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    Clinical Trial Results:
    A randomized, multicenter, double-blind, placebo-controlled, Phase 3 study of the Bruton`s Tyrosine Kinase inhibitor ibrutinib in combination with nab-paclitaxel and gemcitabine versus placebo in combination with nab-paclitaxel and gemcitabine, in the first line treatment of patients with metastatic pancreatic adenocarcinoma

    Summary
    EudraCT number
    2015-000905-38
    Trial protocol
    DE   ES   BE   FR   IT  
    Global end of trial date
    25 Apr 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Jul 2020
    First version publication date
    02 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PCYC-1137-CA
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01744691
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pharmacyclics LLC
    Sponsor organisation address
    995 East Arques Avenue, Sunnyvale, California, United States, 94085
    Public contact
    Clinical Trial information, Pharmacyclics LLC, 001 408-774-0330, info@pcyc.com
    Scientific contact
    Clinical Trial information, Pharmacyclics LLC, 001 408-774-0330, info@pcyc.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
    30 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of ibrutinib in combination with nab-paclitaxel and gemcitabine versus placebo in combination with nab-paclitaxel and gemcitabine, based on investigator assessment of progression-free survival (PFS) and overall survival (OS), for the first line treatment of patients with metastatic pancreatic adenocarcinoma.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and ICH GCP.
    Background therapy
    nab-paclitaxel and gemcitabine as approved for 1st line treatment of patients with pancreatic adenocarcinoma.
    Evidence for comparator
    -
    Actual start date of recruitment
    08 May 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 32
    Country: Number of subjects enrolled
    France: 47
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Italy: 62
    Country: Number of subjects enrolled
    Korea, Republic of: 105
    Country: Number of subjects enrolled
    Spain: 64
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    United States: 70
    Worldwide total number of subjects
    424
    EEA total number of subjects
    249
    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)
    237
    From 65 to 84 years
    186
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Adult subjects with histologically or cytologically confirmed diagnosis of pancreatic carcinoma Stage IV newly diagnosed within 6 weeks of randomization suitable for treatment with nab-paclitaxel and gemcitabine.

    Pre-assignment
    Screening details
    Four hundred twenty-four subjects were randomized (ITT population), and 420 subjects received at least 1 dose of ibrutinib and constituted the all treated population and the safety analysis set.

    Period 1
    Period 1 title
    overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ibrutinib+Nab-paclitaxel+Gemcitabine
    Arm description
    Ibrutinib (560 mg daily) + Nab-paclitaxel (125 mg/m^2) and Gemcitabine (1000 mg/m^2)
    Arm type
    Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib 560 mg (4 x 140-mg capsules) once daily until disease progression or unacceptable toxicity.

    Arm title
    Placebo+Nab-paclitaxel+Gemcitabine
    Arm description
    Ibrutinib Placebo + Nab-paclitaxel (125 mg/m^2) and Gemcitabine (1000 mg/m^2)
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib placebo (4 capsules) once daily until disease progression or unacceptable toxicity.

    Number of subjects in period 1
    Ibrutinib+Nab-paclitaxel+Gemcitabine Placebo+Nab-paclitaxel+Gemcitabine
    Started
    211
    213
    Completed
    193
    191
    Not completed
    18
    22
         Consent withdrawn by subject
    18
    21
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ibrutinib+Nab-paclitaxel+Gemcitabine
    Reporting group description
    Ibrutinib (560 mg daily) + Nab-paclitaxel (125 mg/m^2) and Gemcitabine (1000 mg/m^2)

    Reporting group title
    Placebo+Nab-paclitaxel+Gemcitabine
    Reporting group description
    Ibrutinib Placebo + Nab-paclitaxel (125 mg/m^2) and Gemcitabine (1000 mg/m^2)

    Reporting group values
    Ibrutinib+Nab-paclitaxel+Gemcitabine Placebo+Nab-paclitaxel+Gemcitabine Total
    Number of subjects
    211 213 424
    Age categorical
    Count of Participants
    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)
    108 110 218
        From 65-84 years
    103 102 205
        85 years and over
    0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.1 ± 10.37 62.9 ± 9.33 -
    Gender categorical
    Units: Subjects
        Female
    97 92 189
        Male
    114 121 235

    End points

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    End points reporting groups
    Reporting group title
    Ibrutinib+Nab-paclitaxel+Gemcitabine
    Reporting group description
    Ibrutinib (560 mg daily) + Nab-paclitaxel (125 mg/m^2) and Gemcitabine (1000 mg/m^2)

    Reporting group title
    Placebo+Nab-paclitaxel+Gemcitabine
    Reporting group description
    Ibrutinib Placebo + Nab-paclitaxel (125 mg/m^2) and Gemcitabine (1000 mg/m^2)

    Primary: Overall Survival

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    End point title
    Overall Survival
    End point description
    OS was defined as the time from the date of randomization to the date of death due to any cause.
    End point type
    Primary
    End point timeframe
    The median time on study was 24.3 months for subjects in the Ibr+n-P/G arm and 25.3 months for subjects in the Pbo+n-P/G arm. The median time on treatment was 3.9 months for subjects in the Ibr+n-P/G arm and 5.5 months for subjects in the Pbo+n-P/G arm.
    End point values
    Ibrutinib+Nab-paclitaxel+Gemcitabine Placebo+Nab-paclitaxel+Gemcitabine
    Number of subjects analysed
    211
    213
    Units: months
        number (confidence interval 95%)
    9.69 (8.57 to 10.41)
    10.78 (8.94 to 11.66)
    Statistical analysis title
    median OS
    Statistical analysis description
    Median overall survival estimated by the Kaplan-Meier method.
    Comparison groups
    Ibrutinib+Nab-paclitaxel+Gemcitabine v Placebo+Nab-paclitaxel+Gemcitabine
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3225 [1]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.109
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.903
         upper limit
    1.363
    Notes
    [1] - p-value is based on log-rank test stratified by the 3 randomization stratification factors

    Primary: Progression Free Survival

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    End point title
    Progression Free Survival
    End point description
    PFS assessed by Investigator was defined as the time from the date of randomization to the date of the first documented disease progression per RECIST 1.1 or death due to any cause, whichever occurred first, regardless of the use of subsequent anticancer therapy prior to documented PD or death.
    End point type
    Primary
    End point timeframe
    The median time on study was 24.3 months for subjects in the Ibr+n-P/G arm and 25.3 months for subjects in the Pbo+n-P/G arm. The median time on treatment was 3.9 months for subjects in the Ibr+n-P/G arm and 5.5 months for subjects in the Pbo+n-P/G arm.
    End point values
    Ibrutinib+Nab-paclitaxel+Gemcitabine Placebo+Nab-paclitaxel+Gemcitabine
    Number of subjects analysed
    211
    213
    Units: months
        number (confidence interval 95%)
    5.32 (3.75 to 5.49)
    6.01 (5.45 to 7.16)
    Statistical analysis title
    median PFS
    Statistical analysis description
    mPFS was estimated by the Kaplan-Meier method
    Comparison groups
    Ibrutinib+Nab-paclitaxel+Gemcitabine v Placebo+Nab-paclitaxel+Gemcitabine
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.525
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.241
         upper limit
    1.873
    Notes
    [2] - p-value is from log-rank test stratified by the 3 randomization factors

    Secondary: Overall Response Rate

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    End point title
    Overall Response Rate
    End point description
    Overall Response Rate was defined as the proportion of subjects achieving a best overall response of CR or PR per investigator assessment per RECIST 1.1.
    End point type
    Secondary
    End point timeframe
    The median time on study was 24.3 months for subjects in the Ibr+n-P/G arm and 25.3 months for subjects in the Pbo+n-P/G arm. The median time on treatment was 3.9 months for subjects in the Ibr+n-P/G arm and 5.5 months for subjects in the Pbo+n-P/G arm.
    End point values
    Ibrutinib+Nab-paclitaxel+Gemcitabine Placebo+Nab-paclitaxel+Gemcitabine
    Number of subjects analysed
    211
    213
    Units: percent
        number (confidence interval 95%)
    29.4 (23.3 to 36.0)
    42.3 (35.5 to 49.2)
    Statistical analysis title
    ORR
    Statistical analysis description
    The overall response rate (ORR) was defined as complete response (CR) + partial response (PR) per investigator assessment.
    Comparison groups
    Ibrutinib+Nab-paclitaxel+Gemcitabine v Placebo+Nab-paclitaxel+Gemcitabine
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0058 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Rate Ratio
    Point estimate
    0.695
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.535
         upper limit
    0.903
    Notes
    [3] - P-value for rate ratio is based on Cochran-Mantel-Haenszel (CMH) test adjusted for the three randomization stratification factors.

    Secondary: Carbohydrate Antigen 19-9 response rate

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    End point title
    Carbohydrate Antigen 19-9 response rate
    End point description
    Carbohydrate antigen 19-9 (CA19-9) response rate for 60% reduction was defined as the proportion of subjects with at least a 60% decrease from baseline.
    End point type
    Secondary
    End point timeframe
    The median time on study was 24.3 months for subjects in the Ibr+n-P/G arm and 25.3 months for subjects in the Pbo+n-P/G arm. The median time on treatment was 3.9 months for subjects in the Ibr+n-P/G arm and 5.5 months for subjects in the Pbo+n-P/G arm.
    End point values
    Ibrutinib+Nab-paclitaxel+Gemcitabine Placebo+Nab-paclitaxel+Gemcitabine
    Number of subjects analysed
    211
    213
    Units: percent
        number (confidence interval 95%)
    53.6 (46.6 to 60.4)
    62.9 (56.0 to 69.4)
    Statistical analysis title
    CA19-9 Response Rate
    Comparison groups
    Ibrutinib+Nab-paclitaxel+Gemcitabine v Placebo+Nab-paclitaxel+Gemcitabine
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0488 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Rate Ratio
    Point estimate
    0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.722
         upper limit
    1
    Notes
    [4] - p-value for rate ratio is based on Cochran-Mantel Haenszel (CMH) test adjusted for the 3 randomization stratification factors.

    Secondary: TUDD1 in EORTC Global Health Status

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    End point title
    TUDD1 in EORTC Global Health Status
    End point description
    Time until definitive deterioration (TUDD1) was defined as the time interval between randomization and the first occurrence of a decrease in QLQ-C30.
    End point type
    Secondary
    End point timeframe
    The median time on study was 24.3 months for subjects in the Ibr+n-P/G arm and 25.3 months for subjects in the Pbo+n-P/G arm. The median time on treatment was 3.9 months for subjects in the Ibr+n-P/G arm and 5.5 months for subjects in the Pbo+n-P/G arm.
    End point values
    Ibrutinib+Nab-paclitaxel+Gemcitabine Placebo+Nab-paclitaxel+Gemcitabine
    Number of subjects analysed
    211
    213
    Units: months
        number (confidence interval 95%)
    4.21 (2.86 to 5.82)
    6.14 (4.86 to 8.21)
    Statistical analysis title
    TUDD1
    Comparison groups
    Ibrutinib+Nab-paclitaxel+Gemcitabine v Placebo+Nab-paclitaxel+Gemcitabine
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0782 [5]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.265
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.975
         upper limit
    1.642
    Notes
    [5] - P-value is from log-rank test stratified by the three randomization stratification factors.

    Secondary: Rate of Venous Thromboembolic Events

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    End point title
    Rate of Venous Thromboembolic Events
    End point description
    VTE was defined as the proportion of subjects with TEAE VTE of any grade defined by SMQ terms.
    End point type
    Secondary
    End point timeframe
    The median time on study was 24.3 months for subjects in the Ibr+n-P/G arm and 25.3 months for subjects in the Pbo+n-P/G arm. The median time on treatment was 3.9 months for subjects in the Ibr+n-P/G arm and 5.5 months for subjects in the Pbo+n-P/G arm.
    End point values
    Ibrutinib+Nab-paclitaxel+Gemcitabine Placebo+Nab-paclitaxel+Gemcitabine
    Number of subjects analysed
    211
    213
    Units: percent
        number (confidence interval 95%)
    8.11 (4.8 to 12.6)
    10.8 (7.0 to 15.8)
    Statistical analysis title
    Rate of VTEs
    Statistical analysis description
    VTEs are adverse events defined by SMQ terms as 'embolic and thrombotic events, venous'.
    Comparison groups
    Ibrutinib+Nab-paclitaxel+Gemcitabine v Placebo+Nab-paclitaxel+Gemcitabine
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3343
    Method
    Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were reported from the time the subject signs the Informed Consent Form until 30 days following last dose of study drug. All new malignant tumors were to be reported as adverse events through Long Term Follow-up for OS.
    Adverse event reporting additional description
    An AE is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Ibrutinib + Nab-Paclitaxel + Gemcitabine
    Reporting group description
    Ibrutinib 560 mg (4 x 140-mg capsules) once daily until disease progression or unacceptable toxicity.

    Reporting group title
    Placebo + Nab-Paclitaxel + Gemcitabine
    Reporting group description
    Ibrutinib Placebo (4 capsules) once daily until disease progression or unacceptable toxicity.

    Serious adverse events
    Ibrutinib + Nab-Paclitaxel + Gemcitabine Placebo + Nab-Paclitaxel + Gemcitabine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    112 / 208 (53.85%)
    126 / 212 (59.43%)
         number of deaths (all causes)
    189
    188
         number of deaths resulting from adverse events
    20
    18
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma pancreas
         subjects affected / exposed
    2 / 208 (0.96%)
    3 / 212 (1.42%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cancer pain
         subjects affected / exposed
    2 / 208 (0.96%)
    4 / 212 (1.89%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    6 / 208 (2.88%)
    6 / 212 (2.83%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 8
         deaths causally related to treatment / all
    0 / 5
    0 / 4
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    5 / 208 (2.40%)
    5 / 212 (2.36%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 8
         deaths causally related to treatment / all
    0 / 5
    0 / 4
    Tumour haemorrhage
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arterial haemorrhage
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         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
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 208 (0.96%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         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
    Asthenia
         subjects affected / exposed
    6 / 208 (2.88%)
    7 / 212 (3.30%)
         occurrences causally related to treatment / all
    5 / 8
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    4 / 208 (1.92%)
    5 / 212 (2.36%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Generalised oedema
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    2 / 208 (0.96%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    13 / 208 (6.25%)
    17 / 212 (8.02%)
         occurrences causally related to treatment / all
    2 / 16
    5 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 208 (0.48%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 208 (0.48%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         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 / 208 (0.48%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (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
    3 / 208 (1.44%)
    3 / 212 (1.42%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary thrombosis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (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
    2 / 208 (0.96%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         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
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 208 (0.48%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 208 (0.48%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 208 (0.00%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Bone contusion
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 208 (1.44%)
    4 / 212 (1.89%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 208 (0.00%)
    3 / 212 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 208 (0.48%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 208 (0.48%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (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
    3 / 208 (1.44%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wernicke's encephalopathy
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (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
    7 / 208 (3.37%)
    9 / 212 (4.25%)
         occurrences causally related to treatment / all
    3 / 7
    1 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 208 (0.48%)
    3 / 212 (1.42%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic diathesis
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    6 / 208 (2.88%)
    3 / 212 (1.42%)
         occurrences causally related to treatment / all
    3 / 7
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 208 (1.92%)
    4 / 212 (1.89%)
         occurrences causally related to treatment / all
    8 / 8
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (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 pain
         subjects affected / exposed
    4 / 208 (1.92%)
    11 / 212 (5.19%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 208 (0.48%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 208 (0.00%)
    3 / 212 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 208 (0.96%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    14 / 208 (6.73%)
    9 / 212 (4.25%)
         occurrences causally related to treatment / all
    14 / 17
    8 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    3 / 208 (1.44%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal stenosis
         subjects affected / exposed
    1 / 208 (0.48%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    2 / 208 (0.96%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flatulence
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    2 / 208 (0.96%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (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
    4 / 208 (1.92%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    5 / 6
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         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 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    3 / 208 (1.44%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 208 (0.48%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric vein thrombosis
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 208 (1.44%)
    7 / 212 (3.30%)
         occurrences causally related to treatment / all
    5 / 6
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    0 / 208 (0.00%)
    3 / 212 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 208 (0.00%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumoperitoneum
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retching
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         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
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal ulcer haemorrhage
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 208 (2.40%)
    6 / 212 (2.83%)
         occurrences causally related to treatment / all
    4 / 9
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    0 / 208 (0.00%)
    4 / 212 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary dilatation
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    9 / 208 (4.33%)
    4 / 212 (1.89%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 208 (0.48%)
    3 / 212 (1.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 208 (0.48%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (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 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 208 (0.96%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 208 (0.48%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 208 (0.48%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 208 (0.00%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 208 (0.00%)
    4 / 212 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Azotaemia
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 208 (1.44%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 208 (0.48%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    4 / 208 (1.92%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 208 (0.00%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 208 (0.48%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    3 / 208 (1.44%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    1 / 208 (0.48%)
    3 / 212 (1.42%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    2 / 208 (0.96%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida sepsis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cellulitis
         subjects affected / exposed
    4 / 208 (1.92%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 208 (0.48%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (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
    0 / 208 (0.00%)
    4 / 212 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter bacteraemia
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    3 / 208 (1.44%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 208 (0.96%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (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
    4 / 208 (1.92%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    4 / 208 (1.92%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    2 / 208 (0.96%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 208 (0.48%)
    4 / 212 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    13 / 208 (6.25%)
    8 / 212 (3.77%)
         occurrences causally related to treatment / all
    3 / 14
    9 / 11
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumonia bacterial
         subjects affected / exposed
    1 / 208 (0.48%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (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
    2 / 208 (0.96%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 208 (0.00%)
    4 / 212 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 208 (0.48%)
    3 / 212 (1.42%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    4 / 208 (1.92%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 208 (0.48%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 208 (0.48%)
    5 / 212 (2.36%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enzyme abnormality
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 208 (0.48%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Ibrutinib + Nab-Paclitaxel + Gemcitabine Placebo + Nab-Paclitaxel + Gemcitabine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    208 / 208 (100.00%)
    212 / 212 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 208 (5.29%)
    13 / 212 (6.13%)
         occurrences all number
    33
    34
    Hypotension
         subjects affected / exposed
    12 / 208 (5.77%)
    13 / 212 (6.13%)
         occurrences all number
    15
    15
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    100 / 208 (48.08%)
    93 / 212 (43.87%)
         occurrences all number
    311
    283
    Chills
         subjects affected / exposed
    21 / 208 (10.10%)
    15 / 212 (7.08%)
         occurrences all number
    24
    21
    Fatigue
         subjects affected / exposed
    78 / 208 (37.50%)
    65 / 212 (30.66%)
         occurrences all number
    149
    170
    Mucosal inflammation
         subjects affected / exposed
    24 / 208 (11.54%)
    19 / 212 (8.96%)
         occurrences all number
    36
    29
    Oedema peripheral
         subjects affected / exposed
    60 / 208 (28.85%)
    77 / 212 (36.32%)
         occurrences all number
    97
    143
    Pyrexia
         subjects affected / exposed
    85 / 208 (40.87%)
    82 / 212 (38.68%)
         occurrences all number
    150
    181
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 208 (7.21%)
    42 / 212 (19.81%)
         occurrences all number
    19
    47
    Dyspnoea
         subjects affected / exposed
    25 / 208 (12.02%)
    43 / 212 (20.28%)
         occurrences all number
    34
    64
    Epistaxis
         subjects affected / exposed
    36 / 208 (17.31%)
    21 / 212 (9.91%)
         occurrences all number
    41
    27
    Pleural effusion
         subjects affected / exposed
    9 / 208 (4.33%)
    16 / 212 (7.55%)
         occurrences all number
    14
    22
    Productive cough
         subjects affected / exposed
    7 / 208 (3.37%)
    12 / 212 (5.66%)
         occurrences all number
    7
    16
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    20 / 208 (9.62%)
    34 / 212 (16.04%)
         occurrences all number
    23
    36
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    12 / 208 (5.77%)
    25 / 212 (11.79%)
         occurrences all number
    16
    42
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 208 (3.85%)
    18 / 212 (8.49%)
         occurrences all number
    12
    34
    Neutrophil count decreased
         subjects affected / exposed
    11 / 208 (5.29%)
    19 / 212 (8.96%)
         occurrences all number
    19
    48
    Weight decreased
         subjects affected / exposed
    14 / 208 (6.73%)
    21 / 212 (9.91%)
         occurrences all number
    19
    33
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    20 / 208 (9.62%)
    20 / 212 (9.43%)
         occurrences all number
    22
    22
    Dysgeusia
         subjects affected / exposed
    19 / 208 (9.13%)
    26 / 212 (12.26%)
         occurrences all number
    24
    33
    Headache
         subjects affected / exposed
    21 / 208 (10.10%)
    20 / 212 (9.43%)
         occurrences all number
    25
    24
    Neuropathy peripheral
         subjects affected / exposed
    15 / 208 (7.21%)
    14 / 212 (6.60%)
         occurrences all number
    33
    28
    Neurotoxicity
         subjects affected / exposed
    14 / 208 (6.73%)
    18 / 212 (8.49%)
         occurrences all number
    40
    47
    Paraesthesia
         subjects affected / exposed
    27 / 208 (12.98%)
    20 / 212 (9.43%)
         occurrences all number
    79
    42
    Peripheral motor neuropathy
         subjects affected / exposed
    13 / 208 (6.25%)
    11 / 212 (5.19%)
         occurrences all number
    30
    23
    Peripheral sensory neuropathy
         subjects affected / exposed
    69 / 208 (33.17%)
    63 / 212 (29.72%)
         occurrences all number
    171
    153
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    90 / 208 (43.27%)
    95 / 212 (44.81%)
         occurrences all number
    289
    309
    Leukopenia
         subjects affected / exposed
    15 / 208 (7.21%)
    18 / 212 (8.49%)
         occurrences all number
    19
    61
    Neutropenia
         subjects affected / exposed
    68 / 208 (32.69%)
    84 / 212 (39.62%)
         occurrences all number
    139
    328
    Thrombocytopenia
         subjects affected / exposed
    75 / 208 (36.06%)
    55 / 212 (25.94%)
         occurrences all number
    221
    208
    Eye disorders
    Vision blurred
         subjects affected / exposed
    17 / 208 (8.17%)
    15 / 212 (7.08%)
         occurrences all number
    20
    18
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    13 / 208 (6.25%)
    13 / 212 (6.13%)
         occurrences all number
    15
    13
    Abdominal pain
         subjects affected / exposed
    63 / 208 (30.29%)
    67 / 212 (31.60%)
         occurrences all number
    94
    99
    Abdominal pain upper
         subjects affected / exposed
    38 / 208 (18.27%)
    27 / 212 (12.74%)
         occurrences all number
    64
    40
    Ascites
         subjects affected / exposed
    21 / 208 (10.10%)
    25 / 212 (11.79%)
         occurrences all number
    30
    35
    Constipation
         subjects affected / exposed
    68 / 208 (32.69%)
    78 / 212 (36.79%)
         occurrences all number
    91
    96
    Diarrhoea
         subjects affected / exposed
    147 / 208 (70.67%)
    109 / 212 (51.42%)
         occurrences all number
    357
    240
    Dyspepsia
         subjects affected / exposed
    34 / 208 (16.35%)
    21 / 212 (9.91%)
         occurrences all number
    38
    26
    Nausea
         subjects affected / exposed
    116 / 208 (55.77%)
    107 / 212 (50.47%)
         occurrences all number
    228
    242
    Stomatitis
         subjects affected / exposed
    36 / 208 (17.31%)
    21 / 212 (9.91%)
         occurrences all number
    50
    28
    Vomiting
         subjects affected / exposed
    85 / 208 (40.87%)
    86 / 212 (40.57%)
         occurrences all number
    169
    184
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    90 / 208 (43.27%)
    87 / 212 (41.04%)
         occurrences all number
    130
    119
    Dry skin
         subjects affected / exposed
    14 / 208 (6.73%)
    6 / 212 (2.83%)
         occurrences all number
    16
    7
    Pruritus
         subjects affected / exposed
    8 / 208 (3.85%)
    25 / 212 (11.79%)
         occurrences all number
    8
    36
    Rash erythematous
         subjects affected / exposed
    12 / 208 (5.77%)
    15 / 212 (7.08%)
         occurrences all number
    16
    21
    Rash maculo-papular
         subjects affected / exposed
    23 / 208 (11.06%)
    28 / 212 (13.21%)
         occurrences all number
    28
    42
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    17 / 208 (8.17%)
    26 / 212 (12.26%)
         occurrences all number
    20
    30
    Back pain
         subjects affected / exposed
    25 / 208 (12.02%)
    25 / 212 (11.79%)
         occurrences all number
    31
    38
    Musculoskeletal chest pain
         subjects affected / exposed
    5 / 208 (2.40%)
    11 / 212 (5.19%)
         occurrences all number
    5
    15
    Musculoskeletal pain
         subjects affected / exposed
    11 / 208 (5.29%)
    11 / 212 (5.19%)
         occurrences all number
    13
    13
    Myalgia
         subjects affected / exposed
    28 / 208 (13.46%)
    35 / 212 (16.51%)
         occurrences all number
    36
    58
    Pain in extremity
         subjects affected / exposed
    17 / 208 (8.17%)
    24 / 212 (11.32%)
         occurrences all number
    24
    31
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 208 (3.37%)
    15 / 212 (7.08%)
         occurrences all number
    10
    17
    Urinary tract infection
         subjects affected / exposed
    16 / 208 (7.69%)
    16 / 212 (7.55%)
         occurrences all number
    23
    25
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    85 / 208 (40.87%)
    76 / 212 (35.85%)
         occurrences all number
    135
    129
    Dehydration
         subjects affected / exposed
    5 / 208 (2.40%)
    12 / 212 (5.66%)
         occurrences all number
    5
    14
    Hypoalbuminaemia
         subjects affected / exposed
    17 / 208 (8.17%)
    16 / 212 (7.55%)
         occurrences all number
    24
    28
    Hypokalaemia
         subjects affected / exposed
    25 / 208 (12.02%)
    20 / 212 (9.43%)
         occurrences all number
    37
    32
    Hypomagnesaemia
         subjects affected / exposed
    11 / 208 (5.29%)
    7 / 212 (3.30%)
         occurrences all number
    14
    16
    Platelet count decreased
         subjects affected / exposed
    13 / 208 (6.25%)
    17 / 212 (8.02%)
         occurrences all number
    26
    61

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jun 2015
    · Updated language on randomization; certain criteria for inclusion (ie, added ECOG 0-1 population) and exclusion (ie, decrease in albumin ≥20%); ibrutinib overdose language for consistency with USPI; statistical analysis section · Removal of Child-Pugh score as criteria for excluding subject participation · Inclusion of "maximum clinical benefit" derived from nab-paclitaxel and gemcitabine as a criterion for discontinuing treatment from either of these study treatments. · Revision of Grade 3-4 nausea, vomiting, or diarrhea events to include time limit >3 days before implementing dose modifications · Modified language in DMC section to state that a safety signal would be considered if Grade 3-4 AEs of longer duration and or frequency occurred because of study treatment.
    25 Aug 2015
    · Revised protocol to remove "maximum clinical benefit" defined as "a plateau in radiographic plateau or CA-19-9," as a criterion to discontinue chemotherapy
    18 Sep 2015
    · Updated inclusion criteria to align abstinence language with MHRA guidance and to modify birth control measures for females and males in accordance with nab-paclitaxel and gemcitabine labeling · Updated eligibility criteria to exclude subjects who received a live vaccination within 4 weeks prior to randomization in alignment with gemcitabine labeling
    16 Sep 2016
    · Implemented updates for sections on concomitant therapy, pharmacokinetics, product metabolism, summary of clinical safety, risks per revised ibrutinib IB · Updated contraception methods per current labeling for nab-paclitaxel and gemcitabine · Included live vaccinations in list of prohibited concomitant medications for alignment with gemcitabine labeling · Included instruction if tumor pseudoprogression was suspected · Excluded subjects with currently active and clinically significant hepatic impairment
    16 Dec 2016
    · Increased sample size in alignment with DMC agreement · Removed interim analysis for safety and efficacy in alignment with DMC agreement to mitigate the insufficient power for OS analysis at the planned IA analysis time
    19 Jul 2017
    · Conversion of OS from secondary objective to primary objective · Inclusion of VTE rate as secondary objective · Updated sections for alignment with latest version of ibrutinib IB
    20 Dec 2017
    · Added requirement to periodically monitor subjects clinically for atrial fibrillation · Added requirement to monitor closely and take appropriate actions for subjects at risk of tumor lysis syndrome

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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