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    Clinical Trial Results:
    An Open-Label, Randomized Phase 3 Study of Inotuzumab Ozogamicin Compared to a Defined Investigator’s Choice in Adult Patients with Relapsed or Refractory CD22-Positive Acute Lymphoblastic Leukemia (ALL)

    Summary
    EudraCT number
    2011-005491-41
    Trial protocol
    HU   CZ   SK   SE   ES   GB   DE   FI   IT   NL   BE  
    Global end of trial date
    04 Jan 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    03 Jan 2018
    First version publication date
    23 Mar 2017
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    B1931022
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01564784
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Jan 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study were to compare hematological remission rate (complete remission and complete remission with incomplete hematologic recovery), as assessed by the independent external Endpoint Adjudication Committee (EAC), and overall survival in participants with relapsed or refractory cluster of differentiation (CD) 22 positive B-cell ALL randomized to receive inotuzumab ozogamicin or Investigator’s choice of chemotherapy.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation Good Clinical Practice Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial participants. The final protocol, any amendments and informed consent documentation were reviewed and approved by the Institutional Review Board(s) and/or Independent Ethics Committee(s) at each of the investigational centres participating in the study.
    Background therapy
    -
    Evidence for comparator
    The choice of a comparator was complicated by the small participant population, the heterogeneity of the population, and the lack of an appropriate universal comparator. In the salvage setting, multiple miscellaneous regimens are used ranging from single agents to combination therapies such as combinations with cytarabine (conventional or high-dose), hyper-cyclophosphamide, vincristine, doxorubicin and dexamethasone, combinations with methotrexate and/or asparaginase, etc. Participants with Philadelphia chromosome positive (Ph+) ALL are treated with combinations including tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib. In the second and later salvage settings, treatments used will depend on responses to the treatments used in the frontline and first salvage settings further complicating the choice of comparator in these multiply-treated participants. In the participant population eligible for this study, it was expected that most participants would have been treated with intensive combination chemotherapy including anthracyclines and that physicians would select therapies, such as those shown above, or experimental therapies based on the participant’s condition, prior therapies, as well as standard practice. Therefore, the comparator arm included a defined list of 3 induction chemotherapy regimens commonly used in relapsed and refractory ALL, from which the investigator chose the optimal regimen for the participant: fludarabine, cytarabine, granulocyte colony-stimulating factor (G-CSF) (FLAG); mitoxantrone and cytarabine (MXN/Ara-C); or, high dose cytarabine (HIDAC). To avoid potential bias the investigator must have chosen the treatment of choice before participant randomization.
    Actual start date of recruitment
    02 Aug 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    China: 12
    Country: Number of subjects enrolled
    Czech Republic: 7
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Italy: 26
    Country: Number of subjects enrolled
    Japan: 19
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 12
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Singapore: 3
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    United States: 149
    Country: Number of subjects enrolled
    Australia: 2
    Worldwide total number of subjects
    307
    EEA total number of subjects
    115
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    261
    From 65 to 84 years
    46
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Participants were screened locally for characterization of leukemia, including CD22 immunophenotyping (flow cytometry) from peripheral blood or bone marrow aspirate obtained within 28 days of randomization. If CD22 immunophenotyping was negative per local laboratory results, central results may have been used for determining eligibility.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Inotuzumab Ozogamicin
    Arm description
    Participants were treated with inotuzumab ozogamicin at a starting dose of 1.8 mg/m^2 (according to body surface area) per cycle with a divided-dose regimen using 3 weekly administrations. Participants received 0.8 mg/m^2/cycle on Week 1 (Day 1), followed by 0.5 mg/m^2 on Week 2 (Day 8) and Week 3 (Day 15) of a 21-day cycle, and administered as an intravenous infusion over 60 minutes. For participants who achieved a CR or CRi, or to allow recovery from toxicity, the length of Cycle 1 could be extended up to 28 days (ie, 1 week treatment-free interval starting on Day 21). For participants who achieved CR or CRi, the inotuzumab ozogamicin dose administered on Week 1 was reduced to 0.5 mg/m^2 (for a total cycle dose of 1.5 mg/m^2/cycle) for Cycles 2 through 6 (maximum number of cycles permitted). For Cycles 2 through 6, the cycle length was 28 days for all participants (regardless of remission status).
    Arm type
    Experimental

    Investigational medicinal product name
    Inotuzumab ozogamicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Inotuzumab ozogamicin was administered intravenously at a starting dose of 1.8 mg/m^2 (according to body surface area) per cycle with a divided-dose regimen using 3 weekly administrations. Participants received 0.8 mg/m^2/cycle on Week 1 (Day 1), followed by 0.5 mg/m^2 on Week 2 (Day 8) and Week 3 (Day 15) of a 21-day cycle, and administered as an intravenous infusion over 60 minutes. For participants who achieved a CR or CRi, or to allow recovery from toxicity, the length of Cycle 1 could be extended up to 28 days (ie, 1 week treatment-free interval starting on Day 21). For participants who achieved CR or CRi, the inotuzumab ozogamicin dose administered on Week 1 was reduced to 0.5 mg/m^2 (for a total cycle dose of 1.5 mg/m^2/cycle) for Cycles 2 through 6 (maximum number of cycles permitted). For Cycles 2 through 6, the cycle length was 28 days for all participants (regardless of remission status).

    Arm title
    Defined Investigator’s Choice of Chemotherapy
    Arm description
    Participants received fludarabine, cytarabine, granulocyte-colony stimulating factor (FLAG), mitoxantrone + cytarabine (MXN/Ara-C), or high-dose cytarabine (HIDAC), according to the Investigator’s choice.
    Arm type
    Active comparator

    Investigational medicinal product name
    Participants were treated with FLAG, MXN/Ara-C, or HIDAC, according to the Investigator’s choice.
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants treated with FLAG received cytarabine 2 g/m^2/day intravenous (IV) infusion over 4 hours on Day 1 (could be omitted per local standard of care), fludarabine 30 mg/m^2/day 30-minute IV infusion followed 4 hours later with cytarabine 2 g/m^2/day IV infusion over 4 hours on Days 2 to 6, and G-CSF 5 µg/kg/day or per local standard of care. Participants treated with MXN/Ara-C received mitoxantrone 12 mg/m^2 (dose could be reduced to 8 mg/m^2 based on participant age, comorbidities and prior anthracycline use) IV over 20 minutes on Day 1, cytarabine 200 mg/m^2/day continuous IV infusion over 7 days from Day 1 and mitoxantrone 12 mg/m^2 IV over 20 minutes on Days 2 to 3. Participants treated with HIDAC received cytarabine 3 g/m^2 IV over 1 to 3 hours every 12 hours for up to 12 doses starting on Day 1 of up to 6. For participants ≥55 years of age, the dose of cytarabine could be reduced up to 1.5 g/m^2. For participants over 60 years of age, the dose was reduced to 1.5 g/m^2.

    Number of subjects in period 1
    Inotuzumab Ozogamicin Defined Investigator’s Choice of Chemotherapy
    Started
    164
    143
    Completed
    30
    10
    Not completed
    134
    133
         Death
    131
    126
         Unspecified
    1
    -
         Subject refused further follow-up
    1
    6
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Inotuzumab Ozogamicin
    Reporting group description
    Participants were treated with inotuzumab ozogamicin at a starting dose of 1.8 mg/m^2 (according to body surface area) per cycle with a divided-dose regimen using 3 weekly administrations. Participants received 0.8 mg/m^2/cycle on Week 1 (Day 1), followed by 0.5 mg/m^2 on Week 2 (Day 8) and Week 3 (Day 15) of a 21-day cycle, and administered as an intravenous infusion over 60 minutes. For participants who achieved a CR or CRi, or to allow recovery from toxicity, the length of Cycle 1 could be extended up to 28 days (ie, 1 week treatment-free interval starting on Day 21). For participants who achieved CR or CRi, the inotuzumab ozogamicin dose administered on Week 1 was reduced to 0.5 mg/m^2 (for a total cycle dose of 1.5 mg/m^2/cycle) for Cycles 2 through 6 (maximum number of cycles permitted). For Cycles 2 through 6, the cycle length was 28 days for all participants (regardless of remission status).

    Reporting group title
    Defined Investigator’s Choice of Chemotherapy
    Reporting group description
    Participants received fludarabine, cytarabine, granulocyte-colony stimulating factor (FLAG), mitoxantrone + cytarabine (MXN/Ara-C), or high-dose cytarabine (HIDAC), according to the Investigator’s choice.

    Reporting group values
    Inotuzumab Ozogamicin Defined Investigator’s Choice of Chemotherapy Total
    Number of subjects
    164 143 307
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    134 127 261
        From 65-84 years
    30 16 46
        85 years and over
    0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    45.9 ± 17.07 45.6 ± 16.32 -
    Gender, Male/Female
    Units: Subjects
        Female
    73 51 124
        Male
    91 92 183

    End points

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    End points reporting groups
    Reporting group title
    Inotuzumab Ozogamicin
    Reporting group description
    Participants were treated with inotuzumab ozogamicin at a starting dose of 1.8 mg/m^2 (according to body surface area) per cycle with a divided-dose regimen using 3 weekly administrations. Participants received 0.8 mg/m^2/cycle on Week 1 (Day 1), followed by 0.5 mg/m^2 on Week 2 (Day 8) and Week 3 (Day 15) of a 21-day cycle, and administered as an intravenous infusion over 60 minutes. For participants who achieved a CR or CRi, or to allow recovery from toxicity, the length of Cycle 1 could be extended up to 28 days (ie, 1 week treatment-free interval starting on Day 21). For participants who achieved CR or CRi, the inotuzumab ozogamicin dose administered on Week 1 was reduced to 0.5 mg/m^2 (for a total cycle dose of 1.5 mg/m^2/cycle) for Cycles 2 through 6 (maximum number of cycles permitted). For Cycles 2 through 6, the cycle length was 28 days for all participants (regardless of remission status).

    Reporting group title
    Defined Investigator’s Choice of Chemotherapy
    Reporting group description
    Participants received fludarabine, cytarabine, granulocyte-colony stimulating factor (FLAG), mitoxantrone + cytarabine (MXN/Ara-C), or high-dose cytarabine (HIDAC), according to the Investigator’s choice.

    Subject analysis set title
    Inotuzumab Ozogamicin
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants were treated with inotuzumab ozogamicin at a starting dose of 1.8 mg/m^2 (according to body surface area) per cycle with a divided-dose regimen using 3 weekly administrations. Participants received 0.8 mg/m^2/cycle on Week 1 (Day 1), followed by 0.5 mg/m^2 on Week 2 (Day 8) and Week 3 (Day 15) of a 21-day cycle, and administered as an intravenous infusion over 60 minutes. For participants who achieved a CR or CRi, or to allow recovery from toxicity, the length of Cycle 1 could be extended up to 28 days (ie, 1 week treatment-free interval starting on Day 21). For participants who achieved CR or CRi, the inotuzumab ozogamicin dose administered on Week 1 was reduced to 0.5 mg/m^2 (for a total cycle dose of 1.5 mg/m^2/cycle) for Cycles 2 through 6 (maximum number of cycles permitted). For Cycles 2 through 6, the cycle length was 28 days for all participants (regardless of remission status).

    Subject analysis set title
    Defined Investigator’s Choice of Chemotherapy
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received fludarabine, cytarabine, granulocyte-colony stimulating factor (FLAG), mitoxantrone + cytarabine (MXN/Ara-C), or high-dose cytarabine (HIDAC), according to the Investigator’s choice.

    Subject analysis set title
    Defined Investigator’s Choice of Chemotherapy
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received fludarabine, cytarabine, granulocyte-colony stimulating factor (FLAG), mitoxantrone + cytarabine (MXN/Ara-C), or high-dose cytarabine (HIDAC), according to the Investigator’s choice.

    Primary: Percentage of Participants with Hematologic Remission (complete remission [CR]/complete remission with incomplete hematologic recovery [CRi]) as Assessed by the EAC

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    End point title
    Percentage of Participants with Hematologic Remission (complete remission [CR]/complete remission with incomplete hematologic recovery [CRi]) as Assessed by the EAC
    End point description
    CR was disappearance of leukemia indicated by <5 % marrow blasts & absence of peripheral blood leukemic blasts, with recovery of hematopoiesis defined by absolute neutrophil count (ANC) ≥1000/μL & platelets ≥100,000/μL. C1 extramedullary disease status (i.e. complete disappearance of measurable/non-measurable extramedullary disease with the following exceptions: for participants with at least 1 measurable lesion, all nodal masses >1.5 cm in greatest transverse diameter (GTD) at baseline must have regressed to ≤1.5 cm in GTD; all nodal masses ≥1 cm & ≤1.5 cm in GTD at baseline must have regressed to <1 cm GTD or reduced by 75% in sum of products of greatest diameters, no new lesions, spleen/other previously enlarged organs must have regressed in size & not be palpable) was required. CRi was defined as CR except ANC <1000/μL &/or platelets <100,000/μL. ITT218 population - included the intention-to-treat (ITT) population (all participants randomized) for the initial 218 participants.
    End point type
    Primary
    End point timeframe
    Screening, Day 16 to 28 of Cycles 1, 2 and 3, then every 1 to 2 cycles (or as clinically indicated) up to approximately 4 weeks (end of treatment [EoT]) from the last dose
    End point values
    Inotuzumab Ozogamicin Defined Investigator’s Choice of Chemotherapy
    Number of subjects analysed
    109
    109
    Units: Percentage of Participants
        number (confidence interval 95%)
    80.7 (72.1 to 87.7)
    29.4 (21.0 to 38.8)
    Statistical analysis title
    Statistical Analysis of CR/CRi
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    1-sided p-value based on Chi-square test
    Parameter type
    Rate difference
    Point estimate
    51.4
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    38.4
         upper limit
    64.3

    Primary: Overall Survival (OS)

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    End point title
    Overall Survival (OS) [1]
    End point description
    OS was defined as the time from randomization to date of death due to any cause. Participants last known to be alive were censored at date of last contact.
    End point type
    Primary
    End point timeframe
    Up to 5 years after randomization or 2 years from randomization of the last participant, whichever occurs first. Analysis population = ITT population - included all participants randomized.
    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 baseline period arm for Defined Investigator’s Choice of Chemotherapy includes only those participants treated (i.e. the safety population). This outcome measure was analyzed for all participants randomized (i.e. the intention-to-treat [ITT] population).
    End point values
    Inotuzumab Ozogamicin Defined Investigator’s Choice of Chemotherapy
    Number of subjects analysed
    164
    162
    Units: Months
        median (confidence interval 95%)
    7.7 (6.0 to 9.2)
    6.2 (4.7 to 8.3)
    Statistical analysis title
    Statistical Analysis of OS
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0105
    Method
    1-sided stratified log-rank p-value
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.751
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    0.568
         upper limit
    0.993

    Secondary: Duration of Remission (DoR) for Participants Who Achieved CR/CRi (per Investigator Assessment)

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    End point title
    Duration of Remission (DoR) for Participants Who Achieved CR/CRi (per Investigator Assessment)
    End point description
    DoR was defined as time from date of first response in responders (CR/CRi per Investigator assessment) to date of PFS event (i.e. death, progressive disease [objective progression, relapse from CR/CRi or treatment discontinuation due to global deterioration of health status] or starting new induction therapy or post-therapy stem cell transplant [SCT] without achieving CR/CRi). Responders without PFS events were censored at the last valid disease assessment including follow-up. Analysis population = participants in the ITT218 population who achieved CR/CRi
    End point type
    Secondary
    End point timeframe
    Up to 2 years from randomization
    End point values
    Inotuzumab Ozogamicin Defined Investigator’s Choice of Chemotherapy
    Number of subjects analysed
    85
    32
    Units: Months
        median (confidence interval 95%)
    5.4 (4.3 to 8.0)
    3.5 (2.2 to 6.6)
    Statistical analysis title
    Statistical Analysis of DoR
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0021
    Method
    1-sided stratified log-rank p-value
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.297
         upper limit
    0.809

    Secondary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS) [2]
    End point description
    PFS was defined as time from date of randomization to earliest date of the following events: death, progressive disease (objective progression, relapse from CR/CRi or treatment discontinuation due to global deterioration of health status) & starting new induction therapy or post-therapy SCT without achieving CR/CRi. Participants without a PFS event at time of analysis were censored at the last valid disease assessment. In addition, participants with documentation of an event after an unacceptably long interval (>28 weeks if there was post-baseline disease assessment, or >12 weeks if there was no post-baseline assessment) since the previous disease assessment were censored at the time of the previous assessment (date of randomization if no post-baseline assessment). Post-study treatment follow-up disease assessments was included. Kaplan–Meier method used & 2-sided 95% confidence interval (CI) calculated based on the Brookmeyer & Crowley method. Analysis population = ITT population.
    End point type
    Secondary
    End point timeframe
    Up to 2 years from randomization
    Notes
    [2] - 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 baseline period arm for Defined Investigator’s Choice of Chemotherapy includes only those participants treated (i.e. the safety population). This outcome measure was analyzed for all participants randomized (i.e. the intention-to-treat [ITT] population).
    End point values
    Inotuzumab Ozogamicin Defined Investigator’s Choice of Chemotherapy
    Number of subjects analysed
    164
    162
    Units: Months
        median (confidence interval 95%)
    5.0 (3.9 to 5.8)
    1.7 (1.4 to 2.1)
    Statistical analysis title
    Statistical Analysis of PFS
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    1-sided stratified log-rank p-value
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.45
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    0.336
         upper limit
    0.602

    Secondary: Percentage of Participants who had a Hematopoietic Stem-Cell Transplant (HSCT)

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    End point title
    Percentage of Participants who had a Hematopoietic Stem-Cell Transplant (HSCT) [3]
    End point description
    HSCT rate was defined as the percentage of participants who underwent SCT following treatment with inotuzumab ozogamicin or Investigator's choice of chemotherapy. Analysis population = ITT population.
    End point type
    Secondary
    End point timeframe
    From first dose date to start of post induction therapy
    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 baseline period arm for Defined Investigator’s Choice of Chemotherapy includes only those participants treated (i.e. the safety population). This outcome measure was analyzed for all participants randomized (i.e. the intention-to-treat [ITT] population).
    End point values
    Inotuzumab Ozogamicin Defined Investigator’s Choice of Chemotherapy
    Number of subjects analysed
    164
    162
    Units: Percentage of Participants
        number (confidence interval 95%)
    42.7 (35.0 to 50.6)
    11.1 (6.7 to 17.0)
    Statistical analysis title
    Statistical Analysis of HSCT
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    1-sided p-value based on Chi-square test
    Parameter type
    Rate difference
    Point estimate
    31.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    22.6
         upper limit
    40.6

    Secondary: Percentage of Participants Achieving MRD Negativity (Based on Central Laboratory Analysis) in Participants Achieving a CR/CRi (per EAC Assessment)

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    End point title
    Percentage of Participants Achieving MRD Negativity (Based on Central Laboratory Analysis) in Participants Achieving a CR/CRi (per EAC Assessment)
    End point description
    MRD analysis was performed at least once in participants with prior assessment of CR or CRi. Bone marrow aspirates, collected at screening and during the study, were sent to the central laboratory and analyzed using multiparametric flow cytometry. The antibody combinations were designed to maximize discrimination between normal and abnormal cells of B-cell lineage and similar maturational stage and included antibodies detecting cluster of differentiation (CD) 9, CD10, CD13, CD19, CD20, CD33, CD34, CD38, CD45, CD58, CD66c, and CD123. A peripheral blood sample was provided if a participant had an inadequate bone marrow aspirate at screening. MRD negativity was considered to have been achieved if the lowest value of MRD from the first date of CR/CRi to EoT was <1 × 10^-4 blasts/nucleated cells. Analysis population = participants in the ITT218 population achieving CR/CRi (per EAC Assessment).
    End point type
    Secondary
    End point timeframe
    Up to approximately 4 weeks (EoT) from last dose of study drug
    End point values
    Inotuzumab Ozogamicin Defined Investigator’s Choice of Chemotherapy
    Number of subjects analysed
    88
    32
    Units: Percentage of Participants
        number (confidence interval 95%)
    78.4 (68.4 to 86.5)
    28.1 (13.7 to 46.7)
    Statistical analysis title
    Statistical Analysis of MRD Negativity
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    1-sided p-value based on Chi-Square test
    Confidence interval

    Secondary: Cytogenetic Status (Based on Local Laboratory Analysis) of Participants with CR/CRi (per EAC Assessment)

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    End point title
    Cytogenetic Status (Based on Local Laboratory Analysis) of Participants with CR/CRi (per EAC Assessment)
    End point description
    Karyotyping was required locally, at screening and at least once during the study in participants who had abnormal cytogenetics at baseline and who achieved CR/CRi. Data presented below are for participants who achieved CR/CRi per EAC and had abnormal karyotype at screening. Analysis population = ITT218 population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 4 weeks (EoT) from last dose of study drug
    End point values
    Inotuzumab Ozogamicin Defined Investigator’s Choice of Chemotherapy
    Number of subjects analysed
    88 [4]
    32 [5]
    Units: Percentage of Participants
    number (confidence interval 95%)
        Abnormal at screening in CR/CRi subjects (Group 1)
    61.4 (50.4 to 71.6)
    68.8 (50.0 to 83.9)
        Abnormal after remission in Group 1 subjects
    3.7 (0.5 to 12.7)
    18.2 (5.2 to 40.3)
    Notes
    [4] - n = 54 for participants who achieved CR/CRi per EAC and had abnormal karyotype at screening.
    [5] - n = 22 for participants who achieved CR/CRi per EAC and had abnormal karyotype at screening.
    Statistical analysis title
    Statistical Analysis of Cytogenetics
    Statistical analysis description
    Abnormal after remission
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.216
    Method
    1-sided p-value based on Chi-Square test
    Confidence interval
    Statistical analysis title
    Statistical Analysis of Cytogenetics
    Statistical analysis description
    Abnormal at Screening
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.3168
    Method
    1-sided p-value based on Chi-Square test
    Confidence interval

    Secondary: Maximum Observed Inotuzumab Ozogamicin Serum Concentration (Cmax) and Pre-Dose Inotuzumab Ozogamicin Serum Concentration (Ctrough) Following Single (Cycle 1 Day 1) and Multiple (Cycle 4 Day 1) Dosing

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    End point title
    Maximum Observed Inotuzumab Ozogamicin Serum Concentration (Cmax) and Pre-Dose Inotuzumab Ozogamicin Serum Concentration (Ctrough) Following Single (Cycle 1 Day 1) and Multiple (Cycle 4 Day 1) Dosing [6]
    End point description
    Blood samples were collected and analyzed for inotuzumab ozogamicin serum concentrations using a validated high performance liquid chromatography with tandem mass spectrometry (HPLC/MS/MS) method with a lower limit of quantification of 1.0 nanograms per milliliter (ng/mL). Cmax was the maximum observed concentration occurring between 0-8 hours post-dose. Ctrough was the concentration prior to subsequent dose (pre-dose) occurring after 8 hours. n = number of observations (non-missing concentrations). Analysis population = Pharmacokinetic (PK) evaluable population - included all participants with available PK data.
    End point type
    Secondary
    End point timeframe
    Days 1, 4, 8, and 15 of Cycle 1, Days 1 and 8 of Cycle 2 and Day 1 of Cycle 4
    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: Only participants from the Inotuzumab Ozogamicin treatment arm were planned to be analyzed for this end point.
    End point values
    Inotuzumab Ozogamicin
    Number of subjects analysed
    163
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cmax (Cycle 1 Day 1, 1 hour post-dose) (n=128)
    211 ± 232
        Ctrough (Cycle 4 Day 1, pre-dose) (n=46)
    57.9 ± 29.8
        Cmax (Cycle 4 Day 1, 1 hour post-dose) (n=37)
    308 ± 362
    No statistical analyses for this end point

    Secondary: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 (EORTC QLQ-C30) Score

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    End point title
    Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 (EORTC QLQ-C30) Score [7]
    End point description
    This questionnaire is comprised of 30 questions in total. Within the 30 questions are 9 multi-item scales and 6 single-item measures. There are 5 functional scales; physical, role, cognitive, emotional and social, 3 symptom scales; fatigue, pain and nausea and vomiting, and also a global health status/quality of life (QOL) scale. There are 5 single item measures assessing additional symptoms commonly reported by cancer patients (loss of appetite, insomnia, constipation, diarrhea, and dyspnea) and a single item concerning perceived financial impact of the disease. 999 = not applicable (n=1), 9999 = not applicable (n=0). Analysis population = ITT population.
    End point type
    Secondary
    End point timeframe
    Day 1 of each cycle prior to dosing and EoT
    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 baseline period arm for Defined Investigator’s Choice of Chemotherapy includes only those participants treated (i.e. the safety population). This outcome measure was analyzed for all participants randomized (i.e. the intention-to-treat [ITT] population).
    End point values
    Inotuzumab Ozogamicin Defined Investigator’s Choice of Chemotherapy
    Number of subjects analysed
    164
    162
    Units: Score on a scale
    arithmetic mean (standard error)
        Physical Functioning C2D1
    0.48 ± 1.53
    0.32 ± 3.55
        Physical Functioning C3D1
    3.15 ± 1.97
    -13.33 ± 7.70
        Physical Functioning C4D1
    5.33 ± 2.84
    0.00 ± 999
        Physical Functioning C5D1
    11.52 ± 3.51
    9999 ± 9999
        Physical Functioning C6D1
    7.22 ± 5.94
    9999 ± 9999
        Physical Functioning EoT
    -3.38 ± 2.03
    -8.17 ± 2.67
        Role Functioning C2D1
    5.45 ± 2.79
    -1.59 ± 8.21
        Role Functioning C3D1
    11.81 ± 3.19
    -11.11 ± 5.56
        Role Functioning C4D1
    16.67 ± 5.47
    0.00 ± 999
        Role Functioning C5D1
    12.88 ± 6.10
    9999 ± 9999
        Role Functioning C6D1
    16.67 ± 11.42
    9999 ± 9999
        Role Functioning EoT
    1.32 ± 3.59
    -12.37 ± 4.09
        Emotional Functioning C2D1
    5.21 ± 1.76
    4.76 ± 6.77
        Emotional Functioning C3D1
    7.41 ± 1.85
    -19.44 ± 10.02
        Emotional Functioning C4D1
    5.69 ± 1.63
    0.00 ± 999
        Emotional Functioning C5D1
    6.82 ± 2.83
    9999 ± 9999
        Emotional Functioning C6D1
    2.78 ± 4.27
    9999 ± 9999
        Emotional Functioning EoT
    -0.91 ± 1.80
    4.35 ± 2.96
        Cognitive Functioning C2D1
    4.05 ± 1.47
    0.00 ± 3.98
        Cognitive Functioning C3D1
    5.79 ± 2.11
    -5.56 ± 14.70
        Cognitive Functioning C4D1
    4.58 ± 2.86
    16.67 ± 999
        Cognitive Functioning C5D1
    0.76 ± 4.17
    9999 ± 9999
        Cognitive Functioning C6D1
    -8.33 ± 2.51
    9999 ± 9999
        Cognitive Functioning EoT
    0.83 ± 1.82
    0.54 ± 2.89
        Social Functioning C2D1
    4.20 ± 2.46
    -2.38 ± 7.21
        Social Functioning C3D1
    5.56 ± 3.25
    -27.78 ± 20.03
        Social Functioning C4D1
    10.42 ± 4.95
    0.00 ± 999
        Social Functioning C5D1
    12.88 ± 6.00
    9999 ± 9999
        Social Functioning C6D1
    16.67 ± 5.03
    9999 ± 9999
        Social Functioning EoT
    1.82 ± 2.84
    -2.15 ± 4.78
        Global Health Status C2D1
    3.98 ± 2.03
    0.40 ± 4.62
        Global Health Status C3D1
    9.38 ± 3.15
    -16.67 ± 12.73
        Global Health Status C4D1
    11.25 ± 3.69
    8.33 ± 999
        Global Health Status C5D1
    8.71 ± 6.68
    9999 ± 9999
        Global Health Status C6D1
    0.69 ± 6.76
    9999 ± 9999
        Global Health Status EoT
    0.00 ± 2.83
    -0.40 ± 3.28
        Dyspnoea C2D1
    -5.41 ± 2.72
    -7.94 ± 6.47
        Dyspnoea C3D1
    -7.41 ± 3.24
    11.11 ± 11.11
        Dyspnoea C4D1
    -12.50 ± 4.25
    0.00 ± 999
        Dyspnoea C5D1
    -3.03 ± 6.55
    9999 ± 9999
        Dyspnoea C6D1
    -2.78 ± 6.43
    9999 ± 9999
        Dyspnoea EoT
    -2.31 ± 3.09
    0.54 ± 3.95
        Insomnia C2D1
    -2.40 ± 3.01
    1.59 ± 5.85
        Insomnia C3D1
    -9.26 ± 3.38
    0.00 ± 19.25
        Insomnia C4D1
    -7.50 ± 3.27
    0.00 ± 999
        Insomnia C5D1
    -4.55 ± 4.55
    9999 ± 9999
        Insomnia C6D1
    -11.11 ± 9.48
    9999 ± 9999
        Insomnia EoT
    -2.31 ± 3.09
    0.00 ± 3.91
        Appetite Loss C2D1
    -4.20 ± 2.83
    3.17 ± 7.24
        Appetite Loss C3D1
    -8.33 ± 4.31
    0.00 ± 0.00
        Appetite Loss C4D1
    -11.67 ± 5.54
    0.00 ± 999
        Appetite Loss C5D1
    -6.06 ± 7.80
    9999 ± 9999
        Appetite Loss C6D1
    2.78 ± 9.59
    9999 ± 9999
        Appetite Loss EoT
    -1.32 ± 3.54
    11.83 ± 4.41
        Constipation C2D1
    -1.21 ± 2.47
    0.00 ± 5.14
        Constipation C3D1
    0.47 ± 3.44
    0.00 ± 0.00
        Constipation C4D1
    -2.50 ± 3.66
    0.00 ± 999
        Constipation C5D1
    0.00 ± 5.37
    9999 ± 9999
        Constipation C6D1
    5.56 ± 5.56
    9999 ± 9999
        Constipation EoT
    2.64 ± 2.60
    -0.54 ± 2.71
        Diarrhoea C2D1
    -3.30 ± 2.17
    -1.59 ± 4.87
        Diarrhoea C3D1
    -5.09 ± 2.61
    -11.11 ± 11.11
        Diarrhoea C4D1
    -0.83 ± 3.27
    0.00 ± 999
        Diarrhoea C5D1
    -9.52 ± 4.68
    9999 ± 9999
        Diarrhoea C6D1
    -2.78 ± 4.95
    9999 ± 9999
        Diarrhoea EoT
    2.31 ± 1.89
    3.76 ± 3.35
        Financial Difficulties C2D1
    -1.80 ± 1.99
    0.00 ± 8.72
        Financial Difficulties C3D1
    0.47 ± 3.24
    0.00 ± 0.00
        Financial Difficulties C4D1
    -1.67 ± 3.37
    0.00 ± 999
        Financial Difficulties C5D1
    -3.03 ± 3.74
    9999 ± 9999
        Financial Difficulties C6D1
    -5.56 ± 3.75
    9999 ± 9999
        Financial Difficulties EoT
    0.33 ± 3.09
    2.19 ± 2.80
        Fatigue C2D1
    -4.10 ± 2.40
    5.82 ± 6.88
        Fatigue C3D1
    -8.33 ± 3.02
    22.22 ± 6.42
        Fatigue C4D1
    -9.17 ± 4.64
    -11.11 ± 999
        Fatigue C5D1
    -7.32 ± 5.61
    9999 ± 9999
        Fatigue C6D1
    0.00 ± 6.42
    9999 ± 9999
        Fatigue EoT
    -0.33 ± 2.66
    5.73 ± 3.27
        Nausea and Vomiting C2D1
    0.15 ± 2.16
    -0.79 ± 2.69
        Nausea and Vomiting C3D1
    -4.63 ± 2.80
    0.00 ± 0.00
        Nausea and Vomiting C4D1
    -3.33 ± 3.17
    -16.67 ± 999
        Nausea and Vomiting C5D1
    2.27 ± 2.96
    9999 ± 9999
        Nausea and Vomiting C6D1
    0.00 ± 2.90
    9999 ± 9999
        Nausea and Vomiting EoT
    -0.17 ± 2.33
    3.49 ± 2.43
        Pain C2D1
    -8.86 ± 2.71
    -7.14 ± 7.68
        Pain C3D1
    -8.56 ± 3.73
    -5.56 ± 14.70
        Pain C4D1
    -4.17 ± 3.81
    -33.33 ± 999
        Pain C5D1
    0.76 ± 7.48
    9999 ± 9999
        Pain C6D1
    -2.78 ± 9.59
    9999 ± 9999
        Pain EoT
    -1.98 ± 2.88
    -7.26 ± 3.75
    Statistical analysis title
    Statistical Analysis of EORTC QLQ-C30
    Statistical analysis description
    Physical Functioning
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0139
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    6.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.4
         upper limit
    12.3
    Statistical analysis title
    Statistical Analysis of EORTC QLQ-C30
    Statistical analysis description
    Role Functioning
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0065
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    11.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.2
         upper limit
    19.5
    Statistical analysis title
    Statistical Analysis of EORTC QLQ-C30
    Statistical analysis description
    Emotional Functioning
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.3307
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -2.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.9
         upper limit
    2.3
    Statistical analysis title
    Statistical Analysis of EORTC QLQ-C30
    Statistical analysis description
    Cognitive Functioning
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.1904
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    2.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    7
    Statistical analysis title
    Statistical Analysis of EORTC QLQ-C30
    Statistical analysis description
    Social Functioning
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0336
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    8.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    16.1
    Statistical analysis title
    Statistical Analysis of EORTC QLQ-C30
    Statistical analysis description
    Global Health Status
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.1572
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    4.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.7
         upper limit
    10.3
    Statistical analysis title
    Statistical Analysis of EORTC QLQ-C30
    Statistical analysis description
    Dyspnoea
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.1281
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -4.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.8
         upper limit
    1.4
    Statistical analysis title
    Statistical Analysis of EORTC QLQ-C30
    Statistical analysis description
    Insomnia
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.6207
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -1.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.7
         upper limit
    5.2
    Statistical analysis title
    Statistical Analysis of EORTC QLQ-C30
    Statistical analysis description
    Appetite Loss
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0193
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -8.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16
         upper limit
    -1.4
    Statistical analysis title
    Statistical Analysis of EORTC QLQ-C30
    Statistical analysis description
    Constipation
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.6249
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.4
         upper limit
    7.3
    Statistical analysis title
    Statistical Analysis of EORTC QLQ-C30
    Statistical analysis description
    Diarrhoea
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.1534
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.2
         upper limit
    1.1
    Statistical analysis title
    Statistical Analysis of EORTC QLQ-C30
    Statistical analysis description
    Financial Difficulties
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.4915
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.7
         upper limit
    4.7
    Statistical analysis title
    Statistical Analysis of EORTC QLQ-C30
    Statistical analysis description
    Fatigue
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.1789
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -4.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.8
         upper limit
    2
    Statistical analysis title
    Statistical Analysis of EORTC QLQ-C30
    Statistical analysis description
    Nausea and Vomiting
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.4578
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6
         upper limit
    2.7
    Statistical analysis title
    Statistical Analysis of EORTC QLQ-C30
    Statistical analysis description
    Pain
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.8428
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.3
         upper limit
    6

    Secondary: Change from Baseline inEuroQol Five Dimension Health Questionnaire (EQ-5D) Index Score

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    End point title
    Change from Baseline inEuroQol Five Dimension Health Questionnaire (EQ-5D) Index Score [8]
    End point description
    The EQ-5D self-report questionnaire is a standardized measure of health status developed by the EuroQoL Group. It consists of the EQ-5D descriptive system and a visual analogue scale (VAS), EQ-VAS. The EQ-5D descriptive system measures a participants’ health state on 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels, reflecting “no problems”, “some problems”, and “extreme problems”. The EQ-VAS records the respondent’s self-rated health on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. 999 = not applicable (n=1), 9999 = not applicable (n=0). Analysis population = ITT population.
    End point type
    Secondary
    End point timeframe
    Day 1 of each cycle prior to dosing and EoT
    Notes
    [8] - 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 baseline period arm for Defined Investigator’s Choice of Chemotherapy includes only those participants treated (i.e. the safety population). This outcome measure was analyzed for all participants randomized (i.e. the intention-to-treat [ITT] population).
    End point values
    Inotuzumab Ozogamicin Defined Investigator’s Choice of Chemotherapy
    Number of subjects analysed
    164
    162
    Units: Score on a scale
    arithmetic mean (standard error)
        Cycle 2, Day 1
    0.00 ± 0.02
    0.02 ± 0.03
        Cycle 3, Day 1
    0.01 ± 0.02
    -0.08 ± 0.08
        Cycle 4, Day 1
    0.04 ± 0.03
    0.00 ± 999
        Cycle 5, Day 1
    0.04 ± 0.04
    9999 ± 9999
        Cycle 6, Day 1
    0.03 ± 0.04
    9999 ± 9999
        EoT
    -0.01 ± 0.02
    -0.04 ± 0.02
    Statistical analysis title
    Statistical Analysis of EQ-5D
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.171
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    0.07

    Secondary: Change from Baseline in EQ-5D VAS

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    End point title
    Change from Baseline in EQ-5D VAS [9]
    End point description
    The EQ-5D self-report questionnaire is a standardized measure of health status developed by the EuroQoL Group. It consists of the EQ-5D descriptive system and a visual analogue scale (VAS), EQ-VAS. The EQ-5D descriptive system measures a participants’ health state on 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels, reflecting “no problems”, “some problems”, and “extreme problems”. The EQ-VAS records the respondent’s self-rated health on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. 999 = not applicable (n=1), 9999 = not applicable (n=0). Analysis population = ITT population.
    End point type
    Secondary
    End point timeframe
    Day 1 of each cycle prior to dosing and EoT
    Notes
    [9] - 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 baseline period arm for Defined Investigator’s Choice of Chemotherapy includes only those participants treated (i.e. the safety population). This outcome measure was analyzed for all participants randomized (i.e. the intention-to-treat [ITT] population).
    End point values
    Inotuzumab Ozogamicin Defined Investigator’s Choice of Chemotherapy
    Number of subjects analysed
    164
    162
    Units: Score on a scale
    arithmetic mean (standard error)
        Cycle 2, Day 1
    5.81 ± 2.14
    5.90 ± 4.21
        Cycle 3, Day 1
    8.13 ± 2.53
    19.67 ± 17.80
        Cycle 4, Day 1
    7.13 ± 3.37
    44.00 ± 999
        Cycle 5, Day 1
    7.62 ± 4.43
    9999 ± 9999
        Cycle 6, Day 1
    15.09 ± 9.14
    9999 ± 9999
        EoT
    4.62 ± 2.38
    -0.52 ± 2.88
    Statistical analysis title
    Statistical Analysis of EQ-5D VAS
    Comparison groups
    Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.1172
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    4.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    10.4

    Secondary: Percentage of Participants with Veno-Occlusive Liver Disease (VOD)/Sinusoidal Obstruction Syndrome (SOS) Following Post Study HSCT

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    End point title
    Percentage of Participants with Veno-Occlusive Liver Disease (VOD)/Sinusoidal Obstruction Syndrome (SOS) Following Post Study HSCT
    End point description
    VOD/SOS was defined as the occurrence of 2 out of the following 3 clinical criteria: 1) total serum bilirubin level >34 micromoles per liter (μmol/L) (>2.0 milligrams per deciliter [mg/dL]), 2) an increase in liver size from baseline or development of right upper quadrant pain of liver origin & 3) sudden weight gain >2.5% (eg, within a 72 hour period) because of fluid accumulation in the weeks following infusion of study drug or chemotherapy, or HSCT conditioning/preparative therapy, or development of ascites not present at baseline following such exposures AND the absence of other explanations for these signs & symptoms, OR development of bilirubin elevation, weight gain, or hepatomegaly plus histologic abnormalities on liver biopsy demonstrating hepatocyte necrosis in zone 3 of the liver acinus, sinusoidal fibrosis, & centrilobular hemorrhage, with or without fibrosis of the terminal hepatic venules. Analysis population = participants in the Safety population with post-study HSCT.
    End point type
    Secondary
    End point timeframe
    Up to 2 years from randomization After database lock, a fourth case of VOD/SOS was confirmed in the Defined Investigators Choice of Chemotherapy arm (approx. 3 months after last dose).This was not entered on the CRF & therefore, is not included below.
    End point values
    Inotuzumab Ozogamicin Defined Investigator’s Choice of Chemotherapy
    Number of subjects analysed
    79
    35
    Units: Percentage of Participants
        number (not applicable)
    22.8
    8.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs and non-serious AEs are summarised from Cycle 1 Day 1 up to 42 days after last dose, or any time after Cycle 1 Day1 (treatment-related). Deaths (fatal SAEs) are summarised up to 42 days after last dose.
    Adverse event reporting additional description
    An event may appear as both an AE & SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant & non-serious in another participant, or 1 participant may have experienced both a serious & non-serious event. Events were reported up to at least 28 days after last dose.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Inotuzumab Ozogamicin
    Reporting group description
    Participants were treated with inotuzumab ozogamicin at a starting dose of 1.8 mg/m^2 (according to body surface area) per cycle with a divided-dose regimen using 3 weekly administrations. Participants received 0.8 mg/m^2/cycle on Week 1 (Day 1), followed by 0.5 mg/m^2 on Week 2 (Day 8) and Week 3 (Day 15) of a 21-day cycle, and administered as an intravenous infusion over 60 minutes. For participants who achieved a CR or CRi, or to allow recovery from toxicity, the length of Cycle 1 could be extended up to 28 days (ie, 1 week treatment-free interval starting on Day 21). For participants who achieved CR or CRi, the inotuzumab ozogamicin dose administered on Week 1 was reduced to 0.5 mg/m^2 (for a total cycle dose of 1.5 mg/m^2/cycle) for Cycles 2 through 6 (maximum number of cycles permitted). For Cycles 2 through 6, the cycle length was 28 days for all patients (regardless of remission status).

    Reporting group title
    Defined Investigator’s Choice of Chemotherapy
    Reporting group description
    Patients received fludarabine, cytarabine, granulocyte-colony stimulating factor (FLAG), mitoxantrone + cytarabine (MXN/Ara-C), or high-dose cytarabine (HIDAC), according to the Investigator’s choice.

    Serious adverse events
    Inotuzumab Ozogamicin Defined Investigator’s Choice of Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    85 / 164 (51.83%)
    72 / 143 (50.35%)
         number of deaths (all causes)
    24
    16
         number of deaths resulting from adverse events
    4
    4
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 164 (0.00%)
    3 / 143 (2.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 164 (1.83%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
    Additional description: In the Safety Data Warehouse, events of 'disease progression' may have been coded to 2 preferred terms ('disease progression' and the particular malignancy, e.g. 'acute lymphocytic leukaemia).
         subjects affected / exposed
    8 / 164 (4.88%)
    5 / 143 (3.50%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
         deaths causally related to treatment / all
    1 / 11
    0 / 5
    Fatigue
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
    Additional description: In the 'Investigator Choice' treatment arm 'Multiple organ dysfunction syndrome' appears as a fatal event for 2 participants in the Safety Data Warehouse, but as fatal SAEs of 'Multi-organ failure' in the clinical database.
         subjects affected / exposed
    2 / 164 (1.22%)
    2 / 143 (1.40%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Pain
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 164 (3.05%)
    3 / 143 (2.10%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal stenosis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 164 (1.22%)
    6 / 143 (4.20%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 7
         deaths causally related to treatment / all
    1 / 2
    1 / 3
    Respiratory tract oedema
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 164 (0.61%)
    3 / 143 (2.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Headache
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    19 / 164 (11.59%)
    27 / 143 (18.88%)
         occurrences causally related to treatment / all
    14 / 23
    27 / 31
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    8 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 164 (0.00%)
    2 / 143 (1.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness unilateral
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 164 (1.83%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ileal perforation
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Large intestinal ulcer
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric haemorrhage
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    2 / 164 (1.22%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic vein thrombosis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 164 (0.00%)
    3 / 143 (2.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venoocclusive liver disease
    Additional description: After clinical database lock, a fourth case of VOD/SOS was confirmed in the Defined Investigators Choice of Chemotherapy arm in March 2013 (approximately 3 months after last dose). This was not entered on the CRF and therefore, is not included below.
         subjects affected / exposed
    23 / 164 (14.02%)
    3 / 143 (2.10%)
         occurrences causally related to treatment / all
    27 / 29
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone infarction
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Adenoviral upper respiratory infection
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    3 / 164 (1.83%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bacterial infection
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida infection
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 164 (1.22%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corona virus infection
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus chorioretinitis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis necroticans
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    2 / 164 (1.22%)
    2 / 143 (1.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 164 (0.61%)
    2 / 143 (1.40%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungaemia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Klebsiella infection
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 164 (0.61%)
    2 / 143 (1.40%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Necrotising fasciitis fungal
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    3 / 164 (1.83%)
    4 / 143 (2.80%)
         occurrences causally related to treatment / all
    1 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    10 / 164 (6.10%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    5 / 13
    0 / 0
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    0 / 164 (0.00%)
    3 / 143 (2.10%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pseudomonal bacteraemia
         subjects affected / exposed
    1 / 164 (0.61%)
    2 / 143 (1.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 164 (2.44%)
    10 / 143 (6.99%)
         occurrences causally related to treatment / all
    0 / 5
    4 / 12
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Septic embolus
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    3 / 164 (1.83%)
    3 / 143 (2.10%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Serratia bacteraemia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis fungal
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    2 / 164 (1.22%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Systemic mycosis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection fungal
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucormycosis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Inotuzumab Ozogamicin Defined Investigator’s Choice of Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    159 / 164 (96.95%)
    143 / 143 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 164 (5.49%)
    8 / 143 (5.59%)
         occurrences all number
    12
    8
    Hypotension
         subjects affected / exposed
    12 / 164 (7.32%)
    22 / 143 (15.38%)
         occurrences all number
    13
    27
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    14 / 164 (8.54%)
    14 / 143 (9.79%)
         occurrences all number
    20
    16
    Chest pain
         subjects affected / exposed
    3 / 164 (1.83%)
    9 / 143 (6.29%)
         occurrences all number
    3
    9
    Chills
         subjects affected / exposed
    18 / 164 (10.98%)
    17 / 143 (11.89%)
         occurrences all number
    21
    22
    Fatigue
         subjects affected / exposed
    41 / 164 (25.00%)
    24 / 143 (16.78%)
         occurrences all number
    76
    28
    Mucosal inflammation
         subjects affected / exposed
    6 / 164 (3.66%)
    19 / 143 (13.29%)
         occurrences all number
    7
    21
    Oedema peripheral
         subjects affected / exposed
    13 / 164 (7.93%)
    13 / 143 (9.09%)
         occurrences all number
    19
    16
    Pain
         subjects affected / exposed
    12 / 164 (7.32%)
    8 / 143 (5.59%)
         occurrences all number
    12
    10
    Pyrexia
         subjects affected / exposed
    49 / 164 (29.88%)
    57 / 143 (39.86%)
         occurrences all number
    76
    90
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    22 / 164 (13.41%)
    23 / 143 (16.08%)
         occurrences all number
    25
    28
    Dyspnoea
         subjects affected / exposed
    10 / 164 (6.10%)
    18 / 143 (12.59%)
         occurrences all number
    13
    20
    Epistaxis
         subjects affected / exposed
    24 / 164 (14.63%)
    12 / 143 (8.39%)
         occurrences all number
    27
    12
    Oropharyngeal pain
         subjects affected / exposed
    6 / 164 (3.66%)
    10 / 143 (6.99%)
         occurrences all number
    6
    10
    Pleural effusion
         subjects affected / exposed
    3 / 164 (1.83%)
    8 / 143 (5.59%)
         occurrences all number
    4
    8
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    8 / 164 (4.88%)
    11 / 143 (7.69%)
         occurrences all number
    8
    14
    Depression
         subjects affected / exposed
    4 / 164 (2.44%)
    9 / 143 (6.29%)
         occurrences all number
    4
    9
    Insomnia
         subjects affected / exposed
    24 / 164 (14.63%)
    22 / 143 (15.38%)
         occurrences all number
    24
    25
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    25 / 164 (15.24%)
    18 / 143 (12.59%)
         occurrences all number
    35
    26
    Aspartate aminotransferase increased
         subjects affected / exposed
    37 / 164 (22.56%)
    16 / 143 (11.19%)
         occurrences all number
    61
    23
    Blood alkaline phosphatase increased
         subjects affected / exposed
    21 / 164 (12.80%)
    10 / 143 (6.99%)
         occurrences all number
    28
    10
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    35 / 164 (21.34%)
    12 / 143 (8.39%)
         occurrences all number
    50
    12
    Lipase increased
         subjects affected / exposed
    15 / 164 (9.15%)
    1 / 143 (0.70%)
         occurrences all number
    31
    1
    White blood cell count decreased
         subjects affected / exposed
    10 / 164 (6.10%)
    9 / 143 (6.29%)
         occurrences all number
    18
    13
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    10 / 164 (6.10%)
    3 / 143 (2.10%)
         occurrences all number
    11
    3
    Fall
         subjects affected / exposed
    11 / 164 (6.71%)
    4 / 143 (2.80%)
         occurrences all number
    13
    5
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    6 / 164 (3.66%)
    16 / 143 (11.19%)
         occurrences all number
    6
    21
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    12 / 164 (7.32%)
    16 / 143 (11.19%)
         occurrences all number
    14
    17
    Headache
         subjects affected / exposed
    45 / 164 (27.44%)
    38 / 143 (26.57%)
         occurrences all number
    58
    45
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    54 / 164 (32.93%)
    79 / 143 (55.24%)
         occurrences all number
    155
    191
    Febrile neutropenia
         subjects affected / exposed
    27 / 164 (16.46%)
    52 / 143 (36.36%)
         occurrences all number
    33
    66
    Leukopenia
         subjects affected / exposed
    47 / 164 (28.66%)
    54 / 143 (37.76%)
         occurrences all number
    174
    119
    Lymphopenia
         subjects affected / exposed
    31 / 164 (18.90%)
    36 / 143 (25.17%)
         occurrences all number
    132
    77
    Neutropenia
         subjects affected / exposed
    79 / 164 (48.17%)
    66 / 143 (46.15%)
         occurrences all number
    245
    126
    Thrombocytopenia
         subjects affected / exposed
    80 / 164 (48.78%)
    86 / 143 (60.14%)
         occurrences all number
    286
    297
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 164 (0.61%)
    8 / 143 (5.59%)
         occurrences all number
    1
    8
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    10 / 164 (6.10%)
    2 / 143 (1.40%)
         occurrences all number
    14
    3
    Abdominal pain
         subjects affected / exposed
    19 / 164 (11.59%)
    26 / 143 (18.18%)
         occurrences all number
    23
    29
    Abdominal pain upper
         subjects affected / exposed
    11 / 164 (6.71%)
    12 / 143 (8.39%)
         occurrences all number
    12
    12
    Constipation
         subjects affected / exposed
    28 / 164 (17.07%)
    34 / 143 (23.78%)
         occurrences all number
    31
    39
    Diarrhoea
         subjects affected / exposed
    30 / 164 (18.29%)
    55 / 143 (38.46%)
         occurrences all number
    34
    67
    Dyspepsia
         subjects affected / exposed
    3 / 164 (1.83%)
    9 / 143 (6.29%)
         occurrences all number
    3
    11
    Nausea
         subjects affected / exposed
    52 / 164 (31.71%)
    68 / 143 (47.55%)
         occurrences all number
    72
    89
    Stomatitis
         subjects affected / exposed
    5 / 164 (3.05%)
    9 / 143 (6.29%)
         occurrences all number
    6
    12
    Vomiting
         subjects affected / exposed
    25 / 164 (15.24%)
    35 / 143 (24.48%)
         occurrences all number
    41
    39
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    35 / 164 (21.34%)
    23 / 143 (16.08%)
         occurrences all number
    66
    42
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    7 / 164 (4.27%)
    9 / 143 (6.29%)
         occurrences all number
    9
    10
    Pruritus
         subjects affected / exposed
    8 / 164 (4.88%)
    10 / 143 (6.99%)
         occurrences all number
    9
    11
    Rash
         subjects affected / exposed
    14 / 164 (8.54%)
    27 / 143 (18.88%)
         occurrences all number
    15
    32
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    3 / 164 (1.83%)
    10 / 143 (6.99%)
         occurrences all number
    3
    10
    Arthralgia
         subjects affected / exposed
    9 / 164 (5.49%)
    7 / 143 (4.90%)
         occurrences all number
    10
    7
    Back pain
         subjects affected / exposed
    16 / 164 (9.76%)
    10 / 143 (6.99%)
         occurrences all number
    20
    10
    Pain in extremity
         subjects affected / exposed
    13 / 164 (7.93%)
    16 / 143 (11.19%)
         occurrences all number
    14
    19
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    4 / 164 (2.44%)
    13 / 143 (9.09%)
         occurrences all number
    4
    14
    Pneumonia
         subjects affected / exposed
    4 / 164 (2.44%)
    12 / 143 (8.39%)
         occurrences all number
    5
    13
    Sinusitis
         subjects affected / exposed
    4 / 164 (2.44%)
    8 / 143 (5.59%)
         occurrences all number
    5
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    19 / 164 (11.59%)
    18 / 143 (12.59%)
         occurrences all number
    23
    25
    Fluid overload
         subjects affected / exposed
    2 / 164 (1.22%)
    8 / 143 (5.59%)
         occurrences all number
    2
    8
    Hyperglycaemia
         subjects affected / exposed
    11 / 164 (6.71%)
    12 / 143 (8.39%)
         occurrences all number
    19
    19
    Hypoalbuminaemia
         subjects affected / exposed
    10 / 164 (6.10%)
    7 / 143 (4.90%)
         occurrences all number
    13
    14
    Hypocalcaemia
         subjects affected / exposed
    11 / 164 (6.71%)
    15 / 143 (10.49%)
         occurrences all number
    19
    29
    Hypokalaemia
         subjects affected / exposed
    25 / 164 (15.24%)
    33 / 143 (23.08%)
         occurrences all number
    37
    49
    Hypomagnesaemia
         subjects affected / exposed
    10 / 164 (6.10%)
    12 / 143 (8.39%)
         occurrences all number
    13
    14
    Hyponatraemia
         subjects affected / exposed
    5 / 164 (3.05%)
    9 / 143 (6.29%)
         occurrences all number
    8
    13
    Hypophosphataemia
         subjects affected / exposed
    9 / 164 (5.49%)
    10 / 143 (6.99%)
         occurrences all number
    10
    19

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Apr 2012
    Inclusion and exclusion criteria were added or modified. The assessment of bone marrow biopsies was only required for patients with inadequate hematologic recovery. Patient follow-up time for survival was extended. Requirement for effective contraception was extended to 90 days post therapy. Redundant/unnecessary laboratory tests were removed. Administrative corrections and clarifications were made throughout the protocol.
    24 Jun 2013
    Removed time to progression as a secondary endpoint. Dose of inotuzumab ozogamicin was reduced to 0.5 mg/m^2 at Day 1 of Cycle 2 and beyond in patients achieving either CR or CRi. Revised sites required for study completion from 100 to 190. Changed the statistical power for testing CR/CRi from 88 to 89%. Allowed immunohistochemistry for the determination of CD22 expression at screening in patients with inadequate bone marrow aspirate and no circulating blasts. Added collection of an additional bone marrow sample for analysis of leukemic blast phenotype/genotype by other test methods. Changed the timing of disease assessment to allow bone marrow recovery for patients in the control arm. Updated background information with clinical data for inotuzumab ozogamicin from prior/ongoing studies in patients with relapsed or refractory ALL. Revised and clarified some inclusion/exclusion criteria. Updated study drug administration tables. Modified dose reduction schema to allow for drug related toxicities in the inotuzumab ozogamicin arm. Updated section on destruction of partially used or empty drug vials. Clarified disease assessment including time of radiographic assessment and bone marrow biopsy. Updated SAE reporting section. Added additional details on the sample size calculation. Implemented administrative corrections and clarifications throughout the protocol.
    28 Mar 2014
    Updated the inotuzumab ozogamicin clinical background section. Increased the total sample size from 292 to 325 patients due to higher number of patients in the control arm withdrawing from treatment before start of chemotherapy than initially anticipated and loss of follow-up data in the control arm. Capped the percentage of patients with Ph+ ALL that had failed TKI-based therapies at approximately 20% of the study patient population to reflect the relapsed and refractory ALL adult population. Clarified recommendations to reduce the risk of VOD/SOS for patients proceeding to HSCT; these recommendations included avoidance of hepatotoxic myeloablative regimens for subsequent HSCT and limiting the number of cycles of inotuzumab ozogamicin treatment in patients proceeding to HSCT. Modified CD22 immunophenotyping performed at screening such that patients were eligible for the study if they were considered to be CD22-positive based on assessment by the central laboratory even if they were considered to be CD22-negative based on assessment by the local laboratory. Added requirement for medications used as prophylaxis for hepatotoxicities or for the treatment of VOD/SOS to be reported for up to 2 years from randomization. Implemented administrative corrections and clarifications throughout the protocol.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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