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    Clinical Trial Results:
    A PROSPECTIVE, MULTICENTER, PHASE-II TRIAL EVALUATING EFFICACY AND SAFETY OF BENDAMUSTINE + GA101 (BG) IN PATIENTS WITH RELAPSED CLL FOLLOWED BY MAINTENANCE THERAPY WITH GA101 FOR RESPONDING PATIENTS.

    Summary
    EudraCT number
    2013-001088-22
    Trial protocol
    DE  
    Global end of trial date
    09 May 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    26 May 2023
    First version publication date
    26 May 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLLR3
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02445131
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    PEI: 2121
    Sponsors
    Sponsor organisation name
    Städtisches Klinikum München GmbH
    Sponsor organisation address
    Thalkirchner Str. 48, München, Germany, 80337
    Public contact
    Emily Holmes, Deutsche CLL Studiengruppe, 0049 22147896118, emily.holmes@uk-koeln.de
    Scientific contact
    Nadine Kutsch, Deutsche CLL Studiengruppe, 0049 22147888220, nadine.kutsch@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
    01 Sep 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 May 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    A combination therapy with FC + GA101 (FCG) or B + GA101 (BG) followed by a maintenance therapy with GA101 for responding patients might further improve the therapeutic outcome in relapsed CLL. Therefore, the CLLR3 trial was designed to investigate and to evaluate the efficacy and safety of both immunochemotherapies FCG and BG followed additionally by a maintenance therapy with GA101 for patients responding to therapy. Recruitment of the FCG group was prematurely closed in the course of the study. Thus, the CLLR3 trial follows the objective to evaluate the efficacy and safety of induction therapy with BG followed additionally by a maintenance therapy with GA101 for responding patients.
    Protection of trial subjects
    The most frequent expected treatment emerged events include hematological toxicities and infectious complications. Both of these toxicities are well known side effects in patients with chronic lymphocytic leukemia during chemoimmunotherapy. Hence, the protocol includes a section detailing the prevention and the treatment options in patients with cytopenia or infections. Also, guidance for infusion related reactions and tumour lysis syndrome were included in the protocol, because these events were frequently associated with chemoimmunotherapy. Worsening of pre-existing cardiac conditions might occur in this patient population, hence a section describing measurements are included in the protocol as well.
    Background therapy
    Most patients with CLL will eventually relapse as neither immunochemotherapy nor myeloablative therapy followed by autologous stem cell transplantation have been shown to be curative in CLL. Furthermore, allogeneic stem cell transplantation as curative option is only considered for physically fit patients with a high-risk profile because of a high treatment related mortality. At time point of the planning for this study, there was no standard combination therapy for patients with relapsed or refractory CLL and according to the DGHO guideline, patients with relapsed CLL should be treated within clinical trials, if possible . Cramer et al. showed that therapy regimens chosen for second line treatment after FC or FCR were heterogeneous, which highlights the need to define treatment recommendations for patients with relapsed chronic lymphocytic leukemia in further trials.
    Evidence for comparator
    At time point of the planning of this study, there was evidence that the immunochemotherapy with fludarabine, cyclophosphamide and rituximab (FCR) is active in patients with refractory and relapsed CLL. Badoux et al. showed that FCR in relapsed patients leads to an overall response rate of 74 %, an estimated median PFS of 20.9 months (95 % confidence interval (CI), 18.8-27.6 months), as well as an estimated median survival time of 46.7 months (95 % CI, 41.2-53.4 months), and conclude that FCR is active and well tolerated in patients with relapsed CLL. Besides FCR, the combination of rituximab with bendamustine (BR), a hybrid alkylating agent with properties of a purine-analogue, has been shown to be active in both relapsed and previously untreated CLL patients.
    Actual start date of recruitment
    02 Jun 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 27
    Worldwide total number of subjects
    27
    EEA total number of subjects
    27
    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)
    15
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The first patient was recruited in November 2014. Due to the low recruitment the FCG-arm was closed in September 2016 (amendment 3). 20 patients have been randomized into the study and 10 patients have been included into the BG-arm until amendment 3. The study recruitment was terminated in April 2018. A total of 27 patients were included.

    Pre-assignment
    Screening details
    After obtaining informed consent, eligible patients started screening. To verify the eligibility of patients, an internal medical review of the screening documents was performed. Results of the baseline assessments including the completed screening CRF pages were reviewed and approved, if applicable.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Fludarabine, Cyclophosphamide and Obinutuzumab
    Arm description
    Obinutuzumab is administered before the FC infusion. In the first cycle obinutuzumab was administered on day one (100 mg), day two (900 mg), day eight (1000 mg) and day 15 (1000 mg). Obinutuzumab in cycle 1 could be administered either full dose (1000 mg) on day one if the first infusion of 100 mg was well tolerated by the patient or over two consecutive days (100 mg on first day, remaining 900 mg the following day). For all subsequent cycles patients received 1000 mg obinutuzumab on day one. 25 mg/m2 fludarabine were administered as iv infusion over 15 - 30 minutes on day three to five of cycle one or day two to four when obinutuzumab was completely dosed on day one; and day two to four of cycle two to six. Patients received 250 mg/m2 cyclophosphamide as iv infusion over 15 - 30 minutes on day three to five of cycle one or day two to four when obinutuzumab was completely dosed on day one; and day two to four of cycle two to six.
    Arm type
    Experimental

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    30590.00.00
    Other name
    L01AA01
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Fludarabine iv infusion 25 mg/m2 day 3-5 in cycle 1, respectively day 2-4 q4wks, cycle 2 to 6 Cycle 1 Day 3 25 mg/m2 Day 4 25 mg/m2 Day 5 25 mg/m2 Cycle 2 - 6 Day 2 25 mg/m2 Day 3 25 mg/m2 Day 4 25 mg/m2

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    1001995601
    Other name
    L01AA01
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide iv infusion 250 mg/m2 day 3-5 in cycle 1, respectively day 2-4 q4wks, cycle 2 to 6 Cycle 1 Day 3 250 mg/m2 Day 4 250 mg/m2 Day 5 250 mg/m2 Cycle 2 – 6 Day 2 250 mg/m2 Day 3 250 mg/m2 Day 4 250 mg/m2

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    R05072759
    Other name
    Gazyvaro
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    GA101 iv infusion: Cycle 1 Day 1 100 mg Day 2 900 mg Day 8 1000 mg Day 15 1000 mg Cycle 2 - 6 Day 1 1000 mg In case of a response to the induction therapy, a maintenance therapy consisting of 1000 mg Obinutuzumab i.v. every three months for up to two years is applied.

    Arm title
    Bendamustine and Obinutuzumab
    Arm description
    Patients in the BG arm receive Obinutuzumab i.v. over six cycles. On day one of cycle one, the starting dosage is 100mg which is increased to 900 mg on day two of cycle one. On day 8 and 15 of the first cycle, patients receive 1000 mg. In cycles two to six, patients receive 1000 mg Obinutuzumab at day one of each cycle. Bendamustine is given i.v. at a concentration of 70 mg/m² on day three and four of cycle one and on day two and three of cycles two to six. In case of a response to the induction therapy, a maintenance therapy consisting of 1000 mg Obinutuzumab i.v. every three months for up to two years is applied.
    Arm type
    Experimental

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    R05072759
    Other name
    Gazyvaro
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    GA101 iv infusion: Cycle 1 Day 1 100 mg Day 2 900 mg Day 8 1000 mg Day 15 1000 mg Cycle 2 - 6 Day 1 1000 mg In case of a response to the induction therapy, a maintenance therapy consisting of 1000 mg Obinutuzumab i.v. every three months for up to two years is applied.

    Investigational medicinal product name
    Bendamustine hydrochloride
    Investigational medicinal product code
    70972.00.00
    Other name
    Levact
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bendamustine Treatment Cycle 1 Day 3 70 mg/m² Day 4 70 mg/m² Cycle 2 – 6 Day 2 70 mg/m² Day 3 70 mg/m²

    Number of subjects in period 1
    Fludarabine, Cyclophosphamide and Obinutuzumab Bendamustine and Obinutuzumab
    Started
    10
    17
    Completed
    1
    9
    Not completed
    9
    8
         Consent withdrawn by subject
    2
    -
         Adverse event, non-fatal
    5
    4
         Progressive disease
    2
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fludarabine, Cyclophosphamide and Obinutuzumab
    Reporting group description
    Obinutuzumab is administered before the FC infusion. In the first cycle obinutuzumab was administered on day one (100 mg), day two (900 mg), day eight (1000 mg) and day 15 (1000 mg). Obinutuzumab in cycle 1 could be administered either full dose (1000 mg) on day one if the first infusion of 100 mg was well tolerated by the patient or over two consecutive days (100 mg on first day, remaining 900 mg the following day). For all subsequent cycles patients received 1000 mg obinutuzumab on day one. 25 mg/m2 fludarabine were administered as iv infusion over 15 - 30 minutes on day three to five of cycle one or day two to four when obinutuzumab was completely dosed on day one; and day two to four of cycle two to six. Patients received 250 mg/m2 cyclophosphamide as iv infusion over 15 - 30 minutes on day three to five of cycle one or day two to four when obinutuzumab was completely dosed on day one; and day two to four of cycle two to six.

    Reporting group title
    Bendamustine and Obinutuzumab
    Reporting group description
    Patients in the BG arm receive Obinutuzumab i.v. over six cycles. On day one of cycle one, the starting dosage is 100mg which is increased to 900 mg on day two of cycle one. On day 8 and 15 of the first cycle, patients receive 1000 mg. In cycles two to six, patients receive 1000 mg Obinutuzumab at day one of each cycle. Bendamustine is given i.v. at a concentration of 70 mg/m² on day three and four of cycle one and on day two and three of cycles two to six. In case of a response to the induction therapy, a maintenance therapy consisting of 1000 mg Obinutuzumab i.v. every three months for up to two years is applied.

    Reporting group values
    Fludarabine, Cyclophosphamide and Obinutuzumab Bendamustine and Obinutuzumab Total
    Number of subjects
    10 17 27
    Age categorical
    Age according to categories as below.
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    6 9 15
        From 65-84 years
    4 8 12
        85 years and over
    0 0 0
    Age continuous
    Median age, IQR ( interquartile range: 25% - 75% percentiles)
    Units: years
        median (inter-quartile range (Q1-Q3))
    61.5 (57.3 to 68.8) 63.0 (55.0 to 71.5) -
    Gender categorical
    Sex: male; female
    Units: Subjects
        Female
    2 6 8
        Male
    8 11 19
    CLL-IPI Score
    The International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI) stratifies patients with chronic lymphocytic leukemia into four risk categories.
    Units: Subjects
        Low
    1 1 2
        Intermediate
    4 5 9
        High
    4 8 12
        Very High
    1 2 3
        missing
    0 1 1
    Median CIRS Score
    The Cumulative Illness Rating Scale (CIRS) rates 13 body systems on a five-point pathophysiology severity scale to assess comorbidities in different organ systems.
    Units: Score
        median (inter-quartile range (Q1-Q3))
    3 (0.8 to 4.3) 1 (0.5 to 4.0) -
    Previous treatments for CLL
    Number of previous treatment lines for CLL were counted.
    Units: numbers
        median (inter-quartile range (Q1-Q3))
    1.5 (1 to 2) 1 (1 to 2) -

    End points

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    End points reporting groups
    Reporting group title
    Fludarabine, Cyclophosphamide and Obinutuzumab
    Reporting group description
    Obinutuzumab is administered before the FC infusion. In the first cycle obinutuzumab was administered on day one (100 mg), day two (900 mg), day eight (1000 mg) and day 15 (1000 mg). Obinutuzumab in cycle 1 could be administered either full dose (1000 mg) on day one if the first infusion of 100 mg was well tolerated by the patient or over two consecutive days (100 mg on first day, remaining 900 mg the following day). For all subsequent cycles patients received 1000 mg obinutuzumab on day one. 25 mg/m2 fludarabine were administered as iv infusion over 15 - 30 minutes on day three to five of cycle one or day two to four when obinutuzumab was completely dosed on day one; and day two to four of cycle two to six. Patients received 250 mg/m2 cyclophosphamide as iv infusion over 15 - 30 minutes on day three to five of cycle one or day two to four when obinutuzumab was completely dosed on day one; and day two to four of cycle two to six.

    Reporting group title
    Bendamustine and Obinutuzumab
    Reporting group description
    Patients in the BG arm receive Obinutuzumab i.v. over six cycles. On day one of cycle one, the starting dosage is 100mg which is increased to 900 mg on day two of cycle one. On day 8 and 15 of the first cycle, patients receive 1000 mg. In cycles two to six, patients receive 1000 mg Obinutuzumab at day one of each cycle. Bendamustine is given i.v. at a concentration of 70 mg/m² on day three and four of cycle one and on day two and three of cycles two to six. In case of a response to the induction therapy, a maintenance therapy consisting of 1000 mg Obinutuzumab i.v. every three months for up to two years is applied.

    Primary: Best overall response rate

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    End point title
    Best overall response rate [1]
    End point description
    Best overall response rate (ORR) defined as best response assessed until and including response assessment at follow up 2 (6 months after final restaging/ induction), defined by the proportion of patients that responded to therapy. Response is defined as having achieved a CR/ CRi, clinical CR/ CRi or nPR/ PR as best response based on the ITT (intention to treat) population (= number of patients with best response CR/ CRi, clinical CR/ CRi or nPR/ PR divided by the number of the ITT-population). Non-Response is defined by a reported stable disease or progressive disease as the outcome of therapy at follow up 2.
    End point type
    Primary
    End point timeframe
    This primary endpoint is measured for each patient 6 months after the study treatment has been terminated and the final restaging has been performed.
    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: The primary efficacy analysis was based on the estimation of the ORR and its corresponding exact confidence interval based on the ITT. According to the study protocol, no confirmatory statistical testing was performed.
    End point values
    Fludarabine, Cyclophosphamide and Obinutuzumab Bendamustine and Obinutuzumab
    Number of subjects analysed
    10
    17
    Units: Percentage
    number (not applicable)
        Overall response rate
    40.0
    94.1
        95% Confidence interval: lower bound
    12.2
    71.3
        95% Confidence interval: upper bound
    73.8
    99.9
    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
    BG treatment
    Reporting group description
    -

    Reporting group title
    FCG treatment
    Reporting group description
    -

    Serious adverse events
    BG treatment FCG treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 17 (70.59%)
    7 / 9 (77.78%)
         number of deaths (all causes)
    1
    3
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
    Additional description: Basal cell carcinoma
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
    Additional description: Bowen's disease
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
    Additional description: Myelodysplastic syndrome
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the tongue
    Additional description: Squamous cell carcinoma of the tongue
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
    Additional description: Infusion related reaction
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
    Additional description: Rib fracture
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
    Additional description: Atrial fibrillation
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
    Additional description: Coronary artery disease
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
    Additional description: Cerebral ischaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
    Additional description: Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
    Additional description: Transient ischaemic attack
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (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
    Febrile neutropenia
    Additional description: Febrile neutropenia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
    Additional description: Pancytopenia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
    Additional description: Neutropenia
         subjects affected / exposed
    3 / 17 (17.65%)
    3 / 9 (33.33%)
         occurrences causally related to treatment / all
    3 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
    Additional description: Thrombocytopenia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal ulcer
    Additional description: Anal ulcer
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
    Additional description: Ileus
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
    Additional description: Dysphagia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue ulceration
    Additional description: Tongue ulceration
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (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
    Asthma
    Additional description: Asthma
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chylothorax
    Additional description: Chylothorax
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
    Additional description: Pleural effusion
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
    Additional description: Pulmonary fibrosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis cholestatic
    Additional description: Hepatitis cholestatic
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pemphigoid
    Additional description: Pemphigoid
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panniculitis
    Additional description: Panniculitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (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
    Back pain
    Additional description: Back pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint effusion
    Additional description: Joint effusion
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteolysis
    Additional description: Osteolysis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bursitis infective
    Additional description: Bursitis infective
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
    Additional description: Bronchitis
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 9 (22.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
    Additional description: Atypical pneumonia
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
    Additional description: Infection
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
    Additional description: Erysipelas
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
    Additional description: Diverticulitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia escherichia
    Additional description: Pneumonia escherichia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia chlamydial
    Additional description: Pneumonia chlamydial
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (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
    2 / 17 (11.76%)
    3 / 9 (33.33%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Listeriosis
    Additional description: Listeriosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
    Additional description: Pseudomonal sepsis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (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
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Tumour lysis syndrome
    Additional description: Tumour lysis syndrome
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 9 (22.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    BG treatment FCG treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 17 (100.00%)
    9 / 9 (100.00%)
    Vascular disorders
    Circulatory collapse
    Additional description: Circulatory collapse
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Haematoma
    Additional description: Haematoma
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Flushing
    Additional description: Flushing
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    Hypertension
    Additional description: Hypertension
         subjects affected / exposed
    4 / 17 (23.53%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    Hypertensive crisis
    Additional description: Hypertensive crisis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Hypotension
    Additional description: Hypotension
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
    Additional description: Asthenia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Chills
    Additional description: Chills
         subjects affected / exposed
    4 / 17 (23.53%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    Fatigue
    Additional description: Fatigue
         subjects affected / exposed
    6 / 17 (35.29%)
    0 / 9 (0.00%)
         occurrences all number
    9
    0
    Feeling cold
    Additional description: Feeling cold
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Malaise
    Additional description: Malaise
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Oedema
    Additional description: Oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Oedema peripheral
    Additional description: Oedema peripheral
         subjects affected / exposed
    4 / 17 (23.53%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    Pain
    Additional description: Pain
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Pyrexia
    Additional description: Pyrexia
         subjects affected / exposed
    4 / 17 (23.53%)
    1 / 9 (11.11%)
         occurrences all number
    11
    1
    Swelling face
    Additional description: Swelling face
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Swelling
    Additional description: Swelling
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Hypersensitivity
    Additional description: Hypersensitivity
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Immunodeficiency
    Additional description: Immunodeficiency
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
    Additional description: Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Cough
    Additional description: Cough
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 9 (22.22%)
         occurrences all number
    2
    2
    Bronchial obstruction
    Additional description: Bronchial obstruction
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea exertional
    Additional description: Dyspnoea exertional
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Dysphonia
    Additional description: Dysphonia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
    Additional description: Dyspnoea
         subjects affected / exposed
    5 / 17 (29.41%)
    2 / 9 (22.22%)
         occurrences all number
    5
    2
    Epistaxis
    Additional description: Epistaxis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Haemoptysis
    Additional description: Haemoptysis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Pleural effusion
    Additional description: Pleural effusion
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
    Additional description: Anxiety
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Confusional state
    Additional description: Confusional state
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Insomnia
    Additional description: Insomnia
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 9 (11.11%)
         occurrences all number
    4
    1
    Restlessness
    Additional description: Restlessness
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood urea increased
    Additional description: Blood urea increased
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Blood creatinine increased
    Additional description: Blood creatinine increased
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Blood lactate dehydrogenase increased
    Additional description: Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Blood potassium decreased
    Additional description: Blood potassium decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    C-reactive protein increased
    Additional description: C-reactive protein increased
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    CD4 lymphocytes abnormal
    Additional description: CD4 lymphocytes abnormal
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Immunoglobulins decreased
    Additional description: Immunoglobulins decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Lymphocyte count decreased
    Additional description: Lymphocyte count decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Transaminases increased
    Additional description: Transaminases increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Urine uric acid increased
    Additional description: Urine uric acid increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Weight decreased
    Additional description: Weight decreased
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 9 (11.11%)
         occurrences all number
    3
    1
    Injury, poisoning and procedural complications
    Infusion related reaction
    Additional description: Infusion related reaction
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 9 (11.11%)
         occurrences all number
    2
    2
    Spinal fracture
    Additional description: Spinal fracture
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Tongue injury
    Additional description: Tongue injury
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Wound
    Additional description: Wound
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Traumatic haematoma
    Additional description: Traumatic haematoma
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Cardiac disorders
    Angina pectoris
    Additional description: Angina pectoris
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Cardiovascular disorder
    Additional description: Cardiovascular disorder
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Extrasystoles
    Additional description: Extrasystoles
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Pericardial effusion
    Additional description: Pericardial effusion
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Ventricular extrasystoles
    Additional description: Ventricular extrasystoles
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Nervous system disorders
    Coordination abnormal
    Additional description: Coordination abnormal
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Dizziness
    Additional description: Dizziness
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Dysgeusia
    Additional description: Dysgeusia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Headache
    Additional description: Headache
         subjects affected / exposed
    4 / 17 (23.53%)
    2 / 9 (22.22%)
         occurrences all number
    8
    2
    Memory impairment
    Additional description: Memory impairment
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Orthostatic intolerance
    Additional description: Orthostatic intolerance
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Polyneuropathy
    Additional description: Polyneuropathy
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Restless legs syndrome
    Additional description: Restless legs syndrome
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Tremor
    Additional description: Tremor
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    5 / 17 (29.41%)
    3 / 9 (33.33%)
         occurrences all number
    6
    5
    Febrile neutropenia
    Additional description: Febrile neutropenia
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Leukopenia
    Additional description: Leukopenia
         subjects affected / exposed
    6 / 17 (35.29%)
    4 / 9 (44.44%)
         occurrences all number
    8
    10
    Lymphopenia
    Additional description: Lymphopenia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Pancytopenia
    Additional description: Pancytopenia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Neutropenia
    Additional description: Neutropenia
         subjects affected / exposed
    7 / 17 (41.18%)
    5 / 9 (55.56%)
         occurrences all number
    8
    9
    Thrombocytopenia
    Additional description: Thrombocytopenia
         subjects affected / exposed
    10 / 17 (58.82%)
    4 / 9 (44.44%)
         occurrences all number
    15
    5
    Ear and labyrinth disorders
    Ear pain
    Additional description: Ear pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Hypoacusis
    Additional description: Hypoacusis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Tinnitus
    Additional description: Tinnitus
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Vertigo
    Additional description: Vertigo
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 9 (11.11%)
         occurrences all number
    2
    1
    Eye disorders
    Metamorphopsia
    Additional description: Metamorphopsia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Visual impairment
    Additional description: Visual impairment
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal distension
    Additional description: Abdominal distension
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Abdominal discomfort
    Additional description: Abdominal discomfort
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
    Additional description: Abdominal pain upper
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Angular cheilitis
    Additional description: Angular cheilitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 9 (11.11%)
         occurrences all number
    2
    1
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 9 (11.11%)
         occurrences all number
    4
    1
    Dyspepsia
    Additional description: Dyspepsia
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    Dysphagia
    Additional description: Dysphagia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Dry mouth
    Additional description: Dry mouth
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Inguinal hernia
    Additional description: Inguinal hernia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Oedema mouth
    Additional description: Oedema mouth
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    8 / 17 (47.06%)
    2 / 9 (22.22%)
         occurrences all number
    13
    4
    Stomatitis
    Additional description: Stomatitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    2 / 17 (11.76%)
    4 / 9 (44.44%)
         occurrences all number
    2
    4
    Tongue ulceration
    Additional description: Tongue ulceration
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
    Additional description: Alopecia
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Actinic keratosis
    Additional description: Actinic keratosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Dermal cyst
    Additional description: Dermal cyst
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Dermatitis
    Additional description: Dermatitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Dry skin
    Additional description: Dry skin
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Eczema
    Additional description: Eczema
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Hyperhidrosis
    Additional description: Hyperhidrosis
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Onychoclasis
    Additional description: Onychoclasis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Papule
    Additional description: Papule
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Night sweats
    Additional description: Night sweats
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 9 (22.22%)
         occurrences all number
    1
    2
    Purpura
    Additional description: Purpura
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Rash
    Additional description: Rash
         subjects affected / exposed
    5 / 17 (29.41%)
    0 / 9 (0.00%)
         occurrences all number
    5
    0
    Pruritus
    Additional description: Pruritus
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Solar dermatitis
    Additional description: Solar dermatitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Nocturia
    Additional description: Nocturia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Renal pain
    Additional description: Renal pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Renal failure
    Additional description: Renal failure
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
    Additional description: Arthralgia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Back pain
    Additional description: Back pain
         subjects affected / exposed
    4 / 17 (23.53%)
    0 / 9 (0.00%)
         occurrences all number
    6
    0
    Bone pain
    Additional description: Bone pain
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Myalgia
    Additional description: Myalgia
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Joint swelling
    Additional description: Joint swelling
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Muscle cramp
    Additional description: Muscle cramp
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
    Additional description: Musculoskeletal chest pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
    Additional description: Musculoskeletal pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
    Additional description: Pain in extremity
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Acute sinusitis
    Additional description: Acute sinusitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Bronchitis
    Additional description: Bronchitis
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 9 (11.11%)
         occurrences all number
    2
    1
    Candida infection
    Additional description: Candida infection
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Gingivitis
    Additional description: Gingivitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Febrile infection
    Additional description: Febrile infection
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 9 (11.11%)
         occurrences all number
    3
    1
    Influenza
    Additional description: Influenza
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Infection
    Additional description: Infection
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Herpes zoster
    Additional description: Herpes zoster
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Lyme disease
    Additional description: Lyme disease
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Oral candidiasis
    Additional description: Oral candidiasis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Oral herpes
    Additional description: Oral herpes
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Nasopharyngitis
    Additional description: Nasopharyngitis
         subjects affected / exposed
    5 / 17 (29.41%)
    0 / 9 (0.00%)
         occurrences all number
    6
    0
    Pneumonia
    Additional description: Pneumonia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Sinusitis
    Additional description: Sinusitis
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 9 (22.22%)
         occurrences all number
    1
    2
    Sinobronchitis
    Additional description: Sinobronchitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Sialoadenitis
    Additional description: Sialoadenitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
    Additional description: Rhinitis
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Respiratory tract infection
    Additional description: Respiratory tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    Tinea pedis
    Additional description: Tinea pedis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
    Additional description: Upper respiratory tract infection
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 9 (11.11%)
         occurrences all number
    2
    2
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
    Additional description: Decreased appetite
         subjects affected / exposed
    4 / 17 (23.53%)
    3 / 9 (33.33%)
         occurrences all number
    5
    3
    Dehydration
    Additional description: Dehydration
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Diabetes mellitus
    Additional description: Diabetes mellitus
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Gout
    Additional description: Gout
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Hyperkalaemia
    Additional description: Hyperkalaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Hypocalcaemia
    Additional description: Hypocalcaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
    Additional description: Hypokalaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Type 2 diabetes mellitus
    Additional description: Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 9 (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
    28 Aug 2015
    Introduction of infection prophylaxis for the patients. Approval by competent authority on 28-Aug-2015.
    08 Feb 2016
    New safety data on Obinutuzumab, changes to ICF. Approval by Competent authority on 08-Feb-2016.
    21 Sep 2016
    New safety data on Obinutuzumab, changes to ICF. Due to the low recruitment the FCG-arm was closed in September 2016 ( following the approval of amendment 3)
    01 Jun 2017
    New safety data on Obinutuzumab, changes to ICF.
    23 Jul 2020
    New safety data on Obinutuzumab.

    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.
    A total of 27 pts were enrolled in the study, and the recruitment was not completed due to low interest.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/36423347
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    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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