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    Clinical Trial Results:
    Phase 1/2 Study of TAK-981 in Combination With Rituximab in Patients With Relapsed/Refractory CD20-Positive Non-Hodgkin Lymphoma

    Summary
    EudraCT number
    		 2020-003946-36
    Trial protocol
    		 FR   DE   ES   IT  
    Global end of trial date
    26 Apr 2023

    Results information
    Results version number
    		 v1
    This version publication date
    11 Apr 2024
    First version publication date
    11 Apr 2024
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TAK-981-1501
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04074330
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    95 Hayden Avenue, Lexington, United States, MA 02421
    Public contact
    Study Director, Takeda, TrialDisclosures@takeda.com
    Scientific contact
    Study Director, Takeda, TrialDisclosures@takeda.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
    26 Apr 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Apr 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study is to determine the safety and tolerability of TAK-981 in combination with rituximab in participants with r/r NHL.
    Protection of trial subjects
    Each participant signed an informed consent form before participating in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Oct 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Japan: 4
    Country: Number of subjects enrolled
    United States: 24
    Worldwide total number of subjects
    38
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    17
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants took part in the study at 12 investigative sites in the United States, Canada, and Japan from 15 October 2019 to 26 April 2023.

    Pre-assignment
    Screening details
    		 Participants with a diagnosis of Non-Hodgkin Lymphoma were enrolled in this study consisting of Phase 1 (Dose Escalation), Phase 2 (Dose Expansion) and Japan-Specific lead-in cohort wherein participants to receive TAK-981 and rituximab.

    Period 1
    Period 1 title
    Dose Escalation (up to 19.36 months)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase 1: TAK-981 10mg QW
    Arm description
    		 Participants with indolent or aggressive non-Hodgkin lymphoma (NHL) received TAK-981 10 mg, infusion, intravenously (IV), once weekly (QW) on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 milligram per square meter (mg/m^2), infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or disease progression (PD) or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Investigational medicinal product name
    TAK-981
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    TAK-981 was administered on Days 1 and 8 every 21 days in each 21-day treatment cycle.

    Arm title
    		 Phase 1: TAK-981 40mg QW
    Arm description
    		 Participants with indolent or aggressive NHL received TAK-981 40 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Investigational medicinal product name
    TAK-981
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    TAK-981 was administered on Days 1 and 8 every 21 days in each 21-day treatment cycle.

    Arm title
    		 Phase 1: TAK-981 60mg QW
    Arm description
    		 Participants with indolent or aggressive NHL received TAK-981 60 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Investigational medicinal product name
    TAK-981
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    TAK-981 was administered on Days 1 and 8 every 21 days in each 21-day treatment cycle.

    Arm title
    		 Phase 1: TAK-981 90mg QW
    Arm description
    		 Participants with indolent or aggressive NHL received TAK-981 90 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Investigational medicinal product name
    TAK-981
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    TAK-981 was administered on Days 1 and 8 every 21 days in each 21-day treatment cycle.

    Arm title
    		 Phase 1: TAK-981 90mg BIW
    Arm description
    		 Participants with indolent or aggressive NHL received TAK-981 90 mg, infusion, IV, BIW on Days 1, 4, 8, and 11 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Investigational medicinal product name
    TAK-981
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    TAK-981 was administered on Days 1, 4, 8, and 11 every 21 days in each 21-day treatment cycle.

    Arm title
    		 Phase 1: TAK-981 120mg QW
    Arm description
    		 Participants with indolent or aggressive NHL received TAK-981 120 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Investigational medicinal product name
    TAK-981
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    TAK-981 was administered on Days 1 and 8 every 21 days in each 21-day treatment cycle.

    Arm title
    		 Japan Lead-in: TAK-981 60mg QW
    Arm description
    		 Japanese participants with indolent or aggressive NHL received TAK-981 60 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Investigational medicinal product name
    TAK-981
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    TAK-981 was administered on Days 1 and 8 every 21 days in each 21-day treatment cycle.

    Arm title
    		 Japan Lead-in: TAK-981 60mg BIW
    Arm description
    		 Japanese participants with indolent or aggressive NHL received TAK-981 60 mg, infusion, IV, BIW on Days 1, 4, 8, and 11 every 21 days in each 21-day treatment cycle for up to 12 months or PD or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TAK-981
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    TAK-981 was administered on Days 1, 4, 8, and 11 every 21 days in each 21-day treatment cycle.

    Number of subjects in period 1 [1]
    		Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 60mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW Japan Lead-in: TAK-981 60mg QW Japan Lead-in: TAK-981 60mg BIW
    Started
    3
    4
    3
    7
    8
    6
    1
    3
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    3
    4
    3
    7
    8
    6
    1
    3
         Adverse event, serious fatal
    -
    2
    -
    1
    4
    1
    -
    -
         Consent withdrawn by subject
    1
    1
    1
    -
    2
    1
    -
    -
         Progressive Disease
    2
    -
    -
    5
    2
    2
    1
    2
         Site Terminated by Sponsor
    -
    -
    -
    -
    -
    1
    -
    1
         Start of New Systemic Treatment
    -
    -
    1
    -
    -
    -
    -
    -
         Reason not Specified
    -
    1
    1
    1
    -
    1
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of participants analysed are the participants available for analyses in dose escalation period.
    Period 2
    Period 2 title
    Dose Expansion (up to 42 months)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Phase 2 (A): TAK-981 120 mg
    Arm description
    		 Participants with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) received TAK-981 120 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab infusion, intravenously, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Investigational medicinal product name
    TAK-981
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    TAK-981 was administered on Days 1 and 8 every 21 days in each 21-day treatment cycle.

    Arm title
    		 Phase 2 (C): TAK-981 120 mg
    Arm description
    		 Participants with follicular lymphoma (FL) received TAK-981 120 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab infusion, intravenously, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Investigational medicinal product name
    TAK-981
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    TAK-981 was administered on Days 1 and 8 every 21 days in each 21-day treatment cycle.

    Number of subjects in period 2
    		Phase 2 (A): TAK-981 120 mg Phase 2 (C): TAK-981 120 mg
    Started
    2
    1
    Completed
    0
    0
    Not completed
    2
    1
         Adverse event, serious fatal
    1
    -
         Study Terminated by Sponsor
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1: TAK-981 10mg QW
    Reporting group description
    		 Participants with indolent or aggressive non-Hodgkin lymphoma (NHL) received TAK-981 10 mg, infusion, intravenously (IV), once weekly (QW) on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 milligram per square meter (mg/m^2), infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or disease progression (PD) or unacceptable toxicity.

    Reporting group title
    Phase 1: TAK-981 40mg QW
    Reporting group description
    		 Participants with indolent or aggressive NHL received TAK-981 40 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Phase 1: TAK-981 60mg QW
    Reporting group description
    		 Participants with indolent or aggressive NHL received TAK-981 60 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Phase 1: TAK-981 90mg QW
    Reporting group description
    		 Participants with indolent or aggressive NHL received TAK-981 90 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Phase 1: TAK-981 90mg BIW
    Reporting group description
    		 Participants with indolent or aggressive NHL received TAK-981 90 mg, infusion, IV, BIW on Days 1, 4, 8, and 11 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Phase 1: TAK-981 120mg QW
    Reporting group description
    		 Participants with indolent or aggressive NHL received TAK-981 120 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Japan Lead-in: TAK-981 60mg QW
    Reporting group description
    		 Japanese participants with indolent or aggressive NHL received TAK-981 60 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Japan Lead-in: TAK-981 60mg BIW
    Reporting group description
    		 Japanese participants with indolent or aggressive NHL received TAK-981 60 mg, infusion, IV, BIW on Days 1, 4, 8, and 11 every 21 days in each 21-day treatment cycle for up to 12 months or PD or unacceptable toxicity.

    Reporting group values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 60mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW Japan Lead-in: TAK-981 60mg QW Japan Lead-in: TAK-981 60mg BIW Total
    Number of subjects
    		 3 4 3 7 8 6 1 3
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 64.0 (56.0 to 77.0) 69.3 (60.0 to 80.0) 73.0 (67.0 to 79.0) 57.7 (29.0 to 65.0) 64.8 (46.0 to 78.0) 58.8 (35.0 to 79.0) 61.0 (61.0 to 61.0) 70.3 (68.0 to 72.0) -
    Gender categorical
    Units: Subjects
        Female
    		 1 1 1 2 2 1 1 3 12
        Male
    		 2 3 2 5 6 5 0 0 23
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0 0 0
        Asian
    		 0 1 0 0 0 0 1 3 5
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0 0 0
        Black or African American
    		 0 0 0 0 1 0 0 0 1
        White
    		 3 3 3 7 6 6 0 0 28
        More than one race
    		 0 0 0 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 1 0 0 0 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 0 0 0 0 0
        Not Hispanic or Latino
    		 3 4 2 7 7 6 1 3 33
        Unknown or Not Reported
    		 0 0 1 0 1 0 0 0 2

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Phase 1: TAK-981 10mg QW
    Reporting group description
    		 Participants with indolent or aggressive non-Hodgkin lymphoma (NHL) received TAK-981 10 mg, infusion, intravenously (IV), once weekly (QW) on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 milligram per square meter (mg/m^2), infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or disease progression (PD) or unacceptable toxicity.

    Reporting group title
    Phase 1: TAK-981 40mg QW
    Reporting group description
    		 Participants with indolent or aggressive NHL received TAK-981 40 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Phase 1: TAK-981 60mg QW
    Reporting group description
    		 Participants with indolent or aggressive NHL received TAK-981 60 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Phase 1: TAK-981 90mg QW
    Reporting group description
    		 Participants with indolent or aggressive NHL received TAK-981 90 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Phase 1: TAK-981 90mg BIW
    Reporting group description
    		 Participants with indolent or aggressive NHL received TAK-981 90 mg, infusion, IV, BIW on Days 1, 4, 8, and 11 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Phase 1: TAK-981 120mg QW
    Reporting group description
    		 Participants with indolent or aggressive NHL received TAK-981 120 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Japan Lead-in: TAK-981 60mg QW
    Reporting group description
    		 Japanese participants with indolent or aggressive NHL received TAK-981 60 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Japan Lead-in: TAK-981 60mg BIW
    Reporting group description
    		 Japanese participants with indolent or aggressive NHL received TAK-981 60 mg, infusion, IV, BIW on Days 1, 4, 8, and 11 every 21 days in each 21-day treatment cycle for up to 12 months or PD or unacceptable toxicity.
    Reporting group title
    Phase 2 (A): TAK-981 120 mg
    Reporting group description
    		 Participants with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) received TAK-981 120 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab infusion, intravenously, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Phase 2 (C): TAK-981 120 mg
    Reporting group description
    		 Participants with follicular lymphoma (FL) received TAK-981 120 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab infusion, intravenously, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Subject analysis set title
    Phase 1 + Japan Lead-in: TAK-981 60mg QW
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PK analysis set consisted of participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Overall number of participants analyzed is the number of participants available for analysis. Number of participants analyzed is the number of participants available for analysis during the specified time-point.

    Primary: Phase 1: Number of Participants With One or More Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Phase 1: Number of Participants With One or More Treatment-Emergent Adverse Events (TEAEs) [1] [2]
    End point description
    Adverse event (AE) means any untoward medical occurrence in a participant administered a pharmaceutical product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product. A TEAE was defined as an adverse event which occurred on or after the first dose of study drug and no more than 30 days after the last dose of study drug. Safety Analysis Set consisted of participants who have received at least 1 dose, even if incomplete, of study drug.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive data was collected and analysed only for Phase 1 arms.
    [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: Descriptive data was collected and analysed only for Phase 1 arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 60mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW
    Number of subjects analysed
    3
    4
    3
    7
    8
    6
    Units: participants
    3
    4
    3
    6
    8
    6
    No statistical analyses for this end point

    Primary: Phase 1: Number of Participants With Grade 3 or Higher TEAEs

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    End point title
    		 Phase 1: Number of Participants With Grade 3 or Higher TEAEs [3] [4]
    End point description
    AE means any untoward medical occurrence in a participant administered a pharmaceutical product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product whether or not it is related to the medicinal product. A TEAE was defined as an adverse event which occurred on or after the first dose of study drug and no more than 30 days after the last dose of study drug. A severity grade was evaluated as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0, except for Cytokine Release Syndrome (CRS), which was assessed by American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading criteria. Safety Analysis Set consisted of participants who have received at least 1 dose, even if incomplete, of study drug.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive data was collected and analysed only for Phase 1 arms.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive data was collected and analysed only for Phase 1 arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 60mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW
    Number of subjects analysed
    3
    4
    3
    7
    8
    6
    Units: participants
    1
    4
    1
    2
    7
    3
    No statistical analyses for this end point

    Primary: Phase 1: Duration of TEAEs

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    End point title
    		 Phase 1: Duration of TEAEs [5] [6]
    End point description
    AE means any untoward medical occurrence in a participant administered a pharmaceutical product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product whether or not it is related to the medicinal product. A TEAE was defined as an adverse event which occurred on or after the first dose of study drug and no more than 30 days after the last dose of study drug. Safety Analysis Set consisted of participants who have received at least 1 dose, even if incomplete, of study drug.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive data was collected and analysed only for Phase 1 arms.
    [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: Descriptive data was collected and analysed only for Phase 1 arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW Phase 1 + Japan Lead-in: TAK-981 60mg QW
    Number of subjects analysed
    3
    4
    7
    8
    6
    4
    Units: days
        median (full range (min-max))
    57.0 (1 to 775)
    8.0 (1 to 575)
    2.0 (1 to 360)
    11.0 (1 to 274)
    10.0 (1 to 838)
    13.0 (1 to 473)
    No statistical analyses for this end point

    Primary: Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) per Dose Level

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    End point title
    		 Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) per Dose Level [7] [8]
    End point description
    DLTs were evaluated according to NCI CTCAE, Version 5.0. The DLT-evaluable analysis set will include participants enrolled in the Phase 1 portion of the study who experienced a DLT at any time after initiation of the first infusion of TAK-981 or who completed all planned infusions of TAK-981 as per schedule plus 3 infusions of rituximab without experiencing a DLT. Participants analyzed is the number of participants available for analysis.
    End point type
    Primary
    End point timeframe
    Up to 42 months
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive data was collected and analysed only for Phase 1 arms.
    [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: Descriptive data was collected and analysed only for Phase 1 arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 60mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW
    Number of subjects analysed
    3
    4
    3
    6
    4
    6
    Units: participants
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Phase 2: Overall Response Rate (ORR)

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    End point title
    		 Phase 2: Overall Response Rate (ORR) [9]
    End point description
    ORR was defined as the percentage of participants who achieved complete response (CR) and partial response (PR), as defined by the investigator according to Lugano classification for lymphomas during the study. Response-evaluable analysis set consisted of participants who have received at least 1 dose of study drug, have sites of measurable disease at Baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happens.
    End point type
    Primary
    End point timeframe
    Up to 42 months
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive data was collected and analysed only for Phase 1 arms.
    End point values
    		 Phase 2 (A): TAK-981 120 mg Phase 2 (C): TAK-981 120 mg
    Number of subjects analysed
    2
    1
    Units: percentage of participants
        number (not applicable)
    1
    1
    No statistical analyses for this end point

    Secondary: Cmax: Maximum Observed Plasma Concentration for TAK-981

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    End point title
    		 Cmax: Maximum Observed Plasma Concentration for TAK-981 [10]
    End point description
    Pharmacokinetic (PK) analysis set consisted of participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Participants analyzed is the number of participants available for analysis. Number of participants analyzed is the number of participants available for analysis during the specified time-point.
    End point type
    Secondary
    End point timeframe
    Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion; Cycle 2: Days 1 and 8, pre-infusion and at 10 minutes (mins) post end of infusion (Cycle length = 21 days)
    Notes
    [10] - 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: Descriptive data was collected and analysed for per dose arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW Japan Lead-in: TAK-981 60mg BIW Phase 1 + Japan Lead-in: TAK-981 60mg QW
    Number of subjects analysed
    3
    4
    7
    7
    6
    3
    4
    Units: nanograms per millilitre (ng/ml)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n= 3, 4, 7, 7, 6, 3, 4)
    39.8 ( 19.1 )
    184 ( 139 )
    648 ( 214 )
    810 ( 305 )
    740 ( 491 )
    833 ( 73.3 )
    444 ( 323 )
        Cycle 1 Day 8 (n= 3, 4, 6, 5, 6, 3, 4)
    51.4 ( 13.9 )
    200 ( 152 )
    600 ( 146 )
    967 ( 299 )
    981 ( 272 )
    731 ( 346 )
    595 ( 410 )
    No statistical analyses for this end point

    Secondary: Tmax: Time of First Occurrence of the Maximum Plasma Concentration (Cmax) for TAK-981

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    End point title
    		 Tmax: Time of First Occurrence of the Maximum Plasma Concentration (Cmax) for TAK-981 [11]
    End point description
    PK analysis set consisted of participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Participants analyzed is the number of participants available for analysis. Number of participants analyzed is the number of participants available for analysis during the specified time-point.
    End point type
    Secondary
    End point timeframe
    Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion; Cycle 2: Days 1 and 8, pre-infusion and at 10 mins post end of infusion (Cycle length = 21 days)
    Notes
    [11] - 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: Descriptive data was collected and analysed for per dose arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW Japan Lead-in: TAK-981 60mg BIW Phase 1 + Japan Lead-in: TAK-981 60mg QW
    Number of subjects analysed
    3
    4
    7
    7
    6
    3
    4
    Units: hours
    median (full range (min-max))
        Cycle 1 Day 1 (n= 3, 4, 7, 7, 6, 3, 4)
    1.17 (1.15 to 1.20)
    1.15 (1.14 to 1.42)
    1.14 (1.09 to 1.39)
    1.17 (1.07 to 1.53)
    1.28 (1.10 to 1.95)
    1.12 (1.12 to 1.48)
    1.14 (0.97 to 1.29)
        Cycle 1 Day 8 (n= 3, 4, 6, 5, 6, 3, 4)
    1.15 (1.07 to 1.24)
    1.08 (1.04 to 1.27)
    1.08 (1.02 to 1.72)
    1.05 (1.00 to 1.19)
    1.11 (1.05 to 1.19)
    1.12 (1.04 to 1.67)
    0.95 (0.93 to 1.02)
    No statistical analyses for this end point

    Secondary: AUC0-t: Area Under the Plasma Concentration-time Curve from Time 0 to Time t Over the Dosing Interval for TAK-981

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    End point title
    		 AUC0-t: Area Under the Plasma Concentration-time Curve from Time 0 to Time t Over the Dosing Interval for TAK-981 [12]
    End point description
    PK analysis set consisted of participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Participants analyzed is the number of participants available for analysis. Number of participants analyzed is the number of participants available for analysis during the specified time-point.
    End point type
    Secondary
    End point timeframe
    Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion; Cycle 2: Days 1 and 8, pre-infusion and at 10 mins post end of infusion (Cycle length = 21 days)
    Notes
    [12] - 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: Descriptive data was collected and analysed for per dose arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW Japan Lead-in: TAK-981 60mg BIW Phase 1 + Japan Lead-in: TAK-981 60mg QW
    Number of subjects analysed
    3
    4
    7
    7
    6
    3
    4
    Units: hours per ng/ml (h.ng/ml)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n= 3, 4, 7, 7, 6, 3, 4)
    146 ( 15.0 )
    477 ( 130 )
    1310 ( 380 )
    1490 ( 475 )
    1640 ( 484 )
    1520 ( 103 )
    1070 ( 456 )
        Cycle 1 Day 8 (n= 3, 4, 6, 5, 6, 3, 4)
    140 ( 25.6 )
    517 ( 236 )
    1290 ( 351 )
    1640 ( 483 )
    1780 ( 333 )
    1420 ( 356 )
    1160 ( 510 )
    No statistical analyses for this end point

    Secondary: AUC0-∞: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for TAK-981

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    End point title
    		 AUC0-∞: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for TAK-981 [13]
    End point description
    PK analysis set consisted of participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Participants analyzed is the number of participants available for analysis. Number of participants analyzed is the number of participants available for analysis during the specified time-point.
    End point type
    Secondary
    End point timeframe
    Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion; Cycle 2: Days 1 and 8, pre-infusion and at 10 mins post end of infusion (Cycle length = 21 days)
    Notes
    [13] - 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: Descriptive data was collected and analysed for per dose arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW Japan Lead-in: TAK-981 60mg BIW Phase 1 + Japan Lead-in: TAK-981 60mg QW
    Number of subjects analysed
    3
    4
    7
    6
    6
    3
    4
    Units: h.ng/ml
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n= 3, 4, 7, 6, 6, 3, 4)
    151 ( 15.1 )
    498 ( 128 )
    1360 ( 398 )
    1640 ( 445 )
    1600 ( 550 )
    1560 ( 114 )
    1110 ( 465 )
        Cycle 1 Day 8 (n= 3, 4, 6, 5, 6, 3, 4)
    150 ( 19.2 )
    538 ( 242 )
    1330 ( 359 )
    1780 ( 490 )
    1830 ( 344 )
    1460 ( 382 )
    1210 ( 514 )
    No statistical analyses for this end point

    Secondary: t1/2z: Terminal Disposition Phase Half-life for TAK-981

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    End point title
    		 t1/2z: Terminal Disposition Phase Half-life for TAK-981 [14]
    End point description
    PK analysis set consisted of participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Participants analyzed is the number of participants available for analysis. Number of participants analyzed is the number of participants available for analysis during the specified time-point.
    End point type
    Secondary
    End point timeframe
    Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion; Cycle 2: Days 1 and 8, pre-infusion and at 10 mins post end of infusion (Cycle length = 21 days)
    Notes
    [14] - 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: Descriptive data was collected and analysed for per dose arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW Japan Lead-in: TAK-981 60mg BIW Phase 1 + Japan Lead-in: TAK-981 60mg QW
    Number of subjects analysed
    3
    4
    7
    6
    6
    3
    4
    Units: hours
    median (full range (min-max))
        Cycle 1 Day 1 (n= 3, 4, 7, 6, 6, 3, 4)
    5.06 (4.78 to 5.41)
    5.88 (5.31 to 6.76)
    5.75 (4.50 to 7.01)
    4.88 (4.21 to 7.23)
    5.78 (2.87 to 8.35)
    5.91 (5.12 to 6.00)
    6.02 (5.67 to 6.46)
        Cycle 1 Day 8 (n= 3, 4, 6, 5, 6, 3, 4)
    5.03 (3.15 to 5.92)
    5.92 (5.51 to 6.15)
    5.78 (4.98 to 6.29)
    5.59 (3.10 to 10.93)
    5.73 (5.23 to 6.46)
    5.45 (4.16 to 6.91)
    5.77 (5.12 to 7.14)
    No statistical analyses for this end point

    Secondary: CL: Total Clearance After Intravenous Administration for TAK-981

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    End point title
    		 CL: Total Clearance After Intravenous Administration for TAK-981 [15]
    End point description
    PK analysis set consisted of participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Participants analyzed is the number of participants available for analysis. Number of participants analyzed is the number of participants available for analysis during the specified time-point.
    End point type
    Secondary
    End point timeframe
    Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion; Cycle 2: Days 1 and 8, pre-infusion and at 10 mins post end of infusion (Cycle length = 21 days)
    Notes
    [15] - 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: Descriptive data was collected and analysed for per dose arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW Japan Lead-in: TAK-981 60mg BIW Phase 1 + Japan Lead-in: TAK-981 60mg QW
    Number of subjects analysed
    3
    4
    7
    6
    6
    3
    4
    Units: litres per hour (L/h)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n= 3, 4, 7, 6, 6, 3, 4)
    66.8 ( 6.37 )
    83.8 ( 17.8 )
    72.7 ( 27.2 )
    58.2 ( 15.5 )
    81.8 ( 24.7 )
    38.6 ( 2.78 )
    65.2 ( 37.0 )
        Cycle 1 Day 8 (n= 3, 4, 6, 5, 6, 3, 4)
    67.4 ( 8.23 )
    75.2 ( 43.8 )
    73.3 ( 25.9 )
    53.9 ( 14.6 )
    68.0 ( 16.1 )
    43.2 ( 13.1 )
    57.8 ( 26.2 )
    No statistical analyses for this end point

    Secondary: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981

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    End point title
    		 Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981 [16]
    End point description
    PK analysis set consisted of participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Participants analyzed is the number of participants available for analysis. Number of participants analyzed is the number of participants available for analysis during the specified time-point.
    End point type
    Secondary
    End point timeframe
    Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion; Cycle 2: Days 1 and 8, pre-infusion and at 10 mins post end of infusion (Cycle length = 21 days)
    Notes
    [16] - 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: Descriptive data was collected and analysed for per dose arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW Japan Lead-in: TAK-981 60mg BIW Phase 1 + Japan Lead-in: TAK-981 60mg QW
    Number of subjects analysed
    3
    4
    7
    6
    6
    3
    4
    Units: litres (L)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n= 3, 4, 7, 6, 6, 3, 4)
    396 ( 72.8 )
    517 ( 202 )
    352 ( 136 )
    255 ( 75.5 )
    410 ( 156 )
    154 ( 1.72 )
    406 ( 277 )
        Cycle 1 Day 8 (n= 3, 4, 6, 5, 6, 3, 4)
    352 ( 79.9 )
    456 ( 278 )
    347 ( 110 )
    273 ( 201 )
    307 ( 95.0 )
    189 ( 68.0 )
    332 ( 211 )
    No statistical analyses for this end point

    Secondary: Phase 1: Overall Response Rate (ORR)

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    End point title
    		 Phase 1: Overall Response Rate (ORR) [17]
    End point description
    ORR is defined as the percentage of participants who achieved CR and PR, as defined by the investigator according to Lugano classification for lymphomas during the study. Response-evaluable analysis set consisted of participants who have received at least 1 dose of study drug, have sites of measurable disease at Baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happens.
    End point type
    Secondary
    End point timeframe
    Up to 42 months
    Notes
    [17] - 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: Descriptive data was collected and analysed only for Phase 1 arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 60mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW
    Number of subjects analysed
    3
    4
    3
    7
    6
    6
    Units: percentage of participants
        number (not applicable)
    33.3
    50.0
    66.7
    14.3
    0
    33.3
    No statistical analyses for this end point

    Secondary: Phase 1: Disease Control Rate (DCR)

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    End point title
    		 Phase 1: Disease Control Rate (DCR) [18]
    End point description
    DCR is defined as the percentage of participants who achieved CR, PR, and stable disease (SD) as defined by the investigator according to Lugano classification for Lymphomas during the study. Response-evaluable analysis set consisted of participants who have received at least 1 dose of study drug, have sites of measurable disease at Baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happens.
    End point type
    Secondary
    End point timeframe
    Up to 42 months
    Notes
    [18] - 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: Descriptive data was collected and analysed only for Phase 1 arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 60mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW
    Number of subjects analysed
    3
    4
    3
    7
    6
    6
    Units: percenage of participants
        number (not applicable)
    100
    50.0
    100
    28.6
    16.7
    50.0
    No statistical analyses for this end point

    Secondary: Phase 1: Duration of Response (DOR)

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    End point title
    		 Phase 1: Duration of Response (DOR) [19]
    End point description
    DOR is the time from the date of first documentation of a PR or better to the date of first documentation of PD for responders (PR or better). DOR was assessed by the investigator according to Lugano classification for lymphoma during the study. Response-evaluable analysis set consisted of participants who have received at least 1 dose of study drug, have sites of measurable disease at Baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happens. Participants analyzed is the number of participants with events.
    End point type
    Secondary
    End point timeframe
    Up to 42 months
    Notes
    [19] - 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: Descriptive data was collected and analysed only for Phase 1 arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 60mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW
    Number of subjects analysed
    1
    0 [20]
    0 [21]
    1
    0 [22]
    0 [23]
    Units: months
        median (full range (min-max))
    8.31 (8.31 to 8.31)
    ( to )
    ( to )
    2.73 (2.73 to 2.73)
    ( to )
    ( to )
    Notes
    [20] - Study was terminated. Please refer Global Interruption.
    [21] - Study was terminated. Please refer Global Interruption.
    [22] - Study was terminated. Please refer Global Interruption.
    [23] - Study was terminated. Please refer Global Interruption.
    No statistical analyses for this end point

    Secondary: Phase 1: Time to Progression (TTP)

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    End point title
    		 Phase 1: Time to Progression (TTP) [24]
    End point description
    TTP is defined as the time from the date of first study drug administration to the date of first documented disease progression. TTP was assessed by the investigator according to Lugano classification for lymphoma during the study. Response-evaluable analysis set consisted of participants who have received at least 1 dose of study drug, have sites of measurable disease at Baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happens. Participants analyzed is the number of participants with events. 9.9999 indicates that median was not estimable as there were censored participants with events.
    End point type
    Secondary
    End point timeframe
    Up to 42 months
    Notes
    [24] - 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: Descriptive data was collected and analysed only for Phase 1 arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 60mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW
    Number of subjects analysed
    2
    0 [25]
    0 [26]
    5
    4
    2
    Units: months
        median (full range (min-max))
    12.42 (2.69 to 12.42)
    ( to )
    ( to )
    1.58 (0.95 to 3.98)
    1.48 (0.00 to 3.91)
    9.9999 (0.92 to 19.09)
    Notes
    [25] - Study was terminated. Please refer Global Interruption.
    [26] - Study was terminated. Please refer Global Interruption.
    No statistical analyses for this end point

    Secondary: Phase 1: Progression-Free Survival (PFS)

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    End point title
    		 Phase 1: Progression-Free Survival (PFS) [27]
    End point description
    PFS is defined as the time from the date of the first dose administration to the date of first documentation of PD or death due to any cause, whichever occurs first. PD was determined by Response Evaluation Criteria in Lymphoma. PFS was assessed by the investigator according to Lugano classification for lymphoma during the study. Response-evaluable analysis set consisted of participants who have received at least 1 dose of study drug, have sites of measurable disease at Baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happens. Participants analyzed are the number of participants with events. 9.9999 indicates that median was not estimable as there were censored participants with events.
    End point type
    Secondary
    End point timeframe
    Up to 42 months
    Notes
    [27] - 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: Descriptive data was collected and analysed only for Phase 1 arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 60mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW
    Number of subjects analysed
    2
    0 [28]
    0 [29]
    5
    4
    2
    Units: months
        median (full range (min-max))
    12.42 (2.69 to 12.42)
    ( to )
    ( to )
    1.58 (1.25 to 3.98)
    2.33 (0.43 to 3.91)
    9.9999 (1.61 to 19.09)
    Notes
    [28] - Study was terminated. Please refer Global Interruption.
    [29] - Study was terminated. Please refer Global Interruption.
    No statistical analyses for this end point

    Secondary: Phase 1: Fold Change from Baseline in Levels of TAK-981-Small Ubiquitin-like Modifier (TAK-981-SUMO) Adduct Formation in Blood as Assessed by Flow Cytometry During Phase 1

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    End point title
    		 Phase 1: Fold Change from Baseline in Levels of TAK-981-Small Ubiquitin-like Modifier (TAK-981-SUMO) Adduct Formation in Blood as Assessed by Flow Cytometry During Phase 1 [30]
    End point description
    The level of TAK-981-SUMO adduct formation was evaluated as the percentage of adduct formed in blood. Positive change denotes improvement. Pharmacodynamic analysis set consisted of participants who have provided evaluable blood samples (C1D1 predose sample and at least 1 postdose sample). Number of participants available is the number of participants with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (1 hour, 4 hours, 8 hours) and Day 8 (Pre-dose, 1 hour, 4 hours and 8 hours) (Cycle length = 21 days)
    Notes
    [30] - 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: Descriptive data was collected and analysed only for Phase 1 arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 60mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW
    Number of subjects analysed
    3
    4
    3
    7
    5
    5
    Units: % adduct positive
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 /1 Hour Postdose (n=3,4,3,7,5,5)
    4.1 ( 0.54 )
    5.7 ( 1.47 )
    6.3 ( 1.02 )
    9.5 ( 1.04 )
    7.6 ( 0.73 )
    9.9 ( 2.84 )
        Cycle 1 Day 1 /4 Hours Postdose (n=3,4,3,7,5,2)
    3.6 ( 0.66 )
    4.7 ( 1.18 )
    4.7 ( 1.28 )
    6.7 ( 1.07 )
    4.9 ( 1.69 )
    6.5 ( 0.56 )
        Cycle 1 Day 1 /8 Hours Postdose (n=3,4,3,7,5,4)
    3.7 ( 0.27 )
    4.5 ( 1.22 )
    4.1 ( 1.24 )
    5.6 ( 1.05 )
    4.6 ( 0.72 )
    5.2 ( 0.64 )
        Cycle 1 Day 8 /Predose (n=3,4,3,6,4,5)
    1.8 ( 0.13 )
    1.9 ( 0.68 )
    1.9 ( 0.27 )
    2.5 ( 0.88 )
    2.8 ( 0.51 )
    2.8 ( 1.50 )
        Cycle 1 Day 8 /1 Hour Postdose (n=3,4,3,5,4,5)
    4.6 ( 0.19 )
    6.6 ( 0.96 )
    8.0 ( 0.87 )
    9.1 ( 3.21 )
    7.8 ( 0.61 )
    11.6 ( 6.34 )
        Cycle 1 Day 8 /4 Hours Postdose (n=3,4,3,6,4,2)
    3.9 ( 0.19 )
    6.2 ( 1.87 )
    5.1 ( 0.70 )
    6.1 ( 2.16 )
    5.8 ( 0.65 )
    5.6 ( 1.73 )
        Cycle 1 Day 8 /8 Hours Postdose (n=3,4,3,6,4,5)
    3.2 ( 0.55 )
    4.2 ( 1.34 )
    4.0 ( 0.49 )
    5.3 ( 1.97 )
    4.0 ( 1.43 )
    7.1 ( 2.83 )
    No statistical analyses for this end point

    Secondary: Phase 1: Levels of TAK-981-Small Ubiquitin-like Modifier (TAK-981-SUMO) Adduct Formation in Skin as Assessed by Immunohistochemistry (IHC) During Phase 1

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    End point title
    		 Phase 1: Levels of TAK-981-Small Ubiquitin-like Modifier (TAK-981-SUMO) Adduct Formation in Skin as Assessed by Immunohistochemistry (IHC) During Phase 1 [31]
    End point description
    The level of TAK-981-SUMO adduct formation was evaluated as the percentage of adduct formed in skin. Pharmacodynamic analysis set consisted of participants who have provided evaluable skin biopsies (screening sample and postdose sample). Participants available is the number of participants available for analysis. Number of participants available is the number of participants with data available for analysis at the specified time point. 99999 indicates that standard deviation was not estimable as there was only one participant.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Days 1 and 8 (Cycle length = 21 days)
    Notes
    [31] - 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: Descriptive data was collected and analysed only for Phase 1 arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 60mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW
    Number of subjects analysed
    3
    4
    3
    6
    1
    4
    Units: % adduct positive
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 /Predose (n=3,4,3,6,0,4)
    0.0 ( 0.03 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
        Cycle 1 Day 8 (n=3,4,3,6,1,4)
    1.2 ( 1.15 )
    15.8 ( 12.70 )
    27.0 ( 12.29 )
    22.6 ( 9.47 )
    59.7 ( 99999 )
    11.2 ( 11.35 )
    No statistical analyses for this end point

    Secondary: Phase 1: Fold Change from Baseline in SUMO Pathway Inhibition in Blood as Assessed by Flow Cytometry During Phase 1

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    End point title
    		 Phase 1: Fold Change from Baseline in SUMO Pathway Inhibition in Blood as Assessed by Flow Cytometry During Phase 1 [32]
    End point description
    SUMO pathway inhibition in blood was evaluated by flow cytometry with an antibody recognizing SUMO2/3 chains. Pharmacodynamic analysis set consisted of participants who have provided evaluable blood samples (C1D1 predose sample and at least 1 postdose sample). Participants analyzed are the number of participants available for analysis. Number of participants available is the number of participants with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (1 hour, 4 hours, 8 hours) and Day 8 (Pre-dose, 1 hour, 4 hours and 8 hours) (Cycle length = 21 days)
    Notes
    [32] - 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: Descriptive data was collected and analysed only for Phase 1 arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 60mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW
    Number of subjects analysed
    3
    4
    3
    7
    5
    5
    Units: % Sumo 2/3 positive
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 /1 Hour Postdose (n=3,4,3,7,5,5)
    0.9 ( 0.05 )
    0.8 ( 0.15 )
    0.5 ( 0.36 )
    0.6 ( 0.11 )
    0.5 ( 0.26 )
    0.6 ( 0.22 )
        Cycle 1 Day 1 /4 Hours Postdose (n=3,4,3,7,5,2)
    0.9 ( 0.07 )
    0.8 ( 0.15 )
    0.5 ( 0.34 )
    0.5 ( 0.15 )
    0.4 ( 0.30 )
    0.9 ( 0.14 )
        Cycle 1 Day 1 /8 Hours Postdose (n=3,4,3,7,5,4)
    1.0 ( 0.05 )
    0.8 ( 0.17 )
    0.5 ( 0.33 )
    0.5 ( 0.15 )
    0.5 ( 0.22 )
    0.7 ( 0.28 )
        Cycle 1 Day 8 /Predose (n=3,4,3,6,4,5)
    0.9 ( 0.09 )
    1.1 ( 0.37 )
    0.8 ( 0.12 )
    1.1 ( 0.46 )
    0.9 ( 0.07 )
    1.1 ( 0.25 )
        Cycle 1 Day 8 /1 Hour Postdose (n=3,4,3,5,4,5)
    0.9 ( 0.10 )
    0.8 ( 0.34 )
    0.5 ( 0.19 )
    0.5 ( 0.05 )
    0.5 ( 0.14 )
    0.6 ( 0.10 )
        Cycle 1 Day 8 /4 Hours Postdose (n=3,4,3,6,4,2)
    0.9 ( 0.09 )
    0.7 ( 0.31 )
    0.5 ( 0.23 )
    0.6 ( 0.20 )
    0.7 ( 0.05 )
    0.7 ( 0.10 )
        Cycle 1 Day 8 /8 Hours Postdose (n=3,4,3,6,4,5)
    0.9 ( 0.09 )
    0.7 ( 0.37 )
    0.5 ( 0.04 )
    0.5 ( 0.13 )
    0.5 ( 0.35 )
    0.7 ( 0.17 )
    No statistical analyses for this end point

    Secondary: Phase 1: SUMO Pathway Inhibition in Skin as Assessed by Immunohistochemistry (IHC) During Phase 1

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    End point title
    		 Phase 1: SUMO Pathway Inhibition in Skin as Assessed by Immunohistochemistry (IHC) During Phase 1 [33]
    End point description
    SUMO pathway inhibition in skin was evaluated with skin tissue biopsies by IHC. Pharmacodynamic analysis set consisted of participants who have provided evaluable skin biopsies (screening sample and postdose sample). Participants available is the number of participants available for analysis. Number of participants available is the number of participants with data available for analysis at the specified time point. 99999 indicates that standard deviation was not estimable as there was only one participant.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Days 1 and 8 (Cycle length = 21 days)
    Notes
    [33] - 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: Descriptive data was collected and analysed only for Phase 1 arms.
    End point values
    		 Phase 1: TAK-981 10mg QW Phase 1: TAK-981 40mg QW Phase 1: TAK-981 60mg QW Phase 1: TAK-981 90mg QW Phase 1: TAK-981 90mg BIW Phase 1: TAK-981 120mg QW
    Number of subjects analysed
    3
    4
    3
    6
    1
    4
    Units: % Sumo 2/3 positive
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 /Predose (n=3,4,3,6,0,4)
    83.40383 ( 2.692876 )
    87.7 ( 5.142812 )
    89.6 ( 5.528530 )
    89.6 ( 4.044536 )
    0.0 ( 0.0 )
    75.7 ( 2.586486 )
        Cycle 1 Day 8 (n=3,4,3,6,1,4)
    82.2 ( 2.017705 )
    79.3 ( 10.262143 )
    55.6 ( 19.325964 )
    52.5 ( 15.606775 )
    51.8 ( 99999 )
    63.1 ( 15.415286 )
    No statistical analyses for this end point

    Secondary: Phase 2: Number of Participants With One or More Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Phase 2: Number of Participants With One or More Treatment-Emergent Adverse Events (TEAEs)
    End point description
    Adverse event (AE) means any untoward medical occurrence in a participant administered a pharmaceutical product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product. A TEAE was defined as an adverse event which occurred on or after the first dose of study drug and no more than 30 days after the last dose of study drug. Safety Analysis Set consisted of participants who have received at least 1 dose, even if incomplete, of study drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
    End point values
    		 Phase 2 (A): TAK-981 120 mg Phase 2 (C): TAK-981 120 mg
    Number of subjects analysed
    2
    1
    Units: participants
    2
    1
    No statistical analyses for this end point

    Secondary: Phase 2: Number of Participants With Grade 3 or Higher TEAEs

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    End point title
    		 Phase 2: Number of Participants With Grade 3 or Higher TEAEs
    End point description
    AE means any untoward medical occurrence in a participant administered a pharmaceutical product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product whether or not it is related to the medicinal product. A TEAE was defined as an adverse event which occurred on or after the first dose of study drug and no more than 30 days after the last dose of study drug. A severity grade was evaluated as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0, except for Cytokine Release Syndrome (CRS), which was assessed by American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading criteria. Safety Analysis Set consisted of participants who have received at least 1 dose, even if incomplete, of study drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
    End point values
    		 Phase 2 (A): TAK-981 120 mg Phase 2 (C): TAK-981 120 mg
    Number of subjects analysed
    2
    1
    Units: participants
    2
    1
    No statistical analyses for this end point

    Secondary: Phase 2: Duration of TEAEs

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    End point title
    		 Phase 2: Duration of TEAEs
    End point description
    AE means any untoward medical occurrence in a participant administered a pharmaceutical product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product whether or not it is related to the medicinal product. A TEAE was defined as an adverse event which occurred on or after the first dose of study drug and no more than 30 days after the last dose of study drug. Safety Analysis Set consisted of participants who have received at least 1 dose, even if incomplete, of study drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
    End point values
    		 Phase 2 (A): TAK-981 120 mg Phase 2 (C): TAK-981 120 mg
    Number of subjects analysed
    2
    1
    Units: days
        median (full range (min-max))
    8.0 (1 to 483)
    2.0 (1 to 349)
    No statistical analyses for this end point

    Secondary: Phase 2: Disease Control Rate (DCR)

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    End point title
    		 Phase 2: Disease Control Rate (DCR)
    End point description
    CR is defined as the percentage of participants who achieved CR, PR, and SD as defined by the investigator according to Lugano classification for Lymphomas during the study. Response-evaluable analysis set consisted of participants who have received at least 1 dose of study drug, have sites of measurable disease at Baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happens.
    End point type
    Secondary
    End point timeframe
    Up to 42 months
    End point values
    		 Phase 2 (A): TAK-981 120 mg Phase 2 (C): TAK-981 120 mg
    Number of subjects analysed
    2
    1
    Units: percentage of participants
        number (not applicable)
    1
    1
    No statistical analyses for this end point

    Secondary: Phase 2: Duration of Response (DOR)

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    End point title
    		 Phase 2: Duration of Response (DOR)
    End point description
    DOR is the time from the date of first documentation of a PR or better to the date of first documentation of PD for responders (PR or better). DOR was assessed by the investigator according to Lugano classification for lymphoma during the study. Response-evaluable analysis set consisted of participants who have received at least 1 dose of study drug, have sites of measurable disease at Baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happens.
    End point type
    Secondary
    End point timeframe
    Up to 42 months
    End point values
    		 Phase 2 (A): TAK-981 120 mg Phase 2 (C): TAK-981 120 mg
    Number of subjects analysed
    2
    1
    Units: months
        median (full range (min-max))
    3.32 (3.32 to 3.32)
    0.03 (0.03 to 0.03)
    No statistical analyses for this end point

    Secondary: Phase 2: Time to Progression (TTP)

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    End point title
    		 Phase 2: Time to Progression (TTP)
    End point description
    TTP is defined as the time from the date of first study drug administration to the date of first documented disease progression. TTP was assessed by the investigator according to Lugano classification for lymphoma during the study. Response-evaluable analysis set consisted of participants who have received at least 1 dose of study drug, have sites of measurable disease at Baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happens.
    End point type
    Secondary
    End point timeframe
    Up to 42 months
    End point values
    		 Phase 2 (A): TAK-981 120 mg Phase 2 (C): TAK-981 120 mg
    Number of subjects analysed
    2
    1
    Units: months
        median (full range (min-max))
    5.32 (5.32 to 5.32)
    1.48 (1.48 to 1.48)
    No statistical analyses for this end point

    Secondary: Phase 2: Progression-Free Survival (PFS)

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    End point title
    		 Phase 2: Progression-Free Survival (PFS)
    End point description
    PFS is defined as the time from the date of the first dose administration to the date of first documentation of PD or death due to any cause, whichever occurs first. PD was determined by Response Evaluation Criteria in Lymphoma. PFS was assessed by the investigator according to Lugano classification for lymphoma during the study. Response-evaluable analysis set consisted of participants who have received at least 1 dose of study drug, have sites of measurable disease at Baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happens.
    End point type
    Secondary
    End point timeframe
    Up to 42 months
    End point values
    		 Phase 2 (A): TAK-981 120 mg Phase 2 (C): TAK-981 120 mg
    Number of subjects analysed
    2
    1
    Units: months
        median (full range (min-max))
    3.15 (1.0 to 5.3)
    1.48 (1.48 to 1.48)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
    Adverse event reporting additional description
    Safety Analysis Set consisted of participants who have received at least 1 dose, even if incomplete, of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    Phase 1: TAK981 10mg QW
    Reporting group description
    		 Participants with indolent or aggressive NHL received TAK-981 10 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Phase 1: TAK981 40mg QW
    Reporting group description
    		 Participants with indolent or aggressive NHL received TAK-981 40 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Phase 1: TAK981 60mg QW
    Reporting group description
    		 Participants with indolent or aggressive NHL received TAK-981 60 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Phase 1: TAK981 90mg QW
    Reporting group description
    		 Participants with indolent or aggressive NHL received TAK-981 90 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Phase 1: TAK981 90mg BIW
    Reporting group description
    		 Participants with indolent or aggressive NHL received TAK-981 90 mg, infusion, IV, BIW on Days 1, 4, 8, and 11 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Japan Lead-in: TAK981 60mg BIW
    Reporting group description
    		 Japanese participants with indolent or aggressive NHL received TAK-981 60 mg, infusion, IV, BIW on Days 1, 4, 8, and 11 every 21 days in each 21-day treatment cycle for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Phase 1: TAK981 120mg QW
    Reporting group description
    		 Participants with indolent or aggressive NHL received TAK-981 120 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Japan Lead-in: TAK981 60mg QW
    Reporting group description
    		 Japanese participants with indolent or aggressive NHL received TAK-981 60 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Phase 2 (A): TAK981 120mg
    Reporting group description
    		 Participants with r/r DLBCL received TAK-981 120 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab infusion, intravenously, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Reporting group title
    Phase 2 (C): TAK981 120mg
    Reporting group description
    		 Participants with FL received TAK-981 120 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab infusion, intravenously, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.

    Serious adverse events
    		 Phase 1: TAK981 10mg QW Phase 1: TAK981 40mg QW Phase 1: TAK981 60mg QW Phase 1: TAK981 90mg QW Phase 1: TAK981 90mg BIW Japan Lead-in: TAK981 60mg BIW Phase 1: TAK981 120mg QW Japan Lead-in: TAK981 60mg QW Phase 2 (A): TAK981 120mg Phase 2 (C): TAK981 120mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 4 (50.00%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    5 / 8 (62.50%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    1 / 1 (100.00%)
         number of deaths (all causes)
    0
    2
    0
    1
    4
    0
    1
    0
    1
    0
         number of deaths resulting from adverse events
    0
    2
    0
    1
    2
    0
    0
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 8 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 8 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Hypercreatinaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1: TAK981 10mg QW Phase 1: TAK981 40mg QW Phase 1: TAK981 60mg QW Phase 1: TAK981 90mg QW Phase 1: TAK981 90mg BIW Japan Lead-in: TAK981 60mg BIW Phase 1: TAK981 120mg QW Japan Lead-in: TAK981 60mg QW Phase 2 (A): TAK981 120mg Phase 2 (C): TAK981 120mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    4 / 4 (100.00%)
    3 / 3 (100.00%)
    6 / 7 (85.71%)
    8 / 8 (100.00%)
    3 / 3 (100.00%)
    6 / 6 (100.00%)
    1 / 1 (100.00%)
    2 / 2 (100.00%)
    1 / 1 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Seborrhoeic keratosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Vascular disorders
    Superficial vein thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    3
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    1
    0
    Phlebitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    0
    General disorders and administration site conditions
    Facial pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 1 (100.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Chills
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    3 / 7 (42.86%)
    3 / 8 (37.50%)
    0 / 3 (0.00%)
    5 / 6 (83.33%)
    0 / 1 (0.00%)
    2 / 2 (100.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    6
    3
    0
    20
    0
    8
    0
    Chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Catheter site swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Infusion site pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Gait disturbance
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    2 / 8 (25.00%)
    0 / 3 (0.00%)
    5 / 6 (83.33%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    2
    1
    0
    2
    2
    0
    10
    0
    0
    2
    Infusion site reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Injection site pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    2
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    2 / 3 (66.67%)
    5 / 7 (71.43%)
    3 / 8 (37.50%)
    2 / 3 (66.67%)
    5 / 6 (83.33%)
    1 / 1 (100.00%)
    2 / 2 (100.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    2
    2
    6
    5
    17
    20
    1
    2
    2
    Peripheral swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    1
    0
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Prostatomegaly
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Testicular oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea exertional
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    1
    0
    0
    0
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    2 / 8 (25.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    1
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Nasal crusting
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Pleuritic pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    0
    Throat irritation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    2
    0
    1
    0
    0
    0
    0
    0
    Confusional state
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    3 / 8 (37.50%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    3
    0
    2
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    3 / 8 (37.50%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    2
    0
    3
    0
    1
    0
    1
    0
    Depression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 1 (100.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 1 (100.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Blood sodium decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    CD4 lymphocytes decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    4
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Electrocardiogram P wave abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Electrocardiogram ST segment elevation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    0
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    1 / 1 (100.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    2
    1
    0
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    QRS axis abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    2 / 3 (66.67%)
    0 / 6 (0.00%)
    1 / 1 (100.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    4
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 4 (50.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 1 (100.00%)
    1 / 2 (50.00%)
    1 / 1 (100.00%)
         occurrences all number
    1
    3
    0
    0
    1
    0
    0
    2
    1
    2
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    0
    Contusion
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    2
    0
    0
    0
    Skin laceration
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    2
    0
    0
    0
    Thermal burn
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Wound haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    0
    0
    0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Sinus bradycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    0
    0
    1
    Extrasystoles
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 4 (50.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    2
    0
    1
    0
    0
    0
    0
    2
    0
    Dizziness postural
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    4 / 8 (50.00%)
    3 / 3 (100.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    6
    4
    5
    2
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    2
    0
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    Tremor
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    0
    0
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 8 (25.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    1
    1
    0
    0
    0
    Lymphopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    4
    0
    0
    1
    0
    0
    0
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Eosinophilia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 1 (100.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    3 / 8 (37.50%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    3
    1
    0
    0
    0
    0
    Ear and labyrinth disorders
    Otorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Eye pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Eye oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    2
    1
    0
    1
    0
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 8 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    Flatulence
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Dysphagia
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    1
    0
    Dry mouth
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    2 / 8 (25.00%)
    2 / 3 (66.67%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    0
    4
    2
    2
    4
    0
    2
    0
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    1
    1
    1
    0
    2
    0
    1
    1
    Gingival pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    2 / 3 (66.67%)
    2 / 7 (28.57%)
    4 / 8 (50.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 1 (100.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    2
    2
    4
    1
    0
    1
    1
    0
    Oral mucosal blistering
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    3 / 6 (50.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    1
    1
    0
    4
    0
    0
    0
    Toothache
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Dermatitis bullous
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 1 (100.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Dry skin
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    0
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Lentigo
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Ecchymosis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Skin exfoliation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    0
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 4 (0.00%)
    2 / 3 (66.67%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    2
    0
    2
    6
    15
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    3 / 6 (50.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    3
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    1
    1
    0
    0
    0
    1
    0
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 1 (100.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Hypercreatinaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    0
    0
    Mobility decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Bone pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Osteoarthritis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 1 (100.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Ear infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Campylobacter colitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    1
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    2
    0
    1
    0
    Dehydration
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    0
    0
    0
    Diabetes mellitus
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    2
    0
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 4 (50.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    2 / 8 (25.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    4
    0
    2
    3
    0
    1
    0
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    5
    0
    0
    1
    0
    0
    0
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jul 2019
    The following changes were implemented as per Amendment 1: 1.Stated that a starting dose of TAK-981 that is greater than 3 mg may be considered if emerging safety data from the ongoing TAK-981-1002 single agent study supports it, and that alternative dosing schedules may be investigated. 2. Added that the approximately 34 participants in the phase 1b part of the study must be evaluable for dose-limiting toxicities, and that the approximately 56 participants in the phase 2 part of the study should be response evaluable. 3. Increased the number of sites to approximately 9 sites in phase 1b and up to approximately 20 sites total in North America and/or globally. 4. Added an appendix that defines tumor lysis syndrome (TLS). 5. Added statement that, for laboratory assessments, blood chemistries should be monitored at 6 to 8 hours and at 24 hours after the first rituximab dose, and that electrolyte abnormalities should be corrected. 6. Added statement that for participants who show evidence of prior hepatitis B infection (hepatitis B surface antigen [HBsAg] positive [regardless of antibody status] or HBsAg negative but anti-hepatitis B core antibody positive), they should consult with physicians with expertise in managing hepatitis B regarding monitoring. 7. Added that hematology/chemistry assessments should be made at end of treatment. 8. Added an appendix: Recommendations for Initial Management of Electrolyte Abnormalities and Prevention of TLS. 9. Modified inclusion criterion number 3 to require only 1 prior systemic therapy instead of 2.
    26 Jan 2020
    The following changes were implemented as per Amendment 2: 1. DLT definitions: In response to FDA’s request current for clarifying the DLT criteria due to inconsistency, language was incorporated in the protocol amendment. 2. Added statement in inclusion criteria no. 11, that for fresh tumor biopsies, the lesion must be accessible for a low risk biopsy procedure. 3. Added hematology and chemistry laboratory assessments on Cycle 1 Day 1 as they are required to evaluate the suitability of TAK-981 dosing. 4. Removed window periods for tumor lysis syndrome (TLS)-related laboratory assessment. 5. Added that from Cycle 2 onwards, serum or urine pregnancy test will be performed for women of childbearing potential on Day 1 of each cycle. 6. Added statement that unless triplicate ECG are used as safety ECGs, only the general interpretation of each triplicate needs to be reported to the clinical database. 7. Stated in dose escalation (phase 1b) that the selection of the next recommended dose will be determined by the clinical study team (CST) with Bayesian Logistic Regression Modeling (BLRM) recommendations, and consideration of safety, pharmacokinetic (PK), and pharmacodynamic data, including the emerging safety, PK and pharmacodynamic data from the FIH study (TAK-981-1002). 8. Added a reference for Simon’s 2-stage design for sample size determination. 9. Added window periods to biomarkers sample collection times in Schedule of Events’ Table for Screening, Cycle 1 and 2 Biomarker Sample Collection. 10. Amended language for laboratory assessments under TLS management, that post dose blood chemistries will be monitored in hospitalized participants “due to high risk TLS”.
    18 Jun 2020
    The following changes were implemented as per Amendment 3: 1. Updated information of the preliminary clinical experience. 2. Changed the title of the study from Phase 1b/2 to Phase 1/2. 3. Modified the Phase 2 participant population. 4. Added at least 30 additional recruiting sites and clarified that the study may be conducted outside of North America. 5. Extended the duration of the study. 6. Added an Independent Data Monitoring Committee (IDMC) to the Phase 2 study. 7. Added an Independent Review Committee (IRC) to the Phase 2 study. 8. Updated study schematic figure with the specific tumor types and indications during Phase 2. 9. Deleted measured creatinine clearance from the inclusion criterion and renal function testing. 10. Modified the inclusion criterion regarding radiologically measurable lesions. 11. Replaced Clinical Study Team (CST) with Study Monitoring Committee (SMC), and added a description of the SMC. 12. Removed LYRIC criteria for the evaluation of response. 13. Changed the window for image testing. 14. Modified the coagulation testing and urinalysis window period on Cycle 1 Day 1. 15. Changed the tumor and skin biopsy window. 16. Updated AE definition. 17. Updated serious adverse event (SAE) definition. 18. Amended the statistical description of determination of sample size for Phase 2. 19. Modified the length of infusion time. 20. Added a permitted concomitant treatment. 21. Modified the starting dose based on emerging safety data from the TAK-981-1002 single-agent study. 22. Modified the staggering period within each cohort in dose escalation. 23. Modified the grading of CRS to ASTCT Consensus Grading for CRS. 24. Updated information on Diffuse Large B-cell lymphoma. 25. Updated study objectives and endpoints. 26. Clarified exclusion criteria for participants that have undergone ASCT or cellular therapy. 27. Added text on alternative dosing schedules for TAK-981. 28. Added timepoints for serum and plasma sample collection.
    19 Jan 2021
    The following changes were implemented as per Amendment 4: 1. The creatinine clearance requirement was lowered based on recent PK analysis that showed minimal renal elimination of TAK-981. 2. In Inclusion Criterion 11, clarified that tumor biopsy collection was for participants in Phase 2, Stage 1. 3. In Exclusion Criterion 9, clarified that the washout period for prior anticancer therapy is within 2 weeks or 5 half-lives before dosing, whichever is shorter; the fragment “(up to a maximum of 4 weeks)” was deleted. 4. In Exclusion Criterion 19, added that the washout period for P-glycoprotein inhibitors is 1 week before TAK-981 dosing. 5. Updated alternative dosing schedules. 6. Clarified that body surface area used to determine rituximab dosing was to be calculated using the Du Bois formula. 7. A footnote was added to the table of chemistry and hematology tests to clarify how the units associated with collection of differential laboratory results were to be described. 8. Text defining the type of imaging assessments required at screening was added to align with the schedule of events. 9. Clarification on specimen collection during Phase 2. 10. Text was added to allow for potential remote monitoring of sites due to the COVID-19 pandemic. 11. Modifications to simplify vital signs assessment and immunesafety parameters across the TAK-981 clinical studies. 12. Alignment with recent FDA recommendations.
    31 Mar 2021
    The following changes were implemented as per Amendment 5: 1. Correction and alignment with other TAK-981 protocols. 2. Alignment of exclusion criterion in protocol summary and body. 3. Guidance on benefit/risk assessment for participant participation in the study during the COVID-19 pandemic. 4. Guidance on COVID-19 vaccination timing and procedures during the study. 5. Update to align with current Food and Drug Administration guidance.
    02 Sep 2021
    The following changes were implemented as per Amendment 6: 1. Change made to fulfill Health Authority requirement. 2. Updated pharmacology data. 3. Added nonclinical toxicology and clinical experience section with data from latest Investigator's Brochure. 4. Changes made to fulfill local requirements. 5. Update of biomarker samples collected during Phase 2. 6. Added a section defining possible reasons for study termination. 7. Updates of PK pharmacodynamic SOEs to reflect streamlined sample collection strategy in Phase 2.
    04 Oct 2021
    The following changes were implemented as per Amendment 7: 1. Correction done to align with the investigator’s brochure. 2. Added additional text to include potential predictive biomarkers. 3. Modified description of countries included for conduct of study. 4. Clarification of formula-fixed, paraffin-embedded tissue block.
    20 May 2022
    The following changes were implemented as per Amendment 8: 1. Updated clinical experience with Phase 1 data to support the Phase 2 design. 2. Updated to provide the rationale for the 2 dose levels selected for the Phase 2 Cohorts B and C. 3. Added text noting the addition of approximately 25 participants to each of the 2 new doses within Cohorts B and C. Updated the total number of participants to 180 accordingly. 4. Updated the duration of the entire study. 5. Added information in the event of QT/corrected QT interval prolongation. 6. Added a sentence stating that pre-dose samples may be collected within up to 3 days before the visit. 7. Added wording to clarify when whole blood samples for DNA analyses are collected. 8. Bone marrow biopsy (BMB) was removed at screening; and footnote s was updated to specify BMB at investigator discretion and Lugano guidelines.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 Apr 2023
    The study was terminated due to enrollment challenges.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The study was terminated due to enrollment challenges.
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