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    Clinical Trial Results:
    A Phase 2 Multicenter, Open-label Study to Determine the Efficacy and Safety of Pomalidomide (CC-4047) in Combination With Low-Dose Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma and Moderate or Severe Renal Impairment Including Subjects Undergoing Hemodialysis

    Summary
    EudraCT number
    		 2013-001903-36
    Trial protocol
    		 IT   GR   ES   GB   NL   AT   FR  
    Global end of trial date
    28 Jul 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    02 Sep 2022
    First version publication date
    13 Aug 2022
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CC-4047-MM-013
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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
    03 Sep 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate efficacy of the combination of pomalidomide and low-dose dexamethasone (LD-DEX) in subjects with relapsed or refractory multiple myeloma (RRMM) and impaired renal function.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Greece: 13
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    United Kingdom: 16
    Worldwide total number of subjects
    81
    EEA total number of subjects
    62
    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)
    15
    From 65 to 84 years
    64
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 81 participants treated

    Period 1
    Period 1 title
    Treatment Overall 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
    		 Cohort A
    Arm description
    		 Participants with moderate renal impairment of 30 ≤ eGFR < 45 mL/min/1.73 m^2 are treated with 4 mg/day Pomalidomide on days 1-21 of a 28-day cycle + 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) Dexamethasone on days 1, 8, 15, 22 of a 28-day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old)

    Investigational medicinal product name
    Pomalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    4 mg

    Arm title
    		 Cohort B
    Arm description
    		 Participant with severe renal impairment of eGFR < 30 mL/min/1.73 m^2 not requiring hemodialysis are treated with 4 mg/day Pomalidomide on days 1-21 of a 28-day cycle + 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) Dexamethasone on days 1, 8, 15, 22 of a 28-day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old)

    Investigational medicinal product name
    Pomalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    4 mg

    Arm title
    		 Cohort C
    Arm description
    		 Participant with severe renal impairment Participant with severe renal impairment of eGFR < 30 mL/min/1.73 m^2 requiring hemodialysis are treated with 4 mg/day Pomalidomide on days 1-21 of a 28-day cycle + 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) Dexamethasone on days 1, 8, 15, 22 of a 28-day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old)

    Investigational medicinal product name
    Pomalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    4 mg

    Number of subjects in period 1
    		Cohort A Cohort B Cohort C
    Started
    33
    34
    14
    Completed
    0
    0
    0
    Not completed
    33
    34
    14
         Adverse event, serious fatal
    1
    8
    5
         Consent withdrawn by subject
    1
    1
    1
         Adverse event, non-fatal
    6
    8
    4
         Progressive Disease
    22
    17
    4
         Other reasons
    3
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Participants with moderate renal impairment of 30 ≤ eGFR < 45 mL/min/1.73 m^2 are treated with 4 mg/day Pomalidomide on days 1-21 of a 28-day cycle + 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) Dexamethasone on days 1, 8, 15, 22 of a 28-day cycle

    Reporting group title
    Cohort B
    Reporting group description
    		 Participant with severe renal impairment of eGFR < 30 mL/min/1.73 m^2 not requiring hemodialysis are treated with 4 mg/day Pomalidomide on days 1-21 of a 28-day cycle + 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) Dexamethasone on days 1, 8, 15, 22 of a 28-day cycle

    Reporting group title
    Cohort C
    Reporting group description
    		 Participant with severe renal impairment Participant with severe renal impairment of eGFR < 30 mL/min/1.73 m^2 requiring hemodialysis are treated with 4 mg/day Pomalidomide on days 1-21 of a 28-day cycle + 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) Dexamethasone on days 1, 8, 15, 22 of a 28-day cycle

    Reporting group values
    		 Cohort A Cohort B Cohort C Total
    Number of subjects
    		 33 34 14 81
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 7 4 4 15
        From 65-84 years
    		 24 30 10 64
        85 years and over
    		 2 0 0 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 71.4 ( 8.77 ) 71.6 ( 7.56 ) 68.2 ( 7.20 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 9 18 5 32
        Male
    		 24 16 9 49
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 0 0 0
        White
    		 33 33 14 80
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 0 1 0 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 0 0 2
        Not Hispanic or Latino
    		 31 34 14 79
        Unknown or Not Reported
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Participants with moderate renal impairment of 30 ≤ eGFR < 45 mL/min/1.73 m^2 are treated with 4 mg/day Pomalidomide on days 1-21 of a 28-day cycle + 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) Dexamethasone on days 1, 8, 15, 22 of a 28-day cycle

    Reporting group title
    Cohort B
    Reporting group description
    		 Participant with severe renal impairment of eGFR < 30 mL/min/1.73 m^2 not requiring hemodialysis are treated with 4 mg/day Pomalidomide on days 1-21 of a 28-day cycle + 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) Dexamethasone on days 1, 8, 15, 22 of a 28-day cycle

    Reporting group title
    Cohort C
    Reporting group description
    		 Participant with severe renal impairment Participant with severe renal impairment of eGFR < 30 mL/min/1.73 m^2 requiring hemodialysis are treated with 4 mg/day Pomalidomide on days 1-21 of a 28-day cycle + 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) Dexamethasone on days 1, 8, 15, 22 of a 28-day cycle

    Primary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR) [1]
    End point description
    Overall response rate (ORR) is defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) using the following international myeloma working group (IMWG) uniform response criteria: Complete response (CR): Negative immunofixation of serum and urine, and disappearance of any soft tissue plasmacytomas, and < 5% plasma cells in bone marrow Partial response (PR): ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% or to < 200 mg per 24 hours
    End point type
    Primary
    End point timeframe
    Up to 34 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: Only summary statistics planned for this endpoint.
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    33
    34
    14
    Units: Percentage of Participants
        number (confidence interval 95%)
    39.4 (22.9 to 57.9)
    32.4 (17.4 to 50.5)
    14.3 (1.8 to 42.8)
    No statistical analyses for this end point

    Secondary: Renal Response

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    End point title
    		 Renal Response
    End point description
    Renal response is defined as the percentage of confirmed responders of renal complete response (CRrenal), or renal partial response (PRrenal), or renal minor response (MRrenal) according to the following criteria defined by Ludwig and Dimopoulos: Renal Complete Response (CRrenal): Sustained (ie, at least 2 months) improvement of baseline GFR from < 50 mL/min/1.73 m^2 to ≥ 60 mL/min/1.73 m^2 (stage ≥ 3 to stage 1/2 chronic kidney disease) Renal Partial Response (PRrenal): Sustained improvement of baseline eGFR from < 15 mL/min/1.73 m^2 to 30-59 mL/min/1.73 m^2 Renal Minor Response (MRrenal): Sustained improvement of baseline eGFR of < 15 mL/min/1.73 m^2 to 15-29 mL/min/1.73 m^2
    End point type
    Secondary
    End point timeframe
    Up to 88 months
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    33
    34
    14
    Units: Percentage of participants
        number (confidence interval 95%)
    18.2 (7.0 to 35.5)
    35.3 (19.7 to 53.5)
    7.1 (0.2 to 33.9)
    No statistical analyses for this end point

    Secondary: Time to Response (TTR)

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    End point title
    		 Time to Response (TTR)
    End point description
    Time to response (TTR) is assessed as the time from start of treatment to the first documented response (partial response or better) based on international myeloma working group criteria (IMWG) Partial Response (PR): ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% or to < 200 mg per 24 hours
    End point type
    Secondary
    End point timeframe
    Up to 88 months
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    14
    11
    2
    Units: Months
        median (full range (min-max))
    1.42 (0.9 to 11.3)
    0.95 (0.9 to 5.8)
    1.91 (1.0 to 2.9)
    No statistical analyses for this end point

    Secondary: Time to Renal Response (TTRR)

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    End point title
    		 Time to Renal Response (TTRR)
    End point description
    Time to Renal Response (TTRR) is assessed as the time from start of treatment until the date when criteria defined by Ludwig and Dimopoulos for renal response will be first met Renal Complete Response (CRrenal): Sustained (ie, at least 2 months) improvement of baseline GFR from < 50 mL/min/1.73 m^2 to ≥ 60 mL/min/1.73 m^2 (stage ≥ 3 to stage 1/2 chronic kidney disease) Renal Partial Response (PRrenal): Sustained improvement of baseline eGFR from < 15 mL/min/1.73 m^2 to 30-59 mL/min/1.73 m^2 Renal Minor Response (MRrenal): Sustained improvement of baseline eGFR of < 15 mL/min/1.73 m^2 to 15-29 mL/min/1.73 m^2
    End point type
    Secondary
    End point timeframe
    Up to 88 months
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    6
    12
    1
    Units: Months
        median (full range (min-max))
    1.0 (1.0 to 4.6)
    0.95 (0.9 to 6.0)
    3.1 (3.1 to 3.1)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR)

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    End point title
    		 Duration of Response (DoR)
    End point description
    Duration of response (DoR) is defined as time from the first response (partial response or better) to the first documented progressive disease Partial response (PR): ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% or to < 200 mg per 24 hours 99999= Not estimable
    End point type
    Secondary
    End point timeframe
    Up to 88 months
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    14
    11
    2
    Units: Months
        median (confidence interval 95%)
    10.5 (4.60 to 19.20)
    4.6 (2.79 to 12.53)
    99999 (1.45 to 99999)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    PFS is assessed as the time from start of treatment until the time of progressive disease (PD) or death from any cause on study treatment, whichever comes first. Participants not experiencing a documented progression will be censored at the time of their last tumor assessment PD: Increase of 25% from lowest response value in any one or more of the following: - Serum M-component - Urine M-component - Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be > 10 mg/L) - Bone marrow plasma cell percentage (absolute % must be ≥ 10%) - Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas - Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) that can be attributed solely to the plasma cell proliferative disorder
    End point type
    Secondary
    End point timeframe
    Up to 88 months
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    33
    34
    14
    Units: Months
        median (confidence interval 95%)
    6.9 (4.60 to 9.30)
    4.1 (2.79 to 6.51)
    2.4 (0.95 to 6.41)
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP)

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    End point title
    		 Time to Progression (TTP)
    End point description
    Time to progression (TTP) is assessed as the time from study treatment start until progressive disease. Deaths due to causes other than progression will be censored. Participants not experiencing a documented progression will be censored at the time of their last tumor assessment PD: Increase of 25% from lowest response value in any one or more of the following: - Serum M-component - Urine M-component - Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be > 10 mg/L) - Bone marrow plasma cell percentage (absolute % must be ≥ 10%) - Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas - Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) that can be attributed solely to the plasma cell proliferative disorder 99999= Not Estimable
    End point type
    Secondary
    End point timeframe
    Up to 88 months
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    33
    34
    14
    Units: Months
        median (confidence interval 95%)
    7.4 (4.60 to 14.50)
    4.6 (3.09 to 6.67)
    4.0 (0.95 to 99999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival (OS) is assessed as the time from start of treatment until the time of death from any cause. If no death is recorded, the participant will be censored at the time the participant was last known to be alive
    End point type
    Secondary
    End point timeframe
    Up to 88 months
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    33
    34
    14
    Units: Months
        median (confidence interval 95%)
    16.4 (7.79 to 31.59)
    11.8 (6.35 to 14.27)
    5.2 (1.81 to 9.67)
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Participants with Treatment Emergent Adverse Events (TEAEs)
    End point description
    Treatment Emergent Adverse Event (TEAE) is defined as an adverse event (AE) occurring or worsening on or after the first treatment of study medication graded by the national cancer institute common terminology criteria (version 4.0) Grade 3 = Severe event Grade 4 = Life threatening event
    End point type
    Secondary
    End point timeframe
    From first dose to 28 days after last dose (Up to approximately 10 months)
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    33
    34
    14
    Units: Percentage of participants
    number (not applicable)
        TEAE
    100
    100
    100
        TEAE related to Pomalidomide
    90.9
    85.3
    92.9
        TEAE related to low dose Dexamethasone
    63.6
    50.0
    50.0
        Grade 3-4 TEAE
    93.9
    91.2
    92.9
        Grade 3-4 TEAE related to Pomalidomide
    75.8
    67.6
    85.7
        Grade 3-4 TEAE related to low dose Dexamethasone
    27.3
    26.5
    35.7
        Serious TEAE
    57.6
    67.6
    85.7
        Serious TEAE related to Pomalidomide
    21.2
    35.3
    28.6
        Serious TEAE related to low dose Dexamethasone
    24.2
    17.6
    21.4
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-Time Curve from Time Zero to the Last Measured Time Point (AUC(0-t))

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    End point title
    		 Area Under the Plasma Concentration-Time Curve from Time Zero to the Last Measured Time Point (AUC(0-t))
    End point description
    Area under the Pomalidomide plasma concentration-time curve from time zero to the last measured time point (AUC(0-t))
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1, 2, 3, 4, 6, and 8 hours post-dose on cycle 1 day 8
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    8
    5
    7
    Units: h*ug/L
        geometric mean (geometric coefficient of variation)
    899.84 ( 38.7 )
    944.93 ( 84.5 )
    427.49 ( 140.8 )
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-Time Curve from Time Zero to infinity (AUC(0-inf))

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    End point title
    		 Area Under the Plasma Concentration-Time Curve from Time Zero to infinity (AUC(0-inf))
    End point description
    Area under the Pomalidomide plasma concentration-time curve from time zero to infinity (AUC(0-inf))
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1, 2, 3, 4, 6, and 8 hours post-dose on cycle 1 day 8
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    8
    2
    4
    Units: h*ug/L
        geometric mean (geometric coefficient of variation)
    1581.54 ( 212.0 )
    1570.07 ( 206.8 )
    834.13 ( 50.8 )
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax)

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax)
    End point description
    Maximum observed Pomalidomide plasma concentration (Cmax)
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1, 2, 3, 4, 6, and 8 hours post-dose on cycle 1 day 8
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    8
    5
    7
    Units: ug/L
        geometric mean (geometric coefficient of variation)
    75.64 ( 24.8 )
    111.02 ( 48.3 )
    61.82 ( 74.0 )
    No statistical analyses for this end point

    Secondary: Time of Maximum Observed Plasma Concentration (Tmax)

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    End point title
    		 Time of Maximum Observed Plasma Concentration (Tmax)
    End point description
    Time of maximum observed Pomalidomide plasma concentration (Tmax)
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1, 2, 3, 4, 6, and 8 hours post-dose on cycle 1 day 8
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    8
    5
    7
    Units: Hours
        geometric mean (geometric coefficient of variation)
    3.35 ( 24.6 )
    3.52 ( 55.2 )
    2.33 ( 51.1 )
    No statistical analyses for this end point

    Secondary: Apparent Terminal Half-life (t1/2)

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    End point title
    		 Apparent Terminal Half-life (t1/2)
    End point description
    Pomalidomide terminal half-life (t1/2)
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1, 2, 3, 4, 6, and 8 hours post-dose on cycle 1 day 8
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    8
    2
    4
    Units: Hours
        geometric mean (geometric coefficient of variation)
    11.81 ( 268.5 )
    8.34 ( 75.7 )
    7.16 ( 45.5 )
    No statistical analyses for this end point

    Secondary: Apparent Clearance (CL/F)

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    End point title
    		 Apparent Clearance (CL/F)
    End point description
    Pomalidomide plasma apparent clearance (CL/F)
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1, 2, 3, 4, 6, and 8 hours post-dose on cycle 1 day 8
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    8
    2
    4
    Units: L/h
        geometric mean (geometric coefficient of variation)
    2.53 ( 212.0 )
    2.55 ( 206.8 )
    4.80 ( 50.8 )
    No statistical analyses for this end point

    Secondary: Apparent Terminal Volume of Distribution (Vz/F)

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    End point title
    		 Apparent Terminal Volume of Distribution (Vz/F)
    End point description
    Pomalidomide apparent terminal volume of distribution (Vz/F)
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1, 2, 3, 4, 6, and 8 hours post-dose on cycle 1 day 8
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    8
    2
    4
    Units: (L)
        geometric mean (geometric coefficient of variation)
    43.10 ( 31.1 )
    30.67 ( 68.0 )
    49.51 ( 106.7 )
    No statistical analyses for this end point

    Post-hoc: Overall Response Rate (ORR) Post-hoc

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    End point title
    		 Overall Response Rate (ORR) Post-hoc
    End point description
    Overall response rate (ORR) is defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) using the following international myeloma working group (IMWG) uniform response criteria: Complete response (CR): Negative immunofixation of serum and urine, and disappearance of any soft tissue plasmacytomas, and < 5% plasma cells in bone marrow Partial response (PR): ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% or to < 200 mg per 24 hours
    End point type
    Post-hoc
    End point timeframe
    Up to 88 months
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    33
    34
    14
    Units: Percentage of participants
        number (confidence interval 95%)
    42.4 (25.5 to 60.8)
    32.4 (17.4 to 50.5)
    14.3 (1.8 to 42.8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events and Serious Adverse Events were monitored from first dose to 28 days post last dose (Up to 10 months). Participants were assessed for All Cause Mortality from their first dose until the study was completed (up to 88 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    MedDRA24.0
    Reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Participants with moderate renal impairment of 30 ≤ eGFR < 45 mL/min/1.73 m^2 are treated with 4 mg/day Pomalidomide on days 1-21 of a 28-day cycle + 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old Dexamethasone on days 1, 8, 15, 22 of a 28-day cycle

    Reporting group title
    Cohort C
    Reporting group description
    		 Participant with severe renal impairment Participant with severe renal impairment of eGFR < 30 mL/min/1.73 m^2 requiring hemodialysis are treated with 4 mg/day Pomalidomide on days 1-21 of a 28-day cycle + 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old Dexamethasone on days 1, 8, 15, 22 of a 28-day cycle

    Reporting group title
    Cohort B
    Reporting group description
    		 Participant with severe renal impairment of eGFR < 30 mL/min/1.73 m^2 not requiring hemodialysis are treated with 4 mg/day Pomalidomide on days 1-21 of a 28-day cycle + 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old Dexamethasone on days 1, 8, 15, 22 of a 28-day cycle

    Serious adverse events
    		 Cohort A Cohort C Cohort B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 33 (57.58%)
    12 / 14 (85.71%)
    23 / 34 (67.65%)
         number of deaths (all causes)
    25
    13
    31
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Meningioma
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Plasma cell leukaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 14 (7.14%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypoperfusion
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hyperthermia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 14 (7.14%)
    3 / 34 (8.82%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypogammaglobulinaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 14 (7.14%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    3 / 34 (8.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural hypotension
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    Pericardial disease
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    3 / 34 (8.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    5 / 34 (14.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Neutropenia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Diarrhoea
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pyoderma gangrenosum
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 14 (7.14%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Urinary retention
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Gastroenteritis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Leishmaniasis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 33 (24.24%)
    1 / 14 (7.14%)
    4 / 34 (11.76%)
         occurrences causally related to treatment / all
    3 / 8
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Pneumonia bacterial
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia cytomegaloviral
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Respiratory tract infection fungal
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Electrolyte imbalance
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort A Cohort C Cohort B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 33 (100.00%)
    14 / 14 (100.00%)
    34 / 34 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    2
    Hypertension
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    2 / 34 (5.88%)
         occurrences all number
    0
    1
    2
    Haemorrhage
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Hypotension
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 14 (21.43%)
    4 / 34 (11.76%)
         occurrences all number
    0
    4
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    8 / 33 (24.24%)
    5 / 14 (35.71%)
    5 / 34 (14.71%)
         occurrences all number
    11
    5
    6
    Catheter site pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Chills
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    General physical health deterioration
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    0
    Fatigue
         subjects affected / exposed
    10 / 33 (30.30%)
    4 / 14 (28.57%)
    9 / 34 (26.47%)
         occurrences all number
    11
    5
    12
    Hypothermia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    5 / 33 (15.15%)
    4 / 14 (28.57%)
    7 / 34 (20.59%)
         occurrences all number
    5
    4
    10
    Pyrexia
         subjects affected / exposed
    9 / 33 (27.27%)
    3 / 14 (21.43%)
    8 / 34 (23.53%)
         occurrences all number
    17
    3
    13
    Immune system disorders
    Immunosuppression
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    2
    0
    1
    Cough
         subjects affected / exposed
    5 / 33 (15.15%)
    2 / 14 (14.29%)
    8 / 34 (23.53%)
         occurrences all number
    8
    2
    12
    Dyspnoea
         subjects affected / exposed
    7 / 33 (21.21%)
    1 / 14 (7.14%)
    6 / 34 (17.65%)
         occurrences all number
    8
    1
    7
    Epistaxis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    3
    Rhinorrhoea
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    2
    0
    1
    Productive cough
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    2
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    0
    Confusional state
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 14 (7.14%)
    2 / 34 (5.88%)
         occurrences all number
    1
    1
    2
    Anxiety
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Insomnia
         subjects affected / exposed
    5 / 33 (15.15%)
    1 / 14 (7.14%)
    5 / 34 (14.71%)
         occurrences all number
    6
    1
    5
    Depressed mood
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    0
    Sleep disorder
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 14 (14.29%)
    3 / 34 (8.82%)
         occurrences all number
    0
    4
    4
    Blood calcium decreased
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 14 (14.29%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 14 (7.14%)
    4 / 34 (11.76%)
         occurrences all number
    4
    1
    4
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    Procalcitonin increased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 14 (14.29%)
    0 / 34 (0.00%)
         occurrences all number
    1
    2
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    0
    Fall
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    9
    0
    2
    Procedural hypotension
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 14 (14.29%)
    1 / 34 (2.94%)
         occurrences all number
    1
    3
    1
    Atrial fibrillation
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 14 (21.43%)
    1 / 34 (2.94%)
         occurrences all number
    0
    5
    1
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    0
    Dizziness
         subjects affected / exposed
    4 / 33 (12.12%)
    0 / 14 (0.00%)
    4 / 34 (11.76%)
         occurrences all number
    4
    0
    5
    Headache
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    2
    0
    3
    Paraesthesia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Monoplegia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 14 (21.43%)
    6 / 34 (17.65%)
         occurrences all number
    2
    5
    6
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    3
    Tremor
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    2
    0
    3
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    6 / 33 (18.18%)
    5 / 14 (35.71%)
    8 / 34 (23.53%)
         occurrences all number
    7
    10
    20
    Anaemia
         subjects affected / exposed
    26 / 33 (78.79%)
    9 / 14 (64.29%)
    15 / 34 (44.12%)
         occurrences all number
    46
    20
    23
    Lymphopenia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    3
    Neutropenia
         subjects affected / exposed
    26 / 33 (78.79%)
    9 / 14 (64.29%)
    21 / 34 (61.76%)
         occurrences all number
    67
    25
    43
    Thrombocytopenia
         subjects affected / exposed
    19 / 33 (57.58%)
    9 / 14 (64.29%)
    16 / 34 (47.06%)
         occurrences all number
    23
    21
    21
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    2
    0
    2
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    1
    0
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 14 (7.14%)
    1 / 34 (2.94%)
         occurrences all number
    2
    1
    1
    Abdominal distension
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 14 (7.14%)
    1 / 34 (2.94%)
         occurrences all number
    1
    1
    1
    Constipation
         subjects affected / exposed
    7 / 33 (21.21%)
    1 / 14 (7.14%)
    7 / 34 (20.59%)
         occurrences all number
    8
    1
    8
    Diarrhoea
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 14 (7.14%)
    6 / 34 (17.65%)
         occurrences all number
    11
    1
    6
    Dyspepsia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    2
    0
    1
    Dysphagia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    2
    0
    1
    Haematochezia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 14 (7.14%)
    2 / 34 (5.88%)
         occurrences all number
    1
    1
    2
    Nausea
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 14 (14.29%)
    6 / 34 (17.65%)
         occurrences all number
    2
    2
    7
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 14 (7.14%)
    2 / 34 (5.88%)
         occurrences all number
    2
    1
    2
    Hyperhidrosis
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    2
    0
    1
    Dry skin
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    1
    1
    0
    Pruritus
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 14 (7.14%)
    2 / 34 (5.88%)
         occurrences all number
    2
    1
    2
    Rash maculo-papular
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    2
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    2
    Haematuria
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Renal failure
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    4 / 34 (11.76%)
         occurrences all number
    2
    0
    5
    Back pain
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 14 (7.14%)
    3 / 34 (8.82%)
         occurrences all number
    4
    1
    3
    Bone pain
         subjects affected / exposed
    4 / 33 (12.12%)
    1 / 14 (7.14%)
    4 / 34 (11.76%)
         occurrences all number
    4
    1
    7
    Muscle spasms
         subjects affected / exposed
    6 / 33 (18.18%)
    1 / 14 (7.14%)
    4 / 34 (11.76%)
         occurrences all number
    6
    1
    6
    Pain in extremity
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 14 (7.14%)
    2 / 34 (5.88%)
         occurrences all number
    2
    1
    2
    Neck pain
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    2
    2
    0
    Spinal pain
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    1
    0
    3
    Cellulitis
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    0
    Escherichia infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    2
    0
    2
    Herpes virus infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    2 / 34 (5.88%)
         occurrences all number
    0
    1
    2
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    4 / 34 (11.76%)
         occurrences all number
    2
    0
    5
    Localised infection
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 14 (7.14%)
    4 / 34 (11.76%)
         occurrences all number
    3
    1
    7
    Pneumonia
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 14 (21.43%)
    3 / 34 (8.82%)
         occurrences all number
    2
    3
    3
    Oral candidiasis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    2
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    6 / 33 (18.18%)
    1 / 14 (7.14%)
    2 / 34 (5.88%)
         occurrences all number
    6
    1
    2
    Sepsis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Skin infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 14 (7.14%)
    2 / 34 (5.88%)
         occurrences all number
    4
    2
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    8 / 34 (23.53%)
         occurrences all number
    3
    0
    11
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Decreased appetite
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    5 / 34 (14.71%)
         occurrences all number
    2
    0
    7
    Hyperglycaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 14 (14.29%)
    2 / 34 (5.88%)
         occurrences all number
    0
    4
    2
    Hypercalcaemia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 14 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    2
    0
    1
    Fluid overload
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    2
    Hyperuricaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    1
    1
    0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    2 / 34 (5.88%)
         occurrences all number
    0
    1
    2
    Hyperkalaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 14 (21.43%)
    4 / 34 (11.76%)
         occurrences all number
    3
    4
    6
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 14 (14.29%)
    2 / 34 (5.88%)
         occurrences all number
    1
    2
    2
    Hypocalcaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 14 (14.29%)
    6 / 34 (17.65%)
         occurrences all number
    1
    2
    7
    Hypokalaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    3 / 34 (8.82%)
         occurrences all number
    0
    1
    4
    Hypomagnesaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 14 (7.14%)
    0 / 34 (0.00%)
         occurrences all number
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Nov 2013
    Clarification about concomitant medications and additional assessments
    24 Jun 2014
    Updating biopsy assessments during screening and updated inclusion criteria

    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
    For support, Contact us.
    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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