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    Clinical Trial Results:
    A Randomized, Double-Blind, Phase 3 Study of the JAK1/2 Inhibitor, Ruxolitinib or Placebo in Combination With Capecitabine in Subjects With Advanced or Metastatic Adenocarcinoma of the Pancreas Who Have Failed or Are Intolerant to First-Line Chemotherapy (The JANUS 1 Study)

    Summary
    EudraCT number
    2014-000293-20
    Trial protocol
    IT   ES   BE   GB   AT  
    Global end of trial date
    22 Dec 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Jan 2018
    First version publication date
    06 Jan 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    INCB 18424-362
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02117479
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Incyte Corporation
    Sponsor organisation address
    1801 Augustine Cut-Off, Wilmington, DE, United States, 19803
    Public contact
    Incyte Corporation, Incyte Corporation Call Centre, +44 (0)330 100 3677, globalmedinfo@incyte.com
    Scientific contact
    Incyte Corporation, Incyte Corporation Call Centre, +44 (0)330 100 3677, globalmedinfo@incyte.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
    20 Apr 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Dec 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Evaluate and compare the overall survival (OS) of subjects with advanced or metastatic adenocarcinoma of the pancreas when treated with ruxolitinib in combination with capecitabine versus capecitabine alone.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    19 Mar 2014
    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
    United States: 136
    Country: Number of subjects enrolled
    Australia: 29
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Taiwan: 20
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 20
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Spain: 33
    Country: Number of subjects enrolled
    United Kingdom: 33
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Italy: 15
    Worldwide total number of subjects
    321
    EEA total number of subjects
    104
    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)
    116
    From 65 to 84 years
    202
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    Participants with advanced or metastatic adenocarcinoma of the pancreas who had failed or were intolerant to first-line chemotherapy were randomized in the study.

    Pre-assignment
    Screening details
    Treatment was started as soon as possible after randomization (within 3 days) and consisted of continuous 21-day cycles. Capecitabine was self-administered for the first 14 days of each cycle, and ruxolitinib/placebo was self-administered for the entire cycle.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ruxolitinib plus capecitabine
    Arm description
    Ruxolitinib 5 mg tablets in combination with Capecitabine 500 mg tablets to be administered by mouth twice daily (BID).
    Arm type
    Experimental

    Investigational medicinal product name
    Ruxolitinib
    Investigational medicinal product code
    Other name
    Jakafi ®,Jakavi ®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg tablets to be administered by mouth twice daily (BID).

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg tablets to be administered by mouth twice daily (BID).

    Arm title
    Placebo plus capecitabine
    Arm description
    5 mg matching placebo tablets in combination with Capecitabine 500 mg tablets to be administered by mouth twice daily (BID).
    Arm type
    Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg tablets to be administered by mouth twice daily (BID).

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg tablets to be administered by mouth twice daily (BID).

    Number of subjects in period 1
    Ruxolitinib plus capecitabine Placebo plus capecitabine
    Started
    161
    160
    Completed
    5
    4
    Not completed
    156
    156
         Subject decision
    8
    9
         Death
    13
    8
         Noncompliance with study treatment
    1
    -
         Physician decision
    7
    2
         Other unspecified
    11
    7
         Disease progression
    104
    108
         Adverse Event
    8
    16
         Study terminated by the sponsor
    4
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ruxolitinib plus capecitabine
    Reporting group description
    Ruxolitinib 5 mg tablets in combination with Capecitabine 500 mg tablets to be administered by mouth twice daily (BID).

    Reporting group title
    Placebo plus capecitabine
    Reporting group description
    5 mg matching placebo tablets in combination with Capecitabine 500 mg tablets to be administered by mouth twice daily (BID).

    Reporting group values
    Ruxolitinib plus capecitabine Placebo plus capecitabine Total
    Number of subjects
    161 160 321
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    54 62 116
        From 65-84 years
    104 98 202
        85 years and over
    3 0 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    67.3 ± 9.35 65.6 ± 9.55 -
    Gender categorical
    Units: Subjects
        Female
    66 64 130
        Male
    95 96 191

    End points

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    End points reporting groups
    Reporting group title
    Ruxolitinib plus capecitabine
    Reporting group description
    Ruxolitinib 5 mg tablets in combination with Capecitabine 500 mg tablets to be administered by mouth twice daily (BID).

    Reporting group title
    Placebo plus capecitabine
    Reporting group description
    5 mg matching placebo tablets in combination with Capecitabine 500 mg tablets to be administered by mouth twice daily (BID).

    Primary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall survival is reported here based on the number of deaths from randomization up to 6-months or to the data cutoff 11FEB2016.
    End point type
    Primary
    End point timeframe
    Randomization until death due to any cause; up to the data cutoff 11FEB2016.
    End point values
    Ruxolitinib plus capecitabine Placebo plus capecitabine
    Number of subjects analysed
    161 [1]
    160 [2]
    Units: Count of Participants
    number (not applicable)
        Observed
    113
    124
        Censored
    48
    36
    Notes
    [1] - The intent-to-treat (ITT) population consisted of all participants randomized to the study.
    [2] - The intent-to-treat (ITT) population consisted of all participants randomized to the study.
    Statistical analysis title
    OS: Control vs Active
    Comparison groups
    Ruxolitinib plus capecitabine v Placebo plus capecitabine
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.969
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.747
         upper limit
    1.256

    Secondary: Progression-free Survival (PFS)

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    End point title
    Progression-free Survival (PFS)
    End point description
    Progressive Disease (PD) is defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as at least a 20% increase in the sum of the Longest Diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started, unequivocal progression of non-target lesions, or the appearance of new lesions. PFS is defined as the time from randomization until the earliest date of disease progression determined by investigator assessment of objective radiographic disease assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause if sooner.
    End point type
    Secondary
    End point timeframe
    Randomization to disease progression, or death due to any cause if sooner; up to 12-months or to the data cutoff 11FEB2016.
    End point values
    Ruxolitinib plus capecitabine Placebo plus capecitabine
    Number of subjects analysed
    161 [3]
    160 [4]
    Units: days
        median (confidence interval 95%)
    43.0 (41.0 to 46.0)
    44.0 (42.0 to 48.0)
    Notes
    [3] - The intent-to-treat (ITT) population consisted of all participants randomized to the study.
    [4] - The intent-to-treat (ITT) population consisted of all participants randomized to the study.
    Statistical analysis title
    PFS: Control vs Active
    Comparison groups
    Ruxolitinib plus capecitabine v Placebo plus capecitabine
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.056
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.827
         upper limit
    1.348

    Secondary: Proportion of Subjects Progression Free Survival (PFS)

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    End point title
    Proportion of Subjects Progression Free Survival (PFS)
    End point description
    Progressive Disease (PD) is defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as at least a 20% increase in the sum of the Longest Diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started, unequivocal progression of non-target lesions, or the appearance of new lesions. PFS is defined as the time from randomization until the earliest date of disease progression determined by investigator assessment of objective radiographic disease assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause if sooner.
    End point type
    Secondary
    End point timeframe
    Randomization to disease progression, or death due to any cause if sooner; up to 12-months or to the data cutoff 11FEB2016.
    End point values
    Ruxolitinib plus capecitabine Placebo plus capecitabine
    Number of subjects analysed
    161 [5]
    160 [6]
    Units: percentage of participants
    median (confidence interval 95%)
        Survival rate at 3 months
    0.189 (0.127 to 0.259)
    0.198 (0.136 to 0.268)
        Survival rate at 6 months
    0.061 (0.025 to 0.122)
    0.057 (0.023 to 0.113)
        Survival rate at 9 months
    0.025 (0.005 to 0.075)
    0.034 (0.010 to 0.085)
        Survival rate at 12 months
    0.025 (0.005 to 0.075)
    99.999 (99.999 to 99.999)
    Notes
    [5] - The intent-to-treat (ITT) population consisted of all participants randomized to the study.
    [6] - ITT population 99.999= PFS not evaluable due to the insufficient number of participants with events
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    Objective Response Rate (ORR)
    End point description
    Objective response rate was determined by radiographic disease assessments per RECIST (v1.1), by investigator assessment and was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) by Response Evaluation Criteria in Solid Tumours (RECIST) at any post baseline visit. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by computed tomography (CT) and/or magnetic resonance imaging (MRI) : Complete Response (CR), Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions with no worsening of non-target lesions; Overall Response (OR) = CR + PR.
    End point type
    Secondary
    End point timeframe
    Baseline through end of study; up to 6-months or to the data cutoff 11FEB2016.
    End point values
    Ruxolitinib plus capecitabine Placebo plus capecitabine
    Number of subjects analysed
    161 [7]
    160 [8]
    Units: percentage of participants
    number (not applicable)
        Objective response
    3.7
    1.9
        Complete response
    0
    0
        Partial response
    3.7
    1.9
    Notes
    [7] - The intent-to-treat (ITT) population consisted of all participants randomized to the study.
    [8] - The intent-to-treat (ITT) population consisted of all participants randomized to the study.
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    Duration of Response (DOR)
    End point description
    Duration of overall response was defined as the time in months from Complete Response (CR) or Partial Response (PR) by Response Evaluation Criteria in Solid Tumours (RECIST v1.1) until the first date Progressive Disease (PD) was objectively documented or until the date of death.
    End point type
    Secondary
    End point timeframe
    Baseline through end of study; up to 6-months or to the data cutoff 11FEB2016.
    End point values
    Ruxolitinib plus capecitabine Placebo plus capecitabine
    Number of subjects analysed
    161 [9]
    160 [10]
    Units: days
        median (confidence interval 95%)
    99.999 (99.999 to 99.999)
    99.999 (99.999 to 99.999)
    Notes
    [9] - ITT population: 99.999=DOR not evaluable due to the insufficient number of participants with event
    [10] - ITT population: 99.999=DOR not evaluable due to the insufficient number of participants with event
    No statistical analyses for this end point

    Secondary: Overall Survival Rate

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    End point title
    Overall Survival Rate
    End point description
    Overall survival rates is reported based on the number of deaths from randomization up to 12-months or to the data cutoff 11FEB2016.
    End point type
    Secondary
    End point timeframe
    Randomization until death due to any cause; up to the data cutoff 11FEB2016.
    End point values
    Ruxolitinib plus capecitabine Placebo plus capecitabine
    Number of subjects analysed
    161 [11]
    160 [12]
    Units: percentage of participants
    median (confidence interval 95%)
        Month 3 survival rate
    0.498 (0.413 to 0.577)
    0.528 (0.443 to 0.605)
        Month 6 survival rate
    0.207 (0.135 to 0.289)
    0.201 (0.134 to 0.278)
        Month 9 survival rate
    0.112 (0.056 to 0.189)
    0.062 (0.025 to 0.122)
        Month 12 survival rate
    0.053 (0.014 to 0.134)
    99.999 (99.999 to 99.999)
    Notes
    [11] - The intent-to-treat (ITT) population consisted of all participants randomized to the study.
    [12] - ITT population 99.999= 12-month survival was not evaluable in the placebo group.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study medication through study termination or to the data cutoff 20APR2016.
    Adverse event reporting additional description
    The safety evaluable population consisted of all participants exposed to at least 1 dose of study drug (ruxolitinib or placebo).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Ruxolitinib Plus Capecitabine
    Reporting group description
    Ruxolitinib 5 mg tablets in combination with Capecitabine 500 mg tablets to be administered by mouth twice daily (BID).

    Reporting group title
    Placebo Plus Capecitabine
    Reporting group description
    5 mg matching placebo tablets in combination with Capecitabine 500 mg tablets to be administered by mouth twice daily (BID).

    Serious adverse events
    Ruxolitinib Plus Capecitabine Placebo Plus Capecitabine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    98 / 153 (64.05%)
    86 / 154 (55.84%)
         number of deaths (all causes)
    20
    15
         number of deaths resulting from adverse events
    2
    1
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 153 (0.65%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    3 / 153 (1.96%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    3 / 153 (1.96%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestine carcinoma metastatic
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 153 (0.65%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device leakage
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 153 (0.65%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 153 (0.00%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    3 / 153 (1.96%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    8 / 153 (5.23%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 153 (0.65%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         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 / 153 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (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
    Accidental overdose
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    4 / 153 (2.61%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 153 (0.65%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 153 (1.31%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 153 (3.27%)
    4 / 154 (2.60%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 153 (0.65%)
    5 / 154 (3.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 153 (3.27%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 153 (2.61%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 153 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 153 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pancytopenia
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Complex regional pain syndrome
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 153 (0.65%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unresponsive to stimuli
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    6 / 153 (3.92%)
    19 / 154 (12.34%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    6 / 153 (3.92%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 153 (0.65%)
    5 / 154 (3.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 153 (3.27%)
    4 / 154 (2.60%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    2 / 153 (1.31%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal stenosis
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 153 (0.65%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 153 (1.31%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 153 (0.65%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal infarction
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 153 (0.65%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 153 (0.65%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 153 (2.61%)
    5 / 154 (3.25%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic pseudocyst
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         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 / 153 (0.65%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    3 / 153 (1.96%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 153 (0.65%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    7 / 153 (4.58%)
    4 / 154 (2.60%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    3 / 153 (1.96%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    5 / 153 (3.27%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 153 (0.65%)
    4 / 154 (2.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary dilatation
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biloma
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    3 / 153 (1.96%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 153 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    3 / 153 (1.96%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 153 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         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
    1 / 153 (0.65%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 153 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 153 (0.65%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 153 (1.31%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    8 / 153 (5.23%)
    4 / 154 (2.60%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 153 (0.65%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    3 / 153 (1.96%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    3 / 153 (1.96%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    3 / 153 (1.96%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 153 (1.31%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    6 / 153 (3.92%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 153 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    0 / 153 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    2 / 153 (1.31%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida infection
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis suppurative
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (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
    2 / 153 (1.31%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 153 (2.61%)
    8 / 154 (5.19%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 153 (3.27%)
    5 / 154 (3.25%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 153 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Skin candida
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 154 (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 / 153 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Ruxolitinib Plus Capecitabine Placebo Plus Capecitabine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    146 / 153 (95.42%)
    145 / 154 (94.16%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    8 / 153 (5.23%)
    3 / 154 (1.95%)
         occurrences all number
    8
    3
    Hypertension
         subjects affected / exposed
    8 / 153 (5.23%)
    3 / 154 (1.95%)
         occurrences all number
    9
    3
    Hypotension
         subjects affected / exposed
    12 / 153 (7.84%)
    8 / 154 (5.19%)
         occurrences all number
    13
    11
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    17 / 153 (11.11%)
    18 / 154 (11.69%)
         occurrences all number
    19
    23
    Chills
         subjects affected / exposed
    8 / 153 (5.23%)
    4 / 154 (2.60%)
         occurrences all number
    8
    4
    Fatigue
         subjects affected / exposed
    48 / 153 (31.37%)
    51 / 154 (33.12%)
         occurrences all number
    54
    54
    Oedema
         subjects affected / exposed
    11 / 153 (7.19%)
    3 / 154 (1.95%)
         occurrences all number
    11
    4
    Oedema peripheral
         subjects affected / exposed
    20 / 153 (13.07%)
    35 / 154 (22.73%)
         occurrences all number
    21
    35
    Pyrexia
         subjects affected / exposed
    27 / 153 (17.65%)
    13 / 154 (8.44%)
         occurrences all number
    30
    19
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    13 / 153 (8.50%)
    7 / 154 (4.55%)
         occurrences all number
    13
    8
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    11 / 153 (7.19%)
    4 / 154 (2.60%)
         occurrences all number
    13
    6
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 153 (5.88%)
    4 / 154 (2.60%)
         occurrences all number
    11
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 153 (6.54%)
    3 / 154 (1.95%)
         occurrences all number
    11
    3
    Weight decreased
         subjects affected / exposed
    10 / 153 (6.54%)
    6 / 154 (3.90%)
         occurrences all number
    11
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    45 / 153 (29.41%)
    23 / 154 (14.94%)
         occurrences all number
    63
    31
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 153 (6.54%)
    13 / 154 (8.44%)
         occurrences all number
    11
    13
    Dyspnoea
         subjects affected / exposed
    9 / 153 (5.88%)
    18 / 154 (11.69%)
         occurrences all number
    10
    18
    Hiccups
         subjects affected / exposed
    9 / 153 (5.88%)
    2 / 154 (1.30%)
         occurrences all number
    9
    2
    Pleural effusion
         subjects affected / exposed
    9 / 153 (5.88%)
    2 / 154 (1.30%)
         occurrences all number
    9
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    19 / 153 (12.42%)
    12 / 154 (7.79%)
         occurrences all number
    20
    13
    Dysgeusia
         subjects affected / exposed
    4 / 153 (2.61%)
    8 / 154 (5.19%)
         occurrences all number
    4
    8
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    16 / 153 (10.46%)
    11 / 154 (7.14%)
         occurrences all number
    16
    11
    Abdominal pain
         subjects affected / exposed
    35 / 153 (22.88%)
    43 / 154 (27.92%)
         occurrences all number
    40
    48
    Abdominal pain upper
         subjects affected / exposed
    13 / 153 (8.50%)
    13 / 154 (8.44%)
         occurrences all number
    13
    14
    Ascites
         subjects affected / exposed
    21 / 153 (13.73%)
    19 / 154 (12.34%)
         occurrences all number
    22
    21
    Constipation
         subjects affected / exposed
    35 / 153 (22.88%)
    26 / 154 (16.88%)
         occurrences all number
    36
    30
    Diarrhoea
         subjects affected / exposed
    41 / 153 (26.80%)
    37 / 154 (24.03%)
         occurrences all number
    55
    51
    Dry mouth
         subjects affected / exposed
    3 / 153 (1.96%)
    9 / 154 (5.84%)
         occurrences all number
    3
    9
    Flatulence
         subjects affected / exposed
    9 / 153 (5.88%)
    3 / 154 (1.95%)
         occurrences all number
    9
    3
    Nausea
         subjects affected / exposed
    46 / 153 (30.07%)
    48 / 154 (31.17%)
         occurrences all number
    58
    52
    Stomatitis
         subjects affected / exposed
    30 / 153 (19.61%)
    18 / 154 (11.69%)
         occurrences all number
    32
    21
    Vomiting
         subjects affected / exposed
    30 / 153 (19.61%)
    45 / 154 (29.22%)
         occurrences all number
    49
    56
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    38 / 153 (24.84%)
    26 / 154 (16.88%)
         occurrences all number
    46
    36
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 153 (5.23%)
    4 / 154 (2.60%)
         occurrences all number
    8
    4
    Back pain
         subjects affected / exposed
    19 / 153 (12.42%)
    13 / 154 (8.44%)
         occurrences all number
    19
    13
    Muscular weakness
         subjects affected / exposed
    8 / 153 (5.23%)
    5 / 154 (3.25%)
         occurrences all number
    8
    5
    Pain in extremity
         subjects affected / exposed
    9 / 153 (5.88%)
    2 / 154 (1.30%)
         occurrences all number
    9
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    31 / 153 (20.26%)
    47 / 154 (30.52%)
         occurrences all number
    36
    50
    Dehydration
         subjects affected / exposed
    10 / 153 (6.54%)
    9 / 154 (5.84%)
         occurrences all number
    10
    9
    Hyperglycaemia
         subjects affected / exposed
    4 / 153 (2.61%)
    9 / 154 (5.84%)
         occurrences all number
    12
    9
    Hypokalaemia
         subjects affected / exposed
    17 / 153 (11.11%)
    12 / 154 (7.79%)
         occurrences all number
    21
    15
    Hyponatraemia
         subjects affected / exposed
    9 / 153 (5.88%)
    5 / 154 (3.25%)
         occurrences all number
    11
    5
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    9 / 153 (5.88%)
    6 / 154 (3.90%)
         occurrences all number
    15
    6

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Jun 2014
    The primary purpose of the amendment was to add the exclusion of subjects who had a known hypersensitivity to any of the active substances, including 5-FU, ruxolitinib, or any of their excipients.
    23 Sep 2014
    The primary purpose of the amendment was to provide clarification regarding eligibility criteria, the definition of RMST, the alpha-control plan for secondary endpoints, and the administration of capecitabine. Important changes included: • Defining prior systemic and radiation therapy, measurable and evaluable disease at screening, and subjects who were required to use appropriate contraception. • Clarifying exclusions for cardiac disease. • Adding an exclusion for prior treatment with a JAK inhibitor. • Changing RMST from a secondary analysis of the primary endpoint to an alpha controlled secondary endpoint to be tested after the log rank OS analysis in a sequential testing procedure. • Implementing an alternative, less-conservative alpha-spending plan (HSD using parameter - 4) for secondary endpoints to control familywise error at the overall 0.025 (one-sided level) while maintaining the sequential gatekeeping procedure for testing secondary endpoints. Previously, secondary endpoints were to be tested using the same allocation scheme used for the primary endpoint (HSD using parameter -15), which could have unnecessarily reduced power for the secondary endpoints. • Clarifying that the total daily capecitabine dose (2000 mg/m^2) was to be administered in approximately equal doses BID using only 500 mg capecitabine tablets because of concerns associated with intersubject dose variation using 2 different tablet strengths (150 mg and 500 mg).

    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.
    The study was terminated as other related studies of ruxolitinib did not provide sufficient efficacy to warrant continuation at the recommendation of the Data Monitoring Committee.
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