposed
    22 / 200 (11.00%)
    45 / 411 (10.95%)
         occurrences all number
    29
    64
    Nausea
         subjects affected / exposed
    46 / 200 (23.00%)
    79 / 411 (19.22%)
         occurrences all number
    57
    112
    Vomiting
         subjects affected / exposed
    20 / 200 (10.00%)
    46 / 411 (11.19%)
         occurrences all number
    24
    61
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    27 / 200 (13.50%)
    40 / 411 (9.73%)
         occurrences all number
    30
    43
    Dyspnoea
         subjects affected / exposed
    27 / 200 (13.50%)
    49 / 411 (11.92%)
         occurrences all number
    39
    60
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    10 / 200 (5.00%)
    16 / 411 (3.89%)
         occurrences all number
    10
    17
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    11 / 200 (5.50%)
    11 / 411 (2.68%)
         occurrences all number
    15
    11
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    27 / 200 (13.50%)
    44 / 411 (10.71%)
         occurrences all number
    31
    50
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    51 / 200 (25.50%)
    84 / 411 (20.44%)
         occurrences all number
    58
    99

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 May 2014
    This amendment was proposed to the FDA to enable faster patient recruitment by employing a more traditional Phase 3 oncology design.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    10 Jul 2014
    The agency placed the program on a partial clinical hold to discuss changes to the protocol, as well as manufacturing changes.
    15 Sep 2015

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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