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    Clinical Trial Results:
    A Phase 1b Multicenter, Open-label, Expansion Study to Assess the Safety and Efficacy of AMG 420 in Subjects With Relapsed and/or Refractory Multiple Myeloma

    Summary
    EudraCT number
    		 2018-002879-17
    Trial protocol
    		 BE   ES   FR  
    Global end of trial date
    21 Apr 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    08 Jul 2023
    First version publication date
    14 Apr 2023
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    In main objective of trial: Should be 400 µg/day and and 600 µg/day instead of “mg”.

    Trial information

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    Trial identification
    Sponsor protocol code
    20160370
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03836053
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks,CA, United States,
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, medinfo@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, medinfo@amgen.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
    21 Apr 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Apr 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to establish the safety and tolerability of AMG 420 at dose levels of 400 µg/day and 600 µg/day in participants with relapsed and/or refractory multiple myeloma (RRMM).
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Mar 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    14
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 10 centers in Australia, Belgium, Japan, Switzerland, and the United States from 04 March 2019 to 21 April 2022.

    Pre-assignment
    Screening details
    		 23 participants were enrolled and all 23 of those participants received study drug.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AMG 420 200 µg/day
    Arm description
    		 28 day continuous intravenous infusion of AMG 420 200 µg/day followed by a 2 week treatment-free interval, until progressive disease (PD) or relapse as defined by International Myeloma Working Group (IMWG) response criteria, unacceptable safety events, next anti-multiple myeloma treatment, or other reason for permanent treatment discontinuation
    Arm type
    		 Experimental

    Investigational medicinal product name
    AMG 420
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AMG 420 was given as a 28 day continuous intravenous infusion followed by a 2 week treatment-free interval, until PD or relapse as defined by IMWG response criteria, unacceptable safety events, next anti-multiple myeloma treatment, or other reason for permanent treatment discontinuation

    Arm title
    		 AMG 420 400 µg/day
    Arm description
    		 28 day continuous intravenous infusion of AMG 420 400 µg/day followed by a 2 week treatment-free interval, until PD or relapse as defined by IMWG response criteria, unacceptable safety events, next anti-multiple myeloma treatment, or other reason for permanent treatment discontinuation
    Arm type
    		 Experimental

    Investigational medicinal product name
    AMG 420
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AMG 420 was given as a 28 day continuous intravenous infusion followed by a 2 week treatment-free interval, until PD or relapse as defined by IMWG response criteria, unacceptable safety events, next anti-multiple myeloma treatment, or other reason for permanent treatment discontinuation

    Arm title
    		 AMG 420 600 µg/day
    Arm description
    		 28 day continuous intravenous infusion of AMG 420 600 µg/day followed by a 2 week treatment-free interval, until PD or relapse as defined by IMWG response criteria, unacceptable safety events, next anti-multiple myeloma treatment, or other reason for permanent treatment discontinuation
    Arm type
    		 Experimental

    Investigational medicinal product name
    AMG 420
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AMG 420 was given as a 28 day continuous intravenous infusion followed by a 2 week treatment-free interval, until PD or relapse as defined by IMWG response criteria, unacceptable safety events, next anti-multiple myeloma treatment, or other reason for permanent treatment discontinuation

    Number of subjects in period 1
    		AMG 420 200 µg/day AMG 420 400 µg/day AMG 420 600 µg/day
    Started
    1
    12
    10
    Completed
    0
    2
    0
    Not completed
    1
    10
    10
         Adverse event, serious fatal
    1
    6
    4
         Withdrawal of consent from study
    -
    -
    1
         Protocol-specified criteria
    -
    2
    1
         Decision by sponsor
    -
    2
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AMG 420 200 µg/day
    Reporting group description
    		 28 day continuous intravenous infusion of AMG 420 200 µg/day followed by a 2 week treatment-free interval, until progressive disease (PD) or relapse as defined by International Myeloma Working Group (IMWG) response criteria, unacceptable safety events, next anti-multiple myeloma treatment, or other reason for permanent treatment discontinuation

    Reporting group title
    AMG 420 400 µg/day
    Reporting group description
    		 28 day continuous intravenous infusion of AMG 420 400 µg/day followed by a 2 week treatment-free interval, until PD or relapse as defined by IMWG response criteria, unacceptable safety events, next anti-multiple myeloma treatment, or other reason for permanent treatment discontinuation

    Reporting group title
    AMG 420 600 µg/day
    Reporting group description
    		 28 day continuous intravenous infusion of AMG 420 600 µg/day followed by a 2 week treatment-free interval, until PD or relapse as defined by IMWG response criteria, unacceptable safety events, next anti-multiple myeloma treatment, or other reason for permanent treatment discontinuation

    Reporting group values
    		 AMG 420 200 µg/day AMG 420 400 µg/day AMG 420 600 µg/day Total
    Number of subjects
    		 1 12 10 23
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 1 6 7 14
        From 65-84 years
    		 0 6 3 9
        85 years and over
    		 0 0 0 0
    Age Continuous
    99999 = No data presented because there was only 1 participant analyzed.
    Units: years
        arithmetic mean (standard deviation)
    		 49.0 ± 99999 64.7 ± 6.7 60.8 ± 11.7 -
    Sex: Female, Male
    Units: participants
        Female
    		 1 3 5 9
        Male
    		 0 9 5 14
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0
        Not Hispanic or Latino
    		 1 12 10 23
        Unknown or Not Reported
    		 0 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 1 0 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 2 3 5
        White
    		 0 10 7 17
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    AMG 420 200 µg/day
    Reporting group description
    		 28 day continuous intravenous infusion of AMG 420 200 µg/day followed by a 2 week treatment-free interval, until progressive disease (PD) or relapse as defined by International Myeloma Working Group (IMWG) response criteria, unacceptable safety events, next anti-multiple myeloma treatment, or other reason for permanent treatment discontinuation

    Reporting group title
    AMG 420 400 µg/day
    Reporting group description
    		 28 day continuous intravenous infusion of AMG 420 400 µg/day followed by a 2 week treatment-free interval, until PD or relapse as defined by IMWG response criteria, unacceptable safety events, next anti-multiple myeloma treatment, or other reason for permanent treatment discontinuation

    Reporting group title
    AMG 420 600 µg/day
    Reporting group description
    		 28 day continuous intravenous infusion of AMG 420 600 µg/day followed by a 2 week treatment-free interval, until PD or relapse as defined by IMWG response criteria, unacceptable safety events, next anti-multiple myeloma treatment, or other reason for permanent treatment discontinuation

    Primary: Number of Participants With Dose-limiting Toxicities (DLTs)

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    End point title
    		 Number of Participants With Dose-limiting Toxicities (DLTs) [1]
    End point description
    DLTs were graded using Common Terminology Criteria for Adverse Events (CTCAE) v5.0, with the exception of cytokine release syndrome (CRS) and tumor lysis syndrome (TLS), which graded using the criteria referenced in the publication by Lee et al, 2014 and the Cairo Bishop criteria referenced in the publication by Coiffier et al, 2008 respectively. DLT evaluation analysis set includes participants who completed the DLT evaluable period or experienced a DLT any time during the DLT evaluable period.
    End point type
    Primary
    End point timeframe
    Day 1 to Week 4
    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: No statistical analysis was planned for this end point.
    End point values
    		 AMG 420 200 µg/day AMG 420 400 µg/day AMG 420 600 µg/day
    Number of subjects analysed
    1
    11
    8
    Units: Participants
    1
    1
    0
    No statistical analyses for this end point

    Primary: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)

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    End point title
    		 Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) [2]
    End point description
    The severity of TEAEs were graded using the CTCAE version 5.0 with the exception of CRS and TLS, which graded using the criteria referenced in the publication by Lee et al, 2014 and the Cairo Bishop criteria referenced in the publication by Coiffier et al, 2008. Any clinically significant changes in vital signs, electrocardiograms (ECGs) and clinical laboratory tests were recorded as TEAEs.
    End point type
    Primary
    End point timeframe
    Up to approximately 3 years
    Notes
    [2] - 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: No statistical analysis was planned for this end point.
    End point values
    		 AMG 420 200 µg/day AMG 420 400 µg/day AMG 420 600 µg/day
    Number of subjects analysed
    1
    12
    10
    Units: Participants
    1
    12
    10
    No statistical analyses for this end point

    Primary: Number of Participants Who Experiences a Treatment-related TEAE

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    End point title
    		 Number of Participants Who Experiences a Treatment-related TEAE [3]
    End point description
    The severity of treatment-related TEAEs were graded using the CTCAE version 5.0 with the exception of CRS and TLS, which graded using the criteria referenced in the publication by Lee et al, 2014 and the Cairo Bishop criteria referenced in the publication by Coiffier et al, 2008.
    End point type
    Primary
    End point timeframe
    Up to approximately 3 years
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this end point.
    End point values
    		 AMG 420 200 µg/day AMG 420 400 µg/day AMG 420 600 µg/day
    Number of subjects analysed
    1
    12
    10
    Units: Participants
    1
    12
    9
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    ORR was defined as the percentage of participants for whom the best overall response was a stringent complete response (CR), CR, very good partial response (PR), or partial response as determined by the IMWG Uniform Response Criteria. The ORR along with the associated 95% exact binomial confidence interval (Clopper Pearson Method) was determined.
    End point type
    Secondary
    End point timeframe
    Up to approximately 3 years
    End point values
    		 AMG 420 200 µg/day AMG 420 400 µg/day AMG 420 600 µg/day
    Number of subjects analysed
    1
    12
    10
    Units: Percentage of Participants
        number (confidence interval 95%)
    0 (0.00 to 97.50)
    41.7 (15.17 to 72.33)
    30.0 (6.67 to 65.25)
    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
    DOR was defined as number of months between first objective response to progressive disease or death (due to any cause), whichever occured first. DOR was only calculated for participants who experienced a best overall response of PR or better. Kaplan-Meier methods were used to estimate the distribution of DOR. The median and corresponding two-sided 95% confidence intervals were calculated.
    End point type
    Secondary
    End point timeframe
    Up to approximately 3 years
    End point values
    		 AMG 420 200 µg/day AMG 420 400 µg/day AMG 420 600 µg/day
    Number of subjects analysed
    0 [4]
    5
    3
    Units: Months
        median (confidence interval 95%)
    ( to )
    5.49 (1.41 to 99999)
    99999 (1.45 to 99999)
    Notes
    [4] - No participants with a response to measure
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Minimal Residual Disease (MRD) Negativity Response at CR

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    End point title
    		 Percentage of Participants With Minimal Residual Disease (MRD) Negativity Response at CR
    End point description
    MRD negativity at CR or better assessed by using the IMWG criteria. Percentage of MRD negative responders at CR along with exact 2- sided 95% were provided by using the Clopper Pearson method.
    End point type
    Secondary
    End point timeframe
    Up to approximately 3 years
    End point values
    		 AMG 420 200 µg/day AMG 420 400 µg/day AMG 420 600 µg/day
    Number of subjects analysed
    1
    12
    10
    Units: Percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 97.50)
    8.3 (0.21 to 38.48)
    10.0 (0.25 to 44.50)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 3 years
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    AMG 420 200 µg/day
    Reporting group description
    		 -

    Reporting group title
    AMG 420 400 µg/day
    Reporting group description
    		 -

    Reporting group title
    AMG 420 600 µg/day
    Reporting group description
    		 -

    Reporting group title
    Total
    Reporting group description
    		 -

    Serious adverse events
    		 AMG 420 200 µg/day AMG 420 400 µg/day AMG 420 600 µg/day Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    10 / 12 (83.33%)
    8 / 10 (80.00%)
    19 / 23 (82.61%)
         number of deaths (all causes)
    1
    6
    4
    11
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasmacytoma
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Plasma cell myeloma
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    3 / 23 (13.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 12 (16.67%)
    0 / 10 (0.00%)
    2 / 23 (8.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    Asthenia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    2 / 10 (20.00%)
    2 / 23 (8.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 1 (0.00%)
    5 / 12 (41.67%)
    3 / 10 (30.00%)
    8 / 23 (34.78%)
         occurrences causally related to treatment / all
    0 / 0
    9 / 11
    3 / 3
    12 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion site infection
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    2 / 23 (8.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    2 / 23 (8.70%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 AMG 420 200 µg/day AMG 420 400 µg/day AMG 420 600 µg/day Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    12 / 12 (100.00%)
    10 / 10 (100.00%)
    23 / 23 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    2 / 10 (20.00%)
    3 / 23 (13.04%)
         occurrences all number
    0
    2
    4
    6
    Hypertension
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    4
    1
    5
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 12 (16.67%)
    3 / 10 (30.00%)
    5 / 23 (21.74%)
         occurrences all number
    0
    3
    3
    6
    Malaise
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 1 (0.00%)
    6 / 12 (50.00%)
    6 / 10 (60.00%)
    12 / 23 (52.17%)
         occurrences all number
    0
    9
    13
    22
    Ulcer
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Hypothermia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Fatigue
         subjects affected / exposed
    0 / 1 (0.00%)
    5 / 12 (41.67%)
    6 / 10 (60.00%)
    11 / 23 (47.83%)
         occurrences all number
    0
    7
    8
    15
    Chills
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Oedema
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 12 (16.67%)
    0 / 10 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    3
    0
    3
    Peripheral swelling
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    1 / 1 (100.00%)
    9 / 12 (75.00%)
    7 / 10 (70.00%)
    17 / 23 (73.91%)
         occurrences all number
    2
    28
    20
    50
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 12 (16.67%)
    2 / 10 (20.00%)
    4 / 23 (17.39%)
         occurrences all number
    0
    5
    3
    8
    Dyspnoea
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 12 (16.67%)
    2 / 10 (20.00%)
    4 / 23 (17.39%)
         occurrences all number
    0
    3
    2
    5
    Epistaxis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    2 / 10 (20.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    0
    2
    2
    Hypoxia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    2
    0
    2
    Nasal congestion
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    1
    1
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Respiratory alkalosis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Sinus congestion
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    2 / 10 (20.00%)
    3 / 23 (13.04%)
         occurrences all number
    0
    1
    2
    3
    Wheezing
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Psychiatric disorders
    Substance abuse
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Confusional state
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Disorientation
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Nervousness
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Blood creatine increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    2
    0
    2
    Blood fibrinogen increased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    3
    1
    4
    Carbon dioxide decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    1
    1
    2
    White blood cell count decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    1
    2
    3
    Fibrin D dimer increased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    2 / 10 (20.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    0
    5
    5
    Immature granulocyte count increased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Lipase increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    2
    1
    3
    Neutrophil count decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    8
    0
    8
    Nitrite urine present
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 12 (16.67%)
    1 / 10 (10.00%)
    3 / 23 (13.04%)
         occurrences all number
    0
    5
    5
    10
    Protein total increased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    2
    2
    Weight decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 12 (16.67%)
    2 / 10 (20.00%)
    4 / 23 (17.39%)
         occurrences all number
    0
    2
    2
    4
    Weight increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    3
    3
    Fibula fracture
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    1
    0
    0
    1
    Skin laceration
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Sternal fracture
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Tachycardia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Sinus tachycardia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    1
    1
    2
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    3
    3
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Dizziness
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 12 (16.67%)
    3 / 10 (30.00%)
    5 / 23 (21.74%)
         occurrences all number
    0
    2
    3
    5
    Headache
         subjects affected / exposed
    0 / 1 (0.00%)
    8 / 12 (66.67%)
    4 / 10 (40.00%)
    12 / 23 (52.17%)
         occurrences all number
    0
    16
    9
    25
    Neuralgia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    6
    6
    Presyncope
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Seizure
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Sinus headache
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Tremor
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    1
    1
    2
    Dysgeusia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    2
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 12 (33.33%)
    4 / 10 (40.00%)
    8 / 23 (34.78%)
         occurrences all number
    0
    8
    7
    15
    Leukocyte vacuolisation
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    2 / 10 (20.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    0
    3
    3
    Leukocytosis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    3 / 10 (30.00%)
    3 / 23 (13.04%)
         occurrences all number
    0
    0
    3
    3
    Leukopenia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    2 / 10 (20.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    0
    4
    4
    Lymphopenia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Neutropenia
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 12 (16.67%)
    3 / 10 (30.00%)
    5 / 23 (21.74%)
         occurrences all number
    0
    2
    10
    12
    Neutrophilia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    2 / 10 (20.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    0
    2
    2
    Hyperfibrinogenaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    2
    0
    2
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    1
    1
    2
    Diplopia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Cataract
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Gastrointestinal disorders
    Mouth haemorrhage
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Nausea
         subjects affected / exposed
    0 / 1 (0.00%)
    5 / 12 (41.67%)
    3 / 10 (30.00%)
    8 / 23 (34.78%)
         occurrences all number
    0
    6
    6
    12
    Oral pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Stomatitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    2
    0
    2
    Vomiting
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    2 / 10 (20.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    0
    2
    2
    Lip dry
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    2 / 10 (20.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    0
    2
    2
    Diarrhoea
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 12 (16.67%)
    2 / 10 (20.00%)
    4 / 23 (17.39%)
         occurrences all number
    0
    3
    4
    7
    Constipation
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 12 (25.00%)
    5 / 10 (50.00%)
    8 / 23 (34.78%)
         occurrences all number
    0
    3
    6
    9
    Abdominal pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    2 / 10 (20.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    0
    2
    2
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    2
    0
    2
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    2 / 10 (20.00%)
    3 / 23 (13.04%)
         occurrences all number
    0
    1
    3
    4
    Rash
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    2
    2
    Rash maculo-papular
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Skin exfoliation
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    2 / 10 (20.00%)
    3 / 23 (13.04%)
         occurrences all number
    0
    1
    3
    4
    Dry skin
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 12 (16.67%)
    3 / 10 (30.00%)
    5 / 23 (21.74%)
         occurrences all number
    0
    4
    4
    8
    Arthritis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Back pain
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 12 (25.00%)
    2 / 10 (20.00%)
    5 / 23 (21.74%)
         occurrences all number
    0
    3
    3
    6
    Bone pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Muscle spasms
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 12 (16.67%)
    2 / 10 (20.00%)
    4 / 23 (17.39%)
         occurrences all number
    0
    2
    2
    4
    Muscular weakness
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Neck pain
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    2
    1
    3
    Pain in extremity
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 12 (16.67%)
    2 / 10 (20.00%)
    4 / 23 (17.39%)
         occurrences all number
    0
    2
    2
    4
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Synovial cyst
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    2 / 10 (20.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    0
    2
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Metapneumovirus infection
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Bronchitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Rhinovirus infection
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    2 / 10 (20.00%)
    3 / 23 (13.04%)
         occurrences all number
    0
    2
    2
    4
    Sinusitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    1
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 12 (33.33%)
    1 / 10 (10.00%)
    5 / 23 (21.74%)
         occurrences all number
    0
    4
    1
    5
    Urinary tract infection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    2
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Metabolism and nutrition disorders
    Alkalosis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Dehydration
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    1
    1
    2
    Gout
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Hypercalcaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Hypocalcaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    Decreased appetite
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 12 (16.67%)
    3 / 10 (30.00%)
    5 / 23 (21.74%)
         occurrences all number
    0
    2
    3
    5
    Iron deficiency
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    2
    2
    Hypokalaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 12 (8.33%)
    4 / 10 (40.00%)
    5 / 23 (21.74%)
         occurrences all number
    0
    1
    9
    10
    Hypomagnesaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    Hypophosphataemia
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 12 (16.67%)
    4 / 10 (40.00%)
    6 / 23 (26.09%)
         occurrences all number
    0
    2
    7
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Oct 2018
    The protocol was amended for the following reasons: • DLT criteria was revised to specify the grade and time to resolution for the DLT exceptions of headache, insomnia, and fever. • Removed exclusion for Grade 3 neurological events that improve to Grade 0 or Grade 1 within 14 days from DLT evaluation • Clarification added to indicate mandatory dose interruption for Grade 4 adverse events (AMG 420 related or non-related) and restart after improvement of the toxicity to a specified lower grade. • Incorporated Phase 2 stopping rules that apply to Grade 4 or higher drug-related adverse events, excluding lymphopenia (or reduced lymphocyte counts). • Stopping rules for Phase 2 adjusted to be applied by the DRT after every 20 subjects have had the chance to receive at least 1 cycle of treatment at the determined dose level. • Clarifications/minor corrections for consistency throughout protocol • Clarifications/minor corrections to Schedule of Assessments. • The table of contents and all references are updated accordingly.
    12 Dec 2018
    The protocol was amended for the following reasons: • Language added regarding management of patients who develop fevers during treatment with AMG 420.
    22 May 2019
    The protocol was amended for the following reasons: • Include new phase 1b part 2 combination cohort (AMG 420 + pomalidomide/dexamethasone, maximum 20 additional subjects to be enrolled in this cohort). • Addition of adverse event management guidance for phase 2 study, including dose reduction and discontinuation parameters for discrete event occurring on treatment. • Changes made to clarify guidance on infusion reactions and tumor lysis syndrome. • Adjustment made to platelet count eligibility criteria. • Addition of patient interviews for phase 1b study and patient reported outcome measurement tools to phase 2 study. • Updated timing of imaging assessments for extramedullary disease, providing option for multiple assessments while responders remain on treatment. • Change primary analysis time point.
    20 May 2020
    The protocol was amended for the following reasons: • Removal of Phase 1b Part 2 (combination cohort) and Phase 2 text globally.
    17 Sep 2021
    The protocol was amended for the following reasons: • To put clarifications around delays of treatment cycles in place. To add clarity around treatment free intervals. • To add table for management of COVID infection.

    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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