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    Clinical Trial Results:
    A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) versus Ofatumumab in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

    Summary
    EudraCT number
    2012-000694-23
    Trial protocol
    GB   IE   PL   ES   IT   AT   BE  
    Global end of trial date
    25 Oct 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    08 Nov 2019
    First version publication date
    14 Oct 2016
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Results updated with data from the final analysis.

    Trial information

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    Trial identification
    Sponsor protocol code
    PCYC-1112-CA
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01578707
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    provider NLM_DES study id: S0003GEU
    Sponsors
    Sponsor organisation name
    Pharmacyclics LLC
    Sponsor organisation address
    999 E Arques Ave, Sunnyvale, United States, 94085
    Public contact
    Medinfo, Pharmacyclics LLC, +1 408-774-0330, info@pcyc.com
    Scientific contact
    Medinfo, Pharmacyclics LLC, +1 408-774-0330, 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
    26 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of the study was to evaluate whether treatment with ibrutinib as a monotherapy results in a clinically significant improvement in progression free survival (PFS) as compared to treatment with ofatumumab in patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and ICH GCP.
    Background therapy
    -
    Evidence for comparator
    NCCN and ESMO Guidelines Support the use of ofatumumab in the target patient population.
    Actual start date of recruitment
    22 Jun 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 29
    Country: Number of subjects enrolled
    United States: 192
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    France: 27
    Country: Number of subjects enrolled
    United Kingdom: 73
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Ireland: 9
    Country: Number of subjects enrolled
    Austria: 16
    Worldwide total number of subjects
    391
    EEA total number of subjects
    170
    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)
    152
    From 65 to 84 years
    235
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 391 subjects were enrolled in the study from sites located in the US, Europe, and Australia. The first subject consented 22 June 2012. After the primary analysis patients were followed-up for 5 years until 25 October 2018 (LPLV).

    Pre-assignment
    Screening details
    Patients with previously treated 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 391 subjects were randomized.

    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
    Ofatumumab (Arm A)
    Arm description
    The ofatumumab (IV) dosage and schedule was 12 doses administered over 24 weeks or until disease progression or unacceptable toxicity.
    Arm type
    Active comparator

    Investigational medicinal product name
    ofatumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The ofatumumab (IV) dosage and schedule was 12 doses administered over 24 weeks or until disease progression, unacceptable toxicity. Week 1: 300 mg initial dose Week 2 through 8: 2,000 mg (once weekly) Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks)

    Arm title
    ibrutinib (Arm B)
    Arm description
    Ibrutinib 420 mg daily administered until disease progression or unacceptable toxicity.
    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 420 mg (3 x 140-mg capsules) was administered orally once daily until disease progression or unacceptable toxicity

    Number of subjects in period 1
    Ofatumumab (Arm A) ibrutinib (Arm B)
    Started
    196
    195
    Completed
    185
    180
    Not completed
    11
    15
         Consent withdrawn by subject
    6
    15
         Did not receive study drug
    5
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ofatumumab (Arm A)
    Reporting group description
    The ofatumumab (IV) dosage and schedule was 12 doses administered over 24 weeks or until disease progression or unacceptable toxicity.

    Reporting group title
    ibrutinib (Arm B)
    Reporting group description
    Ibrutinib 420 mg daily administered until disease progression or unacceptable toxicity.

    Reporting group values
    Ofatumumab (Arm A) ibrutinib (Arm B) Total
    Number of subjects
    196 195 391
    Age Categorical
    Units: Subjects
        <=18 years
    0 0 0
        Between 18 and 65 years
    75 77 152
        >=65 years
    121 118 239
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    66.8 ( 8.88 ) 66.1 ( 10.15 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    59 66 125
        Male
    137 129 266

    End points

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    End points reporting groups
    Reporting group title
    Ofatumumab (Arm A)
    Reporting group description
    The ofatumumab (IV) dosage and schedule was 12 doses administered over 24 weeks or until disease progression or unacceptable toxicity.

    Reporting group title
    ibrutinib (Arm B)
    Reporting group description
    Ibrutinib 420 mg daily administered until disease progression or unacceptable toxicity.

    Primary: mPFS (median Progression Free Survival)

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    End point title
    mPFS (median Progression Free Survival)
    End point description
    The primary objective of this study was to evaluate the efficacy of ibrutinib compared to ofatumumab based on progression-free survival (PFS) assessed by the Independent Review Committee (IRC) per International Workshop on Chronic Lymphocytic Leukemia Criteria (IWCLL; Hallek et al, 2008) in subjects with relapsed or refractory CLL/SLL. IRC assessment was discontinued after the primary analysis. Therefore, the present data are based on investigator assessment.
    End point type
    Primary
    End point timeframe
    Analysis was conducted after observing 298 PFS events. Median follow-up time in the study was 65.4 month.
    End point values
    Ofatumumab (Arm A) ibrutinib (Arm B)
    Number of subjects analysed
    196
    195
    Units: months
        number (confidence interval 95%)
    8.1 (7.79 to 8.25)
    44.1 (38.47 to 56.18)
    Statistical analysis title
    PFS (Progression free survival
    Comparison groups
    Ofatumumab (Arm A) v ibrutinib (Arm B)
    Number of subjects included in analysis
    391
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Kaplan-Meier estimates
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.148
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.113
         upper limit
    0.196

    Secondary: mOS (median Overall Survival)

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    End point title
    mOS (median Overall Survival)
    End point description
    Crossover from ofatumumab to ibrutinib treatment upon IRC-confirmed disease progression was instituted starting in August 2013 and 133 of 196 subjects (67.9%) randomized to ofatumumab had crossed over to ibrutinib treatment as subsequent therapy impacting on the outcome of this endpoint.
    End point type
    Secondary
    End point timeframe
    Analysis was conducted after observing 176 death events. Median follow-up time in the study was 65.4 months.
    End point values
    Ofatumumab (Arm A) ibrutinib (Arm B)
    Number of subjects analysed
    196
    195
    Units: months
        number (not applicable)
    65.1
    67.7
    Statistical analysis title
    mOS (median Overall Survival)
    Statistical analysis description
    Analysis confounded by crossover of two thirds of ofatumumab subjects to ibrutinib.
    Comparison groups
    ibrutinib (Arm B) v Ofatumumab (Arm A)
    Number of subjects included in analysis
    391
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1653
    Method
    Kaplan-Meier Estimates
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.602
         upper limit
    1.091

    Secondary: ORR (Overall Response Rate)

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    End point title
    ORR (Overall Response Rate)
    End point description
    ORR was defined as the Proportion of subjects who achieved Complete Response (CR), Complete Response with incomplete marrow recovery (CRi), nodule Partial Response (nPR), or Partial Response (PR) per investigator assessment.
    End point type
    Secondary
    End point timeframe
    Median follow-up time in the study was 65.4 months.
    End point values
    Ofatumumab (Arm A) ibrutinib (Arm B)
    Number of subjects analysed
    196
    195
    Units: percentage
        number (not applicable)
    22.4
    87.7
    Statistical analysis title
    ORR (Overall response rate)
    Comparison groups
    Ofatumumab (Arm A) v ibrutinib (Arm B)
    Number of subjects included in analysis
    391
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Fisher exact
    Confidence interval

    Secondary: PFS2

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    End point title
    PFS2
    End point description
    PFS2 was defined as the time from date of randomization to the date of the earliest of the following 3 types of events: • Progressive disease per investigator response assessment after administration of the first subsequent anti-neoplastic therapy • Death at any time on study due to any cause • Initiation of a second subsequent antineoplastic therapy
    End point type
    Secondary
    End point timeframe
    Assessment after a median time on study of 65.4 months.
    End point values
    Ofatumumab (Arm A) ibrutinib (Arm B)
    Number of subjects analysed
    196
    191
    Units: months
        number (not applicable)
    38.5
    65.4
    No statistical analyses for this end point

    Secondary: Sustained hemoglobin improvement

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    End point title
    Sustained hemoglobin improvement
    End point description
    Sustained hemoglobin improvement was defined as hemoglobin increase >= 20 g/L over baseline continuously for >= 56 days without blood transfusion or growth factors.
    End point type
    Secondary
    End point timeframe
    Analysis was conducted after observing 298 PFS events. Median follow-up time in the study was 65.4 month.
    End point values
    Ofatumumab (Arm A) ibrutinib (Arm B)
    Number of subjects analysed
    196
    195
    Units: patients
    37
    91
    No statistical analyses for this end point

    Secondary: Sustained platelet improvment

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    End point title
    Sustained platelet improvment
    End point description
    Sustained platelet improvement is defined as platelet increase >= 50% over baseline continuously for >= 56 days without blood transfusion or growth factors.
    End point type
    Secondary
    End point timeframe
    Analysis was conducted after observing 298 PFS events. Median follow-up time in the study was 65.4 month.
    End point values
    Ofatumumab (Arm A) ibrutinib (Arm B)
    Number of subjects analysed
    196
    195
    Units: patients
    10
    74
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From June 2012 through October 2018
    Adverse event reporting additional description
    Note: Exposure to ibrutinib at the final analysis has been about 8 times longer (median 41.0 months) as compared to ofatumumab (median 5.3 months). Adverse event reporting has not been adjusted for exposure.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Ofatumumab (Arm A)
    Reporting group description
    An anti-CD20 monoclonal antibody Ofatumumab: The ofatumumab (IV) dosage and schedule was 12 doses administered over 24 weeks or until disease progression, unacceptable toxicity.

    Reporting group title
    ibrutinib (Arm B)
    Reporting group description
    A Bruton Tyrosine Kinase Inhibitor ibrutinib: ibrutinib 420 mg (3 x 140-mg capsules) was administered orally once daily until disease progression or unacceptable toxicity

    Serious adverse events
    Ofatumumab (Arm A) ibrutinib (Arm B)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    59 / 191 (30.89%)
    141 / 195 (72.31%)
         number of deaths (all causes)
    91
    85
         number of deaths resulting from adverse events
    16
    24
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Leukaemia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    3 / 191 (1.57%)
    5 / 195 (2.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Gastrointestinal carcinoma
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Richter's syndrome
         subjects affected / exposed
    0 / 191 (0.00%)
    3 / 195 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Tumour flare
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 191 (0.00%)
    3 / 195 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hodgkin's disease
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone cancer metastatic
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm malignant
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         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 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Desmoid tumour
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Histiocytic sarcoma
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal papillary mucinous neoplasm
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aneurysm
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         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
    Cyst
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         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
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 191 (0.00%)
    3 / 195 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 191 (2.09%)
    15 / 195 (7.69%)
         occurrences causally related to treatment / all
    2 / 4
    7 / 22
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Asthenia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site pain
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         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 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site extravasation
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Effusion
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 191 (0.52%)
    3 / 195 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumopathy
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (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
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract inflammation
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 191 (0.00%)
    4 / 195 (2.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 191 (0.00%)
    3 / 195 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         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
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 191 (0.00%)
    3 / 195 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination, visual
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Immunoglobulins decreased
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         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
    Muscle strain
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    2 / 191 (1.05%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 191 (0.00%)
    6 / 195 (3.08%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Femur fracture
         subjects affected / exposed
    0 / 191 (0.00%)
    4 / 195 (2.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropod bite
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns third degree
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         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 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haematoma
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         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 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         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 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 191 (0.52%)
    11 / 195 (5.64%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 191 (0.52%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 191 (0.00%)
    3 / 195 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 191 (0.52%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve disease
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 191 (0.00%)
    3 / 195 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    4 / 191 (2.09%)
    7 / 195 (3.59%)
         occurrences causally related to treatment / all
    3 / 8
    4 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    4 / 191 (2.09%)
    5 / 195 (2.56%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 191 (1.05%)
    4 / 195 (2.05%)
         occurrences causally related to treatment / all
    1 / 2
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Methaemoglobinaemia
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spontaneous haematoma
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 191 (0.52%)
    6 / 195 (3.08%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 191 (0.52%)
    4 / 195 (2.05%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malabsorption
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 191 (0.00%)
    3 / 195 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal spasm
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poor dental condition
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 191 (0.00%)
    5 / 195 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal discomfort
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucous stools
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal spasm
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyoderma gangrenosum
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         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 impairment
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 191 (1.05%)
    4 / 195 (2.05%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Haematuria
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         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 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         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 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 191 (0.00%)
    4 / 195 (2.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pain in extremity
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal infection
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 191 (1.05%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteroides bacteraemia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 191 (1.05%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 191 (0.52%)
    8 / 195 (4.10%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal infection
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 191 (0.00%)
    4 / 195 (2.05%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Folliculitis
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus sepsis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus bacteraemia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 191 (0.52%)
    3 / 195 (1.54%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 191 (0.52%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impetigo
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 191 (1.05%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 191 (0.00%)
    7 / 195 (3.59%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 191 (1.05%)
    4 / 195 (2.05%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph gland infection
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nocardiosis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (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
    2 / 191 (1.05%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Pneumocystis jirovecii infection
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 191 (0.52%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    12 / 191 (6.28%)
    42 / 195 (21.54%)
         occurrences causally related to treatment / all
    8 / 14
    23 / 60
         deaths causally related to treatment / all
    1 / 3
    1 / 5
    Pneumonia bacterial
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 191 (1.05%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis syndrome
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 191 (1.05%)
    8 / 195 (4.10%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Tonsillitis fungal
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 191 (2.09%)
    4 / 195 (2.05%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Stenotrophomonas infection
         subjects affected / exposed
    2 / 191 (1.05%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 191 (0.00%)
    9 / 195 (4.62%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethritis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 191 (0.52%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    H1N1 influenza
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus infection
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis pneumococcal
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycobacterium avium complex infection
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    2 / 191 (1.05%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection pseudomonal
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 191 (0.00%)
    3 / 195 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 195 (0.51%)
         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
    Ofatumumab (Arm A) ibrutinib (Arm B)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    185 / 191 (96.86%)
    194 / 195 (99.49%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 191 (1.05%)
    18 / 195 (9.23%)
         occurrences all number
    2
    31
    Squamous cell carcinoma
         subjects affected / exposed
    2 / 191 (1.05%)
    13 / 195 (6.67%)
         occurrences all number
    3
    19
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 191 (2.09%)
    40 / 195 (20.51%)
         occurrences all number
    5
    53
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    8 / 191 (4.19%)
    22 / 195 (11.28%)
         occurrences all number
    8
    40
    Fatigue
         subjects affected / exposed
    57 / 191 (29.84%)
    82 / 195 (42.05%)
         occurrences all number
    78
    145
    Oedema peripheral
         subjects affected / exposed
    16 / 191 (8.38%)
    46 / 195 (23.59%)
         occurrences all number
    19
    68
    Pyrexia
         subjects affected / exposed
    27 / 191 (14.14%)
    66 / 195 (33.85%)
         occurrences all number
    39
    123
    Chills
         subjects affected / exposed
    6 / 191 (3.14%)
    16 / 195 (8.21%)
         occurrences all number
    8
    27
    Influenza like illness
         subjects affected / exposed
    5 / 191 (2.62%)
    16 / 195 (8.21%)
         occurrences all number
    5
    27
    Malaise
         subjects affected / exposed
    1 / 191 (0.52%)
    10 / 195 (5.13%)
         occurrences all number
    1
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    43 / 191 (22.51%)
    78 / 195 (40.00%)
         occurrences all number
    55
    135
    Dyspnoea
         subjects affected / exposed
    18 / 191 (9.42%)
    32 / 195 (16.41%)
         occurrences all number
    20
    46
    Epistaxis
         subjects affected / exposed
    5 / 191 (2.62%)
    30 / 195 (15.38%)
         occurrences all number
    6
    41
    Oropharyngeal pain
         subjects affected / exposed
    9 / 191 (4.71%)
    33 / 195 (16.92%)
         occurrences all number
    10
    43
    Rhinorrhoea
         subjects affected / exposed
    6 / 191 (3.14%)
    19 / 195 (9.74%)
         occurrences all number
    6
    22
    Nasal congestion
         subjects affected / exposed
    6 / 191 (3.14%)
    17 / 195 (8.72%)
         occurrences all number
    7
    19
    Dyspnoea exertional
         subjects affected / exposed
    4 / 191 (2.09%)
    14 / 195 (7.18%)
         occurrences all number
    4
    18
    Productive cough
         subjects affected / exposed
    5 / 191 (2.62%)
    14 / 195 (7.18%)
         occurrences all number
    7
    19
    Dysphonia
         subjects affected / exposed
    0 / 191 (0.00%)
    10 / 195 (5.13%)
         occurrences all number
    0
    13
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    16 / 191 (8.38%)
    17 / 195 (8.72%)
         occurrences all number
    16
    20
    Anxiety
         subjects affected / exposed
    9 / 191 (4.71%)
    18 / 195 (9.23%)
         occurrences all number
    9
    20
    Depression
         subjects affected / exposed
    3 / 191 (1.57%)
    17 / 195 (8.72%)
         occurrences all number
    3
    19
    Confusional state
         subjects affected / exposed
    4 / 191 (2.09%)
    11 / 195 (5.64%)
         occurrences all number
    4
    16
    Investigations
    Weight decreased
         subjects affected / exposed
    11 / 191 (5.76%)
    25 / 195 (12.82%)
         occurrences all number
    11
    33
    Blood creatinine increased
         subjects affected / exposed
    0 / 191 (0.00%)
    12 / 195 (6.15%)
         occurrences all number
    0
    18
    Platelet count decreased
         subjects affected / exposed
    0 / 191 (0.00%)
    11 / 195 (5.64%)
         occurrences all number
    0
    13
    Weight increased
         subjects affected / exposed
    0 / 191 (0.00%)
    11 / 195 (5.64%)
         occurrences all number
    0
    17
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    64 / 191 (33.51%)
    0 / 195 (0.00%)
         occurrences all number
    94
    0
    Contusion
         subjects affected / exposed
    6 / 191 (3.14%)
    38 / 195 (19.49%)
         occurrences all number
    6
    52
    Fall
         subjects affected / exposed
    1 / 191 (0.52%)
    18 / 195 (9.23%)
         occurrences all number
    1
    40
    Traumatic haematoma
         subjects affected / exposed
    0 / 191 (0.00%)
    12 / 195 (6.15%)
         occurrences all number
    0
    19
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 191 (0.00%)
    19 / 195 (9.74%)
         occurrences all number
    0
    26
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 191 (6.28%)
    41 / 195 (21.03%)
         occurrences all number
    12
    62
    Dizziness
         subjects affected / exposed
    10 / 191 (5.24%)
    33 / 195 (16.92%)
         occurrences all number
    11
    50
    Paraesthesia
         subjects affected / exposed
    10 / 191 (5.24%)
    14 / 195 (7.18%)
         occurrences all number
    12
    16
    Peripheral sensory neuropathy
         subjects affected / exposed
    26 / 191 (13.61%)
    22 / 195 (11.28%)
         occurrences all number
    33
    27
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    32 / 191 (16.75%)
    62 / 195 (31.79%)
         occurrences all number
    58
    115
    Increased tendency to bruise
         subjects affected / exposed
    4 / 191 (2.09%)
    45 / 195 (23.08%)
         occurrences all number
    4
    60
    Neutropenia
         subjects affected / exposed
    25 / 191 (13.09%)
    60 / 195 (30.77%)
         occurrences all number
    61
    184
    Thrombocytopenia
         subjects affected / exposed
    22 / 191 (11.52%)
    45 / 195 (23.08%)
         occurrences all number
    30
    86
    lymphocytosis
         subjects affected / exposed
    5 / 191 (2.62%)
    10 / 195 (5.13%)
         occurrences all number
    6
    15
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    5 / 191 (2.62%)
    27 / 195 (13.85%)
         occurrences all number
    5
    35
    Dry eye
         subjects affected / exposed
    10 / 191 (5.24%)
    33 / 195 (16.92%)
         occurrences all number
    10
    39
    Vision blurred
         subjects affected / exposed
    6 / 191 (3.14%)
    30 / 195 (15.38%)
         occurrences all number
    6
    36
    Cataract
         subjects affected / exposed
    2 / 191 (1.05%)
    26 / 195 (13.33%)
         occurrences all number
    2
    31
    Visual acuity reduced
         subjects affected / exposed
    1 / 191 (0.52%)
    19 / 195 (9.74%)
         occurrences all number
    1
    25
    Eye irritation
         subjects affected / exposed
    3 / 191 (1.57%)
    17 / 195 (8.72%)
         occurrences all number
    3
    19
    eye pain
         subjects affected / exposed
    5 / 191 (2.62%)
    15 / 195 (7.69%)
         occurrences all number
    6
    20
    Photophobia
         subjects affected / exposed
    4 / 191 (2.09%)
    14 / 195 (7.18%)
         occurrences all number
    4
    21
    Vitreous floaters
         subjects affected / exposed
    3 / 191 (1.57%)
    14 / 195 (7.18%)
         occurrences all number
    3
    15
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    1 / 191 (0.52%)
    19 / 195 (9.74%)
         occurrences all number
    1
    23
    Dyspepsia
         subjects affected / exposed
    6 / 191 (3.14%)
    22 / 195 (11.28%)
         occurrences all number
    6
    32
    Diarrhoea
         subjects affected / exposed
    33 / 191 (17.28%)
    120 / 195 (61.54%)
         occurrences all number
    39
    247
    Constipation
         subjects affected / exposed
    19 / 191 (9.95%)
    45 / 195 (23.08%)
         occurrences all number
    20
    72
    Abdominal pain
         subjects affected / exposed
    19 / 191 (9.95%)
    30 / 195 (15.38%)
         occurrences all number
    21
    39
    Vomiting
         subjects affected / exposed
    11 / 191 (5.76%)
    39 / 195 (20.00%)
         occurrences all number
    14
    81
    Nausea
         subjects affected / exposed
    38 / 191 (19.90%)
    69 / 195 (35.38%)
         occurrences all number
    53
    122
    Stomatitis
         subjects affected / exposed
    5 / 191 (2.62%)
    30 / 195 (15.38%)
         occurrences all number
    5
    41
    Flatulence
         subjects affected / exposed
    2 / 191 (1.05%)
    10 / 195 (5.13%)
         occurrences all number
    2
    11
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 191 (1.57%)
    21 / 195 (10.77%)
         occurrences all number
    3
    23
    Abdominal pain upper
         subjects affected / exposed
    3 / 191 (1.57%)
    16 / 195 (8.21%)
         occurrences all number
    3
    30
    Haemorrhoids
         subjects affected / exposed
    3 / 191 (1.57%)
    10 / 195 (5.13%)
         occurrences all number
    3
    10
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    7 / 191 (3.66%)
    26 / 195 (13.33%)
         occurrences all number
    9
    39
    Pruritus
         subjects affected / exposed
    18 / 191 (9.42%)
    19 / 195 (9.74%)
         occurrences all number
    20
    26
    Rash
         subjects affected / exposed
    7 / 191 (3.66%)
    19 / 195 (9.74%)
         occurrences all number
    9
    32
    Rash erythematous
         subjects affected / exposed
    9 / 191 (4.71%)
    20 / 195 (10.26%)
         occurrences all number
    13
    26
    Petechiae
         subjects affected / exposed
    2 / 191 (1.05%)
    28 / 195 (14.36%)
         occurrences all number
    2
    38
    Night sweats
         subjects affected / exposed
    23 / 191 (12.04%)
    24 / 195 (12.31%)
         occurrences all number
    26
    29
    Skin lesion
         subjects affected / exposed
    5 / 191 (2.62%)
    24 / 195 (12.31%)
         occurrences all number
    5
    40
    Dry skin
         subjects affected / exposed
    3 / 191 (1.57%)
    18 / 195 (9.23%)
         occurrences all number
    3
    22
    Actinic keratosis
         subjects affected / exposed
    5 / 191 (2.62%)
    16 / 195 (8.21%)
         occurrences all number
    5
    21
    Ecchymosis
         subjects affected / exposed
    0 / 191 (0.00%)
    12 / 195 (6.15%)
         occurrences all number
    0
    22
    Onychoclasis
         subjects affected / exposed
    0 / 191 (0.00%)
    12 / 195 (6.15%)
         occurrences all number
    0
    12
    Blood blister
         subjects affected / exposed
    1 / 191 (0.52%)
    10 / 195 (5.13%)
         occurrences all number
    1
    14
    Skin ulcer
         subjects affected / exposed
    0 / 191 (0.00%)
    10 / 195 (5.13%)
         occurrences all number
    0
    13
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    3 / 191 (1.57%)
    19 / 195 (9.74%)
         occurrences all number
    3
    21
    Dysuria
         subjects affected / exposed
    1 / 191 (0.52%)
    12 / 195 (6.15%)
         occurrences all number
    1
    14
    Haematuria
         subjects affected / exposed
    2 / 191 (1.05%)
    12 / 195 (6.15%)
         occurrences all number
    2
    16
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    14 / 191 (7.33%)
    39 / 195 (20.00%)
         occurrences all number
    17
    49
    Arthralgia
         subjects affected / exposed
    14 / 191 (7.33%)
    53 / 195 (27.18%)
         occurrences all number
    17
    103
    Pain in extremity
         subjects affected / exposed
    9 / 191 (4.71%)
    29 / 195 (14.87%)
         occurrences all number
    10
    39
    Myalgia
         subjects affected / exposed
    7 / 191 (3.66%)
    24 / 195 (12.31%)
         occurrences all number
    9
    34
    Muscle spasms
         subjects affected / exposed
    16 / 191 (8.38%)
    46 / 195 (23.59%)
         occurrences all number
    18
    71
    Musculoskeletal pain
         subjects affected / exposed
    9 / 191 (4.71%)
    20 / 195 (10.26%)
         occurrences all number
    10
    23
    Bone pain
         subjects affected / exposed
    3 / 191 (1.57%)
    10 / 195 (5.13%)
         occurrences all number
    4
    11
    Muscular weakness
         subjects affected / exposed
    3 / 191 (1.57%)
    10 / 195 (5.13%)
         occurrences all number
    4
    11
    Neck pain
         subjects affected / exposed
    0 / 191 (0.00%)
    10 / 195 (5.13%)
         occurrences all number
    0
    13
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    12 / 191 (6.28%)
    50 / 195 (25.64%)
         occurrences all number
    15
    77
    Upper respiratory tract infection
         subjects affected / exposed
    17 / 191 (8.90%)
    77 / 195 (39.49%)
         occurrences all number
    19
    124
    Urinary tract infection
         subjects affected / exposed
    10 / 191 (5.24%)
    46 / 195 (23.59%)
         occurrences all number
    11
    76
    Bronchitis
         subjects affected / exposed
    2 / 191 (1.05%)
    28 / 195 (14.36%)
         occurrences all number
    2
    45
    Nasopharyngitis
         subjects affected / exposed
    7 / 191 (3.66%)
    22 / 195 (11.28%)
         occurrences all number
    8
    30
    Conjunctivitis
         subjects affected / exposed
    2 / 191 (1.05%)
    21 / 195 (10.77%)
         occurrences all number
    2
    23
    Pneumonia
         subjects affected / exposed
    3 / 191 (1.57%)
    21 / 195 (10.77%)
         occurrences all number
    4
    29
    Cellulitis
         subjects affected / exposed
    3 / 191 (1.57%)
    15 / 195 (7.69%)
         occurrences all number
    4
    29
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 191 (0.00%)
    15 / 195 (7.69%)
         occurrences all number
    0
    20
    Herpes zoster
         subjects affected / exposed
    3 / 191 (1.57%)
    14 / 195 (7.18%)
         occurrences all number
    5
    15
    Ear infection
         subjects affected / exposed
    2 / 191 (1.05%)
    13 / 195 (6.67%)
         occurrences all number
    2
    16
    Folliculitis
         subjects affected / exposed
    0 / 191 (0.00%)
    10 / 195 (5.13%)
         occurrences all number
    0
    11
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    6 / 191 (3.14%)
    16 / 195 (8.21%)
         occurrences all number
    10
    31
    Hyperuricaemia
         subjects affected / exposed
    4 / 191 (2.09%)
    22 / 195 (11.28%)
         occurrences all number
    4
    26
    Decreased appetite
         subjects affected / exposed
    16 / 191 (8.38%)
    32 / 195 (16.41%)
         occurrences all number
    16
    40
    Hypokalaemia
         subjects affected / exposed
    5 / 191 (2.62%)
    22 / 195 (11.28%)
         occurrences all number
    5
    39
    Hyponatraemia
         subjects affected / exposed
    3 / 191 (1.57%)
    12 / 195 (6.15%)
         occurrences all number
    3
    18

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Sep 2012
    Updated the following information: • Secondary and exploratory objectives/endpoints including corresponding changes to statistical analysis section • Updated response criteria inclusive of the June 2012 clarification to IWCLL 2008 criteria for assessing response with BCR-inhibiting agents, including guidance to assess the clinical improvement in other disease parameters upon observation of lymphocytosis • Guidelines for concomitant use of CYP inhibiting/inducing drugs, QT prolonging medications, and antiplatelet agents and anticoagulants • Revised Inclusion criteria #5 to include subjects age ≥ 70 years who have received ≥ 2 prior lines of systemic therapy • Clarified that 2 separate randomization schemes were to be generated (one for each geographic region [US versus non-US])
    13 Dec 2012
    • Provided instructions on administration of ibrutinib in case of planned or unplanned surgery • Allowed allogeneic stem cell transplant within 6 months prior to randomization with no active graft vs. host disease. • Clarified that pre-treatment FISH should be performed on marrow sample for subjects without lymphocytosis (eg, SLL) • Included provisionary language for supplying ibrutinib to control arm subjects • Allowed screening computed tomography (CT) scan from up to 6 weeks prior to randomization
    08 Aug 2013
    • Allowed subjects treated with ofatumumab and with documented IRC-confirmed progression to receive therapy with ibrutinib at investigator’s discretion • Updated guideline for concomitant use local site or hormonal therapy for non-B cell malignancies and growth factors • Added collection for other malignancies that develop at anytime during study follow-up
    24 Sep 2013
    • Changed the overall two-sided significance level for PFS from 0.01 to 0.05 following review with global regulatory authorities.
    16 Jan 2014
    Pharmacyclics amended this protocol to • allow patients randomized to ofatumumab arm to receive next-line therapy with ibrutinib at investigator's discretion and to remove the requirement of disease progression confirmation by Independent Review Committee (IRC) • reduce the frequency of CT scans to every 24 weeks after 12 months • update Summary of Clinical Safety of Ibrutinib (Section 1.3.2.2.) per Investigator's Brochure version 7
    27 Oct 2014
    Pharmacyclics amended this protocol to • extend the study duration from 3 to 5 years • update Summary of Clinical Safety of Ibrutinib (Section 1.3.2.2.) per Investigator's Brochure version 8 • reduce the frequency of CT scans to annually for patients who have been receiving ibrutinib for 36 months, as well as for patients who were randomized to ofatumumab arm and currently receiving next-line ibrutinib
    28 Sep 2016
    Pharmacyclics is amended this protocol to: • extend the study duration beyond 5 years • implement updates per revised ibrutinib Investigator’s Brochure and label

    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/24881631
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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