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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 GA101 and ibrutinib (BIG) followed by ibrutinib and GA101 maintenance in CLL patients (CLL2-BIG protocol)

    Summary
    EudraCT number
    		 2014-000569-35
    Trial protocol
    		 DE  
    Global end of trial date
    29 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Sep 2020
    First version publication date
    11 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLL2-BIG
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02345863
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 2243/01: PEI
    Sponsors
    Sponsor organisation name
    German CLL Study Group
    Sponsor organisation address
    University Hospital Cologne, Gleuelerstr. 176-178, Cologne, Germany, 50935
    Public contact
    Information Desk, German CLL Study Group, +49 221478 88198, cll-studie@uk-koeln.de
    Scientific contact
    Information Desk, German CLL Study Group, +49 221478 88198, cll-studie@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
    07 Aug 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Mar 2019
    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 GA101 (obinutuzumab) and ibrutinib for induction and maintenance therapy in CLL patients. 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. The response will be assessed according to the iwCLL criteria
    Protection of trial subjects
    Debulking treatment with Bendamustine should be stopped after the 1st cycle only if severe adverse events occur. Obinutuzumab 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
    		 In this prospective single-arm phase-II trial, the feasibility regarding efficacy and safety of a regimen consisting of two cycles of bendamustine for debulking, followed by a sequential application of GA101 (obinutuzumab) and ibrutinib as induction and as maintenance therapy until achievement of a MRD negative remission for up to 2 years of maintenance will be evaluated in both previously untreated or relapsed/refractory and physically fit or unfit CLL patients. A treatment with one of kinase inhibitors, namely ibrutinib and an antibody, namely GA101 combines two targeted and very effective agents with a favourable toxicity profile. Thus, the combination of ibrutinib and GA101 is expected to have a high efficacy without overlapping or increased toxicities. In addition, this combinations appears to be a rational approach because of theoretical considerations: ibrutinib inhibits the migration and adhesion of CLL cells to the protecting microenvironment and thereby leads to a redistribution and mobilization of these cells to peripheral blood and cause a lymphocytosis. All antibodies, especially the highly effective GA101 lead to early infusion-related side effects, such as cytokine-release- and tumor lysis syndromes. Therefore, the combination of a drug that leads to a lymphocytosis through a redistribution of leukemic cells to the peripheral blood and a very effective antibody that acts predominantly in the peripheral blood and targets the redistributed cells, the efficacy of both drugs should be increased through synergistic mechanism of action and could potentially eradicate the residual CLL cells. In order to avoid additional toxicities due to these distinctive features, these two drugs will be started sequentially. And in addition, a debulking treatment with two cycles of chemotherapy with bendamustine will be given ahead of the sequential administration of GA101 (obinutuzumab) and ibrutinib to mitigate the early side effects and to optimize the efficacy.
    Evidence for comparator
    		 n/a
    Actual start date of recruitment
    01 Oct 2014
    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)
    29
    From 65 to 84 years
    36
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 66 patients were enrolled between 01/2015 and 09/2015.

    Pre-assignment
    Screening details
    		 69 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. 3 patients were not eligible for participitation.

    Pre-assignment period milestones
    Number of subjects started
    		 69 [1]
    Number of subjects completed
    		 66

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Protocol deviation: 3
    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: 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. 69 pats were screened and 66 enrolled.
    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Bendamustine/Obinutuzumab/Ibrutinib
    Arm description
    		 Chemotherapy with Bendamustine, obinutuzumab and ibrutinib
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    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
    Obinutuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Phase 2 Induction: Cycle 1 on day 1 100mg, day 1 (or 2) 900mg, day 8 1000mg, day 15 1000mg; Cycle 2-6 on day 1 1000mg Phase 3 Maintenance: every 3 months 1000mg

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Phase 2 Induction: Cycle 2-6 daily 420mg; Phase 3 Maintenance: daily 420mg

    Number of subjects in period 1
    		Bendamustine/Obinutuzumab/Ibrutinib
    Started
    66
    treatment allocation
    66
    treatment
    66
    follow-up
    37
    Completed
    13
    Not completed
    53
         Adverse event, serious fatal
    4
         Consent withdrawn by subject
    5
         Physician decision
    1
         Adverse event, non-fatal
    10
         various reasons
    33

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial 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)
    		 29 29
        From 65-84 years
    		 36 36
        85 years and over
    		 1 1
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 66.5 (61 to 74.75) -
    Gender categorical
    Units: Subjects
        Female
    		 28 28
        Male
    		 38 38

    End points

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    End points reporting groups
    Reporting group title
    Bendamustine/Obinutuzumab/Ibrutinib
    Reporting group description
    		 Chemotherapy with Bendamustine, obinutuzumab and ibrutinib

    Primary: Response at end of induction treatment

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    End point title
    		 Response at end of induction treatment [1]
    End point description
    The primary efficacy parameter (primary endpoint) is the best overall response rate (ORR) at final restaging after induction therapy (end of induction treatment response = EOIT). Best overall response rate is defined by the proportion of patients having achieved a CR/ CRi, clinical CR/CRi, PR or PR with lymphocytosis as best response based on the respective population (= number of patients with best response CR/CRi, clinical CR/CRi, PR or PR with lymphocytosis divided by the number of the respective population).
    End point type
    Primary
    End point timeframe
    The primary endpoint was analyzed after all enrolled patients have achieved the final restaging.
    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 BIG regimen 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/Obinutuzumab/Ibrutinib
    Number of subjects analysed
    61
    Units: number of patients
    61
    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
    21 / 33 (63.64%)
    22 / 33 (66.67%)
         number of deaths (all causes)
    0
    8
         number of deaths resulting from adverse events
    0
    7
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anal cancer
    Additional description: Anal cancer
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
    Additional description: Basal cell carcinoma
         subjects affected / exposed
    5 / 33 (15.15%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    5 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
    Additional description: Bladder cancer
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
    Additional description: Bowen's disease
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm
    Additional description: Brain neoplasm
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoma in situ of skin
    Additional description: Carcinoma in situ of skin
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma in situ
    Additional description: Malignant melanoma in situ
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
    Additional description: Prostate cancer
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (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
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aneurysm
    Additional description: Aneurysm
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Internal fixation of spine
    Additional description: Internal fixation of spine
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
    Additional description: General physical health deterioration
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyserositis
    Additional description: Polyserositis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (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
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
    Additional description: Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Obstructive airways disorder
    Additional description: Obstructive airways disorder
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
    Additional description: Pleural effusion
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 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 / 33 (3.03%)
    0 / 33 (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
    Arterial bypass stenosis
    Additional description: Arterial bypass stenosis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropod bite
    Additional description: Arthropod bite
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Forearm fracture
    Additional description: Forearm fracture
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (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
    2 / 33 (6.06%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
    Additional description: Rib fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
    Additional description: Seroma
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
    Additional description: Tendon rupture
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
    Additional description: Atrial fibrillation
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
    Additional description: Cardiac failure congestive
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
    Additional description: Myocardial infarction
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
    Additional description: Carotid artery stenosis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
    Additional description: Cerebral infarction
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
    Additional description: Cerebrovascular accident
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Demyelinating polyneuropathy
    Additional description: Demyelinating polyneuropathy
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
    Additional description: Headache
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thalamus haemorrhage
    Additional description: Thalamus haemorrhage
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Autoimmune haemolytic anaemia
    Additional description: Autoimmune haemolytic anaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bicytopenia
    Additional description: Bicytopenia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
    Additional description: Febrile neutropenia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         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 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Acute vestibular syndrome
    Additional description: Acute vestibular syndrome
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
    Additional description: Cataract
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
    Additional description: Duodenitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Dysphagia
    Additional description: Dysphagia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal polyp haemorrhage
    Additional description: Gastrointestinal polyp haemorrhage
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
    Additional description: Inguinal hernia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
    Additional description: Cholangitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
    Additional description: Cholecystitis chronic
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
    Additional description: Cholestasis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic artery aneurysm
    Additional description: Hepatic artery aneurysm
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 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 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
    Additional description: Renal failure
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
    Additional description: Bursitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
    Additional description: Intervertebral disc protrusion
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
    Additional description: Musculoskeletal pain
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seronegative arthritis
    Additional description: Seronegative arthritis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
    Additional description: Spinal pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Febrile infection
    Additional description: Febrile infection
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
    Additional description: Lung infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph node abscess
    Additional description: Lymph node abscess
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreas infection
    Additional description: Pancreas infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    Additional description: Pneumonia
         subjects affected / exposed
    4 / 33 (12.12%)
    7 / 33 (21.21%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia bacterial
    Additional description: Pneumonia bacterial
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
    Additional description: Pneumonia fungal
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
    Additional description: Pneumonia influenzal
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
    Additional description: Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia parainfluenzae viral
    Additional description: Pneumonia parainfluenzae viral
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
    Additional description: Pulmonary sepsis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Respiratory tract infection
    Additional description: Respiratory tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
    Additional description: Sepsis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Staphylococcal bacteraemia
    Additional description: Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
    Additional description: Tracheobronchitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Gout
    Additional description: Gout
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Protein deficiency
    Additional description: Protein deficiency
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
    Additional description: Tumour lysis syndrome
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    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
    31 / 33 (93.94%)
    33 / 33 (100.00%)
    Vascular disorders
    Aortic arteriosclerosis
    Additional description: Aortic arteriosclerosis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Arteriosclerosis
    Additional description: Arteriosclerosis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Flushing
    Additional description: Flushing
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Haematoma
    Additional description: Haematoma
         subjects affected / exposed
    3 / 33 (9.09%)
    3 / 33 (9.09%)
         occurrences all number
    3
    5
    Haemorrhage
    Additional description: Haemorrhage
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Hypertension
    Additional description: Hypertension
         subjects affected / exposed
    4 / 33 (12.12%)
    2 / 33 (6.06%)
         occurrences all number
    4
    2
    Thrombophlebitis
    Additional description: Thrombophlebitis
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    Thrombophlebitis superficial
    Additional description: Thrombophlebitis superficial
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Tooth extraction
    Additional description: Tooth extraction
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Asthenia
    Additional description: Asthenia
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Chest discomfort
    Additional description: Chest discomfort
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Chest pain
    Additional description: Chest pain
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    Chills
    Additional description: Chills
         subjects affected / exposed
    3 / 33 (9.09%)
    3 / 33 (9.09%)
         occurrences all number
    3
    3
    Drug intolerance
    Additional description: Drug intolerance
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Face oedema
    Additional description: Face oedema
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Fatigue
    Additional description: Fatigue
         subjects affected / exposed
    14 / 33 (42.42%)
    10 / 33 (30.30%)
         occurrences all number
    17
    12
    Gait disturbance
    Additional description: Gait disturbance
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    General physical health deterioration
    Additional description: General physical health deterioration
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Impaired healing
    Additional description: Impaired healing
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    3
    Inflammation
    Additional description: Inflammation
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Influenza like illness
    Additional description: Influenza like illness
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Infusion site pain
    Additional description: Infusion site pain
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Localised oedema
    Additional description: Localised oedema
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Mucosal dryness
    Additional description: Mucosal dryness
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Mucosal inflammation
    Additional description: Mucosal inflammation
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Nodule
    Additional description: Nodule
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Oedema
    Additional description: Oedema
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Oedema peripheral
    Additional description: Oedema peripheral
         subjects affected / exposed
    4 / 33 (12.12%)
    2 / 33 (6.06%)
         occurrences all number
    6
    2
    Pain
    Additional description: Pain
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Performance status decreased
    Additional description: Performance status decreased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Peripheral swelling
    Additional description: Peripheral swelling
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Pyrexia
    Additional description: Pyrexia
         subjects affected / exposed
    6 / 33 (18.18%)
    4 / 33 (12.12%)
         occurrences all number
    8
    5
    Immune system disorders
    Cytokine release syndrome
    Additional description: Cytokine release syndrome
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Food allergy
    Additional description: Food allergy
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Hypersensitivity
    Additional description: Hypersensitivity
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 33 (0.00%)
         occurrences all number
    4
    0
    Immunodeficiency
    Additional description: Immunodeficiency
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Secondary immunodeficiency
    Additional description: Secondary immunodeficiency
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Pelvic pain
    Additional description: Pelvic pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Uterine prolapse
    Additional description: Uterine prolapse
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
    Additional description: Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Cough
    Additional description: Cough
         subjects affected / exposed
    6 / 33 (18.18%)
    6 / 33 (18.18%)
         occurrences all number
    7
    6
    Dysphonia
    Additional description: Dysphonia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Dyspnoea
    Additional description: Dyspnoea
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Dyspnoea exertional
    Additional description: Dyspnoea exertional
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Epistaxis
    Additional description: Epistaxis
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 33 (3.03%)
         occurrences all number
    2
    2
    Nasal mucosal inflammation
    Additional description: Nasal mucosal inflammation
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
    Additional description: Oropharyngeal pain
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Pleural effusion
    Additional description: Pleural effusion
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Pulmonary fibrosis
    Additional description: Pulmonary fibrosis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Throat irritation
    Additional description: Throat irritation
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Aggression
    Additional description: Aggression
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Agitation
    Additional description: Agitation
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Anxiety
    Additional description: Anxiety
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Depression
    Additional description: Depression
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Insomnia
    Additional description: Insomnia
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Irritability
    Additional description: Irritability
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Sleep disorder
    Additional description: Sleep disorder
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Aspartate aminotransferase increased
    Additional description: Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Bleeding time prolonged
    Additional description: Bleeding time prolonged
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
    Additional description: Blood creatinine increased
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Blood lactate dehydrogenase increased
    Additional description: Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
    Additional description: Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Prostatic specific antigen increased
    Additional description: Prostatic specific antigen increased
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Weight decreased
    Additional description: Weight decreased
         subjects affected / exposed
    3 / 33 (9.09%)
    3 / 33 (9.09%)
         occurrences all number
    3
    3
    Injury, poisoning and procedural complications
    Arthropod bite
    Additional description: Arthropod bite
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Fall
    Additional description: Fall
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Infusion related reaction
    Additional description: Infusion related reaction
         subjects affected / exposed
    9 / 33 (27.27%)
    14 / 33 (42.42%)
         occurrences all number
    9
    15
    Laceration
    Additional description: Laceration
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Muscle rupture
    Additional description: Muscle rupture
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Muscle strain
    Additional description: Muscle strain
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Skin injury
    Additional description: Skin injury
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Tooth injury
    Additional description: Tooth injury
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Traumatic haemorrhage
    Additional description: Traumatic haemorrhage
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Wound
    Additional description: Wound
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Cardiac disorders
    Arrhythmia supraventricular
    Additional description: Arrhythmia supraventricular
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Atrial fibrillation
    Additional description: Atrial fibrillation
         subjects affected / exposed
    3 / 33 (9.09%)
    3 / 33 (9.09%)
         occurrences all number
    3
    3
    Atrial thrombosis
    Additional description: Atrial thrombosis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Cardiac failure
    Additional description: Cardiac failure
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Cardiovascular disorder
    Additional description: Cardiovascular disorder
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Cyanosis
    Additional description: Cyanosis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Palpitations
    Additional description: Palpitations
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 33 (9.09%)
         occurrences all number
    1
    3
    Supraventricular extrasystoles
    Additional description: Supraventricular extrasystoles
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Tachycardia
    Additional description: Tachycardia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Tricuspid valve incompetence
    Additional description: Tricuspid valve incompetence
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Ventricular arrhythmia
    Additional description: Ventricular arrhythmia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Ventricular extrasystoles
    Additional description: Ventricular extrasystoles
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Nervous system disorders
    Arthropod bite
    Additional description: Arthropod bite
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Cluster headache
    Additional description: Cluster headache
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Dizziness
    Additional description: Dizziness
         subjects affected / exposed
    4 / 33 (12.12%)
    2 / 33 (6.06%)
         occurrences all number
    4
    2
    Dysgeusia
    Additional description: Dysgeusia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Headache
    Additional description: Headache
         subjects affected / exposed
    4 / 33 (12.12%)
    4 / 33 (12.12%)
         occurrences all number
    4
    5
    Hypertonia
    Additional description: Hypertonia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Hypoaesthesia
    Additional description: Hypoaesthesia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Memory impairment
    Additional description: Memory impairment
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Migraine
    Additional description: Migraine
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Neuralgia
    Additional description: Neuralgia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
    Additional description: Paraesthesia
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Parosmia
    Additional description: Parosmia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Peripheral sensory neuropathy
    Additional description: Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    3
    Polyneuropathy
    Additional description: Polyneuropathy
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Sciatica
    Additional description: Sciatica
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    3 / 33 (9.09%)
    4 / 33 (12.12%)
         occurrences all number
    4
    6
    Autoimmune haemolytic anaemia
    Additional description: Autoimmune haemolytic anaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Granulocytopenia
    Additional description: Granulocytopenia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Immune thrombocytopenic purpura
    Additional description: Immune thrombocytopenic purpura
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Increased tendency to bruise
    Additional description: Increased tendency to bruise
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Iron deficiency anaemia
    Additional description: Iron deficiency anaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Leukopenia
    Additional description: Leukopenia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Lymph node pain
    Additional description: Lymph node pain
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Lymphadenitis
    Additional description: Lymphadenitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Lymphadenopathy
    Additional description: Lymphadenopathy
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Neutropenia
    Additional description: Neutropenia
         subjects affected / exposed
    9 / 33 (27.27%)
    8 / 33 (24.24%)
         occurrences all number
    11
    13
    Thrombocytopenia
    Additional description: Thrombocytopenia
         subjects affected / exposed
    6 / 33 (18.18%)
    9 / 33 (27.27%)
         occurrences all number
    13
    16
    Ear and labyrinth disorders
    Hyperacusis
    Additional description: Hyperacusis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Tinnitus
    Additional description: Tinnitus
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Vertigo
    Additional description: Vertigo
         subjects affected / exposed
    3 / 33 (9.09%)
    7 / 33 (21.21%)
         occurrences all number
    4
    8
    Vertigo positional
    Additional description: Vertigo positional
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    4
    Eye disorders
    Blepharitis
    Additional description: Blepharitis
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Blindness
    Additional description: Blindness
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Cataract
    Additional description: Cataract
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Conjunctival haemorrhage
    Additional description: Conjunctival haemorrhage
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Eye disorder
    Additional description: Eye disorder
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Eye haemorrhage
    Additional description: Eye haemorrhage
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Eyelid oedema
    Additional description: Eyelid oedema
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Eyelid rash
    Additional description: Eyelid rash
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Hypermetropia
    Additional description: Hypermetropia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Periorbital oedema
    Additional description: Periorbital oedema
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Vision blurred
    Additional description: Vision blurred
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Visual impairment
    Additional description: Visual impairment
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
    Additional description: Abdominal pain upper
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 33 (12.12%)
         occurrences all number
    3
    5
    Aphthous stomatitis
    Additional description: Aphthous stomatitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Ascites
    Additional description: Ascites
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Cheilitis
    Additional description: Cheilitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    14 / 33 (42.42%)
    12 / 33 (36.36%)
         occurrences all number
    18
    16
    Dry mouth
    Additional description: Dry mouth
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Dyspepsia
    Additional description: Dyspepsia
         subjects affected / exposed
    4 / 33 (12.12%)
    4 / 33 (12.12%)
         occurrences all number
    5
    4
    Dysphagia
    Additional description: Dysphagia
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Gastrointestinal disorder
    Additional description: Gastrointestinal disorder
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    2
    Gastrooesophageal reflux disease
    Additional description: Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Gingival discomfort
    Additional description: Gingival discomfort
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Gingival pain
    Additional description: Gingival pain
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoidal haemorrhage
    Additional description: Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Large intestine polyp
    Additional description: Large intestine polyp
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Loose tooth
    Additional description: Loose tooth
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    9 / 33 (27.27%)
    6 / 33 (18.18%)
         occurrences all number
    13
    9
    Oesophagitis
    Additional description: Oesophagitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Oral discomfort
    Additional description: Oral discomfort
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Oral disorder
    Additional description: Oral disorder
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Pancreatitis chronic
    Additional description: Pancreatitis chronic
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Reflux gastritis
    Additional description: Reflux gastritis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Regurgitation
    Additional description: Regurgitation
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Stomatitis
    Additional description: Stomatitis
         subjects affected / exposed
    1 / 33 (3.03%)
    4 / 33 (12.12%)
         occurrences all number
    1
    4
    Swollen tongue
    Additional description: Swollen tongue
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    5 / 33 (15.15%)
    3 / 33 (9.09%)
         occurrences all number
    7
    3
    Hepatobiliary disorders
    Cholangitis
    Additional description: Cholangitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    3
    Cholestasis
    Additional description: Cholestasis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Hyperbilirubinaemia
    Additional description: Hyperbilirubinaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
    Additional description: Alopecia
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    Alopecia areata
    Additional description: Alopecia areata
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Dermatitis
    Additional description: Dermatitis
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Dermatitis acneiform
    Additional description: Dermatitis acneiform
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Dermatitis allergic
    Additional description: Dermatitis allergic
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Dry skin
    Additional description: Dry skin
         subjects affected / exposed
    3 / 33 (9.09%)
    2 / 33 (6.06%)
         occurrences all number
    4
    2
    Ecchymosis
    Additional description: Ecchymosis
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Eczema
    Additional description: Eczema
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Erythema
    Additional description: Erythema
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Erythema exsudativum multiforme
    Additional description: Erythema exsudativum multiforme
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Hyperhidrosis
    Additional description: Hyperhidrosis
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    Nail bed inflammation
    Additional description: Nail bed inflammation
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Nail fold inflammation
    Additional description: Nail fold inflammation
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Night sweats
    Additional description: Night sweats
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Petechiae
    Additional description: Petechiae
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Photodermatosis
    Additional description: Photodermatosis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Pruritus
    Additional description: Pruritus
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 33 (3.03%)
         occurrences all number
    3
    2
    Psoriasis
    Additional description: Psoriasis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Purpura
    Additional description: Purpura
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Rash
    Additional description: Rash
         subjects affected / exposed
    12 / 33 (36.36%)
    7 / 33 (21.21%)
         occurrences all number
    20
    8
    Rash maculo-papular
    Additional description: Rash maculo-papular
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Rash pruritic
    Additional description: Rash pruritic
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Rosacea
    Additional description: Rosacea
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Scab
    Additional description: Scab
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Skin fissures
    Additional description: Skin fissures
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Skin haemorrhage
    Additional description: Skin haemorrhage
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Skin irritation
    Additional description: Skin irritation
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Skin odour abnormal
    Additional description: Skin odour abnormal
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Sweat gland disorder
    Additional description: Sweat gland disorder
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Urticaria
    Additional description: Urticaria
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Bladder dysfunction
    Additional description: Bladder dysfunction
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Bladder pain
    Additional description: Bladder pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Bladder trabeculation
    Additional description: Bladder trabeculation
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Haematuria
    Additional description: Haematuria
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Micturition disorder
    Additional description: Micturition disorder
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Nocturia
    Additional description: Nocturia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Pollakiuria
    Additional description: Pollakiuria
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Polyuria
    Additional description: Polyuria
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Renal colic
    Additional description: Renal colic
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Urinary retention
    Additional description: Urinary retention
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Endocrine disorders
    Hyperthyroidism
    Additional description: Hyperthyroidism
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Hypothyroidism
    Additional description: Hypothyroidism
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
    Additional description: Arthralgia
         subjects affected / exposed
    6 / 33 (18.18%)
    4 / 33 (12.12%)
         occurrences all number
    10
    5
    Back pain
    Additional description: Back pain
         subjects affected / exposed
    7 / 33 (21.21%)
    3 / 33 (9.09%)
         occurrences all number
    9
    3
    Bone pain
    Additional description: Bone pain
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Bursitis
    Additional description: Bursitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Fibromyalgia
    Additional description: Fibromyalgia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Intervertebral disc protrusion
    Additional description: Intervertebral disc protrusion
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Muscle haemorrhage
    Additional description: Muscle haemorrhage
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Muscle spasms
    Additional description: Muscle spasms
         subjects affected / exposed
    3 / 33 (9.09%)
    7 / 33 (21.21%)
         occurrences all number
    3
    7
    Muscle tightness
    Additional description: Muscle tightness
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Musculoskeletal discomfort
    Additional description: Musculoskeletal discomfort
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal stiffness
    Additional description: Musculoskeletal stiffness
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Myalgia
    Additional description: Myalgia
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Neck pain
    Additional description: Neck pain
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Pain in extremity
    Additional description: Pain in extremity
         subjects affected / exposed
    3 / 33 (9.09%)
    2 / 33 (6.06%)
         occurrences all number
    4
    2
    Infections and infestations
    Angular cheilitis
    Additional description: Angular cheilitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Bronchiolitis
    Additional description: Bronchiolitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
    Additional description: Bronchitis
         subjects affected / exposed
    3 / 33 (9.09%)
    5 / 33 (15.15%)
         occurrences all number
    3
    6
    Bronchitis bacterial
    Additional description: Bronchitis bacterial
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Chlamydial infection
    Additional description: Chlamydial infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Chronic sinusitis
    Additional description: Chronic sinusitis
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Conjunctivitis
    Additional description: Conjunctivitis
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 33 (6.06%)
         occurrences all number
    2
    4
    Cystitis
    Additional description: Cystitis
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 33 (3.03%)
         occurrences all number
    3
    6
    Ear infection
    Additional description: Ear infection
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    Escherichia urinary tract infection
    Additional description: Escherichia urinary tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Eye infection
    Additional description: Eye infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Eye infection viral
    Additional description: Eye infection viral
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Febrile infection
    Additional description: Febrile infection
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Fungal skin infection
    Additional description: Fungal skin infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Furuncle
    Additional description: Furuncle
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    2
    Gastroenteritis escherichia coli
    Additional description: Gastroenteritis escherichia coli
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis norovirus
    Additional description: Gastroenteritis norovirus
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal infection
    Additional description: Gastrointestinal infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Gingivitis
    Additional description: Gingivitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Herpes ophthalmic
    Additional description: Herpes ophthalmic
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Herpes simplex
    Additional description: Herpes simplex
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    2
    Herpes virus infection
    Additional description: Herpes virus infection
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 33 (9.09%)
         occurrences all number
    2
    4
    Herpes zoster
    Additional description: Herpes zoster
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Infected bites
    Additional description: Infected bites
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Infection
    Additional description: Infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Influenza
    Additional description: Influenza
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Mucosal infection
    Additional description: Mucosal infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Nail candida
    Additional description: Nail candida
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Nasopharyngitis
    Additional description: Nasopharyngitis
         subjects affected / exposed
    6 / 33 (18.18%)
    16 / 33 (48.48%)
         occurrences all number
    11
    24
    Oral candidiasis
    Additional description: Oral candidiasis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Oral herpes
    Additional description: Oral herpes
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Oropharyngeal candidiasis
    Additional description: Oropharyngeal candidiasis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Otitis media
    Additional description: Otitis media
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    Paronychia
    Additional description: Paronychia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
    Additional description: Pharyngitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Pneumonia
    Additional description: Pneumonia
         subjects affected / exposed
    3 / 33 (9.09%)
    4 / 33 (12.12%)
         occurrences all number
    4
    4
    Pulpitis dental
    Additional description: Pulpitis dental
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Rash pustular
    Additional description: Rash pustular
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Respiratory tract infection
    Additional description: Respiratory tract infection
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    Respiratory tract infection bacterial
    Additional description: Respiratory tract infection bacterial
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Rhinitis
    Additional description: Rhinitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
    Additional description: Sinusitis
         subjects affected / exposed
    4 / 33 (12.12%)
    5 / 33 (15.15%)
         occurrences all number
    7
    7
    Skin infection
    Additional description: Skin infection
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Soft tissue infection
    Additional description: Soft tissue infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
    Additional description: Tonsillitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
    Additional description: Upper respiratory tract infection
         subjects affected / exposed
    3 / 33 (9.09%)
    4 / 33 (12.12%)
         occurrences all number
    4
    7
    Upper respiratory tract infection bacterial
    Additional description: Upper respiratory tract infection bacterial
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    6 / 33 (18.18%)
    7 / 33 (21.21%)
         occurrences all number
    7
    11
    Wound infection
    Additional description: Wound infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
    Additional description: Decreased appetite
         subjects affected / exposed
    4 / 33 (12.12%)
    2 / 33 (6.06%)
         occurrences all number
    4
    2
    Dehydration
    Additional description: Dehydration
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Folate deficiency
    Additional description: Folate deficiency
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Hyperkalaemia
    Additional description: Hyperkalaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Hyperuricaemia
    Additional description: Hyperuricaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Hypocalcaemia
    Additional description: Hypocalcaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Hypokalaemia
    Additional description: Hypokalaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    3
    Tumour lysis syndrome
    Additional description: Tumour lysis syndrome
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Dec 2015
    This amendment was made to provide the following information: - Additional testing timepoint - Additional information to tumour lysis syndrom - Additional information to the adverse drug reactions: infusion-related reactions (IRRs), neutropenia, thrombocytopenia - New information to adverse events - New information to the administration of obinutuzumab to patients with chronic infections and to premedication with obinutuzumab - New information to Hepatitis B reactivation - Additional information to progressive multifocal leukencephalopathy (PML) - New information to immunization
    22 Mar 2017
    This amendment was made to provide the following information: - New potential risk of gastrointestinal perforation with obinutuzumab - New information to the non-hematological adverse event interstitial lung disease

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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