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    Clinical Trial Results:
    A Phase III Randomized Trial of Gemtuzumab Ozogamicin (Mylotarg) Combined With Conventional Chemotherapy for De Novo Acute Myeloid Leukemia (AML) in Children, Adolescents, and Young Adults.

    Summary
    EudraCT number
    		 2016-001533-28
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    31 Mar 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jul 2018
    First version publication date
    25 Jul 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AAML0531
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00372593
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Children's Oncology Group
    Sponsor organisation address
    440 E. Huntington Drive, Arcadia, United States, CA 91006
    Public contact
    Clinical Trials.gov Call Center, Children’s Oncology Group, 1 6264470064, CTGOV@childrensoncologygroup.org
    Scientific contact
    Clinical Trials.gov Call Center, Children’s Oncology Group, 1 6264470064, CTGOV@childrensoncologygroup.org
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001733-PIP02-15
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 May 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the event free survival (EFS) and overall survival (OS) of de novo acute myeloid leukemia (AML) subjects randomized between the best current chemotherapy with or without gemtuzumab ozogamicin (GMTZ).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Aug 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 10 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 958
    Country: Number of subjects enrolled
    Australia: 34
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    New Zealand: 9
    Country: Number of subjects enrolled
    Canada: 67
    Worldwide total number of subjects
    1069
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    4
    Infants and toddlers (28 days-23 months)
    205
    Children (2-11 years)
    435
    Adolescents (12-17 years)
    358
    Adults (18-64 years)
    67
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects with AML were enrolled and were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of gemtuzumab ozogamicin administered once in induction therapy 1 and once in intensification therapy 2. Subjects with down syndrome were non randomly assigned to receive standard chemotherapy.

    Period 1
    Period 1 title
    overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: No Gemtuzumab ozogamicin
    Arm description
    		 Cytarabine(ARA-C) intrathecally(IT) on Day 1 of induction therapy I,intravenous (IV) infusion (inf.) of 100 mg/m^2/twice daily ARA-C on Day 1-10; daunorubicin IV inf. of 50mg/m^2/dose on Day 1,3,5;IV inf. of 100 mg/m^2/dose etoposide on Day 1-5. After 3 weeks,ARA-C IT on Day 1 of induction therapy II,then IV ARA-C inf. of 100 mg/m^2/twice daily on Day 1-8;IV daunorubicin inf. of 50mg/m^2/dose on Day 1, 3, 5;etoposide IV infusion of 100 mg/m^2/dose on Day 1-5. After 3 weeks, ARA-C IT on Day 1 of intensification l and IV ARA-C inf. of 1000 mg/m^2/twice daily and 150 mg/m^2/dose of etoposide on Day 1-5. After 3 weeks,ARA-C IT on Day 1 of intensification (INT) II;IV inf. of 1000 mg/m^2/twice daily of ARA-C on Day 1-4;mitoxantrone IV inf. of 12 mg/m^2/dose on Day 3-6. After 3 weeks,3 hour of IV inf. of high dose of 3000 mg/m^2/per day of ARA-C on Day 1, 2, 8, 9 of INT III and injection of E. Coli L-asparaginase 6000 IU/m^2/dose on Day 2 and 9. Dose was administered on basis of age.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    ARA-C
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intrathecal use, Intravenous use
    Dosage and administration details
    In IND therapy l, subjects received ARA-C (IT) at on Day 1 followed by an IV infusion of 100 mg/m^2/twice daily on Day 1-10. In Induction therapy ll, subjects received ARA-C (IT) on Day 1 followed by an IV infusion of 100 mg/m^2/twice daily on Day 1-8. In intensification therapy I, subjects received ARA-C (IT) on Day 1 followed by an IV infusion of 1000 mg/m^2/twice daily on Day 1-5. In intensification therapy ll, subjects received ARA-C (IT) followed by an IV infusion of 1000 mg/m^2/twice daily of ARA-C on Day 1-4. In intensification therapy III, subjects received an IV infusion of high dose of 3000 mg/m^2/per day of ARA-C on Day 1, 2, 8, and 9.

    Investigational medicinal product name
    Daunorubicin
    Investigational medicinal product code
    DAUN
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In Induction therapy l, subjects received Daunorubicin IV over 6 hours 50mg/m^2/dose on Day 1,3 and 5. In Induction therapy ll, subjects received Daunorubicin IV over 6 hours 50mg/m^2/dose on Day 1,3 and 5.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    ETOP
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In Induction therapy l, subjects received etoposide IV over 4 hours 100 mg/m^2/dose from Day 1 to Day 5. In Induction therapy ll, subjects received Etoposide IV over 4 hours 100 mg/m^2/dose from Day 1 to Day 5. In Intensification therapy I subjects received etoposide IV over 4 hours 150 mg/m^2/dose from Day 1 to Day 5.

    Investigational medicinal product name
    Mitoxantrone
    Investigational medicinal product code
    MITOX
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In Intensification therapy II subjects received Mitoxantrone IV over 1 hour 12 mg/m^2/dose from Day 3 to 6.

    Investigational medicinal product name
    Asparaginase
    Investigational medicinal product code
    LASP
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    In Intensification therapy III subjects received an injection of E. Coli L-asparaginase 6000 IU/m^2/dose on Day 2 and 9.

    Arm title
    		 Arm B: Gemtuzumab ozogamicin
    Arm description
    		 ARA-C (IT) on Day 1 of induction I (IND). IV inf. of 100 mg/m^2/twice daily of ARA-C on Day 1-10;6 hr IV inf. daunorubicin (DAUN), 50mg/m^2/dose on Day 1,3,5; etoposide IV inf. of 100 mg/m^2/dose on Day 1-5;IV inf. of 3mg/m^2/dose of GMTZ on Day 6.After 3 weeks ARA-C IT, Day 1 of IND ll. IV inf. of ARA-C 100 mg/m^2/twice daily on Day 1-8;IV inf. of 50 mg/m^2/dose of DAUN on Day 1,3,5; IV inf. of etoposide (ETOP) of 100 mg/m^2/dose on Day 1-5.After 3 weeks,ARA-C IT on Day 1 of INT I, IV inf. of 1000 mg/m^2/twice daily of ARA-C,150 mg/m^2/dose of ETOP on Day 1-5. After 3 weeks; ARA-C IT on Day 1 of INT II; 1hr IV inf. of ARA-C 1000 mg/m^2/twice daily on Day 1-4; 1 hr IV inf. of 12 mg/m^2/dose of mitoxantrone on Day 3-6. 2 hr inf. of 3mg/m^2/dose of GMTZ on Day 7. After 3 weeks of rest,3 hr of IV inf. of high dose of 3000 mg/m^2/twice daily of ARA-C on Day 1,2,8,9 of INT III and an injection of 6000 IU/m^2/dose of E. coli L-asparaginase on Day 2,9. Dose was administered on basis of age.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    AraC
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intrathecal use, Intravenous use
    Dosage and administration details
    In IND therapy l, subjects received ARA-C intrathecally on Day 1 followed by an IV infusion of 100 mg/m^2/twice daily on Day 1-10. In Induction therapy ll, subjects received ARA-C intrathecally on Day 1 followed by an IV infusion of 100 mg/m^2/twice daily on Day 1-8. In intensification therapy I, subjects received ARA-C intrathecally on Day 1 followed by an IV infusion of 1000 mg/m^2/twice daily on Day 1-5. In intensification therapy ll, subjects received ARA-C intrathecally followed by an IV infusion of 1000 mg/m^2/twice daily of ARA-C on Day 1-4. In intensification therapy III, subjects received an IV infusion of high dose of 3000 mg/m^2/twice daily of ARA-C on Day 1, 2, 8, and 9.

    Investigational medicinal product name
    Daunorubicin
    Investigational medicinal product code
    DAUN
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In Induction therapy I, subjects received Daunorubicin IV over 6 hours 50mg/m^2/dose on Day 1,3 and 5. In Induction therapy II, subjects received Daunorubicin IV over 6 hours 50 mg/m^2/dose on Day 1,3 and 5.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    ETOP
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In Induction therapy l, subjects received Etoposide IV over 4 hours 100 mg/m^2/dose from Day 1 to Day 5. In Induction therapy ll, subjects received Etoposide IV over 4 hours 100 mg/m^2/dose from Day 1 to Day 5. In Intensification therapy I subjects received Etoposide IV over 4 hours 150 mg/m^2/dose from Day 1 to Day 5.

    Investigational medicinal product name
    Mitoxantrone
    Investigational medicinal product code
    MITOX
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In Intensification therapy II subjects received Mitoxantrone IV over 1 hour 3mg/m^2/dose from Day 3 to 6.

    Investigational medicinal product name
    Asparaginase
    Investigational medicinal product code
    LASP
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    In Intensification therapy III, subjects received E.coli asparaginase an injection of 6000 IU/m^2/dose at Day 2 and Day 9.

    Investigational medicinal product name
    Gemtuzimab Ozogamicin
    Investigational medicinal product code
    GMTZ
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In induction therapy I, subjects received Gemtuzumab Ozogamicin IV over 2 hours 3mg/m^2/dose at Day 6. In Intensification therapy II, subjects received Gemtuzumab Ozogamicin IV over 2 hours 3mg/m^2/dose at Day 7.

    Arm title
    		 Arm A: No Gemtuzumab ozogamicin (Down syndrome)
    Arm description
    		 ARA-C (IT) on Day 1 of IND I. IV inf. of ARA-C 100 mg/m^2/twice daily on Day 1-10; a 6 hr IV inf. DAUN 50mg/m^2/dose on Day 1, 3,5; 4-hr IV inf. of etoposide 100 mg/m^2/dose on Day 1-5. After 3 weeks, ARA-C IT on Day 1 of induction therapy ll, then IV inf. of 100 mg/m^2/twice daily of ARA-C on Day 1-8; 6-hr IV inf. of 50mg/m^2/dose of DAUN on Day 1,3,5; a 4 hr IV inf. of etoposide 100 mg/m^2/dose on Day 1-5. After 3 weeks, ARA-C IT on Day 1 of intensification l and IV ARA-C inf. of 1000 mg/m^2/twice daily and 150 mg/m^2/dose of etoposide on Day 1-5. After 3 weeks, ARA-C IT on Day 1 of intensification II; a 1 hr IV inf. of ARA-C 1000 mg/m^2/twice daily on Day 1-4;1 hr IV inf. of mitoxantrone 12 mg/m^2/dose on Day 3-6. After 3 weeks, 3 hr of IV inf. of high dose of 3000 mg/m^2/per day of ARA-C on Day 1,2,8,9 of intensification therapy III, an injection of E. Coli L-asparaginase 6000 IU/m^2/dose on Day 2 and 9. Dose was administered on the basis of age of the subjects.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    ARA-C
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intrathecal use, Intravenous use
    Dosage and administration details
    In Induction therapy l, subjects received ARA-C intrathecally on Day 1 followed by an IV infusion of 100 mg/m^2/twice daily on Day 1-10. In Induction therapy ll, subjects received ARA-C intrathecally on Day 1 followed by an IV infusion of 100 mg/m^2/twice on Day 1-8. In intensification therapy I, subjects received ARA-C intrathecally on Day 1 followed by an IV infusion of 1000 mg/m^2/twice daily on Day 1-5. In intensification therapy ll, subjects received ARA-C intrathecally followed by an IV infusion of 1000 mg/m^2/twice daily of ARA-C on Day 1-4. In intensification therapy III, subjects received an IV infusion of high dose of 3000 mg/m^2/per day of ARA-C on Day 1, 2, 8 and 9.

    Investigational medicinal product name
    Mitoxantrone
    Investigational medicinal product code
    MITOX
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In Intensification therapy II subjects received Mitoxantrone IV over 1 hour 12 mg/m^2/dose from Day 3 to 6.

    Investigational medicinal product name
    Asparaginase
    Investigational medicinal product code
    LASP
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    In Intensification therapy III, subjects received an injection of E. Coli L-asparaginase 6000 IU/m^2/dose on Day 2 and 9.

    Investigational medicinal product name
    Daunorubicin
    Investigational medicinal product code
    DAUN
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In induction therapy I, subjects received Daunorubicin IV over 6 hours 50mg/m^2/dose on Day 1, 3 and 5. In Induction therapy II, subjects received Daunorubicin IV over 6 hours 50mg/m^2/dose on Day 1, 3 and 5.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    ETOP
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In Induction therapy l, subjects received Etoposide IV over 4 hours 100 mg/m^2/dose from Day 1 to Day 5. In Induction therapy ll, subjects received Etoposide IV over 4 hours 100 mg/m^2/dose from Day 1 to Day 5. In Intensification therapy I, subjects received Etoposide IV over 4 hours 150 mg/m^2/dose from Day 1 to Day 5.

    Number of subjects in period 1
    		Arm A: No Gemtuzumab ozogamicin Arm B: Gemtuzumab ozogamicin Arm A: No Gemtuzumab ozogamicin (Down syndrome)
    Started
    531
    532
    6
    Treated
    517
    520
    6
    Completed
    304
    300
    3
    Not completed
    227
    232
    3
         Ineligible
    5
    5
    -
         Consent withdrawn by subject
    8
    14
    -
         Other
    33
    43
    -
         Death
    153
    140
    3
         Lost to follow-up
    28
    30
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: No Gemtuzumab ozogamicin
    Reporting group description
    		 Cytarabine(ARA-C) intrathecally(IT) on Day 1 of induction therapy I,intravenous (IV) infusion (inf.) of 100 mg/m^2/twice daily ARA-C on Day 1-10; daunorubicin IV inf. of 50mg/m^2/dose on Day 1,3,5;IV inf. of 100 mg/m^2/dose etoposide on Day 1-5. After 3 weeks,ARA-C IT on Day 1 of induction therapy II,then IV ARA-C inf. of 100 mg/m^2/twice daily on Day 1-8;IV daunorubicin inf. of 50mg/m^2/dose on Day 1, 3, 5;etoposide IV infusion of 100 mg/m^2/dose on Day 1-5. After 3 weeks, ARA-C IT on Day 1 of intensification l and IV ARA-C inf. of 1000 mg/m^2/twice daily and 150 mg/m^2/dose of etoposide on Day 1-5. After 3 weeks,ARA-C IT on Day 1 of intensification (INT) II;IV inf. of 1000 mg/m^2/twice daily of ARA-C on Day 1-4;mitoxantrone IV inf. of 12 mg/m^2/dose on Day 3-6. After 3 weeks,3 hour of IV inf. of high dose of 3000 mg/m^2/per day of ARA-C on Day 1, 2, 8, 9 of INT III and injection of E. Coli L-asparaginase 6000 IU/m^2/dose on Day 2 and 9. Dose was administered on basis of age.

    Reporting group title
    Arm B: Gemtuzumab ozogamicin
    Reporting group description
    		 ARA-C (IT) on Day 1 of induction I (IND). IV inf. of 100 mg/m^2/twice daily of ARA-C on Day 1-10;6 hr IV inf. daunorubicin (DAUN), 50mg/m^2/dose on Day 1,3,5; etoposide IV inf. of 100 mg/m^2/dose on Day 1-5;IV inf. of 3mg/m^2/dose of GMTZ on Day 6.After 3 weeks ARA-C IT, Day 1 of IND ll. IV inf. of ARA-C 100 mg/m^2/twice daily on Day 1-8;IV inf. of 50 mg/m^2/dose of DAUN on Day 1,3,5; IV inf. of etoposide (ETOP) of 100 mg/m^2/dose on Day 1-5.After 3 weeks,ARA-C IT on Day 1 of INT I, IV inf. of 1000 mg/m^2/twice daily of ARA-C,150 mg/m^2/dose of ETOP on Day 1-5. After 3 weeks; ARA-C IT on Day 1 of INT II; 1hr IV inf. of ARA-C 1000 mg/m^2/twice daily on Day 1-4; 1 hr IV inf. of 12 mg/m^2/dose of mitoxantrone on Day 3-6. 2 hr inf. of 3mg/m^2/dose of GMTZ on Day 7. After 3 weeks of rest,3 hr of IV inf. of high dose of 3000 mg/m^2/twice daily of ARA-C on Day 1,2,8,9 of INT III and an injection of 6000 IU/m^2/dose of E. coli L-asparaginase on Day 2,9. Dose was administered on basis of age.

    Reporting group title
    Arm A: No Gemtuzumab ozogamicin (Down syndrome)
    Reporting group description
    		 ARA-C (IT) on Day 1 of IND I. IV inf. of ARA-C 100 mg/m^2/twice daily on Day 1-10; a 6 hr IV inf. DAUN 50mg/m^2/dose on Day 1, 3,5; 4-hr IV inf. of etoposide 100 mg/m^2/dose on Day 1-5. After 3 weeks, ARA-C IT on Day 1 of induction therapy ll, then IV inf. of 100 mg/m^2/twice daily of ARA-C on Day 1-8; 6-hr IV inf. of 50mg/m^2/dose of DAUN on Day 1,3,5; a 4 hr IV inf. of etoposide 100 mg/m^2/dose on Day 1-5. After 3 weeks, ARA-C IT on Day 1 of intensification l and IV ARA-C inf. of 1000 mg/m^2/twice daily and 150 mg/m^2/dose of etoposide on Day 1-5. After 3 weeks, ARA-C IT on Day 1 of intensification II; a 1 hr IV inf. of ARA-C 1000 mg/m^2/twice daily on Day 1-4;1 hr IV inf. of mitoxantrone 12 mg/m^2/dose on Day 3-6. After 3 weeks, 3 hr of IV inf. of high dose of 3000 mg/m^2/per day of ARA-C on Day 1,2,8,9 of intensification therapy III, an injection of E. Coli L-asparaginase 6000 IU/m^2/dose on Day 2 and 9. Dose was administered on the basis of age of the subjects.

    Reporting group values
    		 Arm A: No Gemtuzumab ozogamicin Arm B: Gemtuzumab ozogamicin Arm A: No Gemtuzumab ozogamicin (Down syndrome) Total
    Number of subjects
    		 531 532 6 1069
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.7 ( 6.4 ) 9.0 ( 6.2 ) 11.5 ( 5.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 260 277 4 541
        Male
    		 271 255 2 528

    End points

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    End points reporting groups
    Reporting group title
    Arm A: No Gemtuzumab ozogamicin
    Reporting group description
    		 Cytarabine(ARA-C) intrathecally(IT) on Day 1 of induction therapy I,intravenous (IV) infusion (inf.) of 100 mg/m^2/twice daily ARA-C on Day 1-10; daunorubicin IV inf. of 50mg/m^2/dose on Day 1,3,5;IV inf. of 100 mg/m^2/dose etoposide on Day 1-5. After 3 weeks,ARA-C IT on Day 1 of induction therapy II,then IV ARA-C inf. of 100 mg/m^2/twice daily on Day 1-8;IV daunorubicin inf. of 50mg/m^2/dose on Day 1, 3, 5;etoposide IV infusion of 100 mg/m^2/dose on Day 1-5. After 3 weeks, ARA-C IT on Day 1 of intensification l and IV ARA-C inf. of 1000 mg/m^2/twice daily and 150 mg/m^2/dose of etoposide on Day 1-5. After 3 weeks,ARA-C IT on Day 1 of intensification (INT) II;IV inf. of 1000 mg/m^2/twice daily of ARA-C on Day 1-4;mitoxantrone IV inf. of 12 mg/m^2/dose on Day 3-6. After 3 weeks,3 hour of IV inf. of high dose of 3000 mg/m^2/per day of ARA-C on Day 1, 2, 8, 9 of INT III and injection of E. Coli L-asparaginase 6000 IU/m^2/dose on Day 2 and 9. Dose was administered on basis of age.

    Reporting group title
    Arm B: Gemtuzumab ozogamicin
    Reporting group description
    		 ARA-C (IT) on Day 1 of induction I (IND). IV inf. of 100 mg/m^2/twice daily of ARA-C on Day 1-10;6 hr IV inf. daunorubicin (DAUN), 50mg/m^2/dose on Day 1,3,5; etoposide IV inf. of 100 mg/m^2/dose on Day 1-5;IV inf. of 3mg/m^2/dose of GMTZ on Day 6.After 3 weeks ARA-C IT, Day 1 of IND ll. IV inf. of ARA-C 100 mg/m^2/twice daily on Day 1-8;IV inf. of 50 mg/m^2/dose of DAUN on Day 1,3,5; IV inf. of etoposide (ETOP) of 100 mg/m^2/dose on Day 1-5.After 3 weeks,ARA-C IT on Day 1 of INT I, IV inf. of 1000 mg/m^2/twice daily of ARA-C,150 mg/m^2/dose of ETOP on Day 1-5. After 3 weeks; ARA-C IT on Day 1 of INT II; 1hr IV inf. of ARA-C 1000 mg/m^2/twice daily on Day 1-4; 1 hr IV inf. of 12 mg/m^2/dose of mitoxantrone on Day 3-6. 2 hr inf. of 3mg/m^2/dose of GMTZ on Day 7. After 3 weeks of rest,3 hr of IV inf. of high dose of 3000 mg/m^2/twice daily of ARA-C on Day 1,2,8,9 of INT III and an injection of 6000 IU/m^2/dose of E. coli L-asparaginase on Day 2,9. Dose was administered on basis of age.

    Reporting group title
    Arm A: No Gemtuzumab ozogamicin (Down syndrome)
    Reporting group description
    		 ARA-C (IT) on Day 1 of IND I. IV inf. of ARA-C 100 mg/m^2/twice daily on Day 1-10; a 6 hr IV inf. DAUN 50mg/m^2/dose on Day 1, 3,5; 4-hr IV inf. of etoposide 100 mg/m^2/dose on Day 1-5. After 3 weeks, ARA-C IT on Day 1 of induction therapy ll, then IV inf. of 100 mg/m^2/twice daily of ARA-C on Day 1-8; 6-hr IV inf. of 50mg/m^2/dose of DAUN on Day 1,3,5; a 4 hr IV inf. of etoposide 100 mg/m^2/dose on Day 1-5. After 3 weeks, ARA-C IT on Day 1 of intensification l and IV ARA-C inf. of 1000 mg/m^2/twice daily and 150 mg/m^2/dose of etoposide on Day 1-5. After 3 weeks, ARA-C IT on Day 1 of intensification II; a 1 hr IV inf. of ARA-C 1000 mg/m^2/twice daily on Day 1-4;1 hr IV inf. of mitoxantrone 12 mg/m^2/dose on Day 3-6. After 3 weeks, 3 hr of IV inf. of high dose of 3000 mg/m^2/per day of ARA-C on Day 1,2,8,9 of intensification therapy III, an injection of E. Coli L-asparaginase 6000 IU/m^2/dose on Day 2 and 9. Dose was administered on the basis of age of the subjects.

    Primary: Event Free Survival (EFS) : Per Protocol Set

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    End point title
    		 Event Free Survival (EFS) : Per Protocol Set [1]
    End point description
    EFS was defined as the time from study entry until death, induction failure, or relapse of any type. The Kaplan-Meier method was used to calculate estimates of EFS. The log-rank test was used to compare survival between treatment groups. Monitoring for efficacy of GMTZ with respect to EFS utilized monitoring based on the Lan-DeMets criterion with Alpha (α) spending function αt^2 (truncated at 3 standard deviations) and 2.5% type I error. Per protocol analysis set included all randomized subjects who received at least one dose of any study treatment and were not considered ineligible as per the protocol. 99999 represents that the 95% C.I. was not reached due to immaturity of events.
    End point type
    Primary
    End point timeframe
    Time from randomization to induction failure, relapse or death (up to 10 years)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for arm A: No Gemtuzumab ozogamicin and arm B: Gemtuzumab ozogamicin only.
    End point values
    		 Arm A: No Gemtuzumab ozogamicin Arm B: Gemtuzumab ozogamicin
    Number of subjects analysed
    511
    511
    Units: Months
        median (confidence interval 95%)
    18.5 (14.9 to 28.3)
    54.6 (21.6 to 99999)
    Statistical analysis title
    		 Statistical analysis of EFS
    Comparison groups
    Arm B: Gemtuzumab ozogamicin v Arm A: No Gemtuzumab ozogamicin
    Number of subjects included in analysis
    1022
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0309
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.827
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.696
         upper limit
    		 0.983
    Notes
    [2] - The study was designed to have 80% power with one-sided 2.5% type I error to detect a 9% improvement in long-term EFS (54% v 45%) between the two study arms.

    Primary: Event Free Survival (EFS) : Full Analysis Set

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    End point title
    		 Event Free Survival (EFS) : Full Analysis Set [3]
    End point description
    EFS was defined as the time from study entry until death, induction failure, or relapse of any type. The Kaplan-Meier method was used to calculate estimates of EFS. The log-rank test was used to compare survival between treatment groups. Monitoring for efficacy of GMTZ with respect to EFS utilized monitoring based on the Lan-DeMets criterion with α-spending function αt^2 (truncated at 3 standard deviations) and 2.5% type I error . Full analysis set included all randomized subjects. 99999 represents that the 95% C.I. was not reached due to immaturity of events.
    End point type
    Primary
    End point timeframe
    Time from randomization to induction failure, relapse or death (up to 10 years)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for arm A: No Gemtuzumab ozogamicin and arm B: Gemtuzumab ozogamicin only.
    End point values
    		 Arm A: No Gemtuzumab ozogamicin Arm B: Gemtuzumab ozogamicin
    Number of subjects analysed
    531
    532
    Units: months
        median (confidence interval 95%)
    18.4 (14.9 to 28.3)
    47.8 (21.1 to 99999)
    Statistical analysis title
    		 Statistical analysis of EFS
    Comparison groups
    Arm A: No Gemtuzumab ozogamicin v Arm B: Gemtuzumab ozogamicin
    Number of subjects included in analysis
    1063
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0431
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.838
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.706
         upper limit
    		 0.995

    Primary: Overall Survival (OS): Per Protocol Set

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    End point title
    		 Overall Survival (OS): Per Protocol Set [4]
    End point description
    OS was defined as time from randomization to the date of death due to any cause. The Kaplan-Meier method was used to calculate estimates of OS. Monitoring for efficacy of GMTZ with respect to OS utilized monitoring based on the Lan-DeMets criterion with α-spending function αt^2 (truncated at 3 standard deviations) and 2.5% type I error. Per protocol analysis set included all randomized subjects who received at least one dose of any study treatment and were not considered ineligible as per the protocol. 99999 represents that median and 95% C.I. was not reached due to immaturity of events.
    End point type
    Primary
    End point timeframe
    From randomization until death due to any cause (up to 10 years)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for arm A: No Gemtuzumab ozogamicin and arm B: Gemtuzumab ozogamicin only.
    End point values
    		 Arm A: No Gemtuzumab ozogamicin Arm B: Gemtuzumab ozogamicin
    Number of subjects analysed
    511
    511
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Statistical Analysis of OS
    Comparison groups
    Arm A: No Gemtuzumab ozogamicin v Arm B: Gemtuzumab ozogamicin
    Number of subjects included in analysis
    1022
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2638
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.879
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.103

    Primary: Overall Survival (OS) : Full Analysis Set

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    End point title
    		 Overall Survival (OS) : Full Analysis Set [5]
    End point description
    OS was defined as time from randomization to the date of death due to any cause. The Kaplan-Meier method was used to calculate estimates of OS. Monitoring for efficacy of GMTZ with respect to OS utilized monitoring based on the Lan-DeMets criterion with α-spending function αt^2 (truncated at 3 standard deviations) and 2.5% type I error. Full analysis set included all randomized subjects. 99999 represents that median and 95% C.I. was not reached due to immaturity of events.
    End point type
    Primary
    End point timeframe
    From randomization until death due to any cause (up to 10 years)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for arm A: No Gemtuzumab ozogamicin and arm B: Gemtuzumab ozogamicin only.
    End point values
    		 Arm A: No Gemtuzumab ozogamicin Arm B: Gemtuzumab ozogamicin
    Number of subjects analysed
    531
    532
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Statistical Analysis of OS: Full analysis set
    Comparison groups
    Arm A: No Gemtuzumab ozogamicin v Arm B: Gemtuzumab ozogamicin
    Number of subjects included in analysis
    1063
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3799
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.904
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.721
         upper limit
    		 1.133

    Secondary: Percentage of Subjects With Complete Remission (CR) : Full Analysis Set

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    End point title
    		 Percentage of Subjects With Complete Remission (CR) : Full Analysis Set [6]
    End point description
    CR was defined as percentage of subjects who had presence of < 5% blast cells and absence of extramedullary disease in the bone marrow or absence of leukemic blasts in the peripheral blood at the end of induction therapy ll. Full analysis set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From Randomization up to Day 56 (end of induction therapy ll)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for arm A: No Gemtuzumab ozogamicin and arm B: Gemtuzumab ozogamicin only.
    End point values
    		 Arm A: No Gemtuzumab ozogamicin Arm B: Gemtuzumab ozogamicin
    Number of subjects analysed
    531
    532
    Units: Percentage of Subjects
        number (confidence interval 95%)
    76.1 (72.2 to 79.7)
    78.8 (75.0 to 82.2)
    Statistical analysis title
    		 Statistical analysis of (CR) : Full Analysis Set
    Comparison groups
    Arm A: No Gemtuzumab ozogamicin v Arm B: Gemtuzumab ozogamicin
    Number of subjects included in analysis
    1063
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3052
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.7
         upper limit
    		 2.3

    Secondary: Percentage of Subjects With Complete Remission (CR) : Per Protocol Set

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    End point title
    		 Percentage of Subjects With Complete Remission (CR) : Per Protocol Set [7]
    End point description
    CR was defined as percentage of subjects who had presence of < 5% blast cells and absence of extramedullary disease in the bone marrow or absence of leukemic blasts in the peripheral blood at the end of induction therapy ll. Per protocol analysis set included all randomized subjects who received at least one dose of any study treatment and were not considered ineligible as per protocol.
    End point type
    Secondary
    End point timeframe
    From Randomization up to Day 56 (end of induction therapy ll)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for arm A: No Gemtuzumab ozogamicin and arm B: Gemtuzumab ozogamicin only.
    End point values
    		 Arm A: No Gemtuzumab ozogamicin Arm B: Gemtuzumab ozogamicin
    Number of subjects analysed
    511
    511
    Units: Percentage of Subjects
        number (confidence interval 95%)
    78.7 (74.9 to 82.1)
    81.6 (78.0 to 84.9)
    Statistical analysis title
    		 Statistical analysis CR : Per Protocol Set
    Comparison groups
    Arm A: No Gemtuzumab ozogamicin v Arm B: Gemtuzumab ozogamicin
    Number of subjects included in analysis
    1022
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2723
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.8
         upper limit
    		 2

    Secondary: Disease-free Survival (DFS) : Full Analysis Set

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    End point title
    		 Disease-free Survival (DFS) : Full Analysis Set
    End point description
    DFS was defined as the time from the end of Intensification- I to death or relapse. Full analysis set included all randomized subjects. As specified in statistical analysis plan (SAP), due to change in planned analysis, data for disease free survival was not evaluated.
    End point type
    Secondary
    End point timeframe
    From Day 84 (end of intensification therapy l) up to death or relapse, whichever occurred first
    End point values
    		 Arm A: No Gemtuzumab ozogamicin Arm B: Gemtuzumab ozogamicin Arm A: No Gemtuzumab ozogamicin (Down syndrome)
    Number of subjects analysed
    0 [8]
    0 [9]
    0 [10]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    Notes
    [8] - Due to change in planned analysis no subject was analyzed for DFS.
    [9] - Due to change in planned analysis no subject was analyzed for DFS.
    [10] - Due to change in planned analysis no subject was analyzed for DFS.
    No statistical analyses for this end point

    Secondary: Disease-free Survival (DFS) : Per Protocol Set

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    End point title
    		 Disease-free Survival (DFS) : Per Protocol Set
    End point description
    DFS was defined as the time from the end of Intensification- I to death or relapse. As specified in SAP, due to change in planned analysis, data for disease free survival was not evaluated. Per protocol analysis set included all randomized subjects who received at least one dose of any study treatment and were not considered ineligible as per the protocol.
    End point type
    Secondary
    End point timeframe
    From Day 84 (end of intensification therapy l) up to death or relapse, whichever occurred first
    End point values
    		 Arm A: No Gemtuzumab ozogamicin Arm B: Gemtuzumab ozogamicin Arm A: No Gemtuzumab ozogamicin (Down syndrome)
    Number of subjects analysed
    0 [11]
    0 [12]
    0 [13]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    Notes
    [11] - Due to change in planned analysis no subject was analyzed for DFS.
    [12] - Due to change in planned analysis no subject was analyzed for DFS.
    [13] - Due to change in planned analysis no subject was analyzed for DFS.
    No statistical analyses for this end point

    Secondary: Duration of Recovery of Platelets and Neutrophils

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    End point title
    		 Duration of Recovery of Platelets and Neutrophils
    End point description
    Time to neutrophil recovery was defined as the time from the first dose to the first date when neutrophil count was greater than 500 per milliliter (/mL). Time to platelet recovery was defined as the time from the first dose to the first date when platelet count were greater than 50,000/mL for 7 Days without transfusion. Here, ‘n’ subjects that were evaluable for a specified time point only. Safety analysis set included all patients who received at least 1 dose of any study treatment. 99999 represents that the 95% C.I. was not reached due to immaturity of events.
    End point type
    Secondary
    End point timeframe
    Induction therapy I, Intensification therapy II
    End point values
    		 Arm A: No Gemtuzumab ozogamicin Arm B: Gemtuzumab ozogamicin Arm A: No Gemtuzumab ozogamicin (Down syndrome)
    Number of subjects analysed
    517
    520
    6
    Units: Days
    median (confidence interval 95%)
        Induction I : Platelets (n=517,520,6)
    29.0 (28.0 to 29.0)
    31.0 (30.0 to 31.0)
    30.5 (19.0 to 99999)
        Induction I : Neutrophils (n=517,520,6)
    33.0 (33.0 to 34.0)
    33.0 (32.0 to 34.0)
    29.5 (27.0 to 34.0)
        Intensification II : Platelets (n=304,326,4)
    47.0 (43.0 to 51.0)
    53.0 (49.0 to 59.0)
    81.0 (42.0 to 99.0)
        Intensification II : Neutrophils (n=304,326,4)
    40.0 (38.0 to 43.0)
    42.0 (40.0 to 45.0)
    54.5 (27.0 to 78.0)
    No statistical analyses for this end point

    Secondary: Number of Subjects with Toxicities

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    End point title
    		 Number of Subjects with Toxicities
    End point description
    Number of subjects with at least one grade 3 or higher adverse event during therapy were reported in this endpoint. Safety analysis set included all subjects who received at least one dose of any study treatment.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment up till end of study (up to 10 years)
    End point values
    		 Arm A: No Gemtuzumab ozogamicin Arm B: Gemtuzumab ozogamicin Arm A: No Gemtuzumab ozogamicin (Down syndrome)
    Number of subjects analysed
    517
    520
    6
    Units: Subjects
    489
    490
    5
    No statistical analyses for this end point

    Secondary: Summary of Deaths

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    End point title
    		 Summary of Deaths
    End point description
    Safety analysis set included all subjects who received at least one dose of any study treatment.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment through 30 Days of last dose (up to 10 years)
    End point values
    		 Arm A: No Gemtuzumab ozogamicin Arm B: Gemtuzumab ozogamicin Arm A: No Gemtuzumab ozogamicin (Down syndrome)
    Number of subjects analysed
    517
    520
    6
    Units: Subjects
    15
    20
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 30 Days after last dose of study treatment (up to 10 years)
    Adverse event reporting additional description
    Same event may appear as an adverse event(AE) and Serious AE(i.e.only Grade 4 unexpected AEs that were related to protocol or any Grade 5 event).Events presented are distinct events.An event may be categorized as serious in one subject and as non-serious in another subject,or one subject may have experienced both SAEs and Non-SAEs during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Arm A: No Gemtuzumab ozogamicin
    Reporting group description
    		 ARA-C (IT) on Day 1 of induction therapy I, then IV infusion of 100 mg/m^2/twice daily ARA-C on Day 1-10; daunorubicin IV infusion of 50mg/m^2/dose on Day 1,3,5; and IV inf. of 100 mg/m^2/dose etoposide on Day 1-5.After 3 weeks, ARA-C IT on Day 1 of induction therapy II,then IV ARA-C inf. of 100 mg/m^2/twice daily on Day 1-8;IV daunorubicin inf. of 50mg/m^2/dose on Day 1, 3, 5;etoposide IV infusion of 100 mg/m^2/dose on Day 1-5.After 3 weeks, ARA-C IT on Day 1 of intensification l and IV ARA-C inf. of 1000 mg/m^2/twice daily and 150 mg/m^2/dose of etoposide on Day 1-5. After 3 weeks, ARA-C IT on Day 1 of intensification therapy II;IV inf. of 1000 mg/m^2/twice daily of ARA-C on Day 1-4;mitoxantrone IV inf. of 12 mg/m^2/dose on Day 3-6. After 3 weeks, 3 hour of IV inf. of high dose of 3000 mg/m^2/per day of ARA-C on Day 1, 2, 8, 9 of intensification therapy III and injection of E. Coli L-asparaginase 6000 IU/m^2/dose on Day 2 and 9. Dose was administered on basis of age of subjects.

    Reporting group title
    Arm B: Gemtuzumab ozogamicin
    Reporting group description
    		 ARA-C (IT) on Day 1 of induction I (IND). IV inf. of 100 mg/m^2/twice daily of ARA-C on Day 1-10;6 hr IV inf. daunorubicin (DAUN), 50mg/m^2/dose on Day 1,3,5; etoposide IV inf. of 100 mg/m^2/dose on Day 1-5;IV inf. of 3mg/m^2/dose of GMTZ on Day 6.After 3 weeks ARA-C IT, Day 1 of IND ll. IV inf. of ARA-C 100 mg/m^2/twice daily on Day 1-8;IV inf. of 50 mg/m^2/dose of DAUN on Day 1,3,5; IV inf. of etoposide (ETOP) of 100 mg/m^2/dose on Day 1-5.After 3 weeks,ARA-C IT on Day 1 of INT I, IV inf. of 1000 mg/m^2/twice daily of ARA-C,150 mg/m^2/dose of ETOP on Day 1-5. After 3 weeks; ARA-C IT on Day 1 of INT II; 1hr IV inf. of ARA-C 1000 mg/m^2/twice daily on Day 1-4; 1 hr IV inf. of 12 mg/m^2/dose of mitoxantrone on Day 3-6. 2 hr inf. of 3mg/m^2/dose of GMTZ on Day 7. After 3 weeks of rest,3 hr of IV inf. of high dose of 3000 mg/m^2/twice daily of ARA-C on Day 1,2,8,9 of INT III and an injection of 6000 IU/m^2/dose of E. coli L-asparaginase on Day 2,9. Dose was administered on basis of age.

    Reporting group title
    Arm A: No Gemtuzumab ozogamicin (Down syndrome)
    Reporting group description
    		 ARA-C (IT) on Day 1 of IND I. IV inf. of ARA-C 100 mg/m^2/twice daily on Day 1-10; a 6 hr IV inf. DAUN 50mg/m^2/dose on Day 1, 3,5; 4-hr IV inf. of etoposide 100 mg/m^2/dose on Day 1-5. After 3 weeks, ARA-C IT on Day 1 of induction therapy ll, then IV inf. of 100 mg/m^2/twice daily of ARA-C on Day 1-8; 6-hr IV inf. of 50mg/m^2/dose of DAUN on Day 1,3,5; a 4 hr IV inf. of etoposide 100 mg/m^2/dose on Day 1-5. After 3 weeks, ARA-C IT on Day 1 of intensification l and IV ARA-C inf. of 1000 mg/m^2/twice daily and 150 mg/m^2/dose of etoposide on Day 1-5. After 3 weeks, ARA-C IT on Day 1 of intensification II; a 1 hr IV inf. of ARA-C 1000 mg/m^2/twice daily on Day 1-4;1 hr IV inf. of mitoxantrone 12 mg/m^2/dose on Day 3-6. After 3 weeks, 3 hr of IV inf. of high dose of 3000 mg/m^2/per day of ARA-C on Day 1,2,8,9 of intensification therapy III, an injection of E. Coli L-asparaginase 6000 IU/m^2/dose on Day 2 and 9. Dose was administered on the basis of age of the subjects.

    Serious adverse events
    		 Arm A: No Gemtuzumab ozogamicin Arm B: Gemtuzumab ozogamicin Arm A: No Gemtuzumab ozogamicin (Down syndrome)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 517 (5.22%)
    33 / 520 (6.35%)
    2 / 6 (33.33%)
         number of deaths (all causes)
    21
    23
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Second primary malignancy
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    6 / 517 (1.16%)
    4 / 520 (0.77%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    Venoocclusive disease
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 517 (0.19%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    Disease progression
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 520 (0.19%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    6 / 517 (1.16%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 6
    0 / 2
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    4 / 517 (0.77%)
    7 / 520 (1.35%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hypoxia
         subjects affected / exposed
    7 / 517 (1.35%)
    6 / 520 (1.15%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    Pleural effusion
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 517 (0.39%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Investigations
    Alanine aminotransferase
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Amylase
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase
         subjects affected / exposed
    1 / 517 (0.19%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood fibrinogen
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heart rate decreased
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Lipase
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    3 / 517 (0.58%)
    5 / 520 (0.96%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Restrictive cardiomyopathy
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Central nervous system haemorrhage
         subjects affected / exposed
    0 / 517 (0.00%)
    6 / 520 (1.15%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    2 / 517 (0.39%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reflux gastritis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    8 / 517 (1.55%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal infection
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Infection
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Kidney infection
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 517 (0.58%)
    3 / 520 (0.58%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Rhinitis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    12 / 517 (2.32%)
    16 / 520 (3.08%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 22
    0 / 0
         deaths causally related to treatment / all
    0 / 5
    0 / 8
    0 / 0
    Splenic infection
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    3 / 517 (0.58%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperammonaemia
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 517 (0.19%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm A: No Gemtuzumab ozogamicin Arm B: Gemtuzumab ozogamicin Arm A: No Gemtuzumab ozogamicin (Down syndrome)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    489 / 517 (94.58%)
    490 / 520 (94.23%)
    5 / 6 (83.33%)
    Vascular disorders
    Capillary leak syndrome
         subjects affected / exposed
    0 / 517 (0.00%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Embolism
         subjects affected / exposed
    3 / 517 (0.58%)
    9 / 520 (1.73%)
    0 / 6 (0.00%)
         occurrences all number
    3
    9
    0
    Haematoma
         subjects affected / exposed
    1 / 517 (0.19%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Haemorrhage
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Hypertension
         subjects affected / exposed
    22 / 517 (4.26%)
    38 / 520 (7.31%)
    0 / 6 (0.00%)
         occurrences all number
    25
    42
    0
    Hypotension
         subjects affected / exposed
    80 / 517 (15.47%)
    80 / 520 (15.38%)
    3 / 6 (50.00%)
         occurrences all number
    102
    92
    4
    Vasculitis
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Venoocclusive disease
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Surgical and medical procedures
    Brain operation
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Parenteral nutrition
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    General disorders and administration site conditions
    Catheter site haemorrhage
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Catheter site pain
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Chest pain
         subjects affected / exposed
    7 / 517 (1.35%)
    6 / 520 (1.15%)
    0 / 6 (0.00%)
         occurrences all number
    8
    6
    0
    Chills
         subjects affected / exposed
    2 / 517 (0.39%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    0
    Complication associated with device
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Death
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Device related thrombosis
         subjects affected / exposed
    5 / 517 (0.97%)
    5 / 520 (0.96%)
    0 / 6 (0.00%)
         occurrences all number
    5
    5
    0
    Disease progression
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Facial pain
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Fatigue
         subjects affected / exposed
    7 / 517 (1.35%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    7
    5
    0
    Ill-defined disorder
         subjects affected / exposed
    4 / 517 (0.77%)
    7 / 520 (1.35%)
    0 / 6 (0.00%)
         occurrences all number
    4
    8
    0
    Localised oedema
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 517 (0.00%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Oedema
         subjects affected / exposed
    3 / 517 (0.58%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Pain
         subjects affected / exposed
    12 / 517 (2.32%)
    10 / 520 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    16
    10
    0
    Pyrexia
         subjects affected / exposed
    27 / 517 (5.22%)
    20 / 520 (3.85%)
    0 / 6 (0.00%)
         occurrences all number
    31
    24
    0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    Ulcer
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    Adverse drug reaction
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    25 / 517 (4.84%)
    32 / 520 (6.15%)
    1 / 6 (16.67%)
         occurrences all number
    32
    39
    1
    Engraftment syndrome
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Graft versus host disease
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Hypersensitivity
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Dysmenorrhoea
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Ovarian failure
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Pelvic pain
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Penile pain
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Perineal pain
         subjects affected / exposed
    2 / 517 (0.39%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    2
    4
    0
    Uterine haemorrhage
         subjects affected / exposed
    2 / 517 (0.39%)
    6 / 520 (1.15%)
    0 / 6 (0.00%)
         occurrences all number
    2
    11
    0
    Uterine pain
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 517 (0.19%)
    6 / 520 (1.15%)
    0 / 6 (0.00%)
         occurrences all number
    1
    8
    0
    Vulvovaginal pain
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    21 / 517 (4.06%)
    37 / 520 (7.12%)
    0 / 6 (0.00%)
         occurrences all number
    22
    37
    0
    Apnoea
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Aspiration
         subjects affected / exposed
    2 / 517 (0.39%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    Atelectasis
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Bronchial haemorrhage
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Bronchospasm
         subjects affected / exposed
    1 / 517 (0.19%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    1
    5
    0
    Cough
         subjects affected / exposed
    6 / 517 (1.16%)
    6 / 520 (1.15%)
    0 / 6 (0.00%)
         occurrences all number
    6
    6
    0
    Dyspnoea
         subjects affected / exposed
    22 / 517 (4.26%)
    24 / 520 (4.62%)
    0 / 6 (0.00%)
         occurrences all number
    26
    24
    0
    Epistaxis
         subjects affected / exposed
    16 / 517 (3.09%)
    23 / 520 (4.42%)
    0 / 6 (0.00%)
         occurrences all number
    25
    44
    0
    Hypoxia
         subjects affected / exposed
    76 / 517 (14.70%)
    84 / 520 (16.15%)
    1 / 6 (16.67%)
         occurrences all number
    92
    96
    1
    Idiopathic pneumonia syndrome
         subjects affected / exposed
    3 / 517 (0.58%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    3
    1
    0
    Laryngeal oedema
         subjects affected / exposed
    1 / 517 (0.19%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Lung disorder
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Lung infiltration
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal disorder
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Organising pneumonia
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Pharyngeal haemorrhage
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Pharyngeal inflammation
         subjects affected / exposed
    5 / 517 (0.97%)
    5 / 520 (0.96%)
    0 / 6 (0.00%)
         occurrences all number
    5
    5
    0
    Pleural effusion
         subjects affected / exposed
    19 / 517 (3.68%)
    16 / 520 (3.08%)
    0 / 6 (0.00%)
         occurrences all number
    19
    16
    0
    Pleuritic pain
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Pneumonitis
         subjects affected / exposed
    39 / 517 (7.54%)
    29 / 520 (5.58%)
    0 / 6 (0.00%)
         occurrences all number
    44
    30
    0
    Pneumothorax
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Pulmonary haemorrhage
         subjects affected / exposed
    2 / 517 (0.39%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    2
    4
    0
    Pulmonary hypertension
         subjects affected / exposed
    4 / 517 (0.77%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    4
    3
    0
    Pulmonary oedema
         subjects affected / exposed
    2 / 517 (0.39%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    Respiratory disorder
         subjects affected / exposed
    6 / 517 (1.16%)
    9 / 520 (1.73%)
    0 / 6 (0.00%)
         occurrences all number
    6
    10
    0
    Respiratory distress
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Respiratory failure
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Upper airway obstruction
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    2 / 517 (0.39%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    2
    4
    0
    Anxiety
         subjects affected / exposed
    2 / 517 (0.39%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    2
    4
    0
    Confusional state
         subjects affected / exposed
    4 / 517 (0.77%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    4
    4
    0
    Depression
         subjects affected / exposed
    6 / 517 (1.16%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    8
    3
    0
    Euphoric mood
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Insomnia
         subjects affected / exposed
    3 / 517 (0.58%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    Mental disorder
         subjects affected / exposed
    6 / 517 (1.16%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    6
    3
    0
    Personality disorder
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Activated partial thromboplastin time
         subjects affected / exposed
    13 / 517 (2.51%)
    15 / 520 (2.88%)
    0 / 6 (0.00%)
         occurrences all number
    13
    15
    0
    Alanine aminotransferase
         subjects affected / exposed
    84 / 517 (16.25%)
    105 / 520 (20.19%)
    0 / 6 (0.00%)
         occurrences all number
    118
    132
    0
    Amylase
         subjects affected / exposed
    16 / 517 (3.09%)
    8 / 520 (1.54%)
    0 / 6 (0.00%)
         occurrences all number
    17
    8
    0
    Aspartate aminotransferase
         subjects affected / exposed
    55 / 517 (10.64%)
    74 / 520 (14.23%)
    0 / 6 (0.00%)
         occurrences all number
    62
    86
    0
    Audiogram
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Blood alkaline phosphatase
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Blood bicarbonate decreased
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Blood creatine phosphokinase
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    Blood creatinine
         subjects affected / exposed
    13 / 517 (2.51%)
    8 / 520 (1.54%)
    0 / 6 (0.00%)
         occurrences all number
    14
    10
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Blood fibrinogen
         subjects affected / exposed
    7 / 517 (1.35%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    7
    3
    0
    Blood lactate dehydrogenase
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Coagulation test abnormal
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    71 / 517 (13.73%)
    68 / 520 (13.08%)
    0 / 6 (0.00%)
         occurrences all number
    101
    99
    0
    Gamma-glutamyltransferase
         subjects affected / exposed
    25 / 517 (4.84%)
    41 / 520 (7.88%)
    0 / 6 (0.00%)
         occurrences all number
    29
    60
    0
    Glomerular filtration rate
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Haemoglobin
         subjects affected / exposed
    10 / 517 (1.93%)
    8 / 520 (1.54%)
    0 / 6 (0.00%)
         occurrences all number
    14
    11
    0
    International normalised ratio
         subjects affected / exposed
    5 / 517 (0.97%)
    5 / 520 (0.96%)
    0 / 6 (0.00%)
         occurrences all number
    5
    5
    0
    Lipase
         subjects affected / exposed
    27 / 517 (5.22%)
    21 / 520 (4.04%)
    0 / 6 (0.00%)
         occurrences all number
    28
    21
    0
    Neutrophil count
         subjects affected / exposed
    15 / 517 (2.90%)
    9 / 520 (1.73%)
    0 / 6 (0.00%)
         occurrences all number
    24
    11
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Platelet count
         subjects affected / exposed
    13 / 517 (2.51%)
    11 / 520 (2.12%)
    0 / 6 (0.00%)
         occurrences all number
    20
    14
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Protein total decreased
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Troponin I
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Troponin T
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Urine analysis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    21 / 517 (4.06%)
    12 / 520 (2.31%)
    0 / 6 (0.00%)
         occurrences all number
    26
    18
    0
    Weight increased
         subjects affected / exposed
    16 / 517 (3.09%)
    16 / 520 (3.08%)
    0 / 6 (0.00%)
         occurrences all number
    16
    16
    0
    White blood cell count
         subjects affected / exposed
    11 / 517 (2.13%)
    8 / 520 (1.54%)
    0 / 6 (0.00%)
         occurrences all number
    14
    10
    0
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Infusion related reaction
         subjects affected / exposed
    2 / 517 (0.39%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    0
    Procedural complication
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Procedural haemorrhage
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Thermal burn
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Tracheal haemorrhage
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Venous injury
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Wound haemorrhage
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Cardiac disorders
    Left ventricular dysfunction
    alternative assessment type: Systematic
         subjects affected / exposed
    119 / 517 (23.02%)
    106 / 520 (20.38%)
    1 / 6 (16.67%)
         occurrences all number
    210
    196
    1
    Myocarditis
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Pericardial effusion
         subjects affected / exposed
    8 / 517 (1.55%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    8
    4
    0
    Pericarditis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Restrictive cardiomyopathy
         subjects affected / exposed
    4 / 517 (0.77%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    4
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Ventricular tachycardia
         subjects affected / exposed
    2 / 517 (0.39%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    2
    4
    0
    Sinus tachycardia
         subjects affected / exposed
    6 / 517 (1.16%)
    10 / 520 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    6
    12
    0
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Atrial tachycardia
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Bradycardia
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 517 (0.39%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Cor pulmonale
         subjects affected / exposed
    3 / 517 (0.58%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    3 / 517 (0.58%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    Central nervous system haemorrhage
         subjects affected / exposed
    2 / 517 (0.39%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Cranial nerve disorder
         subjects affected / exposed
    0 / 517 (0.00%)
    5 / 520 (0.96%)
    0 / 6 (0.00%)
         occurrences all number
    0
    5
    0
    Dizziness
         subjects affected / exposed
    1 / 517 (0.19%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Encephalopathy
         subjects affected / exposed
    5 / 517 (0.97%)
    5 / 520 (0.96%)
    0 / 6 (0.00%)
         occurrences all number
    5
    5
    0
    Headache
         subjects affected / exposed
    19 / 517 (3.68%)
    27 / 520 (5.19%)
    0 / 6 (0.00%)
         occurrences all number
    25
    35
    0
    Hemiparesis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Hydrocephalus
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorder
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Neuralgia
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Peripheral motor neuropathy
         subjects affected / exposed
    2 / 517 (0.39%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    2
    4
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    3 / 517 (0.58%)
    6 / 520 (1.15%)
    0 / 6 (0.00%)
         occurrences all number
    4
    6
    0
    Seizure
         subjects affected / exposed
    7 / 517 (1.35%)
    5 / 520 (0.96%)
    0 / 6 (0.00%)
         occurrences all number
    7
    5
    0
    Somnolence
         subjects affected / exposed
    3 / 517 (0.58%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    3
    4
    0
    Syncope
         subjects affected / exposed
    5 / 517 (0.97%)
    9 / 520 (1.73%)
    0 / 6 (0.00%)
         occurrences all number
    6
    9
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Disseminated intravascular coagulation
         subjects affected / exposed
    6 / 517 (1.16%)
    13 / 520 (2.50%)
    0 / 6 (0.00%)
         occurrences all number
    6
    13
    0
    Febrile neutropenia
         subjects affected / exposed
    267 / 517 (51.64%)
    285 / 520 (54.81%)
    4 / 6 (66.67%)
         occurrences all number
    505
    543
    8
    Lymphadenopathy
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Thrombotic microangiopathy
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    External ear pain
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Tinnitus
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Chalazion
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Eye pain
         subjects affected / exposed
    1 / 517 (0.19%)
    5 / 520 (0.96%)
    1 / 6 (16.67%)
         occurrences all number
    1
    5
    1
    Iritis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Ocular surface disease
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Photophobia
         subjects affected / exposed
    3 / 517 (0.58%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    3
    4
    0
    Retinal haemorrhage
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Uveitis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    2 / 517 (0.39%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    3 / 517 (0.58%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    3
    4
    0
    Abdominal pain
         subjects affected / exposed
    38 / 517 (7.35%)
    45 / 520 (8.65%)
    0 / 6 (0.00%)
         occurrences all number
    50
    62
    0
    Abdominal pain upper
         subjects affected / exposed
    5 / 517 (0.97%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    0
    Anal fissure
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Anal fistula
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Anal inflammation
         subjects affected / exposed
    5 / 517 (0.97%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    5
    4
    0
    Anal ulcer
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Ascites
         subjects affected / exposed
    18 / 517 (3.48%)
    19 / 520 (3.65%)
    0 / 6 (0.00%)
         occurrences all number
    18
    20
    0
    Cheilitis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Colitis
         subjects affected / exposed
    42 / 517 (8.12%)
    38 / 520 (7.31%)
    0 / 6 (0.00%)
         occurrences all number
    47
    43
    0
    Constipation
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Diarrhoea
         subjects affected / exposed
    80 / 517 (15.47%)
    58 / 520 (11.15%)
    1 / 6 (16.67%)
         occurrences all number
    96
    77
    2
    Dyspepsia
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Dysphagia
         subjects affected / exposed
    4 / 517 (0.77%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    4
    3
    0
    Enteritis
         subjects affected / exposed
    3 / 517 (0.58%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    3
    3
    0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Gastritis
         subjects affected / exposed
    5 / 517 (0.97%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    6
    1
    0
    Gastrointestinal fistula
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Haematemesis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Ileus
         subjects affected / exposed
    7 / 517 (1.35%)
    9 / 520 (1.73%)
    0 / 6 (0.00%)
         occurrences all number
    8
    9
    0
    Intussusception
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Lip pain
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 517 (0.77%)
    5 / 520 (0.96%)
    0 / 6 (0.00%)
         occurrences all number
    4
    5
    0
    Malabsorption
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Mouth haemorrhage
         subjects affected / exposed
    4 / 517 (0.77%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    4
    1
    0
    Nausea
         subjects affected / exposed
    49 / 517 (9.48%)
    62 / 520 (11.92%)
    1 / 6 (16.67%)
         occurrences all number
    67
    84
    1
    Oesophageal haemorrhage
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Oesophageal pain
         subjects affected / exposed
    3 / 517 (0.58%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    Oesophagitis
         subjects affected / exposed
    12 / 517 (2.32%)
    13 / 520 (2.50%)
    0 / 6 (0.00%)
         occurrences all number
    14
    17
    0
    Oral pain
         subjects affected / exposed
    28 / 517 (5.42%)
    37 / 520 (7.12%)
    0 / 6 (0.00%)
         occurrences all number
    33
    45
    0
    Pancreatitis
         subjects affected / exposed
    4 / 517 (0.77%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    4
    5
    0
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Proctalgia
         subjects affected / exposed
    19 / 517 (3.68%)
    15 / 520 (2.88%)
    0 / 6 (0.00%)
         occurrences all number
    22
    17
    0
    Proctitis
         subjects affected / exposed
    3 / 517 (0.58%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    3
    1
    0
    Rectal fissure
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    Reflux gastritis
         subjects affected / exposed
    4 / 517 (0.77%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    5
    4
    0
    Small intestinal haemorrhage
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Stomatitis
         subjects affected / exposed
    82 / 517 (15.86%)
    95 / 520 (18.27%)
    2 / 6 (33.33%)
         occurrences all number
    109
    126
    5
    Tooth disorder
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Toothache
         subjects affected / exposed
    3 / 517 (0.58%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    3
    1
    0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 517 (0.19%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    0
    Vomiting
         subjects affected / exposed
    34 / 517 (6.58%)
    44 / 520 (8.46%)
    0 / 6 (0.00%)
         occurrences all number
    41
    52
    0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    4 / 517 (0.77%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    4
    2
    0
    Gallbladder necrosis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Gallbladder obstruction
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    Gallbladder pain
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatic failure
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatitis
         subjects affected / exposed
    6 / 517 (1.16%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    7
    1
    0
    Hepatobiliary disease
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Hepatic pain
         subjects affected / exposed
    13 / 517 (2.51%)
    16 / 520 (3.08%)
    0 / 6 (0.00%)
         occurrences all number
    13
    16
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    57 / 517 (11.03%)
    60 / 520 (11.54%)
    0 / 6 (0.00%)
         occurrences all number
    69
    70
    0
    Portal hypertension
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 517 (0.19%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Erythema multiforme
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Exfoliative rash
         subjects affected / exposed
    26 / 517 (5.03%)
    30 / 520 (5.77%)
    0 / 6 (0.00%)
         occurrences all number
    27
    34
    0
    Pain of skin
         subjects affected / exposed
    2 / 517 (0.39%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    2
    4
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 517 (0.19%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Pruritus
         subjects affected / exposed
    5 / 517 (0.97%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    5
    4
    0
    Purpura
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Skin disorder
         subjects affected / exposed
    1 / 517 (0.19%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Urticaria
         subjects affected / exposed
    3 / 517 (0.58%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    Renal and urinary disorders
    Bladder obstruction
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Bladder pain
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Micturition urgency
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Proteinuria
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    Renal failure
         subjects affected / exposed
    11 / 517 (2.13%)
    26 / 520 (5.00%)
    1 / 6 (16.67%)
         occurrences all number
    11
    26
    1
    Renal necrosis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Renal pain
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Ureteric stenosis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Urethral pain
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary bladder haemorrhage
         subjects affected / exposed
    2 / 517 (0.39%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    0
    Urogenital haemorrhage
         subjects affected / exposed
    1 / 517 (0.19%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    1
    5
    0
    Endocrine disorders
    Diabetes insipidus
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 517 (0.58%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    4
    2
    0
    Arthritis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Back pain
         subjects affected / exposed
    14 / 517 (2.71%)
    11 / 520 (2.12%)
    0 / 6 (0.00%)
         occurrences all number
    16
    14
    0
    Bone infarction
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Bone pain
         subjects affected / exposed
    2 / 517 (0.39%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    3
    3
    0
    Cytarabine syndrome
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Joint effusion
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    Muscular weakness
         subjects affected / exposed
    3 / 517 (0.58%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    4
    3
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 517 (0.00%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    0
    Musculoskeletal disorder
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 517 (0.39%)
    5 / 520 (0.96%)
    0 / 6 (0.00%)
         occurrences all number
    2
    5
    0
    Myalgia
         subjects affected / exposed
    1 / 517 (0.19%)
    6 / 520 (1.15%)
    0 / 6 (0.00%)
         occurrences all number
    1
    6
    0
    Myositis
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    Neck pain
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    Osteonecrosis
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Pain in extremity
         subjects affected / exposed
    14 / 517 (2.71%)
    18 / 520 (3.46%)
    0 / 6 (0.00%)
         occurrences all number
    19
    19
    0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    1 / 517 (0.19%)
    6 / 520 (1.15%)
    0 / 6 (0.00%)
         occurrences all number
    1
    7
    0
    Anal infection
         subjects affected / exposed
    8 / 517 (1.55%)
    9 / 520 (1.73%)
    0 / 6 (0.00%)
         occurrences all number
    8
    10
    0
    Anorectal infection
         subjects affected / exposed
    5 / 517 (0.97%)
    10 / 520 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    6
    11
    0
    Appendicitis
         subjects affected / exposed
    9 / 517 (1.74%)
    6 / 520 (1.15%)
    0 / 6 (0.00%)
         occurrences all number
    9
    6
    0
    Arthritis infective
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Biliary tract infection
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Bronchitis
         subjects affected / exposed
    7 / 517 (1.35%)
    9 / 520 (1.73%)
    0 / 6 (0.00%)
         occurrences all number
    7
    9
    0
    Cellulitis
         subjects affected / exposed
    61 / 517 (11.80%)
    43 / 520 (8.27%)
    1 / 6 (16.67%)
         occurrences all number
    66
    49
    1
    Cholecystitis infective
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Corneal infection
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Cystitis
         subjects affected / exposed
    15 / 517 (2.90%)
    19 / 520 (3.65%)
    0 / 6 (0.00%)
         occurrences all number
    25
    24
    0
    Device related infection
         subjects affected / exposed
    4 / 517 (0.77%)
    5 / 520 (0.96%)
    0 / 6 (0.00%)
         occurrences all number
    4
    6
    0
    Encephalitis
         subjects affected / exposed
    6 / 517 (1.16%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    6
    2
    0
    Endocarditis
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Enteritis infectious
         subjects affected / exposed
    10 / 517 (1.93%)
    5 / 520 (0.96%)
    0 / 6 (0.00%)
         occurrences all number
    13
    6
    0
    Enterococcal infection
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Eye infection
         subjects affected / exposed
    2 / 517 (0.39%)
    8 / 520 (1.54%)
    0 / 6 (0.00%)
         occurrences all number
    2
    8
    0
    Fungal infection
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Gastric infection
         subjects affected / exposed
    4 / 517 (0.77%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    4
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Gingivitis
         subjects affected / exposed
    11 / 517 (2.13%)
    13 / 520 (2.50%)
    0 / 6 (0.00%)
         occurrences all number
    13
    14
    0
    Herpes simplex
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Infection
         subjects affected / exposed
    20 / 517 (3.87%)
    24 / 520 (4.62%)
    0 / 6 (0.00%)
         occurrences all number
    22
    26
    0
    Infectious colitis
         subjects affected / exposed
    95 / 517 (18.38%)
    75 / 520 (14.42%)
    0 / 6 (0.00%)
         occurrences all number
    142
    89
    0
    Infective myositis
         subjects affected / exposed
    3 / 517 (0.58%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    3
    1
    0
    Kidney infection
         subjects affected / exposed
    1 / 517 (0.19%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Lip infection
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Lymphangitis
         subjects affected / exposed
    2 / 517 (0.39%)
    6 / 520 (1.15%)
    0 / 6 (0.00%)
         occurrences all number
    2
    6
    0
    Mediastinitis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Meningitis
         subjects affected / exposed
    3 / 517 (0.58%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    3
    4
    0
    Mucosal infection
         subjects affected / exposed
    5 / 517 (0.97%)
    10 / 520 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    6
    14
    0
    Nail infection
         subjects affected / exposed
    1 / 517 (0.19%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Neutropenic infection
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Oesophageal infection
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Opportunistic infection
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Oral candidiasis
         subjects affected / exposed
    11 / 517 (2.13%)
    16 / 520 (3.08%)
    0 / 6 (0.00%)
         occurrences all number
    11
    17
    0
    Oral herpes
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Osteomyelitis
         subjects affected / exposed
    2 / 517 (0.39%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    0
    Otitis externa
         subjects affected / exposed
    2 / 517 (0.39%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    Otitis media
         subjects affected / exposed
    6 / 517 (1.16%)
    5 / 520 (0.96%)
    1 / 6 (16.67%)
         occurrences all number
    6
    5
    1
    Penile infection
         subjects affected / exposed
    0 / 517 (0.00%)
    5 / 520 (0.96%)
    0 / 6 (0.00%)
         occurrences all number
    0
    6
    0
    Periorbital cellulitis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Peritonitis
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Pharyngitis
         subjects affected / exposed
    4 / 517 (0.77%)
    7 / 520 (1.35%)
    0 / 6 (0.00%)
         occurrences all number
    4
    7
    0
    Pneumonia
         subjects affected / exposed
    101 / 517 (19.54%)
    92 / 520 (17.69%)
    0 / 6 (0.00%)
         occurrences all number
    131
    107
    0
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Pulmonary mycosis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    15 / 517 (2.90%)
    11 / 520 (2.12%)
    0 / 6 (0.00%)
         occurrences all number
    19
    11
    0
    Scrotal infection
         subjects affected / exposed
    0 / 517 (0.00%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Sepsis
         subjects affected / exposed
    361 / 517 (69.83%)
    374 / 520 (71.92%)
    4 / 6 (66.67%)
         occurrences all number
    887
    920
    11
    Sialoadenitis
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Sinusitis
         subjects affected / exposed
    13 / 517 (2.51%)
    22 / 520 (4.23%)
    0 / 6 (0.00%)
         occurrences all number
    13
    28
    0
    Soft tissue infection
         subjects affected / exposed
    8 / 517 (1.55%)
    8 / 520 (1.54%)
    0 / 6 (0.00%)
         occurrences all number
    8
    11
    0
    Splenic infection
         subjects affected / exposed
    1 / 517 (0.19%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    0
    Tooth infection
         subjects affected / exposed
    3 / 517 (0.58%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    3
    3
    0
    Tracheitis
         subjects affected / exposed
    4 / 517 (0.77%)
    6 / 520 (1.15%)
    0 / 6 (0.00%)
         occurrences all number
    8
    7
    0
    Upper aerodigestive tract infection
         subjects affected / exposed
    1 / 517 (0.19%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    0
    Upper respiratory tract infection
         subjects affected / exposed
    23 / 517 (4.45%)
    24 / 520 (4.62%)
    1 / 6 (16.67%)
         occurrences all number
    24
    30
    1
    Urinary tract infection
         subjects affected / exposed
    35 / 517 (6.77%)
    31 / 520 (5.96%)
    0 / 6 (0.00%)
         occurrences all number
    50
    35
    0
    Uterine infection
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Vaginal infection
         subjects affected / exposed
    2 / 517 (0.39%)
    2 / 520 (0.38%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    Vulvitis
         subjects affected / exposed
    7 / 517 (1.35%)
    3 / 520 (0.58%)
    0 / 6 (0.00%)
         occurrences all number
    8
    3
    0
    Wound infection
         subjects affected / exposed
    12 / 517 (2.32%)
    13 / 520 (2.50%)
    0 / 6 (0.00%)
         occurrences all number
    17
    14
    0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    7 / 517 (1.35%)
    12 / 520 (2.31%)
    0 / 6 (0.00%)
         occurrences all number
    7
    13
    0
    Alkalosis
         subjects affected / exposed
    2 / 517 (0.39%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    2
    4
    0
    Decreased appetite
         subjects affected / exposed
    144 / 517 (27.85%)
    166 / 520 (31.92%)
    2 / 6 (33.33%)
         occurrences all number
    228
    290
    2
    Dehydration
         subjects affected / exposed
    16 / 517 (3.09%)
    16 / 520 (3.08%)
    0 / 6 (0.00%)
         occurrences all number
    17
    18
    0
    Diabetes mellitus
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Hypercalcaemia
         subjects affected / exposed
    2 / 517 (0.39%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    2
    4
    0
    Hyperglycaemia
         subjects affected / exposed
    117 / 517 (22.63%)
    126 / 520 (24.23%)
    1 / 6 (16.67%)
         occurrences all number
    153
    153
    1
    Hyperkalaemia
         subjects affected / exposed
    25 / 517 (4.84%)
    41 / 520 (7.88%)
    1 / 6 (16.67%)
         occurrences all number
    28
    46
    1
    Hypermagnesaemia
         subjects affected / exposed
    5 / 517 (0.97%)
    14 / 520 (2.69%)
    0 / 6 (0.00%)
         occurrences all number
    5
    15
    0
    Hypernatraemia
         subjects affected / exposed
    7 / 517 (1.35%)
    16 / 520 (3.08%)
    1 / 6 (16.67%)
         occurrences all number
    7
    17
    1
    Hyperphosphataemia
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    3 / 517 (0.58%)
    6 / 520 (1.15%)
    0 / 6 (0.00%)
         occurrences all number
    3
    6
    0
    Hyperuricaemia
         subjects affected / exposed
    2 / 517 (0.39%)
    7 / 520 (1.35%)
    0 / 6 (0.00%)
         occurrences all number
    2
    7
    0
    Hypoalbuminaemia
         subjects affected / exposed
    24 / 517 (4.64%)
    25 / 520 (4.81%)
    0 / 6 (0.00%)
         occurrences all number
    26
    26
    0
    Hypocalcaemia
         subjects affected / exposed
    55 / 517 (10.64%)
    45 / 520 (8.65%)
    1 / 6 (16.67%)
         occurrences all number
    62
    51
    1
    Hypoglycaemia
         subjects affected / exposed
    3 / 517 (0.58%)
    4 / 520 (0.77%)
    0 / 6 (0.00%)
         occurrences all number
    3
    4
    0
    Hypokalaemia
         subjects affected / exposed
    169 / 517 (32.69%)
    191 / 520 (36.73%)
    1 / 6 (16.67%)
         occurrences all number
    261
    299
    1
    Hypomagnesaemia
         subjects affected / exposed
    17 / 517 (3.29%)
    9 / 520 (1.73%)
    0 / 6 (0.00%)
         occurrences all number
    20
    10
    0
    Hyponatraemia
         subjects affected / exposed
    59 / 517 (11.41%)
    65 / 520 (12.50%)
    1 / 6 (16.67%)
         occurrences all number
    71
    70
    1
    Hypophagia
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    43 / 517 (8.32%)
    58 / 520 (11.15%)
    0 / 6 (0.00%)
         occurrences all number
    52
    65
    0
    Tumour lysis syndrome
         subjects affected / exposed
    9 / 517 (1.74%)
    9 / 520 (1.73%)
    0 / 6 (0.00%)
         occurrences all number
    9
    9
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25092781
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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