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    Clinical Trial Results:
    Daratumumab (HuMax-CD38) Safety Study in Multiple Myeloma – Open-label, Dose-Escalation Followed by Open-Label, Single-Arm Study

    Summary
    EudraCT number
    		 2007-003783-22
    Trial protocol
    		 DK   SE   NL  
    Global end of trial date
    31 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Apr 2018
    First version publication date
    15 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DARA-GEN501
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00574288
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route, Raritan, United States, 08869
    Public contact
    Clinical Registry group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.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
    31 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to establish the safety profile of daratumumab when given as monotherapy in subjects with multiple myeloma relapsed from or refractory to at least 2 different cytoreductive therapies and without further established treatment options.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety evaluations included for both Part 1 and Part 2 and were based on medical history, measurements of vital signs, and physical examinations, treatment emergent adverse events (TEAEs) and serious TEAEs, clinical laboratory tests. Electrocardiogram (ECG) findings also were performed to assess for potential toxicities.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Mar 2008
    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
    Denmark: 30
    Country: Number of subjects enrolled
    Netherlands: 32
    Country: Number of subjects enrolled
    Sweden: 22
    Country: Number of subjects enrolled
    United States: 20
    Worldwide total number of subjects
    104
    EEA total number of subjects
    84
    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)
    63
    From 65 to 84 years
    41
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 In total 104 subjects enrolled in this two part study. In Part 1, 32 subjects were treated with daratumumab in which twenty subjects received daratumumab at doses <4 mg/kg, while 3 subjects in each dose group received 4 mg/kg, 8 mg/kg, 16 mg/kg, and 24 mg/kg of daratumumab. In Part 2, 72 subjects were treated with daratumumab.

    Period 1
    Period 1 title
    End of Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1: Daratumumab Less Than (<) 4 mg/kg
    Arm description
    		 Subjects were administered with 7 full intravenous (IV) infusion of 0.005, 0.05, 0.1, 0.5, 1 and 2 milligram per kilogram body weight (mg/kg) daratumumab once weekly, along with this subjects also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daratumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 7 full intravenous (IV) infusion of 0.005, 0.05, 0.1, 0.5, 1 and 2 milligram per kilogram body weight (mg/kg) daratumumab once weekly.

    Arm title
    		 Part 1:Daratumumab 4 mg/kg
    Arm description
    		 Subjects were administered with 7 full IV infusion of 4 mg/kg daratumumab once weekly, along with this subjects also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daratumumab 4 mg/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 7 full IV infusion of 4 mg/kg daratumumab once weekly.

    Arm title
    		 Part 1:Daratumumab 8 mg/kg
    Arm description
    		 Subjects were administered with 7 full IV infusion of 8 mg/kg daratumumab once weekly, along with this subjecs also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daratumumab 8 mg/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 7 full IV infusion of 8 mg/kg daratumumab once weekly.

    Arm title
    		 Part 1:Daratumumab 16 mg/kg
    Arm description
    		 Subjects were administered with 7 full IV infusion of 16 mg/kg daratumumab once weekly, along with this subjects also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daratumumab 16 mg/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 7 full IV infusion of 16 mg/kg daratumumab once weekly.

    Arm title
    		 Part 1:Daratumumab 24 mg/kg
    Arm description
    		 Subjects were administered with 7 full IV infusion of 24 mg/kg daratumumab once weekly, along with this subjects also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daratumumab 24 mg/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 7 full IV infusion of 24 mg/kg daratumumab once weekly.

    Arm title
    		 Part 2: Daratumumab 8 mg/kg
    Arm description
    		 Subjects were administered with 8 full IV infusions of 8 mg/kg daratumumab once weekly for 8 weeks, then every 2 weeks (q2w) for 16 weeks, then every 4 weeks (q4w) until the subject experienced disease progression or unmanageable toxicity whichever came first, along with this subjects also received methylprednisolone 100 mg IV before treatment and 20–25 mg methylprednisolone orally for 2 days after all full infusions.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daratumumab 8 mg/kg IV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 8 mg/kg daratumumab weekly once for 8 weeks, then q2w for 16 weeks or until the subject experienced disease progression or unmanageable toxicity, whichever came first.

    Arm title
    		 Part 2: Daratumumab 16 mg/kg
    Arm description
    		 Subjects were administered with 8 full IV infusions of 16 mg/kg daratumumab once weekly for 7 weeks, then every 2 weeks (q2w) for 14 weeks, then every 4 weeks (q4w) until the subject experienced disease progression or unmanageable toxicity whichever came first, along with this subjects also received methylprednisolone 100 mg IV before treatment and 20–25 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daratumumab 16 mg/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 8 full IV infusions of 16 mg/kg daratumumab once weekly for 7 weeks, then q2w for 14 weeks or until the subject experienced disease progression or unmanageable toxicity, whichever came first.

    Number of subjects in period 1
    		Part 1: Daratumumab Less Than (<) 4 mg/kg Part 1:Daratumumab 4 mg/kg Part 1:Daratumumab 8 mg/kg Part 1:Daratumumab 16 mg/kg Part 1:Daratumumab 24 mg/kg Part 2: Daratumumab 8 mg/kg Part 2: Daratumumab 16 mg/kg
    Started
    20
    3
    3
    3
    3
    30
    42
    Completed
    0
    0
    0
    1
    1
    4
    14
    Not completed
    20
    3
    3
    2
    2
    26
    28
         Adverse event, non-fatal
    2
    -
    -
    -
    1
    -
    -
         Other: progressive disease
    17
    2
    3
    2
    1
    -
    -
         Study Terminated By Sponsor
    -
    -
    -
    -
    -
    -
    5
         Unspecified
    1
    1
    -
    -
    -
    -
    -
         Lost to follow-up
    -
    -
    -
    -
    -
    1
    2
         Other: death
    -
    -
    -
    -
    -
    25
    21

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Daratumumab Less Than (<) 4 mg/kg
    Reporting group description
    		 Subjects were administered with 7 full intravenous (IV) infusion of 0.005, 0.05, 0.1, 0.5, 1 and 2 milligram per kilogram body weight (mg/kg) daratumumab once weekly, along with this subjects also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Reporting group title
    Part 1:Daratumumab 4 mg/kg
    Reporting group description
    		 Subjects were administered with 7 full IV infusion of 4 mg/kg daratumumab once weekly, along with this subjects also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Reporting group title
    Part 1:Daratumumab 8 mg/kg
    Reporting group description
    		 Subjects were administered with 7 full IV infusion of 8 mg/kg daratumumab once weekly, along with this subjecs also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Reporting group title
    Part 1:Daratumumab 16 mg/kg
    Reporting group description
    		 Subjects were administered with 7 full IV infusion of 16 mg/kg daratumumab once weekly, along with this subjects also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Reporting group title
    Part 1:Daratumumab 24 mg/kg
    Reporting group description
    		 Subjects were administered with 7 full IV infusion of 24 mg/kg daratumumab once weekly, along with this subjects also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Reporting group title
    Part 2: Daratumumab 8 mg/kg
    Reporting group description
    		 Subjects were administered with 8 full IV infusions of 8 mg/kg daratumumab once weekly for 8 weeks, then every 2 weeks (q2w) for 16 weeks, then every 4 weeks (q4w) until the subject experienced disease progression or unmanageable toxicity whichever came first, along with this subjects also received methylprednisolone 100 mg IV before treatment and 20–25 mg methylprednisolone orally for 2 days after all full infusions.

    Reporting group title
    Part 2: Daratumumab 16 mg/kg
    Reporting group description
    		 Subjects were administered with 8 full IV infusions of 16 mg/kg daratumumab once weekly for 7 weeks, then every 2 weeks (q2w) for 14 weeks, then every 4 weeks (q4w) until the subject experienced disease progression or unmanageable toxicity whichever came first, along with this subjects also received methylprednisolone 100 mg IV before treatment and 20–25 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Reporting group values
    		 Part 1: Daratumumab Less Than (<) 4 mg/kg Part 1:Daratumumab 4 mg/kg Part 1:Daratumumab 8 mg/kg Part 1:Daratumumab 16 mg/kg Part 1:Daratumumab 24 mg/kg Part 2: Daratumumab 8 mg/kg Part 2: Daratumumab 16 mg/kg Total
    Number of subjects
    		 20 3 3 3 3 30 42 104
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 11 2 2 3 2 21 22 63
        From 65 to 84 years
    		 9 1 1 0 1 9 20 41
        85 years and over
    		 0 0 0 0 0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.8 ± 9.24 64.0 ± 2.00 61.3 ± 6.11 53.0 ± 1.73 59.0 ± 9.54 58.6 ± 10.05 63.8 ± 8.27 -
    Title for Gender
    Units: subjects
        Female
    		 7 2 0 0 0 9 15 33
        Male
    		 13 1 3 3 3 21 27 71

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Daratumumab Less Than (<) 4 mg/kg
    Reporting group description
    		 Subjects were administered with 7 full intravenous (IV) infusion of 0.005, 0.05, 0.1, 0.5, 1 and 2 milligram per kilogram body weight (mg/kg) daratumumab once weekly, along with this subjects also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Reporting group title
    Part 1:Daratumumab 4 mg/kg
    Reporting group description
    		 Subjects were administered with 7 full IV infusion of 4 mg/kg daratumumab once weekly, along with this subjects also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Reporting group title
    Part 1:Daratumumab 8 mg/kg
    Reporting group description
    		 Subjects were administered with 7 full IV infusion of 8 mg/kg daratumumab once weekly, along with this subjecs also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Reporting group title
    Part 1:Daratumumab 16 mg/kg
    Reporting group description
    		 Subjects were administered with 7 full IV infusion of 16 mg/kg daratumumab once weekly, along with this subjects also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Reporting group title
    Part 1:Daratumumab 24 mg/kg
    Reporting group description
    		 Subjects were administered with 7 full IV infusion of 24 mg/kg daratumumab once weekly, along with this subjects also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Reporting group title
    Part 2: Daratumumab 8 mg/kg
    Reporting group description
    		 Subjects were administered with 8 full IV infusions of 8 mg/kg daratumumab once weekly for 8 weeks, then every 2 weeks (q2w) for 16 weeks, then every 4 weeks (q4w) until the subject experienced disease progression or unmanageable toxicity whichever came first, along with this subjects also received methylprednisolone 100 mg IV before treatment and 20–25 mg methylprednisolone orally for 2 days after all full infusions.

    Reporting group title
    Part 2: Daratumumab 16 mg/kg
    Reporting group description
    		 Subjects were administered with 8 full IV infusions of 16 mg/kg daratumumab once weekly for 7 weeks, then every 2 weeks (q2w) for 14 weeks, then every 4 weeks (q4w) until the subject experienced disease progression or unmanageable toxicity whichever came first, along with this subjects also received methylprednisolone 100 mg IV before treatment and 20–25 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Primary: Number of Subjects with Adverse Events

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    End point title
    		 Number of Subjects with Adverse Events [1]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. All-Treated Analysis Set included all enrolled subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to Week 28 (for Part 1) and up to approximately 2.5 years (for Part 2)
    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: Only descriptive statistical analysis was performed for this outcome measure.
    End point values
    		 Part 1: Daratumumab Less Than (<) 4 mg/kg Part 1:Daratumumab 4 mg/kg Part 1:Daratumumab 8 mg/kg Part 1:Daratumumab 16 mg/kg Part 1:Daratumumab 24 mg/kg Part 2: Daratumumab 8 mg/kg Part 2: Daratumumab 16 mg/kg
    Number of subjects analysed
    20
    3
    3
    3
    3
    30
    42
    Units: Subjects
    19
    3
    3
    3
    3
    30
    41
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORT)

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    End point title
    		 Overall Response Rate (ORT) [2]
    End point description
    Overall response defined as percentage of subjects who achieved sCR, CR ,VGPR or PR. Per IMWG criteria, sCR: defined as normal FLC ratio, and PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry; CR: Negative immunofixation on serum, urine and disappearance of tissue plasmacytomas and < 5% plasma cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or >= 90% reduction in serum M-protein plus urine M-protein level < 100mg/24 hrs; PR: >= 50% reduction of serum M-protein and reduction in 24 hrs urinary M-protein by >= 90% or <200 mg/24 hrs; if serum and urine M-protein are not measurable, decrease of >=50% in difference between involved and uninvolved FLC levels is required in place of M-protein criteria. All-Treated analysis set included subjects received at least 1 dose of study drug. Part 1, subjects treated with >=4 mg/kg daratumumab used for efficacy and <4 mg/kg considered therapeutic level.
    End point type
    Secondary
    End point timeframe
    Up to Week 28 (for Part 1) and Week 27 (for Part 2)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be reported for the specified arms only.
    End point values
    		 Part 1:Daratumumab 4 mg/kg Part 1:Daratumumab 8 mg/kg Part 1:Daratumumab 16 mg/kg Part 1:Daratumumab 24 mg/kg Part 2: Daratumumab 8 mg/kg Part 2: Daratumumab 16 mg/kg
    Number of subjects analysed
    3
    3
    3
    3
    30
    42
    Units: Percentage of subjects
        number (confidence interval 95%)
    33.3 (0.8 to 90.6)
    0 (0 to 0)
    33.6 (0.8 to 90.6)
    66.7 (9.4 to 99.2)
    10.0 (2.1 to 26.5)
    35.7 (21.6 to 52.0)
    No statistical analyses for this end point

    Secondary: Part 1: Time to Response

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    End point title
    		 Part 1: Time to Response [3]
    End point description
    Time to first response was defined as the time from the date of first dose of daratumumab to the date of initial documentation of a response (PR or better). Time to best response was defined as the time between the date of first dose of daratumumab and the date of the initial evaluation of the best response (PR or better) to treatment. Kaplan-Meier method was used to estimate the distribution of time to response and time to best response. All-Treated Analysis Set included enrolled subjects received at least 1 dose of study drug. Here '-99999' and '99999' means 'not estimable' due to less number of subjects with response. Daratumumab 4 mg/kg arm median and upper limit of CI was not estimable due to less number of subjects with events. 3 subjects on 16 mg/kg, 1 subject had event, median was set to uncensored value of time to event no lower or upper bound of 95% CI . For 8mg/kg, median and CI was not estimable due to less number of subjects.
    End point type
    Secondary
    End point timeframe
    Up to Week 28
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be reported for the specified arms only.
    End point values
    		 Part 1:Daratumumab 4 mg/kg Part 1:Daratumumab 8 mg/kg Part 1:Daratumumab 16 mg/kg Part 1:Daratumumab 24 mg/kg
    Number of subjects analysed
    3
    3
    3
    3
    Units: Months
    median (confidence interval 95%)
        Time to first response
    99999 (1.2 to 99999)
    99999 (-99999 to 99999)
    8.4 (-99999 to 99999)
    1.9 (0.5 to 1.9)
        Time to best response
    99999 (1.2 to 99999)
    99999 (-99999 to 99999)
    8.4 (-99999 to 99999)
    1.9 (0.5 to 1.9)
    No statistical analyses for this end point

    Secondary: Part 2: Time to Progression (TTP)

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    End point title
    		 Part 2: Time to Progression (TTP) [4]
    End point description
    TTP was defined as the number of days from the date of first infusion (Day 1) to the date of first record of disease progression. Disease progression (IMWG criteria): increase of 25 percent (%) from lowest response level in Serum M-component and/or (the absolute increase must be >=0.5 g/dL); urine M-component and/or (the absolute increase must be >=200 mg/24 hour; only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels (absolute increase must be >10 mg/dL); Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder. Median TTP was estimated by using the Kaplan-Meier method. All-Treated Analysis Set included enrolled subjects received at least 1 dose of study drug. Here "99999" indicates no upper limit of CI was not estimable due to less number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Up to Week 27
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be reported for the specified arms only.
    End point values
    		 Part 2: Daratumumab 8 mg/kg Part 2: Daratumumab 16 mg/kg
    Number of subjects analysed
    30
    42
    Units: Months
        median (confidence interval 95%)
    2.4 (1.4 to 3.5)
    5.6 (4.7 to 99999)
    No statistical analyses for this end point

    Secondary: Part 2: Duration of Response as Assessed Using the Method of Kaplan-Meier

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    End point title
    		 Part 2: Duration of Response as Assessed Using the Method of Kaplan-Meier [5]
    End point description
    Duration of response was calculated from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease, as defined in the International Myeloma Working Group (IMWG) criteria. Subset of All-Treated Analysis Set included all the subjects who had overall response in Part 2. Here "N" (number of subjects analyzed) signifies the number of subjects who were evaluable for this outcome measure. Here "99999" indicates that median and upper limit of CI was not estimable due to insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Up to Week 27
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be reported for the specified arms only.
    End point values
    		 Part 2: Daratumumab 8 mg/kg Part 2: Daratumumab 16 mg/kg
    Number of subjects analysed
    3
    15
    Units: Months
        median (full range (min-max))
    6.9 (6.2 to 10.6)
    99999 (5.6 to 99999)
    No statistical analyses for this end point

    Secondary: Part 2: Progression-Free Survival

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    End point title
    		 Part 2: Progression-Free Survival [6]
    End point description
    Progression free survival (PFS) was defined as the time between the date of first dose of daratumumab and either disease progression or death, whichever occurs first. All-Treated Analysis Set included all enrolled subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to Week 27
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be reported for the specified arms only.
    End point values
    		 Part 2: Daratumumab 8 mg/kg Part 2: Daratumumab 16 mg/kg
    Number of subjects analysed
    30
    42
    Units: Months
        median (confidence interval 95%)
    2.4 (1.4 to 3.5)
    5.6 (4.2 to 8.1)
    No statistical analyses for this end point

    Secondary: Part 2: Time to Response

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    End point title
    		 Part 2: Time to Response [7]
    End point description
    Time to first response was defined as the time from the date of first dose of daratumumab to the date of initial documentation of a response (PR or better). Time to best response was defined as the time between the date of first dose of daratumumab and the date of the initial evaluation of the best response (PR or better) to treatment. Time to VGPR (very good partial response) was defined as the time from the date of first dose of daratumumab to the date of initial documentation of VGPR response. The Kaplan-Meier method was used to estimate time to response. All-Treated analysis set included all enrolled subjects who received at least 1 dose of study drug. Here 'n' signifies number of subjects analyzed at specific time point. Here "99999" indicates no subject had VGPR or better response in daratumumab 8 mg/kg group. Hence, data was not analyzed.
    End point type
    Secondary
    End point timeframe
    Up to Week 27
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be reported for the specified arms only.
    End point values
    		 Part 2: Daratumumab 8 mg/kg Part 2: Daratumumab 16 mg/kg
    Number of subjects analysed
    30
    42
    Units: Months
    arithmetic mean (standard deviation)
        Time to first response (n=3, 15)
    1.36 ± 0.774
    1.33 ± 0.995
        Time to best response (n=3, 15)
    1.36 ± 0.774
    2.46 ± 2.800
        Time to VGPR or better response (n=0, 4)
    99999 ± 99999
    0.49 ± 0.000
    No statistical analyses for this end point

    Secondary: Part 2: Overall Survival

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    End point title
    		 Part 2: Overall Survival [8]
    End point description
    Overall Survival (OS) was defined as the number of days from administration of the first infusion (Day 1) to date of death. Median Overall Survival was estimated by using the Kaplan-Meier method. All-Treated Analysis Set included all enrolled subjects who received at least 1 dose of study drug. Here "99999" indicates CI was not estimable due to insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Approximately 3 years
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be reported for the specified arms only.
    End point values
    		 Part 2: Daratumumab 8 mg/kg Part 2: Daratumumab 16 mg/kg
    Number of subjects analysed
    30
    42
    Units: Months
        median (confidence interval 95%)
    18.2 (7.5 to 22.6)
    34.3 (19.9 to 99999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 28 (for Part 1) and approximately 2.5 years
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Part 1: Daratumumab < 4 mg/kg
    Reporting group description
    		 Subjects were administered with 7 full intravenous (IV) infusion of 0.005, 0.05, 0.1, 0.5, 1 and 2 milligram per kilogram body weight (mg/kg) daratumumab once weekly, along with this subjects also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Reporting group title
    Part 1:Daratumumab 4 mg/kg
    Reporting group description
    		 Subjects were administered with 7 full IV infusion of 4 mg/kg daratumumab once weekly, along with this subjects also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Reporting group title
    Part 1:Daratumumab 8 mg/kg (Experimental)
    Reporting group description
    		 Subjects were administered with 7 full IV infusion of 8 mg/kg daratumumab once weekly, along with this subjects also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Reporting group title
    Part 1 - Daratumumab 16 mg/kg
    Reporting group description
    		 Subjects were administered with 7 full IV infusion of 16 mg/kg daratumumab once weekly, along with this subjects also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Reporting group title
    Part 1 - Daratumumab 24 mg/kg
    Reporting group description
    		 Subjects were administered with 7 full IV infusion of 24 mg/kg daratumumab once weekly, along with this subjects also received methylprednisolone 80 mg IV injection before first 2 infusions and 40 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Reporting group title
    Part 2 - Daratumumab 8 mg/kg
    Reporting group description
    		 Subjects were administered with 8 full IV infusions of 8 mg/kg daratumumab once weekly for 8 weeks, then every 2 weeks (q2w) for 16 weeks, then every 4 weeks (q4w) until the subject experienced disease progression or unmanageable toxicity whichever came first, along with this subjects also received methylprednisolone 100 mg IV before treatment and 20–25 mg methylprednisolone orally for 2 days after all full infusions.

    Reporting group title
    Part 2 - Daratumumab 16 mg/kg
    Reporting group description
    		 Subjects were administered with 8 full IV infusions of 16 mg/kg daratumumab once weekly for 7 weeks, then every 2 weeks (q2w) for 14 weeks, then every 4 weeks (q4w) until the subject experienced disease progression or unmanageable toxicity whichever came first, along with this subjects also received methylprednisolone 100 mg IV before treatment and 20–25 mg methylprednisolone orally for 2 days after all full infusions. First 2 infusions were separated by 3 week washout period.

    Serious adverse events
    		 Part 1: Daratumumab < 4 mg/kg Part 1:Daratumumab 4 mg/kg Part 1:Daratumumab 8 mg/kg (Experimental) Part 1 - Daratumumab 16 mg/kg Part 1 - Daratumumab 24 mg/kg Part 2 - Daratumumab 8 mg/kg Part 2 - Daratumumab 16 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 20 (35.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    12 / 30 (40.00%)
    16 / 42 (38.10%)
         number of deaths (all causes)
    1
    0
    0
    1
    0
    25
    21
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasmacytoma
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine Release Syndrome
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    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
    Investigations
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crossmatch Incompatible
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Free Haemoglobin Present
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    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
    International Normalised Ratio Increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Limb Traumatic Amputation
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    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
    Atrial Flutter
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vith Nerve Paralysis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    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
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic Function Abnormal
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    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
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoporotic Fracture
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial Sepsis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Herpes Zoster
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metapneumovirus Infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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
    Pneumonia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    3 / 30 (10.00%)
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory Syncytial Virus Infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    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
    		 Part 1: Daratumumab < 4 mg/kg Part 1:Daratumumab 4 mg/kg Part 1:Daratumumab 8 mg/kg (Experimental) Part 1 - Daratumumab 16 mg/kg Part 1 - Daratumumab 24 mg/kg Part 2 - Daratumumab 8 mg/kg Part 2 - Daratumumab 16 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 20 (95.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    30 / 30 (100.00%)
    41 / 42 (97.62%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal Cell Carcinoma
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    3 / 42 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    6
    Benign Neoplasm of Skin
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    1 / 42 (2.38%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    1
    Hot Flush
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 30 (6.67%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    0
    0
    0
    9
    1
    Hypertension
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    3
    Hypotension
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Chest Discomfort
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    1
    0
    0
    6
    1
    Chest Pain
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    5 / 42 (11.90%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    5
    Chills
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 30 (10.00%)
    5 / 42 (11.90%)
         occurrences all number
    0
    0
    0
    0
    0
    9
    5
    Fatigue
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    13 / 30 (43.33%)
    19 / 42 (45.24%)
         occurrences all number
    3
    0
    0
    0
    0
    22
    22
    Influenza Like Illness
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    1 / 42 (2.38%)
         occurrences all number
    4
    0
    0
    1
    0
    1
    1
    Oedema Peripheral
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 30 (10.00%)
    1 / 42 (2.38%)
         occurrences all number
    1
    0
    0
    0
    0
    3
    1
    Pyrexia
         subjects affected / exposed
    7 / 20 (35.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    12 / 30 (40.00%)
    9 / 42 (21.43%)
         occurrences all number
    10
    0
    0
    6
    0
    16
    13
    Immune system disorders
    Cytokine Release Syndrome
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Hypersensitivity
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    0 / 42 (0.00%)
         occurrences all number
    1
    3
    0
    0
    0
    2
    0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 30 (3.33%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    1
    0
    Cough
         subjects affected / exposed
    4 / 20 (20.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    6 / 30 (20.00%)
    11 / 42 (26.19%)
         occurrences all number
    4
    1
    0
    0
    1
    10
    18
    Dysphonia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    8 / 30 (26.67%)
    7 / 42 (16.67%)
         occurrences all number
    0
    5
    0
    0
    0
    14
    7
    Epistaxis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 30 (6.67%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    Laryngitis Allergic
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 30 (10.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    1
    Nasal Congestion
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    4 / 30 (13.33%)
    7 / 42 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    4
    8
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 30 (6.67%)
    5 / 42 (11.90%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    7
    Productive Cough
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 30 (10.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    Rhinitis Allergic
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    12 / 30 (40.00%)
    10 / 42 (23.81%)
         occurrences all number
    1
    0
    0
    0
    0
    14
    10
    Throat Irritation
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    3 / 42 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    3
    Throat Tightness
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 30 (13.33%)
    5 / 42 (11.90%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    6
    Investigations
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    2 / 42 (4.76%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    Electrocardiogram QT Prolonged
         subjects affected / exposed
    5 / 20 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    10
    0
    0
    0
    0
    0
    2
    Free Haemoglobin Present
         subjects affected / exposed
    4 / 20 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    10
    0
    0
    0
    0
    0
    0
    Haptoglobin Decreased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Lymphocyte Count Decreased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    2
    Supraventricular Extrasystoles
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    5 / 30 (16.67%)
    4 / 42 (9.52%)
         occurrences all number
    4
    0
    0
    0
    0
    8
    6
    Dysgeusia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 30 (6.67%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Headache
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 30 (10.00%)
    4 / 42 (9.52%)
         occurrences all number
    1
    2
    0
    0
    0
    4
    5
    Hypoaesthesia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    2 / 42 (4.76%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    2
    Paraesthesia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    2
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    5 / 30 (16.67%)
    1 / 42 (2.38%)
         occurrences all number
    0
    1
    1
    0
    0
    5
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 20 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    3 / 42 (7.14%)
         occurrences all number
    6
    0
    0
    0
    0
    1
    3
    Haemolysis
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    0
    0
    Leukopenia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    5
    Lymphopenia
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    0 / 42 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    1
    0
    Monocytopenia
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    8
    1
    0
    0
    0
    0
    0
    Neutropenia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    4
    Thrombocytopenia
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 30 (6.67%)
    3 / 42 (7.14%)
         occurrences all number
    4
    0
    0
    0
    0
    2
    3
    Eye disorders
    Ocular Hyperaemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Vision Blurred
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 30 (6.67%)
    5 / 42 (11.90%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    5
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Aphthous Stomatitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 30 (6.67%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Constipation
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 30 (13.33%)
    4 / 42 (9.52%)
         occurrences all number
    1
    0
    0
    0
    0
    4
    4
    Diarrhoea
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    9 / 30 (30.00%)
    6 / 42 (14.29%)
         occurrences all number
    1
    1
    0
    0
    1
    12
    14
    Dry Mouth
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    0
    Dyspepsia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 30 (10.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    3
    Lip Oedema
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Mouth Ulceration
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 30 (13.33%)
    10 / 42 (23.81%)
         occurrences all number
    2
    2
    1
    0
    0
    5
    14
    Oesophagitis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 30 (10.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    1
    Vomiting
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    5 / 30 (16.67%)
    2 / 42 (4.76%)
         occurrences all number
    0
    1
    0
    0
    1
    6
    2
    Hepatobiliary disorders
    Hepatic Function Abnormal
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Eczema Asteatotic
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 30 (10.00%)
    2 / 42 (4.76%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    2
    Pruritus
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 30 (6.67%)
    1 / 42 (2.38%)
         occurrences all number
    0
    2
    0
    2
    0
    3
    1
    Rash
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 30 (13.33%)
    2 / 42 (4.76%)
         occurrences all number
    1
    1
    1
    0
    0
    5
    2
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Proteinuria
         subjects affected / exposed
    9 / 20 (45.00%)
    1 / 3 (33.33%)
    3 / 3 (100.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    12
    2
    3
    1
    1
    0
    0
    Renal Impairment
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 30 (13.33%)
    8 / 42 (19.05%)
         occurrences all number
    2
    0
    0
    0
    0
    5
    9
    Back Pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    3 / 30 (10.00%)
    14 / 42 (33.33%)
         occurrences all number
    1
    0
    0
    0
    1
    4
    16
    Bone Pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    6 / 30 (20.00%)
    4 / 42 (9.52%)
         occurrences all number
    1
    0
    0
    0
    0
    7
    4
    Kyphosis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 30 (10.00%)
    4 / 42 (9.52%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    6
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 30 (6.67%)
    4 / 42 (9.52%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    5
    Myalgia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    6 / 30 (20.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    0
    0
    0
    11
    1
    Pain in Extremity
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    6 / 42 (14.29%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    7
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Herpes Zoster
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 30 (13.33%)
    2 / 42 (4.76%)
         occurrences all number
    1
    0
    0
    0
    0
    4
    2
    Nasopharyngitis
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    7 / 30 (23.33%)
    16 / 42 (38.10%)
         occurrences all number
    2
    0
    0
    0
    2
    15
    26
    Oral Candidiasis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 30 (10.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    1
    Pneumonia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    1 / 42 (2.38%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    1
    Sinusitis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    4
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    8 / 30 (26.67%)
    11 / 42 (26.19%)
         occurrences all number
    0
    0
    0
    1
    0
    10
    20
    Urinary Tract Infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 30 (6.67%)
    2 / 42 (4.76%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    2
    Viral Infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Vulvovaginal Candidiasis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    4 / 42 (9.52%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    4
    Enzyme Abnormality
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 30 (3.33%)
    5 / 42 (11.90%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    13
    Hyponatraemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 30 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    2

    More information

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

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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