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    Clinical Trial Results:
    A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib versus Chlorambucil in Patients 65 Years or Older with Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (RESONATE™-2)

    Summary
    EudraCT number
    2012-003967-23
    Trial protocol
    BE   IE   CZ   DE   ES   GB   IT  
    Global end of trial date
    04 May 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    PCYC-1115-CA
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01722487
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    provider NLM_DES study id: S0003U0X
    Sponsors
    Sponsor organisation name
    Pharmacyclics LLC
    Sponsor organisation address
    999 E Arques Ave, Sunnyvale, United States, 94085
    Public contact
    Deepali Suri, Pharmacyclics LLC, 001 855-427-8846, medinfo@pcyc.com
    Scientific contact
    Dr. Lori Styles, Medical Monitor, Pharmacyclics LLC, 001 408-215-3770, lstyles@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
    28 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    04 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of ibrutinib compared with chlorambucil based on the independent review committee (IRC) assessment of PFS in subjects 65 years of age or older with treatment-naive CLL or SLL.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and ICH GCP.
    Background therapy
    -
    Evidence for comparator
    Chlorambucil alone or in combination is often used in this patient population.
    Actual start date of recruitment
    21 Mar 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 60
    Country: Number of subjects enrolled
    United Kingdom: 30
    Country: Number of subjects enrolled
    Italy: 27
    Country: Number of subjects enrolled
    Poland: 20
    Country: Number of subjects enrolled
    Ukraine: 13
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Czech Republic: 10
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    Russian Federation: 1
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Israel: 16
    Country: Number of subjects enrolled
    New Zealand: 13
    Country: Number of subjects enrolled
    China: 11
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Turkey: 10
    Worldwide total number of subjects
    269
    EEA total number of subjects
    116
    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)
    0
    From 65 to 84 years
    258
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted in 88 sites: 16 in the US, 36 in the EEA, and 36 sites in 8 additional countries incl. Canada, China, and Australia. The first subject consented on 21 March 2013 and the data cutoff for the last visit of the last subject was on 04 May 2015.

    Pre-assignment
    Screening details
    Patients with previously untreated CLL were screened for potential participation by the investigators based on the eligibility criteria. Patients who met the criteria were asked whether they were willing to participate in the study. A total of 269 subjects were randomized and evaluated in this study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ibrutinib
    Arm description
    Ibrutinib 420 mg daily
    Arm type
    Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    PCI-32765
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib was supplied as hard gelatin 140-mg capsules for oral (PO) administration. Ibrutinib 420 mg (3 x 140-mg capsules) was administered orally once daily. The first dose was delivered in the clinic on Day 1, after which subsequent dosing was typically on an outpatient basis. Ibrutinib was dispensed to patients in bottles at each visit.

    Arm title
    Chlorambucil
    Arm description
    Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles
    Arm type
    Active comparator

    Investigational medicinal product name
    Chlorambucil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Chlorambucil was supplied as 2-mg tablets for PO administration. Chlorambucil was administered orally on Days 1 and 15 of each 28-day cycle. The starting dosage (Cycle 1) was 0.5 mg/kg. If well tolerated, the Chlorambucil dose could be increased starting at Cycle 2, with increments of 0.1 mg/kg on Day 1 of each cycle to a maximum of 0.8 mg/kg.

    Number of subjects in period 1
    Ibrutinib Chlorambucil
    Started
    136
    133
    Completed
    134
    126
    Not completed
    2
    7
         Consent withdrawn by subject
    2
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ibrutinib
    Reporting group description
    Ibrutinib 420 mg daily

    Reporting group title
    Chlorambucil
    Reporting group description
    Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles

    Reporting group values
    Ibrutinib Chlorambucil Total
    Number of subjects
    136 133 269
    Age Categorical
    Units: Subjects
        <=18 years
    0 0 0
        Between 18 and 65 years
    0 0 0
        >=65 years
    136 133 269
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    73.1 ± 5.67 73.4 ± 5.95 -
    Gender, Male/Female
    Units: Subjects
        Female
    48 52 100
        Male
    88 81 169

    End points

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    End points reporting groups
    Reporting group title
    Ibrutinib
    Reporting group description
    Ibrutinib 420 mg daily

    Reporting group title
    Chlorambucil
    Reporting group description
    Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles

    Primary: PFS (Progression Free Survival)

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    End point title
    PFS (Progression Free Survival)
    End point description
    The primary objective of this study was to evaluate the efficacy of Ibrutinib compared with Chlorambucil based on the independent review committee (IRC) assessment of PFS. Progressive disease according to 2008 IWCLL guidelines was defined as: • Group A o Lymphadenopathy, increase ≥50% o Hepatomegaly, increase ≥50% o Splenomegaly, increase ≥50% o Blood lymphocytes, increase ≥ 50% over baseline • Group B o Platelets counts, decrease of ≥ 50% from baseline secondary to CLL o Hemoglobin, decrease of > 2 g/dL from baseline secondary to CLL
    End point type
    Primary
    End point timeframe
    Analysis was conducted when 15 months had elapsed after the last subject was randomized. The median follow-up time is 18 month. Median PFS has not been reached in the ibrutinib group, therefore, PFS rates at 18 months are presented.
    End point values
    Ibrutinib Chlorambucil
    Number of subjects analysed
    136
    133
    Units: percentage
        number (confidence interval 95%)
    89.9 (83.2 to 94)
    51.5 (41.9 to 60.3)
    Statistical analysis title
    PFS (Progression free survival)
    Comparison groups
    Ibrutinib v Chlorambucil
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.09
         upper limit
    0.28

    Secondary: ORR (Overall Response Rate)

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    End point title
    ORR (Overall Response Rate)
    End point description
    ORR is defined as the proportion of subjects who achieved complete response (CR), complete response with incomplete marrow recovery (CRi), nodule partial response (nPR) or PR per IRC assessment. Response criteria are as outlined in the International Workshop on CLL (iwCLL) 2008 criteria with the 2012 iwCLL modification stating that treatment-related lymphocytosis in the setting of improvement in other parameters was not considered as PD and the 2013 iwCLL clarification of criteria for a partial response to therapy.
    End point type
    Secondary
    End point timeframe
    Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.
    End point values
    Ibrutinib Chlorambucil
    Number of subjects analysed
    136
    133
    Units: percentage of participants
        number (not applicable)
    82.4
    35.3
    Statistical analysis title
    ORR (Overall Response Rate)
    Comparison groups
    Ibrutinib v Chlorambucil
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Overall survival

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    End point title
    Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    Analysis was conducted when 15 months had elapsed after the last subject was randomized. The median follow-up time is 18 month. Median OS has not been reached in the ibrutinib group, therefore, OS rates at 18 months are presented.
    End point values
    Ibrutinib Chlorambucil
    Number of subjects analysed
    136
    133
    Units: percentage
        number (confidence interval 95%)
    97.8 (93.3 to 99.3)
    87.2 (79.9 to 92)
    Statistical analysis title
    OS (overall survival)
    Comparison groups
    Chlorambucil v Ibrutinib
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.05
         upper limit
    0.56

    Secondary: Proportion of Sustained Hemoglobin Improvement

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    End point title
    Proportion of Sustained Hemoglobin Improvement
    End point description
    The proportion of subjects who achieved Hemoglobin >11 g/dL or increase ≥ 2 g/dL over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.
    End point type
    Secondary
    End point timeframe
    Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.
    End point values
    Ibrutinib Chlorambucil
    Number of subjects analysed
    136
    133
    Units: Percentage
        number (not applicable)
    45.6
    20.3
    Statistical analysis title
    Proportion of Sustained Hemoglobin Improvement
    Comparison groups
    Ibrutinib v Chlorambucil
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Chi-squared
    Confidence interval

    Secondary: Proportion of Sustained Hemoglobin Improvement in Subjects With Baseline Anemia

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    End point title
    Proportion of Sustained Hemoglobin Improvement in Subjects With Baseline Anemia
    End point description
    In randomized subjects with baseline hemoglobin ≤ 11 g/dL, the proportion of subjects who achieved Hemoglobin >11 g/dL or increase ≥ 2 g/dL over baseline persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.
    End point type
    Secondary
    End point timeframe
    Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.
    End point values
    Ibrutinib Chlorambucil
    Number of subjects analysed
    51
    55
    Units: percentage
        number (not applicable)
    84.3
    45.5
    Statistical analysis title
    Sustained HGB improvement in baseline anemia
    Comparison groups
    Ibrutinib v Chlorambucil
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Chi-squared
    Confidence interval

    Secondary: Proportion of Sustained Platelet Improvement

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    End point title
    Proportion of Sustained Platelet Improvement
    End point description
    The proportion of subjects who achieved platelet >100 x 10^9/L or increase ≥50% over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.
    End point type
    Secondary
    End point timeframe
    Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.
    End point values
    Ibrutinib Chlorambucil
    Number of subjects analysed
    136
    133
    Units: percentage
        number (not applicable)
    27.2
    11.3
    Statistical analysis title
    Proportion of sustained platelet improvement
    Comparison groups
    Ibrutinib v Chlorambucil
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0009
    Method
    Chi-squared
    Confidence interval

    Secondary: Proportion of Sustained Platelet Improvement in Subjects With Baseline Thrombocytopenia

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    End point title
    Proportion of Sustained Platelet Improvement in Subjects With Baseline Thrombocytopenia
    End point description
    In randomized subjects with baseline platelet ≤ 100 x 10^9/L, the proportion of subjects who achieved platelet >100 x 10^9/L or increase ≥50% over baseline persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.
    End point type
    Secondary
    End point timeframe
    Analysis was conducted when 15 months had elapsed after the last subject was randomized with cutoff date of 4 May 2015. The median follow-up time is 18 month.
    End point values
    Ibrutinib Chlorambucil
    Number of subjects analysed
    35
    28
    Units: percentage
        number (not applicable)
    77.1
    42.9
    Statistical analysis title
    Sustained PLT Impr. in baseline thrombocytopenia
    Comparison groups
    Ibrutinib v Chlorambucil
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0054
    Method
    Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug to within 30 days of last dose or starting new anti-cancer therapy, whichever occurs earlier.
    Adverse event reporting additional description
    269 subjects were randomized on the study of which 2 subjects withdrew without treatment and were not included in the number of participants at risk. Investigators assess the occurrence of AEs and SAEs at all patient evaluation time points during the study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Chlorambucil
    Reporting group description
    Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles

    Reporting group title
    Ibrutinib
    Reporting group description
    Ibrutinib 420 mg daily.

    Serious adverse events
    Chlorambucil Ibrutinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 132 (25.00%)
    55 / 135 (40.74%)
         number of deaths (all causes)
    4
    3
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 132 (0.76%)
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Basosquamous carcinoma of skin
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 132 (0.00%)
    5 / 135 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery aneurysm
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (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 / 132 (0.00%)
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 132 (3.79%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Immune system disorders
    Immunodeficiency
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung infiltration
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 132 (1.52%)
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Somatoform disorder cardiovascular
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Fibrin D dimer increased
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart rate irregular
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Upper limb fracture
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle strain
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haematoma
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 132 (0.76%)
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve disease mixed
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve disease
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (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
    1 / 132 (0.76%)
    0 / 135 (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
    2 / 132 (1.52%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cauda equina syndrome
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 132 (1.52%)
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 132 (1.52%)
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 132 (1.52%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vascular occlusion
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyphaema
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blindness unilateral
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (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
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis toxic
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash macular
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous emphysema
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal haemorrhage
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure chronic
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acute hepatitis B
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 132 (1.52%)
    5 / 135 (3.70%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 132 (0.76%)
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         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 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung infection pseudomonal
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 132 (0.00%)
    3 / 135 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Chlorambucil Ibrutinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    123 / 132 (93.18%)
    133 / 135 (98.52%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 132 (0.00%)
    7 / 135 (5.19%)
         occurrences all number
    0
    9
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 132 (0.00%)
    18 / 135 (13.33%)
         occurrences all number
    0
    34
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    17 / 132 (12.88%)
    22 / 135 (16.30%)
         occurrences all number
    26
    24
    Fatigue
         subjects affected / exposed
    50 / 132 (37.88%)
    41 / 135 (30.37%)
         occurrences all number
    85
    57
    Oedema peripheral
         subjects affected / exposed
    12 / 132 (9.09%)
    25 / 135 (18.52%)
         occurrences all number
    12
    38
    Asthenia
         subjects affected / exposed
    0 / 132 (0.00%)
    10 / 135 (7.41%)
         occurrences all number
    0
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 132 (15.15%)
    30 / 135 (22.22%)
         occurrences all number
    24
    45
    Dyspnoea
         subjects affected / exposed
    13 / 132 (9.85%)
    14 / 135 (10.37%)
         occurrences all number
    16
    23
    Oropharyngeal pain
         subjects affected / exposed
    0 / 132 (0.00%)
    8 / 135 (5.93%)
         occurrences all number
    0
    11
    Epistaxis
         subjects affected / exposed
    0 / 132 (0.00%)
    8 / 135 (5.93%)
         occurrences all number
    0
    10
    Pleural effusion
         subjects affected / exposed
    0 / 132 (0.00%)
    9 / 135 (6.67%)
         occurrences all number
    0
    15
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    9 / 132 (6.82%)
    11 / 135 (8.15%)
         occurrences all number
    11
    12
    Anxiety
         subjects affected / exposed
    0 / 132 (0.00%)
    7 / 135 (5.19%)
         occurrences all number
    0
    8
    Investigations
    Weight decreased
         subjects affected / exposed
    16 / 132 (12.12%)
    14 / 135 (10.37%)
         occurrences all number
    16
    15
    Platelet count decreased
         subjects affected / exposed
    0 / 132 (0.00%)
    7 / 135 (5.19%)
         occurrences all number
    0
    45
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 132 (0.00%)
    11 / 135 (8.15%)
         occurrences all number
    0
    21
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 132 (0.00%)
    7 / 135 (5.19%)
         occurrences all number
    0
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 132 (9.85%)
    16 / 135 (11.85%)
         occurrences all number
    23
    27
    Dizziness
         subjects affected / exposed
    16 / 132 (12.12%)
    15 / 135 (11.11%)
         occurrences all number
    22
    18
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    29 / 132 (21.97%)
    20 / 135 (14.81%)
         occurrences all number
    51
    33
    Anaemia
         subjects affected / exposed
    27 / 132 (20.45%)
    24 / 135 (17.78%)
         occurrences all number
    56
    52
    Thrombocytopenia
         subjects affected / exposed
    17 / 132 (12.88%)
    11 / 135 (8.15%)
         occurrences all number
    29
    29
    Increased tendency to bruise
         subjects affected / exposed
    0 / 132 (0.00%)
    8 / 135 (5.93%)
         occurrences all number
    0
    9
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    8 / 132 (6.06%)
    18 / 135 (13.33%)
         occurrences all number
    10
    35
    Vision blurred
         subjects affected / exposed
    10 / 132 (7.58%)
    18 / 135 (13.33%)
         occurrences all number
    10
    21
    Dry eye
         subjects affected / exposed
    0 / 132 (0.00%)
    23 / 135 (17.04%)
         occurrences all number
    0
    30
    Eye pain
         subjects affected / exposed
    0 / 132 (0.00%)
    8 / 135 (5.93%)
         occurrences all number
    0
    8
    Visual acuity reduced
         subjects affected / exposed
    0 / 132 (0.00%)
    15 / 135 (11.11%)
         occurrences all number
    0
    19
    Vitreous floaters
         subjects affected / exposed
    0 / 132 (0.00%)
    8 / 135 (5.93%)
         occurrences all number
    0
    10
    Cataract
         subjects affected / exposed
    0 / 132 (0.00%)
    7 / 135 (5.19%)
         occurrences all number
    0
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    14 / 132 (10.61%)
    17 / 135 (12.59%)
         occurrences all number
    14
    22
    Diarrhoea
         subjects affected / exposed
    22 / 132 (16.67%)
    57 / 135 (42.22%)
         occurrences all number
    33
    99
    Nausea
         subjects affected / exposed
    52 / 132 (39.39%)
    30 / 135 (22.22%)
         occurrences all number
    74
    40
    Constipation
         subjects affected / exposed
    21 / 132 (15.91%)
    20 / 135 (14.81%)
         occurrences all number
    21
    24
    Vomiting
         subjects affected / exposed
    27 / 132 (20.45%)
    18 / 135 (13.33%)
         occurrences all number
    41
    19
    Dyspepsia
         subjects affected / exposed
    0 / 132 (0.00%)
    15 / 135 (11.11%)
         occurrences all number
    0
    19
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 132 (0.00%)
    9 / 135 (6.67%)
         occurrences all number
    0
    9
    Stomatitis
         subjects affected / exposed
    0 / 132 (0.00%)
    11 / 135 (8.15%)
         occurrences all number
    0
    16
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    7 / 132 (5.30%)
    8 / 135 (5.93%)
         occurrences all number
    16
    9
    Night sweats
         subjects affected / exposed
    10 / 132 (7.58%)
    9 / 135 (6.67%)
         occurrences all number
    12
    9
    Rash erythematous
         subjects affected / exposed
    0 / 132 (0.00%)
    13 / 135 (9.63%)
         occurrences all number
    0
    21
    Dry skin
         subjects affected / exposed
    0 / 132 (0.00%)
    7 / 135 (5.19%)
         occurrences all number
    0
    7
    Rash maculo-papular
         subjects affected / exposed
    0 / 132 (0.00%)
    8 / 135 (5.93%)
         occurrences all number
    0
    16
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 132 (0.00%)
    8 / 135 (5.93%)
         occurrences all number
    0
    9
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    9 / 132 (6.82%)
    16 / 135 (11.85%)
         occurrences all number
    9
    19
    Pain in extremity
         subjects affected / exposed
    7 / 132 (5.30%)
    13 / 135 (9.63%)
         occurrences all number
    7
    13
    Arthralgia
         subjects affected / exposed
    9 / 132 (6.82%)
    22 / 135 (16.30%)
         occurrences all number
    15
    33
    Muscle spasms
         subjects affected / exposed
    7 / 132 (5.30%)
    15 / 135 (11.11%)
         occurrences all number
    8
    18
    Musculoskeletal pain
         subjects affected / exposed
    0 / 132 (0.00%)
    11 / 135 (8.15%)
         occurrences all number
    0
    11
    Myalgia
         subjects affected / exposed
    0 / 132 (0.00%)
    8 / 135 (5.93%)
         occurrences all number
    0
    11
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    23 / 132 (17.42%)
    22 / 135 (16.30%)
         occurrences all number
    29
    29
    Urinary tract infection
         subjects affected / exposed
    10 / 132 (7.58%)
    13 / 135 (9.63%)
         occurrences all number
    15
    23
    Herpes zoster
         subjects affected / exposed
    7 / 132 (5.30%)
    0 / 135 (0.00%)
         occurrences all number
    8
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 132 (0.00%)
    11 / 135 (8.15%)
         occurrences all number
    0
    20
    Skin infection
         subjects affected / exposed
    0 / 132 (0.00%)
    7 / 135 (5.19%)
         occurrences all number
    0
    7
    Cellulitis
         subjects affected / exposed
    0 / 132 (0.00%)
    8 / 135 (5.93%)
         occurrences all number
    0
    8
    Sinusitis
         subjects affected / exposed
    0 / 132 (0.00%)
    7 / 135 (5.19%)
         occurrences all number
    0
    8
    Nasopharyngitis
         subjects affected / exposed
    0 / 132 (0.00%)
    10 / 135 (7.41%)
         occurrences all number
    0
    13
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    19 / 132 (14.39%)
    13 / 135 (9.63%)
         occurrences all number
    26
    16
    Hypokalaemia
         subjects affected / exposed
    0 / 132 (0.00%)
    8 / 135 (5.93%)
         occurrences all number
    0
    9
    Hyponatraemia
         subjects affected / exposed
    0 / 132 (0.00%)
    7 / 135 (5.19%)
         occurrences all number
    0
    11
    Hyperuricaemia
         subjects affected / exposed
    0 / 132 (0.00%)
    8 / 135 (5.93%)
         occurrences all number
    0
    9

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jan 2013
    • Removed the 12-month time limit after last chlorambucil dose to receive second-line ibrutinib in Study 1116 • Updated guidance on missed dose, treatment-related lymphocytosis, use of anti-coagulant, anti-platelet and QT-prolonging agents • Added guidance on perioperative management of ibrutinib • Required that SAEs that occur >30 days after the last dose of study drug, if deemed ibrutinib-related, be reported to the Sponsor • Added that other malignancies were to be reported throughout the study • Updated the Summary of Safety section to align with the IB and the FDA approved product label
    05 Mar 2014
    • Updated the guidance for the management of ibrutinib with concomitant CYP3A inhibitors or inducers • Required screening FISH analysis results to be available prior to randomization
    17 Feb 2015
    • Clarified that in the event that a bone marrow sample for MRD assessment could not be • obtained, a peripheral blood sample should be submitted • Clarified criteria for hematological improvement • Specified that PFS will not be censored at the start of new anti-cancer therapy • Clarified criteria defining PR and PRL based on updated response criteria (Hallek et al, 2013; Cheson et al, 2012; Hallek et al, 2012) • Updated safety information and concomitant medication administration sections to align with the IB and the FDA-approved product label • Revised assessment of EFS and revised the schedule for subjects confirmed as MRD negative in the marrow to be followed by peripheral blood MRD analyses, from every 3 months to every 4 months to be consistent with the 4-month visit schedule

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/26639149
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