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    Clinical Trial Results:
    A Randomized, Open-label, Safety and Efficacy Study of Ibrutinib in Pediatric and Young Adult Patients With Relapsed or Refractory Mature B-cell non-Hodgkin Lymphoma

    Summary
    EudraCT number
    2016-000259-28
    Trial protocol
    GB   IT   BE   CZ   HU   DE   NL   ES   PL   BG   Outside EU/EEA   SE  
    Global end of trial date
    11 Jun 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Dec 2021
    First version publication date
    22 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    54179060LYM3003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02703272
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International N.V.
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium, B-2340
    Public contact
    Clinical Registry Group, Janssen-Cilag International N.V., ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen-Cilag International N.V., ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001397-PIP03-14
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Jun 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jun 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objectives of this trial was to confirm that the pharmacokinetics (PK) in pediatric subjects was consistent with that in adults (Part 1) and to assess efficacy (event free survival [EFS]) of ibrutinib in combination with RICE (rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone) or RVICI (rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone) background therapy compared to RICE or RVICI background therapy alone (Part 2).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Known instances of nonconformance were documented and are not considered to have had an impact on the overall conclusions of this study. Safety assessments were based upon the occurrence, type, and severity of adverse events (AEs) reported throughout the study, AEs of interest, vital signs, electrocardiogram (ECG), clinical laboratory tests (that is, hematology, serum chemistry, viral serology), and physical examinations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Dec 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Korea, Republic of: 10
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    Ukraine: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    France: 7
    Worldwide total number of subjects
    72
    EEA total number of subjects
    39
    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)
    25
    Adolescents (12-17 years)
    41
    Adults (18-64 years)
    6
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 72 subjects (21 subjects in Part 1 and 51 subjects in Part 2) were enrolled in this study. Total of 72 subjects, 71 subjects received the study treatment. One of the 51 subjects, randomized to chemotherapy (CIT) group, withdrew consent following randomization and did not receive study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part 1: Ibrutinib+RICE
    Arm description
    Subjects received ibrutinib based on age group and body surface area (BSA) in combination with chemoimmunotherapy (CIT) (investigator choice of RICE [rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone]) for 3 treatment cycles with each cycle 28 or 21 days long. The RICE regimen was composed of rituximab 750 milligrams per meter square (mg/m^2), ifosfamide 9 grams per meter square (g/m^2), carboplatin 635 mg/m^2, etoposide 300 mg/m^2, and dexamethasone 100 mg/m^2. Study treatment continued for 3 cycles, unless the subject experienced unacceptable toxicity or disease progression.
    Arm type
    Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    JNJ-54179060
    Pharmaceutical forms
    Concentrate for oral suspension, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ibrutinib orally once daily, starting at Cycle 1 Day 1 with a maximum dose of 440 mg/m^2 in Part 1.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received cumulative dose of 750 milligrams per meter square (mg/m^2) rituximab as part of RICE in Part 1.

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received cumulative dose of 9 grams per meter square (g/m^2) ifosfamide as part of RICE in Part 1.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received cumulative dose of 635 mg/m^2 carboplatin as part of RICE in Part 1.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received cumulative dose of 300 mg/m^2 etoposide as part of RICE in Part 1.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received cumulative dose of 100 mg/m^2 dexamethasone as part of RICE in Part 1.

    Arm title
    Part 1: Ibrutinib+RVICI
    Arm description
    Subjects received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RVICI [rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone]) for 3 treatment cycles with each cycle 28 or 21 days long. The RVICI regimen was composed of rituximab 750 mg/m^2, vincristine 1.6 mg/m^2, ifosfamide 10 g/m^2, carboplatin 800 mg/m^2, idarubicin 20 mg/m^2, and dexamethasone 100 mg/m^2. Study treatment continued for 3 cycles, unless the subject experienced unacceptable toxicity or disease progression.
    Arm type
    Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    JNJ-54179060
    Pharmaceutical forms
    Capsule, Concentrate for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ibrutinib orally once daily, starting at Cycle 1 Day 1 with a maximum dose of 440 mg/m^2 in Part 1.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received cumulative dose of 750 mg/m^2 rituximab as part of RVICI in Part 1.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received cumulative dose of 1.6 mg/m^2 vincristine as part of RVICI in Part 1.

    Investigational medicinal product name
    Idarubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received cumulative dose of 20 mg/m^2 idarubicin as part of RVICI in Part 1.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received cumulative dose of 800 mg/m^2 carboplatin as part of RVICI in Part 1.

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received cumulative dose of 10 g/m^2 ifosfamide as part of RVICI in Part 1.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received cumulative dose of 100 mg/m^2 dexamethasone as part of RVICI in Part 1

    Arm title
    Part 2: Ibrutinib+CIT (RICE or RVICI)
    Arm description
    Subjects received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RICE or RVICI) until 3 treatment cycles, transplantation if indicated, or until progressive disease (PD) or unacceptable toxicity.
    Arm type
    Experimental

    Investigational medicinal product name
    Chemoimmunotherapy (CIT) (RICE or RVICI)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received CIT (investigator choice of RICE or RVICI) in Part 2.

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    JNJ-54179060
    Pharmaceutical forms
    Capsule, Concentrate for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ibrutinib orally once daily, starting at Cycle 1 Day 1 with a maximum dose of 440 mg/m^2 in Part 2.

    Arm title
    Part 2: Chemotherapy (CIT)
    Arm description
    Subjects received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until progressive disease (PD) or unacceptable toxicity.
    Arm type
    Active comparator

    Investigational medicinal product name
    CIT (RICE or RVICI)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received CIT (investigator choice of RICE or RVICI) alone in Part 2.

    Number of subjects in period 1
    Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemotherapy (CIT)
    Started
    11
    10
    35
    16
    Completed
    0
    0
    0
    0
    Not completed
    11
    10
    35
    16
         Other
    1
    -
    -
    -
         Adverse event, serious fatal
    4
    9
    19
    10
         Study terminated by sponsor
    6
    1
    12
    4
         Consent withdrawn by subject
    -
    -
    4
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Ibrutinib+RICE
    Reporting group description
    Subjects received ibrutinib based on age group and body surface area (BSA) in combination with chemoimmunotherapy (CIT) (investigator choice of RICE [rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone]) for 3 treatment cycles with each cycle 28 or 21 days long. The RICE regimen was composed of rituximab 750 milligrams per meter square (mg/m^2), ifosfamide 9 grams per meter square (g/m^2), carboplatin 635 mg/m^2, etoposide 300 mg/m^2, and dexamethasone 100 mg/m^2. Study treatment continued for 3 cycles, unless the subject experienced unacceptable toxicity or disease progression.

    Reporting group title
    Part 1: Ibrutinib+RVICI
    Reporting group description
    Subjects received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RVICI [rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone]) for 3 treatment cycles with each cycle 28 or 21 days long. The RVICI regimen was composed of rituximab 750 mg/m^2, vincristine 1.6 mg/m^2, ifosfamide 10 g/m^2, carboplatin 800 mg/m^2, idarubicin 20 mg/m^2, and dexamethasone 100 mg/m^2. Study treatment continued for 3 cycles, unless the subject experienced unacceptable toxicity or disease progression.

    Reporting group title
    Part 2: Ibrutinib+CIT (RICE or RVICI)
    Reporting group description
    Subjects received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RICE or RVICI) until 3 treatment cycles, transplantation if indicated, or until progressive disease (PD) or unacceptable toxicity.

    Reporting group title
    Part 2: Chemotherapy (CIT)
    Reporting group description
    Subjects received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until progressive disease (PD) or unacceptable toxicity.

    Reporting group values
    Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI Part 2: Ibrutinib+CIT (RICE or RVICI) Part 2: Chemotherapy (CIT) Total
    Number of subjects
    11 10 35 16 72
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    6 8 7 4 25
        Adolescents (12-17 years)
    5 2 23 11 41
        Adults (18-64 years)
    0 0 5 1 6
        From 65 to 84 years
    0 0 0 0 0
        85 years and over
    0 0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    10.5 ± 4.91 8.3 ± 3.43 13.9 ± 3.94 13.3 ± 4.51 -
    Title for Gender
    Units: subjects
        Female
    3 1 12 3 19
        Male
    8 9 23 13 53

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Ibrutinib+RICE
    Reporting group description
    Subjects received ibrutinib based on age group and body surface area (BSA) in combination with chemoimmunotherapy (CIT) (investigator choice of RICE [rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone]) for 3 treatment cycles with each cycle 28 or 21 days long. The RICE regimen was composed of rituximab 750 milligrams per meter square (mg/m^2), ifosfamide 9 grams per meter square (g/m^2), carboplatin 635 mg/m^2, etoposide 300 mg/m^2, and dexamethasone 100 mg/m^2. Study treatment continued for 3 cycles, unless the subject experienced unacceptable toxicity or disease progression.

    Reporting group title
    Part 1: Ibrutinib+RVICI
    Reporting group description
    Subjects received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RVICI [rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone]) for 3 treatment cycles with each cycle 28 or 21 days long. The RVICI regimen was composed of rituximab 750 mg/m^2, vincristine 1.6 mg/m^2, ifosfamide 10 g/m^2, carboplatin 800 mg/m^2, idarubicin 20 mg/m^2, and dexamethasone 100 mg/m^2. Study treatment continued for 3 cycles, unless the subject experienced unacceptable toxicity or disease progression.

    Reporting group title
    Part 2: Ibrutinib+CIT (RICE or RVICI)
    Reporting group description
    Subjects received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RICE or RVICI) until 3 treatment cycles, transplantation if indicated, or until progressive disease (PD) or unacceptable toxicity.

    Reporting group title
    Part 2: Chemotherapy (CIT)
    Reporting group description
    Subjects received CIT (investigator choice of RICE or RVICI) alone based on age group and BSA until 3 treatment cycles, transplantation if indicated, or until progressive disease (PD) or unacceptable toxicity.

    Subject analysis set title
    Part 1: Ibrutinib+RICE
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received ibrutinib based on age group and body surface area (BSA) in combination with chemoimmunotherapy (CIT) (investigator choice of RICE [rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone]) in Part 1.

    Subject analysis set title
    Part 1: Ibrutinib+RVICI
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RVICI [rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone]) in Part 1.

    Subject analysis set title
    Part 2: Ibrutinib+CIT
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received ibrutinib based on age group and BSA in combination with CIT (investigator choice of RICE or RVICI) in Part 2.

    Subject analysis set title
    Part 2: Chemotherapy (CIT)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received CIT (investigator choice of RICE or RVICI) alone in Part 2.

    Subject analysis set title
    Part 1: Ibrutinub: 240 mg/m^2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received 240 mg/m^2 ibrutinib based on age group for 3 treatment cycles with each cycle 28 or 21 days long in part 1.

    Subject analysis set title
    Part 1: Ibrutinub; 329 mg/m^2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received 329 mg/m^2 ibrutinib based on age group for 3 treatment cycles with each cycle 28 or 21 days long in part 1.

    Subject analysis set title
    Part 1: Ibrutinub; 440 mg/m^2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received 440 mg/m^2 ibrutinib based on age group for 3 treatment cycles with each cycle 28 or 21 days long in part 1.

    Subject analysis set title
    Part 2: Ibrutinub; 329 mg/m^2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received 329 mg/m^2 ibrutinib based on age group for 3 treatment cycles with each cycle 28 or 21 days long in Part 2.

    Subject analysis set title
    Part 2: Ibrutinub; 440 mg/m^2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received 440 mg/m^2 ibrutinib based on age group for 3 treatment cycles with each cycle 28 or 21 days long in part 2.

    Subject analysis set title
    Part 1 and Part 2: Disease Specific Biomarkers
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received ibrutinib to assess the disease specific biomarkers (SYK, STAT3, caspase-3, BCL-xL and cIAP1 expression) in both Parts.

    Subject analysis set title
    Part 1: Ibrutinib
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received ibrutinib based on age group and BSA in Part 1.

    Subject analysis set title
    Part 2: Ibrutinib
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received ibrutinib based on age group and BSA in Part 2.

    Primary: Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib

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    End point title
    Part 1: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib [1]
    End point description
    AUC is defined as area under the plasma concentration-time curve. Pharmacokinetic analysis set included subjects in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib. PK parameters were presented per dose group (240 mg/m2, 329 mg/m2 and 440 mg/m2) and age group (1-5, 6-11, 12-17 and >18 years). Here, "n (number analysed)" is defined as number of subjects analyzed for specified category. Here "99999" denotes upper limit which does not have any value.
    End point type
    Primary
    End point timeframe
    Cycle 1: Day 1, Day 7 or 8 and Day 14; Cycle 2: Day 1; Cycle 3: Day 1 (each cycle of 28 days)
    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: Descriptive statistics was done, no inferential statistical analysis was performed.
    End point values
    Part 1: Ibrutinub: 240 mg/m^2 Part 1: Ibrutinub; 329 mg/m^2 Part 1: Ibrutinub; 440 mg/m^2
    Number of subjects analysed
    21
    21
    21
    Units: hours*nanogram per milliliter (h*ng/mL)
    median (full range (min-max))
        1-5 year (n=2, n=1, n=3)
    143 (116 to 170)
    386 (386 to 386)
    310 (230 to 543)
        6-11 year (n=3, n=10, n=7)
    145 (140 to 233)
    349 (238 to 562)
    324 (185 to 538)
        12-17 year (n=3, n=8, n=0)
    1210 (939 to 1450)
    661 (394 to 778)
    99999 (99999 to 99999)
        18+ year (n=0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Primary: Part 1: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib

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    End point title
    Part 1: Apparent (Oral) Plasma Clearance (CL/F) of Ibrutinib [2]
    End point description
    CL/F is defined as apparent plasma clearance of ibrutinib. Pharmacokinetic analysis set included subjects in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib. PK parameters were presented per dose group (240 mg/m2, 329 mg/m2 and 440 mg/m2) and age group (1-5, 6-11, 12-17 and >18 years). Here, "n (number analysed)" is defined as number of subjects analyzed for specified category. Here "99999" denotes upper limit which does not have any value.
    End point type
    Primary
    End point timeframe
    Cycle 1: Day 1, Day 7 or 8 and Day 14; Cycle 2: Day 1; Cycle 3: Day 1 (each cycle of 28 days)
    Notes
    [2] - 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: Descriptive statistics was done, no inferential statistical analysis was performed.
    End point values
    Part 1: Ibrutinub: 240 mg/m^2 Part 1: Ibrutinub; 329 mg/m^2 Part 1: Ibrutinub; 440 mg/m^2
    Number of subjects analysed
    21
    21
    21
    Units: mL/h (milliliter per hour)
    median (full range (min-max))
        1-5 year (n=2, n=1, n=3)
    1220 (1000 to 1430)
    508 (508 to 508)
    1200 (838 to 1550)
        6-11 year (n=3, n=10, n=7)
    1450 (1080 to 1500)
    805 (664 to 1100)
    1300 (910 to 2460)
        12-17 year (n=3, n=8), n=0)
    348 (340 to 433)
    729 (568 to 1330)
    99999 (99999 to 99999)
        18+ year (n=0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Primary: Part 1: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib

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    End point title
    Part 1: Apparent (Oral) Volume of Distribution (Vd/F) of Ibrutinib [3]
    End point description
    Vd/F is defined as apparent (oral) volume of distribution of ibrutinib. Pharmacokinetic analysis set included subjects in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib. PK parameters were presented per dose group (240 mg/m2, 329 mg/m2 and 440 mg/m2) and age group (1-5, 6-11, 12-17 and >18 years). Here, "n (number analysed)" is defined as number of subjects analyzed for specified category. Here "99999" denotes upper limit which does not have any value.
    End point type
    Primary
    End point timeframe
    Cycle 1: Day 1, Day 7 or 8 and Day 14; Cycle 2: Day 1; Cycle 3: Day 1 (each cycle of 28 days)
    Notes
    [3] - 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: Descriptive statistics was done, no inferential statistical analysis was performed.
    End point values
    Part 1: Ibrutinub: 240 mg/m^2 Part 1: Ibrutinub; 329 mg/m^2 Part 1: Ibrutinub; 440 mg/m^2
    Number of subjects analysed
    21
    21
    21
    Units: litre(s)
    median (full range (min-max))
        1-5 year (n=2, n=1, n=3)
    11.1 (8.26 to 13.9)
    5.18 (5.18 to 5.18)
    7.63 (5.34 to 11.1)
        6-11 year (n=3, n=10, n=7)
    18 (10.8 to 29.9)
    7.55 (2.89 to 15.6)
    19 (6.09 to 55.9)
        12-17 year (n=3, n=8, n=0)
    3.63 (2.32 to 4.77)
    11.3 (6.34 to 18.5)
    99999 (99999 to 99999)
        18+ year (n=0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Primary: Part 1: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib

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    End point title
    Part 1: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib [4]
    End point description
    Cmax is defined as maximum plasma concentration of ibrutinib. Pharmacokinetic analysis set included subjects in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib. PK parameters were presented per dose group (240 mg/m2, 329 mg/m2 and 440 mg/m2) and age group (1-5, 6-11, 12-17 and >18 years). Here, "n (number analysed)" is defined as number of subjects analyzed for specified category. Here "99999" denotes upper limit which does not have any value.
    End point type
    Primary
    End point timeframe
    Cycle 1: Day, Day 7 or 8, Day 14; Cycle 2: Day 1; Cycle 3: Day 1 (each cycle of 28 days)
    Notes
    [4] - 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: Descriptive statistics was done, no inferential statistical analysis was performed.
    End point values
    Part 1: Ibrutinub: 240 mg/m^2 Part 1: Ibrutinub; 329 mg/m^2 Part 1: Ibrutinub; 440 mg/m^2
    Number of subjects analysed
    21
    21
    21
    Units: ng/mL (nanograms per milliliter)
    median (full range (min-max))
        1-5 year (n=2,n=1, n=3)
    3.86 (3.75 to 3.98)
    4.48 (4.48 to 4.48)
    5.07 (4.5 to 5.14)
        6-11 year (n=3, n=10, n=7)
    3.46 (3.12 to 3.6)
    3.64 (3.32 to 4.59)
    3.88 (3.2 to 4.44)
        12-17 year (n=3, n=8, n=0)
    4.88 (4.76 to 5.4)
    4.73 (4.07 to 5.07)
    99999 (99999 to 99999)
        18+ year (n=0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Primary: Part 1: Relationship between Pharmacokinetic (PK) Parameters and Age or Body Size

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    End point title
    Part 1: Relationship between Pharmacokinetic (PK) Parameters and Age or Body Size [5]
    End point description
    The relationship between ibrutinib metrics of systemic exposure with age or body size was assessed to determine the impact on PK parameters which were presented per dose groups (240 mg/m^2, 329 mg/m^2 and 440 mg/m^2) and age groups (1-5, 6-11, 12-17 and >18 years). Separated PK/pharmacodynamics analysis was not performed due to the small sample size of the study. Pharmacokinetic analysis set included subjects in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib. Here "99999" denotes upper limit which does not have any value.
    End point type
    Primary
    End point timeframe
    Up to Cycle 3 (each cycle of 28 days)
    Notes
    [5] - 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: Descriptive statistics was done, no inferential statistical analysis was performed.
    End point values
    Part 1: Ibrutinib
    Number of subjects analysed
    21
    Units: Years
    median (full range (min-max))
        n=0
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Primary: Part 2: Event Free Survival (EFS) Between the 2 Treatment Groups

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    End point title
    Part 2: Event Free Survival (EFS) Between the 2 Treatment Groups [6]
    End point description
    EFS is the time interval from randomization to death, disease progression, or lack of complete response (CR) or partial response (PR) after 3 cycles of treatment, whichever occurs first based on blinded independent event review by the Independent Review Committee (IRC). The intent-to-treat (ITT) population consisted of all randomized subjects; subjects analyzed based on randomization, regardless of study drug received. Here "N" (number of subjects analysed) is the number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Time from Randomization to death, disease progression, or lack of CR or PR after 3 cycles of treatment (up to 3 years)
    Notes
    [6] - 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: Descriptive statistics was done, no inferential statistical analysis was performed.
    End point values
    Part 2: Ibrutinib+CIT Part 2: Chemotherapy (CIT)
    Number of subjects analysed
    22
    12
    Units: Months
        median (confidence interval 90%)
    6.05 (2.99 to 8.84)
    6.97 (2.60 to 11.07)
    No statistical analyses for this end point

    Secondary: Part 1 and Part 2: Number of Subjects with Adverse Events as Measure of Safety and Tolerability

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    End point title
    Part 1 and Part 2: Number of Subjects with Adverse Events as Measure of Safety and Tolerability
    End point description
    An AE is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Safety population consisted of all subjects who received at least 1 dose of treatment. Here "N" (number of subjects analysed) is the number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 4.5 years
    End point values
    Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI Part 2: Ibrutinib+CIT Part 2: Chemotherapy (CIT)
    Number of subjects analysed
    11
    10
    35
    15
    Units: Subjects
    11
    10
    35
    15
    No statistical analyses for this end point

    Secondary: Part 1 and Part 2: Overall Response Rate (ORR)

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    End point title
    Part 1 and Part 2: Overall Response Rate (ORR)
    End point description
    ORR is defined as the percentage of subjects achieving a best overall response of either complete response (CR) (including CR biopsy-negative [CRb] and unconfirmed CR [CRu]) or partial response (PR) as evaluated by IRC. The ITT Population consisted of all randomized subjects; subjects analyzed based on randomization, regardless of study drug received. The primary efficacy analysis is based on the ITT population for data collected in the Part 2.
    End point type
    Secondary
    End point timeframe
    Up to 4.5 year
    End point values
    Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI Part 2: Ibrutinib+CIT Part 2: Chemotherapy (CIT)
    Number of subjects analysed
    11
    10
    35
    16
    Units: Percentage of Subjects
        number (not applicable)
    9
    5
    24
    13
    No statistical analyses for this end point

    Secondary: Part 1 and Part 2: Change from baseline with Disease-specific Biomarkers

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    End point title
    Part 1 and Part 2: Change from baseline with Disease-specific Biomarkers
    End point description
    Blood samples were taken to evaluate the levels of biomarkers such as Phospho- Bruton’s tyrosine kinase (BTK), spleen tyrosine kinase (SYK), p-signal transducer, activator of transcription 3 (STAT3), Caspase-3 and B-cell receptor (BCR)/CD79B, CARD11, and myeloid differentiation factor (MYD) mutations. Biomarker analyses were conducted on the ITT population.
    End point type
    Secondary
    End point timeframe
    Cycle 1: Days 1, and 7 or 8, Cycle 2: Day 1, and Cycle 3: Day 1 (each cycle of 28 days) and End of treatment visit [30 days after last dose] (Up to 4.5 year)
    End point values
    Part 1 and Part 2: Disease Specific Biomarkers
    Number of subjects analysed
    27
    Units: Transcripts per million
    arithmetic mean (standard deviation)
        BCL-2L1 (BCL-xl)
    62.09 ± 52.570
        BIRC2 (cIAP1)
    44.35 ± 14.742
        Caspase 3 (CASP3)
    49.24 ± 24.760
        STAT3
    524.47 ± 391.214
        SYK
    668.14 ± 441.224
    No statistical analyses for this end point

    Secondary: Part 1 and Part 2: Bruton’s Tyrosine Kinase (BTK) Percent Occupancy

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    End point title
    Part 1 and Part 2: Bruton’s Tyrosine Kinase (BTK) Percent Occupancy
    End point description
    Blood samples were collected to assess BTK occupancy. Biomarker analyses were conducted on the ITT population. Here "N" (number of subjects analysed) is the number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    4 hours postdose on Day 1, Day 7 or 8 of Cycle 1, predose on Cycle 2 Day 1 or Cycle 3 Day 1 (each cycle of 28 days), and the End-of-Treatment visit [30 days after last dose] (up to 4.5 years)
    End point values
    Part 1: Ibrutinib Part 2: Ibrutinib
    Number of subjects analysed
    15
    13
    Units: Percentage
        number (not applicable)
    90
    90
    No statistical analyses for this end point

    Secondary: Part 1 and Part 2: Visual Analog Scale (VAS) Score for Palatability

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    End point title
    Part 1 and Part 2: Visual Analog Scale (VAS) Score for Palatability
    End point description
    Palatability of ibrutinib was measured by using a VAS. The scale is a 5-point visual analog scale incorporating a facial hedonic scale designed to span pediatric ages and levels of participant comprehension with a score range of 1 to 5, where 1 represents best score and 5 is worst palatability. The Safety population consisted of all subjects who received at least 1 dose of treatment. Here "n (number analysed)" is defined as number of subjects analyzed for specified category.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1 and Cycle 3
    End point values
    Part 1: Ibrutinib+RICE Part 1: Ibrutinib+RVICI Part 2: Ibrutinib+CIT
    Number of subjects analysed
    11
    10
    35
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n=11, n=10, n=32)
    2.6 ± 1.21
    3.2 ± 1.40
    2.4 ± 1.16
        Cycle 3 Day 1 (n=8, n=3, n=16)
    3.3 ± 1.39
    2.3 ± 1.15
    2.6 ± 0.89
    No statistical analyses for this end point

    Secondary: Part 2: Tumor Volume Reduction Rate at Day 14

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    End point title
    Part 2: Tumor Volume Reduction Rate at Day 14
    End point description
    The tumor volume reduction rate is defined as percent decrease in the sum of the products of the lesion diameters at Day 14. It was measured as the mean change in the sum of the products of the lesion diameters (SPD) at Day 14. The ITT Population consisted of all randomized subjects; subjects was analyzed based on randomization, regardless of study drug received. Here "N" (number of subjects analysed) is the number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    At Day 14
    End point values
    Part 2: Ibrutinib+CIT Part 2: Chemotherapy (CIT)
    Number of subjects analysed
    30
    11
    Units: Percent change
        least squares mean (standard deviation)
    -49.7 ± 33.41
    -58.60 ± 34.04
    No statistical analyses for this end point

    Secondary: Part 2: Number of Subjects who Proceeded to Stem Cell Transplantation

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    End point title
    Part 2: Number of Subjects who Proceeded to Stem Cell Transplantation
    End point description
    Number of subjects who proceeded to stem cell transplantation was reported. The ITT Population consisted of all randomized subjects; subjects was analyzed based on randomization, regardless of study drug received.
    End point type
    Secondary
    End point timeframe
    Up to end of the study (Up to 4.5 years)
    End point values
    Part 2: Ibrutinib+CIT Part 2: Chemotherapy (CIT)
    Number of subjects analysed
    35
    16
    Units: Subjects
    13
    7
    No statistical analyses for this end point

    Secondary: Part 2: Time to Response

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    End point title
    Part 2: Time to Response
    End point description
    Time to response defined as the time interval from the first dose of ibrutinib to the first documented response for those subjects who responded. Time to response was summarized for subjects who achieved either CR (including CRb and CRu) or PR. The ITT Population consisted of all randomized subjects; subjects was analyzed based on randomization, regardless of study drug received.
    End point type
    Secondary
    End point timeframe
    Up to 4.5 years
    End point values
    Part 2: Ibrutinib+CIT Part 2: Chemotherapy (CIT)
    Number of subjects analysed
    35
    16
    Units: Months
        median (confidence interval 90%)
    0.89 (0.49 to 1.87)
    0.82 (0.46 to 1.94)
    No statistical analyses for this end point

    Secondary: Part 2: Duration of Response

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    End point title
    Part 2: Duration of Response
    End point description
    Duration of response defined as the duration from date of initial documentation of a response (CR or PR) to the date of first documented evidence of progressive disease (PD) or death, whichever occurs first. Duration of response was summarized for subjects who achieved either CR (including CRb and CRu) or PR. The ITT Population consisted of all randomized subjects; subjects was analyzed based on randomization, regardless of study drug received. Here "99999"denotes upper limit which does not have any value.
    End point type
    Secondary
    End point timeframe
    Up to 4.5 year
    End point values
    Part 2: Ibrutinib+CIT Part 2: Chemotherapy (CIT)
    Number of subjects analysed
    35
    16
    Units: Months
        median (confidence interval 90%)
    6.01 (3.06 to 99999)
    6.51 (4.53 to 10.64)
    No statistical analyses for this end point

    Secondary: Part 2: Number of Subjects with EFS

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    End point title
    Part 2: Number of Subjects with EFS
    End point description
    EFS is the time interval from randomization to death, disease progression, or lack of complete response (CR) or partial response (PR) after 3 cycles of treatment, whichever occurs first based on blinded independent event review by the Independent Review Committee (IRC). The ITT Population consisted of all randomized subjects; subjects was analyzed based on randomization, regardless of study drug received.
    End point type
    Secondary
    End point timeframe
    2 years and 3 years
    End point values
    Part 2: Ibrutinib+CIT Part 2: Chemotherapy (CIT)
    Number of subjects analysed
    35
    16
    Units: Number of subjects
    number (not applicable)
        2 year
    5
    2
        3 year
    3
    2
    No statistical analyses for this end point

    Secondary: Part 2: Overall Survival

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    End point title
    Part 2: Overall Survival
    End point description
    Overall survival is defined as duration from the date of randomization to the date of the subject’s death. The ITT Population consisted of all randomized subjects; subjects was analyzed based on randomization, regardless of study drug received. Here "99999" denotes upper limit which does not have any value.
    End point type
    Secondary
    End point timeframe
    Up to 4.5 years
    End point values
    Part 2: Ibrutinib+CIT Part 2: Chemotherapy (CIT)
    Number of subjects analysed
    35
    16
    Units: Months
        median (confidence interval 90%)
    14.13 (5.98 to 99999)
    11.07 (7.39 to 99999)
    No statistical analyses for this end point

    Secondary: Part 2: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib

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    End point title
    Part 2: Area Under the Plasma Concentration-time Curve (AUC) of Ibrutinib
    End point description
    AUC is defined as area under the plasma concentration-time curve. Pharmacokinetic analysis set included subjects in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib. Data of PK parameters of ibrutinib is reported basis of stratified age groups (1-5, 6-11, 12-17 and >18 years). Here, "n (number analysed)" is defined as number of subjects analyzed for specified category. Here "99999" denotes upper limit which does not have any value.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1, 2, and 4 hours post-dose on Cycle 1 Day 14 (each cycle of 28 days)
    End point values
    Part 2: Ibrutinub; 329 mg/m^2 Part 2: Ibrutinub; 440 mg/m^2
    Number of subjects analysed
    52
    52
    Units: h*ng/mL
    median (full range (min-max))
        1-5 year (n=0,n=0, n=2)
    99999 (99999 to 099999)
    298 (268 to 327)
        6-11year (n=0, n=0, n=3)
    99999 (99999 to 99999)
    655 (428 to 879)
        12-17 year (n=1, n=19, n=0)
    499 (262 to 887)
    99999 (99999 to 99999)
        18+ year (n=0, n=2, n=0)
    423 (348 to 498)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Part 2: Relationship between Pharmacokinetic (PK) Parameters and Age or Body Size

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    End point title
    Part 2: Relationship between Pharmacokinetic (PK) Parameters and Age or Body Size
    End point description
    The relationship between ibrutinib metrics of systemic exposure with age or body size was assessed to determine the impact on PK parameters which were presented per dose groups (240 mg/m^2, 329 mg/m^2 and 440 mg/m^2) and age groups (1-5, 6-11, 12-17 and >18 years). Separated PK/pharmacodynamics analysis was not performed due to the small sample size of the study. Pharmacokinetic analysis set included subjects in the ibrutinib group that received ibrutinib doses and had quantifiable plasma concentration of ibrutinib. Here "99999" denotes upper limit which does not have any value.
    End point type
    Secondary
    End point timeframe
    Up to Cycle 3 (each cycle of 28 days)
    End point values
    Part 2: Ibrutinib
    Number of subjects analysed
    52
    Units: Years
    median (full range (min-max))
        n=0
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 4.5 years (from first subject signs informed consent form to end of the study)
    Adverse event reporting additional description
    The safety population consisted of all subjects who received at least 1 dose of treatment. The population used for all safety analyses and subjects was analyzed based on actual study drug received.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Part 1: Ibrutinib+RICE
    Reporting group description
    Subjects received Ibrutinib based on age group and body weight in combination with chemoimmunotherapy (CIT) (investigator choice of RICE [rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone]) in Part 1.

    Reporting group title
    Part 1: IBRUTINIB+RVICI
    Reporting group description
    Subjects received Ibrutinib based on age group and body weight in combination with CIT (investigator choice of RVICI [rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone]) in Part 1.

    Reporting group title
    Part 2: IBRUTINIB+CIT
    Reporting group description
    Subjects received Ibrutinib based on age group and body weight in combination with CIT (investigator choice of RICE or RVICI) in Part 2.

    Reporting group title
    Part 2: CIT
    Reporting group description
    Subjects received CIT (investigator choice of RICE or RVICI) alone in Part 2.

    Serious adverse events
    Part 1: Ibrutinib+RICE Part 1: IBRUTINIB+RVICI Part 2: IBRUTINIB+CIT Part 2: CIT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 11 (90.91%)
    9 / 10 (90.00%)
    25 / 35 (71.43%)
    11 / 15 (73.33%)
         number of deaths (all causes)
    4
    9
    19
    10
         number of deaths resulting from adverse events
    Vascular disorders
    Capillary Leak Syndrome
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic Reaction
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion Related Hypersensitivity Reaction
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Mucosal Inflammation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Organ Dysfunction Syndrome
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic Inflammatory Response Syndrome
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychotic Disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural Haematoma
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural Haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Bilirubin Increased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coagulation Test Abnormal
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil Count Decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    3 / 35 (8.57%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White Blood Cell Count Decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Sinus Tachycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumomediastinum
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    3 / 15 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile Bone Marrow Aplasia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    4 / 11 (36.36%)
    3 / 10 (30.00%)
    21 / 35 (60.00%)
    6 / 15 (40.00%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 7
    19 / 35
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    3 / 15 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 10 (10.00%)
    2 / 35 (5.71%)
    3 / 15 (20.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    4 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    3 / 35 (8.57%)
    4 / 15 (26.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Altered State of Consciousness
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage Intracranial
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Encephalopathy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Cord Haematoma
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid Haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonic Convulsion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic Encephalopathy
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Optic Atrophy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric Ulcer
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Inflammation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis Haemorrhagic
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic Failure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypernatraemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anorectal Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Capnocytophaga Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Corynebacterium Infection
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cryptosporidiosis Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Escherichia Sepsis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella Sepsis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic Sepsis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    3 / 35 (8.57%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Pulmonary Mycosis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 11 (9.09%)
    4 / 10 (40.00%)
    5 / 35 (14.29%)
    3 / 15 (20.00%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 5
    3 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    Septic Shock
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    3 / 35 (8.57%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Staphylococcal Infection
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular Device Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part 1: Ibrutinib+RICE Part 1: IBRUTINIB+RVICI Part 2: IBRUTINIB+CIT Part 2: CIT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 11 (100.00%)
    10 / 10 (100.00%)
    35 / 35 (100.00%)
    15 / 15 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 11 (9.09%)
    4 / 10 (40.00%)
    2 / 35 (5.71%)
    1 / 15 (6.67%)
         occurrences all number
    1
    5
    2
    1
    Hypotension
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 10 (20.00%)
    5 / 35 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    6
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin Papilloma
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Hypersensitivity
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypogammaglobulinaemia
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Catheter Site Granuloma
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Catheter Site Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Chest Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    3 / 35 (8.57%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    4
    2
    Chills
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Device Related Thrombosis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Face Oedema
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    5 / 35 (14.29%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    5
    0
    Generalised Oedema
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    2
    1
    Hypothermia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Mucosal Inflammation
         subjects affected / exposed
    2 / 11 (18.18%)
    4 / 10 (40.00%)
    9 / 35 (25.71%)
    3 / 15 (20.00%)
         occurrences all number
    2
    5
    10
    4
    Mucosal Ulceration
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    3 / 11 (27.27%)
    3 / 10 (30.00%)
    14 / 35 (40.00%)
    5 / 15 (33.33%)
         occurrences all number
    4
    10
    35
    7
    Swelling
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Swelling Face
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    1
    Anxiety
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Confusional State
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    1
    2
    Depression
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    1
    2
    Hallucination
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    1
    Insomnia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    4 / 35 (11.43%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Irritability
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    1
    Post-Traumatic Stress Disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    Penile Swelling
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Buttock Injury
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Contusion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Fall
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Fractured Sacrum
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infusion Related Reaction
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    4 / 35 (11.43%)
    1 / 15 (6.67%)
         occurrences all number
    1
    2
    5
    1
    Procedural Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    4 / 35 (11.43%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Transfusion Reaction
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Traumatic Haematoma
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    4 / 11 (36.36%)
    0 / 10 (0.00%)
    7 / 35 (20.00%)
    6 / 15 (40.00%)
         occurrences all number
    18
    0
    17
    11
    Amylase Increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    2
    Antithrombin Iii Decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    5 / 11 (45.45%)
    0 / 10 (0.00%)
    6 / 35 (17.14%)
    5 / 15 (33.33%)
         occurrences all number
    14
    0
    10
    8
    Blood Bilirubin Increased
         subjects affected / exposed
    3 / 11 (27.27%)
    1 / 10 (10.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    3
    3
    2
    0
    Blood Lactate Dehydrogenase Increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    0
    C-Reactive Protein Increased
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    3 / 35 (8.57%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    8
    0
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 10 (10.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    8
    1
    2
    0
    Haemoglobin Decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    1
    0
    International Normalised Ratio Increased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    1
    2
    Lipase Increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Lymphocyte Count Decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    4 / 35 (11.43%)
    2 / 15 (13.33%)
         occurrences all number
    12
    0
    30
    8
    Neutrophil Count Decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 10 (20.00%)
    12 / 35 (34.29%)
    9 / 15 (60.00%)
         occurrences all number
    3
    9
    30
    30
    Pancreatic Enzymes Decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Platelet Count Decreased
         subjects affected / exposed
    5 / 11 (45.45%)
    2 / 10 (20.00%)
    12 / 35 (34.29%)
    8 / 15 (53.33%)
         occurrences all number
    39
    31
    98
    27
    Staphylococcus Test Positive
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Weight Decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    3 / 35 (8.57%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Weight Increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    3
    White Blood Cell Count Decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 10 (20.00%)
    8 / 35 (22.86%)
    6 / 15 (40.00%)
         occurrences all number
    2
    2
    18
    17
    Cardiac disorders
    Pericardial Effusion
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Sinus Tachycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    5 / 35 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    6
    2
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    2 / 35 (5.71%)
    4 / 15 (26.67%)
         occurrences all number
    2
    2
    4
    5
    Dyspnoea
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    1
    2
    2
    0
    Epistaxis
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 10 (10.00%)
    8 / 35 (22.86%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    11
    1
    Hypoxia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Laryngospasm
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nasal Congestion
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    1
    Respiratory Alkalosis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 11 (72.73%)
    9 / 10 (90.00%)
    29 / 35 (82.86%)
    14 / 15 (93.33%)
         occurrences all number
    61
    80
    147
    45
    Coagulopathy
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Febrile Bone Marrow Aplasia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    1
    Febrile Neutropenia
         subjects affected / exposed
    5 / 11 (45.45%)
    2 / 10 (20.00%)
    6 / 35 (17.14%)
    1 / 15 (6.67%)
         occurrences all number
    5
    2
    7
    1
    Hypofibrinogenaemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Leukopenia
         subjects affected / exposed
    3 / 11 (27.27%)
    1 / 10 (10.00%)
    10 / 35 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    24
    2
    60
    17
    Lymphopenia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    5
    Macrocytosis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Neutropenia
         subjects affected / exposed
    6 / 11 (54.55%)
    6 / 10 (60.00%)
    14 / 35 (40.00%)
    4 / 15 (26.67%)
         occurrences all number
    33
    23
    68
    14
    Thrombocytopenia
         subjects affected / exposed
    6 / 11 (54.55%)
    8 / 10 (80.00%)
    19 / 35 (54.29%)
    4 / 15 (26.67%)
         occurrences all number
    47
    68
    153
    18
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Depressed Level of Consciousness
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Encephalopathy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    1
    Headache
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    16 / 35 (45.71%)
    3 / 15 (20.00%)
         occurrences all number
    1
    1
    28
    8
    Hypersomnia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Muscle Spasticity
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Myoclonus
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Neuralgia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Seizure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    1
    Somnolence
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Spinal Cord Haematoma
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Toxic Encephalopathy
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tremor
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Eye Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Eyelid Oedema
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eyelid Ptosis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Keratitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pupils Unequal
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Vision Blurred
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Xerophthalmia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ear and labyrinth disorders
    Ear Pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vertigo
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Abdominal Pain
         subjects affected / exposed
    3 / 11 (27.27%)
    5 / 10 (50.00%)
    12 / 35 (34.29%)
    2 / 15 (13.33%)
         occurrences all number
    3
    6
    23
    3
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    6 / 35 (17.14%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    8
    1
    Anal Erythema
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    3
    1
    Anal Inflammation
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Anal Ulcer
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Anorectal Ulcer
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Aphthous Ulcer
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Chapped Lips
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Colitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    1
    Constipation
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 10 (30.00%)
    8 / 35 (22.86%)
    3 / 15 (20.00%)
         occurrences all number
    1
    6
    12
    3
    Dental Caries
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    4 / 11 (36.36%)
    6 / 10 (60.00%)
    10 / 35 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    5
    11
    18
    4
    Dyspepsia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    5 / 35 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    12
    2
    Dysphagia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    3 / 35 (8.57%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Enterocolitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrointestinal Inflammation
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Gastrointestinal Motility Disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gingival Bleeding
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Gingival Oedema
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haematemesis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Haematochezia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Ileus
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Intestinal Haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Melaena
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Mouth Haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Mouth Ulceration
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Nausea
         subjects affected / exposed
    7 / 11 (63.64%)
    5 / 10 (50.00%)
    21 / 35 (60.00%)
    2 / 15 (13.33%)
         occurrences all number
    8
    6
    45
    8
    Odynophagia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oesophageal Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oesophagitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Proctalgia
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    4
    0
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Stomatitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    7 / 35 (20.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    1
    12
    3
    Toothache
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    1
    Vomiting
         subjects affected / exposed
    5 / 11 (45.45%)
    5 / 10 (50.00%)
    25 / 35 (71.43%)
    4 / 15 (26.67%)
         occurrences all number
    12
    11
    56
    7
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    5 / 35 (14.29%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Hypotonic Urinary Bladder
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal Impairment
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    1
    Renal Tubular Injury
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urinary Retention
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hepatobiliary disorders
    Hepatic Failure
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Decubitus Ulcer
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Ecchymosis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    1
    Petechiae
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    3 / 35 (8.57%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Pruritus
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Rash
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    4 / 35 (11.43%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    5
    0
    Rash Maculo-Papular
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Skin Lesion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Urticaria
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    5 / 35 (14.29%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    6
    0
    Back Pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    5 / 35 (14.29%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    5
    0
    Bone Pain
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    4 / 35 (11.43%)
    1 / 15 (6.67%)
         occurrences all number
    1
    3
    4
    1
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Myalgia
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 10 (10.00%)
    4 / 35 (11.43%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    5
    0
    Neck Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Pain in Extremity
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 10 (0.00%)
    7 / 35 (20.00%)
    1 / 15 (6.67%)
         occurrences all number
    3
    0
    7
    1
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 10 (30.00%)
    3 / 35 (8.57%)
    0 / 15 (0.00%)
         occurrences all number
    0
    4
    4
    0
    Fluid Retention
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    2
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Hyperphosphataemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 11 (27.27%)
    5 / 10 (50.00%)
    7 / 35 (20.00%)
    2 / 15 (13.33%)
         occurrences all number
    4
    10
    13
    3
    Hypocalcaemia
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 10 (30.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    1
    9
    3
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 11 (18.18%)
    6 / 10 (60.00%)
    12 / 35 (34.29%)
    6 / 15 (40.00%)
         occurrences all number
    11
    20
    38
    10
    Hypomagnesaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 10 (20.00%)
    6 / 35 (17.14%)
    5 / 15 (33.33%)
         occurrences all number
    0
    6
    21
    6
    Hyponatraemia
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 10 (10.00%)
    4 / 35 (11.43%)
    2 / 15 (13.33%)
         occurrences all number
    3
    4
    4
    3
    Hypophosphataemia
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 10 (20.00%)
    5 / 35 (14.29%)
    0 / 15 (0.00%)
         occurrences all number
    3
    4
    9
    0
    Infections and infestations
    Anal Abscess
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    1
    Aspergillus Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Bacteraemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Bk Virus Infection
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Device Related Infection
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 10 (0.00%)
    3 / 35 (8.57%)
    1 / 15 (6.67%)
         occurrences all number
    3
    0
    3
    2
    Escherichia Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Fungal Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Fusarium Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Geotrichum Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Herpes Zoster
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 10 (20.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Klebsiella Infection
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Oral Herpes
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    2 / 35 (5.71%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    2
    1
    Pneumonia
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 10 (20.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Pseudomonal Bacteraemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 35 (2.86%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    3
    Rhinovirus Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    2 / 35 (5.71%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Sepsis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    1
    Urinary Tract Infection
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    1
    Urinary Tract Infection Pseudomonal
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Vascular Device Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 35 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 35 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jun 2016
    The overall reason for the Amendment 1 was to address changes requested during Health Authority review; Subjects in the 2 older age groups (6-11 years, 12-17 years) to be enrolled and treated prior to opening enrollment to subjects in the younger age group (1-5 years); Central assessment of viral serologies to be performed at screening; Tetanus and pneumococcal antibody titers were added at screening; Guidance for dosing of ibrutinib around the time of lumbar procedures were added due to risk of bleeding.
    24 Apr 2017
    The overall reason for the Amendment-2 was to address changes requested during Health Authority review; Contraception language changed to clarify length of time subjects should avoid pregnancy after the last dose of any study agent (example, year); women of childbearing potential are required to use contraceptives while taking ibrutinib and women using hormonal methods of contraception were required to add a barrier method of contraception; Added exclusion criteria for subjects with a diagnosis of post transplant lymphoproliferative disease (PTLD); and for subjects who received an allogeneic bone marrow transplant within 6 months; Recommended use of non-azole antifungal prophylaxis for aspergillosis and concomitant granulocyte colony stimulating factor added to rituximab, vincristine, idarubicin, carboplatin, ifosfamide, and dexamethasone (RVICI) regimen as prophylaxis against neutropenia; Bone marrow on Cycle 2 Day 1 (C2D1) only obtained if clinically indicated; Intrathecal therapy administered not more than 24 hours before D1 of each cycle; Lumbar puncture and bone marrow procedures may be performed the day prior to the start of a treatment cycle for logistical reasons as needed.
    07 Jul 2017
    The overall reason for the Amendment-3 was to allow for collection of additional exposure data from subjects in the 2 younger age groups (ages 1-5 and 6-11 years) to facilitate dose confirmation for Part 2; Increased the number of subjects to be enrolled into Part 1 (from 12 to up to approximately 24 subjects) to allow for collection of additional exposure data from subjects in the 2 younger age groups (ages 1-5 and 6-11 years) for dose confirmation for Part 2 in these younger age groups. Clarified that at a minimum, the first 2 subjects in each age group were to be enrolled into Part 1 before recruitment of children in that age group was to begin in Part 2.

    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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