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    Clinical Trial Results:
    A prospective, open-label, multicentre phase-II trial to evaluate the efficacy and safety of a sequential regimen of bendamustine followed by ofatumumab and ibrutinib followed by ibrutinib and ofatumumab maintenance in CLL patients (CLL2-BIO-trial of the GCLLSG)

    Summary
    EudraCT number
    		 2014-000590-39
    Trial protocol
    		 DE  
    Global end of trial date
    06 Feb 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Feb 2021
    First version publication date
    24 Feb 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLL2-BIO
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02689141
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Uni-Sponsor No: UNI-KOELN-1773
    Sponsors
    Sponsor organisation name
    University of Cologne
    Sponsor organisation address
    Albertus-Magnus-Platz, Cologne, Germany, 50923
    Public contact
    Information Desk, German CLL Study Group, 0049 0221478 88220, cllstudie@uk-koeln.de
    Scientific contact
    Information Desk, German CLL Study Group, 0049 0221478 88220, cllstudie@uk-koeln.de
    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
    04 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Apr 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the efficacy of a regimen of two debulking cycles of bendamustine chemotherapy followed by a sequential combination therapy of ofatumumab and ibrutinib for induction and maintenance treatment in CLL patients. The primary efficacy parameter (primary endpoint) is the overall response rate (ORR) by investigator assessement. For this, the overall response rate (ORR) at final restaging (RE) 12 weeks after start of the last cycle of induction therapy (end of induction treatment response = EOIT) will be used as primary parameter of efficacy. In the ORR all patients achieving a (clinical) complete response (CR) / complete response with incomplete recovery of the bone marrow (CRi), partial response (PR) and PR with lymphocytosis will be included.
    Protection of trial subjects
    Debulking treatment with Bendamustine should be stopped after the 1st cycle only if severe adverse events occur. Ofatumumab must be administered in a clinical setting (inpatient or outpatient). Patients should be under close supervision of the investigator at all times; resuscitation equipment and medications (including epinephrine for subcutaneous injections, corticosteroids, antihistamines for i.v. injection) should be available for immediate use.
    Background therapy
    		 -
    Evidence for comparator
    		 not available, single-arm phase II trial.
    Actual start date of recruitment
    23 Nov 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 66
    Worldwide total number of subjects
    66
    EEA total number of subjects
    66
    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)
    37
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between 4th February and 4th October 2016, 66 patients were enrolled; one first-line patient with less than two induction cycles (treatment discontinuation due to a generalized seizure on day 4 of induction cycle 2) was excluded from the efficacy analysis as predefined by the protocol but remained in the safety population

    Pre-assignment
    Screening details
    		 68 patients diagnosed with CLL were registered for central screening. The central screening was performed by the GCLLSG central study office in Cologne, Germany and included immunophenotyping, FISH, evaluation of the comorbidity and renal function. 2 patients were not eligible for participitation.

    Pre-assignment period milestones
    Number of subjects started
    		 68 [1]
    Number of subjects completed
    		 66

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Physician decision: 2
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Justification: To verify the eligibility of patients, a central medical review of the screening data was performed and were reviewed by one of the GCLLSG study physicians together with the results of the baseline assessments in the central laboratories, including immunophenotyping and cytogenetics, for confirmation of the eligibility of the patient. 68 pats were screened and 66 enrolled
    Period 1
    Period 1 title
    Overall trial period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Bendamustine/Ofatumumab/Ibrutinib
    Arm description
    		 Chemotherapy with Bendamustine (2 optional cycles), Anti-Cd20 monoclobnal antibody Ofatumumab and BTK-inhibitor Ibrutinib
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    MA number: 70972.00.00
    Other name
    Levact
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Phase 1 Debulking: Cycle 1-2 on days 1 and 2: 70mg/m2 iv

    Investigational medicinal product name
    Ofatumumab
    Investigational medicinal product code
    EU/1/10/625/001
    Other name
    Arzerra
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Induction, cycle 1, day 1: 300 mg; 0.3 mg/ml; Induction cycle 1, days 8 and 15, cycles 2 - 6, day 1,: 1000 mg; 1 mg/ml; Maintenance: cycles 1 – 8, day 1: 1000 mg; 1 mg/ml

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    EU/1/14/945/001
    Other name
    Imbruvica
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Induction, Cycle 1: - -, Cycles 2-6: Days 1-28: Ibrutinib 420 mg (3 tabl.) p.o.; Maintenance, cycles 1-8, days 1-84: Ibrutinib 420 mg (3 tabl.) p.o.

    Number of subjects in period 1
    		Bendamustine/Ofatumumab/Ibrutinib
    Started
    66
    Completed
    45
    Not completed
    21
         Adverse event, serious fatal
    1
         Consent withdrawn by subject
    2
         Adverse event, non-fatal
    10
         Lack of efficacy
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial period
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial period Total
    Number of subjects
    		 66 66
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 37 37
        From 65-84 years
    		 29 29
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 61.0 (51.5 to 72.0) -
    Gender categorical
    Units: Subjects
        Female
    		 24 24
        Male
    		 42 42

    End points

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    End points reporting groups
    Reporting group title
    Bendamustine/Ofatumumab/Ibrutinib
    Reporting group description
    		 Chemotherapy with Bendamustine (2 optional cycles), Anti-Cd20 monoclobnal antibody Ofatumumab and BTK-inhibitor Ibrutinib

    Primary: Primary endpoint

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    End point title
    		 Primary endpoint [1]
    End point description
    The primary efficacy parameter is the overall response rate (ORR) by investigator assessment at the final restaging (RE) 12 weeks after the start of the last cycle of induction therapy (end of induction treatment response = EOIT) including all patients achieving • a (clinical) complete response (CR), • a (clinical) CR with incomplete recovery of the bone marrow (CRi) or • a partial response (PR) or • PR with lymphocytosis
    End point type
    Primary
    End point timeframe
    The primary efficacy parameter is the overall response rate (ORR) by investigator assessment at the final restaging (RE) 12 weeks after the start of the last cycle of induction therapy (end of induction treatment response = EOIT).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the hypothesis states that the efficacy of the BIO regimen is assessed uninteresting if the ORR rate is less than 75% and is confirmed if the ORR (at final restaging) is at least 90% and as there are no further comparisons between different treatment arms, a frequency tabulation with no further statistical analyses was sufficient. So there are no statistical values available to provide.
    End point values
    		 Bendamustine/Ofatumumab/Ibrutinib
    Number of subjects analysed
    65
    Units: percent
        number (confidence interval 95%)
    92.3 (83.0 to 97.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    FL patient
    Reporting group description
    		 -

    Reporting group title
    RR patient
    Reporting group description
    		 -

    Serious adverse events
    		 FL patient RR patient
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 40 (62.50%)
    19 / 26 (73.08%)
         number of deaths (all causes)
    2
    4
         number of deaths resulting from adverse events
    2
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
    Additional description: Basal cell carcinoma
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial carcinoma
    Additional description: Bronchial carcinoma
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
    Additional description: Lung adenocarcinoma
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rectal adenocarcinoma
    Additional description: Rectal adenocarcinoma
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
    Additional description: Squamous cell carcinoma
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
    Additional description: Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Radiotherapy
    Additional description: Radiotherapy
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         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
    General physical health deterioration
    Additional description: General physical health deterioration
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
    Additional description: Impaired healing
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
    Additional description: Pyrexia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
    Additional description: Anaphylactic reaction
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
    Additional description: Drug hypersensitivity
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
    Additional description: Hypersensitivity
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (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
    Bronchitis chronic
    Additional description: Bronchitis chronic
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
    Additional description: Cough
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
    Additional description: Dyspnoea
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
    Additional description: Pneumonitis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory gas exchange disorder
    Additional description: Respiratory gas exchange disorder
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
    Additional description: Blood creatinine increased
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fibula fracture
    Additional description: Fibula fracture
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
    Additional description: Infusion related reaction
         subjects affected / exposed
    6 / 40 (15.00%)
    7 / 26 (26.92%)
         occurrences causally related to treatment / all
    10 / 10
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis chemical
    Additional description: Pneumonitis chemical
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
    Additional description: Rib fracture
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
    Additional description: Spinal fracture
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
    Additional description: Acute coronary syndrome
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
    Additional description: Atrial fibrillation
         subjects affected / exposed
    4 / 40 (10.00%)
    3 / 26 (11.54%)
         occurrences causally related to treatment / all
    5 / 5
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
    Additional description: Cardiac failure
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extrasystoles
    Additional description: Extrasystoles
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
    Additional description: Myocardial infarction
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral microangiopathy
    Additional description: Cerebral microangiopathy
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
    Additional description: Headache
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
    Additional description: Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Seizure
    Additional description: Seizure
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
    Additional description: Syncope
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
    Additional description: Transient ischaemic attack
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolysis
    Additional description: Haemolysis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
    Additional description: Lymphadenopathy
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
    Additional description: Thrombocytopenia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
    Additional description: Cataract
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dacryostenosis acquired
    Additional description: Dacryostenosis acquired
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucoma
    Additional description: Glaucoma
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
    Additional description: Ascites
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Eosinophilic cellulitis
    Additional description: Eosinophilic cellulitis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
    Additional description: Rash
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Solar dermatitis
    Additional description: Solar dermatitis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic epidermal necrolysis
    Additional description: Toxic epidermal necrolysis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
    Additional description: Acute kidney injury
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
    Additional description: Musculoskeletal chest pain
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
    Additional description: Abscess limb
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
    Additional description: Atypical pneumonia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
    Additional description: Bronchitis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
    Additional description: Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis infective
    Additional description: Bursitis infective
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
    Additional description: Clostridium difficile colitis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
    Additional description: Diverticulitis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
    Additional description: Erysipelas
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Infection
    Additional description: Febrile Infection
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
    Additional description: Gastroenteritis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis clostridial
    Additional description: Gastroenteritis clostridial
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
    Additional description: Gastroenteritis norovirus
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
    Additional description: Infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
    Additional description: Infectious pleural effusion
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis meningococcal
    Additional description: Meningitis meningococcal
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
    Additional description: Neutropenic infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
    Additional description: Oesophageal candidiasis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis infective
    Additional description: Pericarditis infective
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    Additional description: Pneumonia
         subjects affected / exposed
    0 / 40 (0.00%)
    6 / 26 (23.08%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
    Additional description: Pneumonia influenzal
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia legionella
    Additional description: Pneumonia legionella
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
    Additional description: Pulmonary sepsis
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
    Additional description: Sepsis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
    Additional description: Septic shock
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
    Additional description: Hypercalcaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
    Additional description: Tumour lysis syndrome
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 FL patient RR patient
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 40 (100.00%)
    26 / 26 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma of liver
    Additional description: Haemangioma of liver
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Seborrhoeic keratosis
    Additional description: Seborrhoeic keratosis
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    Vascular disorders
    Circulatory collapse
    Additional description: Circulatory collapse
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Flushing
    Additional description: Flushing
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Haematoma
    Additional description: Haematoma
         subjects affected / exposed
    3 / 40 (7.50%)
    6 / 26 (23.08%)
         occurrences all number
    4
    7
    Hypertension
    Additional description: Hypertension
         subjects affected / exposed
    9 / 40 (22.50%)
    1 / 26 (3.85%)
         occurrences all number
    9
    1
    Hypertensive crisis
    Additional description: Hypertensive crisis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Hypotension
    Additional description: Hypotension
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Raynaud's phenomenon
    Additional description: Raynaud's phenomenon
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Thrombophlebitis
    Additional description: Thrombophlebitis
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Vascular calcification
    Additional description: Vascular calcification
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Vasculitis
    Additional description: Vasculitis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Cataract operation
    Additional description: Cataract operation
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    2
    Dental implantation
    Additional description: Dental implantation
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Phlebectomy
    Additional description: Phlebectomy
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Tooth extraction
    Additional description: Tooth extraction
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Chest discomfort
    Additional description: Chest discomfort
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Chest pain
    Additional description: Chest pain
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Chills
    Additional description: Chills
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 26 (7.69%)
         occurrences all number
    2
    2
    Extravasation
    Additional description: Extravasation
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Fatigue
    Additional description: Fatigue
         subjects affected / exposed
    16 / 40 (40.00%)
    10 / 26 (38.46%)
         occurrences all number
    18
    12
    Gait disturbance
    Additional description: Gait disturbance
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    General physical health deterioration
    Additional description: General physical health deterioration
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Impaired healing
    Additional description: Impaired healing
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Injection site phlebitis
    Additional description: Injection site phlebitis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Mucosal inflammation
    Additional description: Mucosal inflammation
         subjects affected / exposed
    4 / 40 (10.00%)
    1 / 26 (3.85%)
         occurrences all number
    7
    1
    Oedema
    Additional description: Oedema
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Oedema peripheral
    Additional description: Oedema peripheral
         subjects affected / exposed
    5 / 40 (12.50%)
    7 / 26 (26.92%)
         occurrences all number
    5
    9
    Pain
    Additional description: Pain
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Peripheral swelling
    Additional description: Peripheral swelling
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Pyrexia
    Additional description: Pyrexia
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 26 (3.85%)
         occurrences all number
    5
    1
    Soft tissue inflammation
    Additional description: Soft tissue inflammation
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Immune system disorders
    Drug hypersensitivity
    Additional description: Drug hypersensitivity
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Hypersensitivity
    Additional description: Hypersensitivity
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Hypogammaglobulinaemia
    Additional description: Hypogammaglobulinaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Immunodeficiency
    Additional description: Immunodeficiency
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Immunodeficiency common variable
    Additional description: Immunodeficiency common variable
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Social circumstances
    Menopause
    Additional description: Menopause
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
    Additional description: Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Menorrhagia
    Additional description: Menorrhagia
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Prostatitis
    Additional description: Prostatitis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Uterine prolapse
    Additional description: Uterine prolapse
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchial wall thickening
    Additional description: Bronchial wall thickening
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Cough
    Additional description: Cough
         subjects affected / exposed
    4 / 40 (10.00%)
    4 / 26 (15.38%)
         occurrences all number
    6
    4
    Dyspnoea
    Additional description: Dyspnoea
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Dyspnoea exertional
    Additional description: Dyspnoea exertional
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    Emphysema
    Additional description: Emphysema
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
    Additional description: Epistaxis
         subjects affected / exposed
    6 / 40 (15.00%)
    4 / 26 (15.38%)
         occurrences all number
    8
    4
    Nasal dryness
    Additional description: Nasal dryness
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Nasal mucosal disorder
    Additional description: Nasal mucosal disorder
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
    Additional description: Oropharyngeal pain
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Pleural effusion
    Additional description: Pleural effusion
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Pneumonitis
    Additional description: Pneumonitis
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Rhinorrhoea
    Additional description: Rhinorrhoea
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Agitation
    Additional description: Agitation
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Burnout syndrome
    Additional description: Burnout syndrome
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Depression
    Additional description: Depression
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Insomnia
    Additional description: Insomnia
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 26 (7.69%)
         occurrences all number
    3
    2
    Sleep disorder
    Additional description: Sleep disorder
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Hepatobiliary disorders
    Cholecystitis chronic
    Additional description: Cholecystitis chronic
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Hepatic steatosis
    Additional description: Hepatic steatosis
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Hepatotoxicity
    Additional description: Hepatotoxicity
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Steatohepatitis
    Additional description: Steatohepatitis
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Investigations
    blood bilirubin increased
    Additional description: blood bilirubin increased
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
    Additional description: Blood creatinine increased
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Borrelia test negative
    Additional description: Borrelia test negative
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Endoscopy upper gastrointestinal tract
    Additional description: Endoscopy upper gastrointestinal tract
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Eosinophil count increased
    Additional description: Eosinophil count increased
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Gamma-glutamyltransferase increased
    Additional description: Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Haematocrit increased
    Additional description: Haematocrit increased
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Hepatic enzyme increased
    Additional description: Hepatic enzyme increased
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Laboratory test interference
    Additional description: Laboratory test interference
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Prostatic specific antigen increased
    Additional description: Prostatic specific antigen increased
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Weight decreased
    Additional description: Weight decreased
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 26 (7.69%)
         occurrences all number
    2
    2
    Weight increased
    Additional description: Weight increased
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Arthropod bite
    Additional description: Arthropod bite
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Contusion
    Additional description: Contusion
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Fracture
    Additional description: Fracture
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Head injury
    Additional description: Head injury
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Infusion related reaction
    Additional description: Infusion related reaction
         subjects affected / exposed
    14 / 40 (35.00%)
    9 / 26 (34.62%)
         occurrences all number
    30
    14
    Joint dislocation
    Additional description: Joint dislocation
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Lumbar vertebral fracture
    Additional description: Lumbar vertebral fracture
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Pneumonitis chemical
    Additional description: Pneumonitis chemical
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Post procedural haematoma
    Additional description: Post procedural haematoma
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Scratch
    Additional description: Scratch
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Thermal burn
    Additional description: Thermal burn
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Thoracic vertebral fracture
    Additional description: Thoracic vertebral fracture
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    Tooth fracture
    Additional description: Tooth fracture
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Congenital, familial and genetic disorders
    Gilbert's syndrome
    Additional description: Gilbert's syndrome
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrial fibrillation
    Additional description: Atrial fibrillation
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    Cardiovascular disorder
    Additional description: Cardiovascular disorder
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Coronary artery disease
    Additional description: Coronary artery disease
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Diastolic dysfunction
    Additional description: Diastolic dysfunction
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Extrasystoles
    Additional description: Extrasystoles
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Mitral valve incompetence
    Additional description: Mitral valve incompetence
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Palpitations
    Additional description: Palpitations
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Tricuspid valve incompetence
    Additional description: Tricuspid valve incompetence
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Nervous system disorders
    Burning sensation
    Additional description: Burning sensation
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Carpal tunnel syndrome
    Additional description: Carpal tunnel syndrome
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Cerebral amyloid angiopathy
    Additional description: Cerebral amyloid angiopathy
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Cerebral atrophy
    Additional description: Cerebral atrophy
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Cluster headache
    Additional description: Cluster headache
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Dizziness
    Additional description: Dizziness
         subjects affected / exposed
    4 / 40 (10.00%)
    2 / 26 (7.69%)
         occurrences all number
    4
    2
    Encephalopathy
    Additional description: Encephalopathy
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Headache
    Additional description: Headache
         subjects affected / exposed
    7 / 40 (17.50%)
    2 / 26 (7.69%)
         occurrences all number
    10
    2
    Hyperaesthesia
    Additional description: Hyperaesthesia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Hypoaesthesia
    Additional description: Hypoaesthesia
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Hypotonia
    Additional description: Hypotonia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Memory impairment
    Additional description: Memory impairment
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Mental impairment
    Additional description: Mental impairment
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Muscle spasticity
    Additional description: Muscle spasticity
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Nerve compression
    Additional description: Nerve compression
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorder
    Additional description: Nervous system disorder
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Paraesthesia
    Additional description: Paraesthesia
         subjects affected / exposed
    4 / 40 (10.00%)
    1 / 26 (3.85%)
         occurrences all number
    4
    1
    Peripheral sensory neuropathy
    Additional description: Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Polyneuropathy
    Additional description: Polyneuropathy
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Sciatica
    Additional description: Sciatica
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Syncope
    Additional description: Syncope
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Tremor
    Additional description: Tremor
         subjects affected / exposed
    1 / 40 (2.50%)
    3 / 26 (11.54%)
         occurrences all number
    1
    3
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    3 / 40 (7.50%)
    4 / 26 (15.38%)
         occurrences all number
    5
    4
    Leukopenia
    Additional description: Leukopenia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Lymph node pain
    Additional description: Lymph node pain
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    Neutropenia
    Additional description: Neutropenia
         subjects affected / exposed
    16 / 40 (40.00%)
    9 / 26 (34.62%)
         occurrences all number
    21
    17
    Perisplenitis
    Additional description: Perisplenitis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Thrombocytopenia
    Additional description: Thrombocytopenia
         subjects affected / exposed
    4 / 40 (10.00%)
    4 / 26 (15.38%)
         occurrences all number
    4
    4
    Ear and labyrinth disorders
    Ear pain
    Additional description: Ear pain
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Inner ear disorder
    Additional description: Inner ear disorder
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    2
    Tinnitus
    Additional description: Tinnitus
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Vertigo
    Additional description: Vertigo
         subjects affected / exposed
    5 / 40 (12.50%)
    4 / 26 (15.38%)
         occurrences all number
    6
    5
    Eye disorders
    Blepharitis
    Additional description: Blepharitis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Cataract
    Additional description: Cataract
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Conjunctival haemorrhage
    Additional description: Conjunctival haemorrhage
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Dry eye
    Additional description: Dry eye
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Exophthalmos
    Additional description: Exophthalmos
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Eye haematoma
    Additional description: Eye haematoma
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Eye haemorrhage
    Additional description: Eye haemorrhage
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Eyelid oedema
    Additional description: Eyelid oedema
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Glaucoma
    Additional description: Glaucoma
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Lacrimation increased
    Additional description: Lacrimation increased
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    Periorbital oedema
    Additional description: Periorbital oedema
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Vision blurred
    Additional description: Vision blurred
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Visual impairment
    Additional description: Visual impairment
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    Abdominal discomfort
    Additional description: Abdominal discomfort
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Abdominal distension
    Additional description: Abdominal distension
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Abdominal pain
    Additional description: Abdominal pain
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 26 (7.69%)
         occurrences all number
    2
    3
    Abdominal pain upper
    Additional description: Abdominal pain upper
         subjects affected / exposed
    5 / 40 (12.50%)
    4 / 26 (15.38%)
         occurrences all number
    6
    5
    Anal haemorrhage
    Additional description: Anal haemorrhage
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Aphthous ulcer
    Additional description: Aphthous ulcer
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    4 / 40 (10.00%)
    2 / 26 (7.69%)
         occurrences all number
    5
    2
    Dental caries
    Additional description: Dental caries
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    21 / 40 (52.50%)
    9 / 26 (34.62%)
         occurrences all number
    38
    15
    Diverticulum
    Additional description: Diverticulum
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Dry mouth
    Additional description: Dry mouth
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    Dyspepsia
    Additional description: Dyspepsia
         subjects affected / exposed
    3 / 40 (7.50%)
    2 / 26 (7.69%)
         occurrences all number
    5
    2
    Endocrine disorders
    Additional description: Endocrine disorders
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Faecaloma
    Additional description: Faecaloma
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Faeces discoloured
    Additional description: Faeces discoloured
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Flatulence
    Additional description: Flatulence
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 26 (7.69%)
         occurrences all number
    2
    3
    Gastric ulcer
    Additional description: Gastric ulcer
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Gastritis
    Additional description: Gastritis
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Gastritis erosive
    Additional description: Gastritis erosive
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Gastrointestinal disorder
    Additional description: Gastrointestinal disorder
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Gastrointestinal pain
    Additional description: Gastrointestinal pain
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Gastrooesophageal reflux disease
    Additional description: Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 40 (7.50%)
    5 / 26 (19.23%)
         occurrences all number
    3
    6
    Gingival bleeding
    Additional description: Gingival bleeding
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoidal haemorrhage
    Additional description: Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoids
    Additional description: Haemorrhoids
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Hiatus hernia
    Additional description: Hiatus hernia
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Inguinal hernia
    Additional description: Inguinal hernia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Large intestine polyp
    Additional description: Large intestine polyp
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    Leukoplakia oral
    Additional description: Leukoplakia oral
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    12 / 40 (30.00%)
    7 / 26 (26.92%)
         occurrences all number
    18
    10
    Oral dysaesthesia
    Additional description: Oral dysaesthesia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia oral
    Additional description: Paraesthesia oral
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Periodontal disease
    Additional description: Periodontal disease
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Stomatitis
    Additional description: Stomatitis
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Tooth loss
    Additional description: Tooth loss
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    2
    Toothache
    Additional description: Toothache
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Acne
    Additional description: Acne
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Actinic keratosis
    Additional description: Actinic keratosis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Alopecia
    Additional description: Alopecia
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Blood blister
    Additional description: Blood blister
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Decubitus ulcer
    Additional description: Decubitus ulcer
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Dermatitis
    Additional description: Dermatitis
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Dermatitis allergic
    Additional description: Dermatitis allergic
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Dry skin
    Additional description: Dry skin
         subjects affected / exposed
    3 / 40 (7.50%)
    2 / 26 (7.69%)
         occurrences all number
    3
    2
    Ecchymosis
    Additional description: Ecchymosis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Eczema
    Additional description: Eczema
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Erythema
    Additional description: Erythema
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 26 (3.85%)
         occurrences all number
    3
    2
    Hyperhidrosis
    Additional description: Hyperhidrosis
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 26 (11.54%)
         occurrences all number
    2
    3
    Hypotrichosis
    Additional description: Hypotrichosis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Nail ridging
    Additional description: Nail ridging
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Night sweats
    Additional description: Night sweats
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Onychoclasis
    Additional description: Onychoclasis
         subjects affected / exposed
    7 / 40 (17.50%)
    1 / 26 (3.85%)
         occurrences all number
    8
    1
    Petechiae
    Additional description: Petechiae
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 26 (11.54%)
         occurrences all number
    2
    3
    Pruritus
    Additional description: Pruritus
         subjects affected / exposed
    7 / 40 (17.50%)
    2 / 26 (7.69%)
         occurrences all number
    7
    2
    Pruritus generalised
    Additional description: Pruritus generalised
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Psoriasis
    Additional description: Psoriasis
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Rash
    Additional description: Rash
         subjects affected / exposed
    15 / 40 (37.50%)
    8 / 26 (30.77%)
         occurrences all number
    19
    8
    Rash maculo-papular
    Additional description: Rash maculo-papular
         subjects affected / exposed
    4 / 40 (10.00%)
    0 / 26 (0.00%)
         occurrences all number
    6
    0
    Rash papular
    Additional description: Rash papular
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Skin burning sensation
    Additional description: Skin burning sensation
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Skin fissures
    Additional description: Skin fissures
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Skin lesion
    Additional description: Skin lesion
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Skin ulcer
    Additional description: Skin ulcer
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    5
    Renal and urinary disorders
    Acute kidney injury
    Additional description: Acute kidney injury
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Chronic kidney disease
    Additional description: Chronic kidney disease
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Cystitis noninfective
    Additional description: Cystitis noninfective
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    2
    Dysuria
    Additional description: Dysuria
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Haematuria
    Additional description: Haematuria
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Nocturia
    Additional description: Nocturia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Pollakiuria
    Additional description: Pollakiuria
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Strangury
    Additional description: Strangury
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Urge incontinence
    Additional description: Urge incontinence
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Urinary tract disorder
    Additional description: Urinary tract disorder
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Urinary tract obstruction
    Additional description: Urinary tract obstruction
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Endocrine disorders
    Hyperthyroidism
    Additional description: Hyperthyroidism
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Hypothyroidism
    Additional description: Hypothyroidism
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    Thyroid cyst
    Additional description: Thyroid cyst
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Thyroid mass
    Additional description: Thyroid mass
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
    Additional description: Arthralgia
         subjects affected / exposed
    8 / 40 (20.00%)
    5 / 26 (19.23%)
         occurrences all number
    11
    7
    Arthritis
    Additional description: Arthritis
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    Back pain
    Additional description: Back pain
         subjects affected / exposed
    7 / 40 (17.50%)
    2 / 26 (7.69%)
         occurrences all number
    8
    2
    Bone pain
    Additional description: Bone pain
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Bursitis
    Additional description: Bursitis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Gouty arthritis
    Additional description: Gouty arthritis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Intervertebral disc protrusion
    Additional description: Intervertebral disc protrusion
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Joint swelling
    Additional description: Joint swelling
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Muscle spasms
    Additional description: Muscle spasms
         subjects affected / exposed
    5 / 40 (12.50%)
    8 / 26 (30.77%)
         occurrences all number
    10
    10
    Muscle tightness
    Additional description: Muscle tightness
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
    Additional description: Musculoskeletal chest pain
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
    Additional description: Musculoskeletal pain
         subjects affected / exposed
    3 / 40 (7.50%)
    2 / 26 (7.69%)
         occurrences all number
    4
    2
    Myalgia
    Additional description: Myalgia
         subjects affected / exposed
    10 / 40 (25.00%)
    2 / 26 (7.69%)
         occurrences all number
    12
    2
    Myosclerosis
    Additional description: Myosclerosis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Neck pain
    Additional description: Neck pain
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Osteoarthritis
    Additional description: Osteoarthritis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Osteoporosis
    Additional description: Osteoporosis
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Pain in extremity
    Additional description: Pain in extremity
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 26 (7.69%)
         occurrences all number
    2
    3
    Plantar fasciitis
    Additional description: Plantar fasciitis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Polyarthritis
    Additional description: Polyarthritis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Synovial cyst
    Additional description: Synovial cyst
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Tendon disorder
    Additional description: Tendon disorder
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Tendonitis
    Additional description: Tendonitis
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Trigger finger
    Additional description: Trigger finger
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Infections and infestations
    Abscess
    Additional description: Abscess
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Abscess limb
    Additional description: Abscess limb
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Anal abscess
    Additional description: Anal abscess
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Angular cheilitis
    Additional description: Angular cheilitis
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Bacterial infection
    Additional description: Bacterial infection
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Balanitis candida
    Additional description: Balanitis candida
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Borrelia infection
    Additional description: Borrelia infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
    Additional description: Bronchitis
         subjects affected / exposed
    14 / 40 (35.00%)
    5 / 26 (19.23%)
         occurrences all number
    16
    8
    Bursitis infective
    Additional description: Bursitis infective
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Chronic sinusitis
    Additional description: Chronic sinusitis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Conjunctivitis
    Additional description: Conjunctivitis
         subjects affected / exposed
    3 / 40 (7.50%)
    4 / 26 (15.38%)
         occurrences all number
    3
    4
    Cystitis
    Additional description: Cystitis
         subjects affected / exposed
    4 / 40 (10.00%)
    3 / 26 (11.54%)
         occurrences all number
    5
    10
    Diarrhoea infectious
    Additional description: Diarrhoea infectious
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Enterocolitis infectious
    Additional description: Enterocolitis infectious
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Erythema migrans
    Additional description: Erythema migrans
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Eyelid infection
    Additional description: Eyelid infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Febrile Infection
    Additional description: Febrile Infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Gastric infection
    Additional description: Gastric infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
    Additional description: Gastroenteritis
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 26 (0.00%)
         occurrences all number
    5
    0
    Gastroenteritis viral
    Additional description: Gastroenteritis viral
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal infection
    Additional description: Gastrointestinal infection
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Genital infection fungal
    Additional description: Genital infection fungal
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Gingivitis
    Additional description: Gingivitis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Herpes virus infection
    Additional description: Herpes virus infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Herpes zoster
    Additional description: Herpes zoster
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Infected bite
    Additional description: Infected bite
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Infection
    Additional description: Infection
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 26 (7.69%)
         occurrences all number
    2
    3
    Infection susceptibility increased
    Additional description: Infection susceptibility increased
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Influenza
    Additional description: Influenza
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    Lip infection
    Additional description: Lip infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Localised infection
    Additional description: Localised infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
    Additional description: Nasopharyngitis
         subjects affected / exposed
    21 / 40 (52.50%)
    8 / 26 (30.77%)
         occurrences all number
    32
    13
    Neutropenic infection
    Additional description: Neutropenic infection
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    2
    Onychomycosis
    Additional description: Onychomycosis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Oral candidiasis
    Additional description: Oral candidiasis
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Oral herpes
    Additional description: Oral herpes
         subjects affected / exposed
    5 / 40 (12.50%)
    2 / 26 (7.69%)
         occurrences all number
    7
    2
    Osteomyelitis
    Additional description: Osteomyelitis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Otitis media
    Additional description: Otitis media
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Paronychia
    Additional description: Paronychia
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    5
    0
    Parotitis
    Additional description: Parotitis
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Periodontitis
    Additional description: Periodontitis
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Pertussis
    Additional description: Pertussis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
    Additional description: Pharyngitis
         subjects affected / exposed
    5 / 40 (12.50%)
    2 / 26 (7.69%)
         occurrences all number
    7
    2
    Pneumonia
    Additional description: Pneumonia
         subjects affected / exposed
    4 / 40 (10.00%)
    3 / 26 (11.54%)
         occurrences all number
    4
    3
    Pseudomonas infection
    Additional description: Pseudomonas infection
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Respiratory tract infection
    Additional description: Respiratory tract infection
         subjects affected / exposed
    3 / 40 (7.50%)
    4 / 26 (15.38%)
         occurrences all number
    3
    5
    Rhinitis
    Additional description: Rhinitis
         subjects affected / exposed
    4 / 40 (10.00%)
    2 / 26 (7.69%)
         occurrences all number
    6
    2
    Root canal infection
    Additional description: Root canal infection
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Sinusitis
    Additional description: Sinusitis
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 26 (11.54%)
         occurrences all number
    3
    6
    Skin infection
    Additional description: Skin infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Soft tissue infection
    Additional description: Soft tissue infection
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Systemic infection
    Additional description: Systemic infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
    Additional description: Tonsillitis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
    Additional description: Upper respiratory tract infection
         subjects affected / exposed
    9 / 40 (22.50%)
    2 / 26 (7.69%)
         occurrences all number
    11
    3
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    7 / 40 (17.50%)
    1 / 26 (3.85%)
         occurrences all number
    11
    4
    Viral oesophagitis
    Additional description: Viral oesophagitis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Viral pharyngitis
    Additional description: Viral pharyngitis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Wound infection
    Additional description: Wound infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Abnormal loss of weight
    Additional description: Abnormal loss of weight
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Decreased appetite
    Additional description: Decreased appetite
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Gout
    Additional description: Gout
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Hypercalcaemia
    Additional description: Hypercalcaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Hypercholesterolaemia
    Additional description: Hypercholesterolaemia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Hyperglycaemia
    Additional description: Hyperglycaemia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Hyperkalaemia
    Additional description: Hyperkalaemia
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Hyperuricaemia
    Additional description: Hyperuricaemia
         subjects affected / exposed
    4 / 40 (10.00%)
    1 / 26 (3.85%)
         occurrences all number
    5
    1
    Hypokalaemia
    Additional description: Hypokalaemia
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 26 (7.69%)
         occurrences all number
    1
    3
    Iron overload
    Additional description: Iron overload
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Vitamin D deficiency
    Additional description: Vitamin D deficiency
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Weight fluctuation
    Additional description: Weight fluctuation
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jul 2016
    Due to one case of interstitial lung disease, which is described in an addendum to the IB of ibrutinib, this risk and recommendations for the potential management were included into the protocol. The recommendation for the interval between administration of allopurinol and bendamustine was aligned with the recommendation of other GCLLSG protocols, e.g. the CLL2-BAG protocol. It is now stated that the interval between allopurinol and bendamustine administration should be ≥ 24-48 hrs. Due to the expiry of the patent protection for bendamustine in Germany and because commercially available bendamustine is used for the debulking treatment in this trial, an addendum for the protocol was used to allow the pharmacists to use generic medicinal products which they have in stock. With this amendment, this is now also implemented in the trial protocol and the specification of the tradename was deleted throughout the protocol. Due to HBV reactivation in another trial in a patient who did not receive a prophylactic treatment for HBV despite a positive anti-HBc, this is now recommended Due to queries by the treating physicians/investigators if heparine can be used concomitantly with ibrutinib, this information was also included in the protocol. Also, the information regarding the use of vitamin k antagonists and novel anticoagulants was updated
    09 May 2017
    Ofatumumab is now also licensed in combination with fludarabine and cyclophosphamide (FC) for the use in patients with relapsed CLL, this was included in the second chapter “ General aspects of the drugs used in the trial” Additional information on the potential risk of liver failure with ibrutinib was included into the paragraph “diarrhea and gastrointestinal AEs” Frequent updates of the IB for ibrutinib and publication of addenda to the IB have necessitated amendments of trial protocol and patient´s informed consent without adding clinically relevant information. Therefore and because ibrutinib is approved since 2014, it was decided together with the leading EC to change the safety reference document from IB to SMPC.
    12 Mar 2018
    Additional information regarding safety of vaccinations with live, attenuated vaccines and safety and efficacy of other vaccinations were included into chapter “8.5.2 Prohibited medications and medications to be used with caution” Additional information regarding a potential fetal B-cell depletion was included into the Paragraph “Ofatumumab” in chapter “8.8.1.4 Teratogenicity and mutagenicity”. Additional information on the potential risk of Hepatitis B reactivation with ibrutinib was included into the paragraph “Cytopenias and infections with ibrutinib” and as a new paragraph into the chapter “Potential risks with Ibrutinib”. As ibrutinib may also cause other types of cardiac arrhythmias, this information was included and the title of the respective chapter was re-named from “Atrial fibrillation and worsening of pre-exsisting cardiac conditions” to “Cardiac arrythmias and worsening of …”. Based on the experiences from the primary endpoint analyses of the CLL2-BIG and CLL2-BAG trials, the statistical sections of the protocol were updated. The per protocol analysis was removed. The CLL2-BIO protocol still contains two populations, the safety population and the full analysis set. The latter comprises of all enrolled patients who received at least two complete cycles of induction therapy. This already represents a relatively strict definition due to the target number of treatment cycles. According to our experiences from the final analyses of the CLL2-BIG and CLL2-BAG trials, most of the critical protocol violations were prevented by our central screening process. Thus, the per protocol population and the full analysis set were somewhat identical.

    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.
    On 28 February 2019, the European Commission withdrew the marketing authorisation for Arzerra (ofatumumab) in the European Union (EU). The withdrawal was at the request of the marketing authorisation holder, Novartis Europharm Limited.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32107341
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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