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    Clinical Trial Results:
    A Phase 1b/2a Study to Evaluate the Safety and Efficacy of AMG 592 in Subjects With Active Rheumatoid Arthritis With Inadequate Response to Standard of Care Therapy

    Summary
    EudraCT number
    		 2017-001944-36
    Trial protocol
    		 ES   PL   BG  
    Global end of trial date
    10 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 May 2021
    First version publication date
    27 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20170149
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03410056
    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, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@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
    10 Dec 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Dec 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the safety and tolerability of subcutaneous (SC) dose administrations of AMG 592 in participants with active rheumatoid arthritis (RA).
    Protection of trial subjects
    This study was conducted in accordance with the protocol and with: • Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines • Applicable ICH Good Clinical Practice (GCP) Guidelines • Applicable laws and regulations
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 May 2018
    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
    Bulgaria: 3
    Country: Number of subjects enrolled
    Poland: 18
    Country: Number of subjects enrolled
    United States: 15
    Worldwide total number of subjects
    36
    EEA total number of subjects
    21
    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)
    31
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants in phase 1b were to be enrolled into 1 of 4 planned dosing cohorts and randomized in a 3:1 ratio to receive AMG 592 or placebo according to 1 of 2 dosing schedules; A (less frequent) and B (more frequent).

    Pre-assignment
    Screening details
    		 Enrollment of the phase 1b part of this study was stopped as of 30 September 2019, due to data that suggested that there is not sufficient benefit-risk for the use of AMG 592 plus standard of care therapy in this study population. The study was terminated prior to the enrollment of any participants into phase 1b Cohort 4 and phase 2a cohorts.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase 1b and Phase 2a: Placebo
    Arm description
    		 Phase 1b: Matching placebo administered via subcutaneous injection for a total of up to 12 weeks. Participants received placebo in 1 of 2 dosing schedules (i.e. dosing schedule A [less frequent] or schedule B [more frequent]). Phase 2a: Matching placebo administered via subcutaneous injection, depending on the recommended phase 2 dose (RP2D) and dosing schedule as determined in phase 1b, for a total of up to 12 weeks. The study was terminated prior to the start of phase 2a and no participants were enrolled.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo administered via subcutaneous injection.

    Arm title
    		 Phase 1b and Phase 2a: AMG 592
    Arm description
    		 Phase 1b: AMG 592 at a low, medium, medium/high, or high dose administered via subcutaneous injection for a total of up to 12 weeks. Participants received AMG 592 in 1 of 2 dosing schedules (i.e. dosing schedule A [less frequent] or schedule B [more frequent]). Phase 2a: AMG 592 administered via subcutaneous injection depending on the RP2D and dosing schedule determined in phase 1b, for up to a total of up to 12 weeks. The study was terminated prior to the start of phase 2a and no participants were enrolled in phase 2a or into the medium/high dose cohort of phase 1b.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AMG 592
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    AMG 592 at a low, medium, medium/high, or high dose, administered via subcutaneous injection.

    Number of subjects in period 1
    		Phase 1b and Phase 2a: Placebo Phase 1b and Phase 2a: AMG 592
    Started
    8
    28
    Received treatment
    8
    28
    Started Phase 1b
    8
    28
    Started Phase 2a
    0 [1]
    0 [2]
    Completed
    8
    13
    Not completed
    0
    15
         Consent withdrawn by subject
    -
    12
         Decision by Sponsor
    -
    3
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The study was terminated prior to the start of phase 2a and no participants were enrolled.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The study was terminated prior to the start of phase 2a and no participants were enrolled.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall study
    Reporting group description
    		 -

    Reporting group values
    		 Overall study Total
    Number of subjects
    		 36 36
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 31 31
        From 65-84 years
    		 5 5
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.9 ( 12.4 ) -
    Sex: Female, Male
    Units:
        Female
    		 27 27
        Male
    		 9 9
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 4 4
        Not Hispanic or Latino
    		 32 32
        Unknown or Not Reported
    		 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Black or African American
    		 3 3
        White
    		 33 33
    Subject analysis sets

    Subject analysis set title
    Phase 1b: Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Matching placebo administered via subcutaneous injection for a total of up to 12 weeks. Participants received placebo in 1 of 2 dosing schedules (i.e. dosing schedule A [less frequent] or schedule B [more frequent]).

    Subject analysis set title
    Phase 1b: AMG 592 Cohort 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    A low dose of AMG 592 administered via subcutaneous injection using dosing schedule A (less frequent than schedule B) for a total of up to 12 weeks.

    Subject analysis set title
    Phase 1b: AMG 592 Cohort 2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    A high dose of AMG 592 administered via subcutaneous injection using dosing schedule A (less frequent than schedule B) for a total of up to 12 weeks.

    Subject analysis set title
    Phase 1b: AMG 592 Cohort 3
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    A medium dose of AMG 592 administered via subcutaneous injection using dosing schedule B (more frequent than schedule A) for a total of up to 12 weeks.

    Subject analysis sets values
    		 Phase 1b: Placebo Phase 1b: AMG 592 Cohort 1 Phase 1b: AMG 592 Cohort 2 Phase 1b: AMG 592 Cohort 3
    Number of subjects
    8
    6
    11
    11
    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
    5
    10
    9
        From 65-84 years
    1
    1
    1
    2
        85 years and over
    0
    0
    0
    0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    46.4 ( 12.1 )
    57.8 ( 8.4 )
    53.1 ( 10.7 )
    51.4 ( 15.3 )
    Sex: Female, Male
    Units:
        Female
    4
    6
    9
    8
        Male
    4
    0
    2
    3
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    1
    0
    2
    1
        Not Hispanic or Latino
    7
    6
    9
    10
        Unknown or Not Reported
    0
    0
    0
    0
    Race/Ethnicity, Customized
    Units: Subjects
        Black or African American
    2
    1
    0
    0
        White
    6
    5
    11
    11

    End points

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    End points reporting groups
    Reporting group title
    Phase 1b and Phase 2a: Placebo
    Reporting group description
    		 Phase 1b: Matching placebo administered via subcutaneous injection for a total of up to 12 weeks. Participants received placebo in 1 of 2 dosing schedules (i.e. dosing schedule A [less frequent] or schedule B [more frequent]). Phase 2a: Matching placebo administered via subcutaneous injection, depending on the recommended phase 2 dose (RP2D) and dosing schedule as determined in phase 1b, for a total of up to 12 weeks. The study was terminated prior to the start of phase 2a and no participants were enrolled.

    Reporting group title
    Phase 1b and Phase 2a: AMG 592
    Reporting group description
    		 Phase 1b: AMG 592 at a low, medium, medium/high, or high dose administered via subcutaneous injection for a total of up to 12 weeks. Participants received AMG 592 in 1 of 2 dosing schedules (i.e. dosing schedule A [less frequent] or schedule B [more frequent]). Phase 2a: AMG 592 administered via subcutaneous injection depending on the RP2D and dosing schedule determined in phase 1b, for up to a total of up to 12 weeks. The study was terminated prior to the start of phase 2a and no participants were enrolled in phase 2a or into the medium/high dose cohort of phase 1b.

    Subject analysis set title
    Phase 1b: Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Matching placebo administered via subcutaneous injection for a total of up to 12 weeks. Participants received placebo in 1 of 2 dosing schedules (i.e. dosing schedule A [less frequent] or schedule B [more frequent]).

    Subject analysis set title
    Phase 1b: AMG 592 Cohort 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    A low dose of AMG 592 administered via subcutaneous injection using dosing schedule A (less frequent than schedule B) for a total of up to 12 weeks.

    Subject analysis set title
    Phase 1b: AMG 592 Cohort 2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    A high dose of AMG 592 administered via subcutaneous injection using dosing schedule A (less frequent than schedule B) for a total of up to 12 weeks.

    Subject analysis set title
    Phase 1b: AMG 592 Cohort 3
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    A medium dose of AMG 592 administered via subcutaneous injection using dosing schedule B (more frequent than schedule A) for a total of up to 12 weeks.

    Primary: Phase 1b: Number of Participants who Experienced a Treatment-emergent Adverse Event (TEAE)

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    End point title
    		 Phase 1b: Number of Participants who Experienced a Treatment-emergent Adverse Event (TEAE) [1]
    End point description
    TEAEs were events with an onset after the administration of the first dose of study treatment. TEAEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE). Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limited age appropriate instrumental activities of daily life (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization indicated; disabling; limited self care ADL. Grade 4 Life-threatening consequences; urgent interventions indicated. Serious adverse events (SAEs) were defined as meeting at least 1 of the following criteria: - Results in death (fatal) - Immediately life-threatening - Requires in-patient hospitalization or prolongation of existing hospitalization - Results in persistent or significant disability/incapacity - Is a congenital anomaly/birth defect - Other medically important serious event
    End point type
    Primary
    End point timeframe
    Day 1 up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)
    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 formal statistical analyses were planned.
    End point values
    		 Phase 1b: Placebo Phase 1b: AMG 592 Cohort 1 Phase 1b: AMG 592 Cohort 2 Phase 1b: AMG 592 Cohort 3
    Number of subjects analysed
    8
    6
    11
    11
    Units: Participants
        TEAEs
    3
    5
    11
    11
        Grade ≥ 2 TEAEs
    2
    3
    8
    8
        Grade ≥ 3 TEAEs
    0
    0
    1
    0
        Grade ≥ 4 TEAEs
    0
    0
    0
    0
        SAEs
    0
    0
    1
    0
        TEAEs leading to discontinuation of treatment
    0
    1
    7
    3
        Life-threatening TEAEs
    0
    0
    0
    0
        Fatal TEAEs
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Phase 1b: Number of Participants who Experienced a Clinically Significant Change in Vital Signs

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    End point title
    		 Phase 1b: Number of Participants who Experienced a Clinically Significant Change in Vital Signs [2]
    End point description
    Any changes in systolic/diastolic blood pressure, heart rate, respiratory rate, and temperature that were deemed as clinically significant by the Investigator were reported.
    End point type
    Primary
    End point timeframe
    Baseline up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)
    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 formal statistical analyses were planned.
    End point values
    		 Phase 1b: Placebo Phase 1b: AMG 592 Cohort 1 Phase 1b: AMG 592 Cohort 2 Phase 1b: AMG 592 Cohort 3
    Number of subjects analysed
    8
    6
    11
    11
    Units: Participants
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Phase 1b: Number of Participants who Experienced a Clinically Significant Change in Laboratory Safety Tests

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    End point title
    		 Phase 1b: Number of Participants who Experienced a Clinically Significant Change in Laboratory Safety Tests [3]
    End point description
    Laboratory safety tests included chemistry and hematology parameters. Clinically significant laboratory safety tests were any events assessed as CTCAE Grade ≥3 at any post-baseline visit. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization indicated; disabling; limited self care ADL. Grade 4 Life-threatening consequences; urgent interventions indicated.
    End point type
    Primary
    End point timeframe
    Baseline up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)
    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 formal statistical analyses were planned.
    End point values
    		 Phase 1b: Placebo Phase 1b: AMG 592 Cohort 1 Phase 1b: AMG 592 Cohort 2 Phase 1b: AMG 592 Cohort 3
    Number of subjects analysed
    8
    6
    11
    11
    Units: Participants
    0
    0
    1
    0
    No statistical analyses for this end point

    Primary: Phase 1b: Number of Participants who Experienced a Clinically Significant Change in Electrocardiograms (ECGs)

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    End point title
    		 Phase 1b: Number of Participants who Experienced a Clinically Significant Change in Electrocardiograms (ECGs) [4]
    End point description
    Any changes in ECG parameters that were deemed clinically significant by the investigator were reported.
    End point type
    Primary
    End point timeframe
    Baseline up to end of treatment maximum of 12 weeks
    Notes
    [4] - 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 formal statistical analyses were planned.
    End point values
    		 Phase 1b: Placebo Phase 1b: AMG 592 Cohort 1 Phase 1b: AMG 592 Cohort 2 Phase 1b: AMG 592 Cohort 3
    Number of subjects analysed
    8
    6
    11
    11
    Units: Participants
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Phase 2a: Number of Participants who Achieved an American College of Rheumatology 20 Percent Improvement Criteria (ACR 20) at Week 12

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    End point title
    		 Phase 2a: Number of Participants who Achieved an American College of Rheumatology 20 Percent Improvement Criteria (ACR 20) at Week 12 [5]
    End point description
    ACR 20 response defined as at least 20 percent improvement from baseline in both tender and swollen joint counts, and a 20 percent improvement or more in at least 3 of the following 5 criteria: - physician global assessment of disease activity (PGA) - subject global assessment of disease activity (SGA) - patient global assessment of joint pain - subject self-assessment of disability (HAQ-DI) - C-Reactive Protein (CRP)
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analyses were planned.
    End point values
    		 Phase 1b and Phase 2a: Placebo Phase 1b and Phase 2a: AMG 592
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: Participants
    Notes
    [6] - No participants were enrolled for Phase 2a.
    [7] - No participants were enrolled for Phase 2a.
    No statistical analyses for this end point

    Secondary: Phase 1b: AMG 592 Serum Concentrations

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    End point title
    		 Phase 1b: AMG 592 Serum Concentrations
    End point description
    A summary of mean serum concentrations of AMG 592 over time is presented. Any results below the lower limit of quantification were set to 0.00. 99999 = insufficient samples were collected to assess SD.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose), 6 and 12 hours post-dose, and days 2, 3, 4, 8, 11, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and Day 85 (pre-dose), 6 and 12 hours post-dose and days 86, 87, 88, 92, 99, 113 and 127
    End point values
    		 Phase 1b: AMG 592 Cohort 1 Phase 1b: AMG 592 Cohort 2 Phase 1b: AMG 592 Cohort 3
    Number of subjects analysed
    6 [8]
    11 [9]
    11 [10]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 (pre-dose)
    0.00 ( 0.00 )
    0.00 ( 0.00 )
    0.00 ( 0.00 )
        Day 1 (6 hours post-dose)
    1.35 ( 0.795 )
    7.67 ( 8.01 )
    2.13 ( 2.98 )
        Day 1 (12 hours post-dose)
    2.43 ( 0.867 )
    14.6 ( 12.1 )
    4.09 ( 4.70 )
        Day 2
    2.59 ( 0.875 )
    22.0 ( 11.5 )
    5.44 ( 5.09 )
        Day 3
    1.70 ( 0.850 )
    18.6 ( 9.16 )
    3.65 ( 3.13 )
        Day 4
    0.727 ( 0.277 )
    7.65 ( 5.85 )
    2.36 ( 2.84 )
        Day 8
    0.0555 ( 0.0924 )
    0.108 ( 0.146 )
    0.0284 ( 0.0624 )
        Day 11
    0.0230 ( 0.0514 )
    0.0115 ( 0.0364 )
    0.930 ( 0.780 )
        Day 15
    0.00 ( 0.00 )
    0.00 ( 0.00 )
    0.107 ( 0.150 )
        Day 22
    0.0830 ( 0.144 )
    0.0703 ( 0.112 )
    0.235 ( 0.373 )
        Day 29
    0.00 ( 0.00 )
    0.00 ( 0.00 )
    0.217 ( 0.344 )
        Day 36
    0.0644 ( 0.144 )
    0.102 ( 0.203 )
    0.239 ( 0.425 )
        Day 43
    0.00 ( 0.00 )
    0.00 ( 0.00 )
    0.104 ( 0.275 )
        Day 50
    0.205 ( 0.304 )
    0.105 ( 0.210 )
    0.122 ( 0.322 )
        Day 57
    0.0368 ( 0.0735 )
    0.00 ( 0.00 )
    0.0886 ( 0.234 )
        Day 64
    0.336 ( 99999 )
    0.212 ( 0.424 )
    0.0294 ( 0.0657 )
        Day 71
    0.0635 ( 99999 )
    0.00 ( 0.00 )
    0.00 ( 0.00 )
        Day 78
    0.154 ( 0.267 )
    0.355 ( 0.614 )
    0.0508 ( 0.0819 )
        Day 85 (pre-dose)
    0.00 ( 0.00 )
    0.00 ( 0.00 )
    0.0578 ( 0.0958 )
        Day 85 (6 hours post-dose)
    2.41 ( 1.56 )
    5.91 ( 99999 )
    1.92 ( 2.64 )
        Day 85 (12 hours post-dose)
    4.00 ( 2.05 )
    12.9 ( 99999 )
    2.92 ( 4.03 )
        Day 86
    3.60 ( 2.07 )
    12.3 ( 99999 )
    2.97 ( 4.48 )
        Day 87
    2.10 ( 1.15 )
    4.39 ( 99999 )
    1.87 ( 2.43 )
        Day 88
    1.48 ( 0.623 )
    1.01 ( 99999 )
    0.903 ( 1.17 )
        Day 92
    0.113 ( 99999 )
    0.00 ( 99999 )
    0.0953 ( 0.115 )
        Day 99
    0.00 ( 0.00 )
    0.00 ( 99999 )
    0.110 ( 0.268 )
        Day 113
    0.00 ( 0.00 )
    0.00 ( 99999 )
    0.00 ( 0.00 )
        Day 127
    0.00 ( 0.00 )
    0.00 ( 99999 )
    0.00 ( 0.00 )
    Notes
    [8] - N values range from 6 to 1 participant(s)
    [9] - N values range from 11 to 2 participants.
    [10] - N values range from 11 to 5 participants.
    No statistical analyses for this end point

    Secondary: Phase 1b: Maximum Observed Serum Concentration (Cmax) of AMG 592

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    End point title
    		 Phase 1b: Maximum Observed Serum Concentration (Cmax) of AMG 592
    End point description
    99999 = Insufficient samples were collected to assess mean Cmax.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose) and 6 to 48 hours post-dose, and days 4, 8, 11, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, Day 85 (pre-dose) and 6 to 72 hours post-dose, and days 92, 99, 113 and 127
    End point values
    		 Phase 1b: AMG 592 Cohort 1 Phase 1b: AMG 592 Cohort 2 Phase 1b: AMG 592 Cohort 3
    Number of subjects analysed
    6 [11]
    11 [12]
    11 [13]
    Units: ng/mL
    arithmetic mean (standard deviation)
        First dose (Day 1)
    2.66 ( 0.852 )
    23.0 ( 11.2 )
    5.71 ( 5.10 )
        Last dose (Day 85)
    4.00 ( 2.05 )
    99999 ( 99999 )
    3.22 ( 4.35 )
    Notes
    [11] - Day 85 N = 4
    [12] - Day 85 N = 2
    [13] - Day 85 N = 6
    No statistical analyses for this end point

    Secondary: Phase 1b: Time to Maximum Observed Serum Concentration (Tmax) of AMG 592

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    End point title
    		 Phase 1b: Time to Maximum Observed Serum Concentration (Tmax) of AMG 592
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose) and 6 to 48 hours post-dose, and days 4, 8, 11, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, Day 85 (pre-dose) and 6 to 72 hours post-dose, and days 92, 99, 113 and 127
    End point values
    		 Phase 1b: AMG 592 Cohort 1 Phase 1b: AMG 592 Cohort 2 Phase 1b: AMG 592 Cohort 3
    Number of subjects analysed
    6 [14]
    11 [15]
    11 [16]
    Units: hours
    median (full range (min-max))
        First dose (Day 1)
    18 (12 to 24)
    24 (24 to 48)
    24 (12 to 72)
        Last dose (Day 85)
    12 (12 to 12)
    30 (12 to 48)
    12 (6.0 to 24)
    Notes
    [14] - Day 85 N = 4
    [15] - Day 85 N = 2
    [16] - Day 85 N = 6
    No statistical analyses for this end point

    Secondary: Phase 1b: Area Under the Concentration-time Curve from Time 0 to 14 Days (AUC0-14) Post Dose

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    End point title
    		 Phase 1b: Area Under the Concentration-time Curve from Time 0 to 14 Days (AUC0-14) Post Dose
    End point description
    AUC0-14 was only assessed for the participants who received AMG 592 using dosing schedule A. 99999 = Insufficient samples were collected to assess AUC0-14.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose) and 6 to 48 hours post-dose, and days 4, 8, 11 and 15, Day 85 (pre-dose) and 6 to 72 hours post-dose, and days 92 and 99
    End point values
    		 Phase 1b: AMG 592 Cohort 1 Phase 1b: AMG 592 Cohort 2
    Number of subjects analysed
    6 [17]
    10 [18]
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        First dose (Day 1)
    167 ( 60.9 )
    1570 ( 859 )
        Last dose (Day 85)
    282 ( 207 )
    99999 ( 99999 )
    Notes
    [17] - Day 85 N = 4
    [18] - Day 85 N = 2
    No statistical analyses for this end point

    Secondary: Phase 1b: Area Under the Concentration-time Curve from Time 0 to 7 Days (AUC0-7) Post Dose

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    End point title
    		 Phase 1b: Area Under the Concentration-time Curve from Time 0 to 7 Days (AUC0-7) Post Dose
    End point description
    AUC0-7 was only assessed for the participants who received AMG 592 using dosing schedule B.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose) and 6 to 48 hours post-dose, and days 4 and 8, Day 85 (pre-dose) and 6 to 72 hours post-dose, and Day 92
    End point values
    		 Phase 1b: AMG 592 Cohort 3
    Number of subjects analysed
    10 [19]
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        First dose (Day 1)
    315 ( 239 )
        Last dose (Day 85)
    195 ( 264 )
    Notes
    [19] - Day 85 N = 6
    No statistical analyses for this end point

    Secondary: Phase 1b: Number of Participants with Anti-AMG 592 Binding Antibodies and Anti-Interleukin (IL-2) Binding Antibodies

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    End point title
    		 Phase 1b: Number of Participants with Anti-AMG 592 Binding Antibodies and Anti-Interleukin (IL-2) Binding Antibodies
    End point description
    Number of participants who tested positive for anti-AMG 592 binding antibodies and number of those participants who cross-reacted with native human IL-2 (i.e. with anti-IL-2 binding antibodies) are reported. Binding anti-AMG 592 antibody positive post-baseline with a negative or no result at baseline. Binding anti-IL2 antibody positive post-baseline with a negative or no result at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)
    End point values
    		 Phase 1b: Placebo Phase 1b: AMG 592 Cohort 1 Phase 1b: AMG 592 Cohort 2 Phase 1b: AMG 592 Cohort 3
    Number of subjects analysed
    8 [20]
    6 [21]
    11 [22]
    11 [23]
    Units: Participants
        Binding anti-AMG 592 antibody positive
    2
    3
    6
    5
        Binding anti-IL2 antibody positive
    0
    0
    1
    1
    Notes
    [20] - anti-IL2 antibody positive N = 3
    [21] - anti-IL2 antibody positive N = 3
    [22] - anti-IL2 antibody positive N = 8
    [23] - anti-IL2 antibody positive N = 5
    No statistical analyses for this end point

    Secondary: Phase 1b: Number of Participants with Anti-AMG 592 Neutralizing Antibodies and Anti-IL-2 Neutralizing Antibodies

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    End point title
    		 Phase 1b: Number of Participants with Anti-AMG 592 Neutralizing Antibodies and Anti-IL-2 Neutralizing Antibodies
    End point description
    The number of participants who tested positive for anti-AMG 592 neutralizing antibodies and number of participants with anti-IL2 neutralizing antibodies who tested negative or no result at baseline are reported. Neutralizing anti-AMG592 antibodies positive post-baseline with a negative or no result at baseline. Neutralizing anti-IL2 antibody positive post-baseline with a negative or no result at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)
    End point values
    		 Phase 1b: Placebo Phase 1b: AMG 592 Cohort 1 Phase 1b: AMG 592 Cohort 2 Phase 1b: AMG 592 Cohort 3
    Number of subjects analysed
    8 [24]
    5 [25]
    11 [26]
    10 [27]
    Units: Participants
        Neutralizing anti-AMG592 antibodies positive
    2
    1
    7
    5
        Neutralizing anti-IL2 antibody positive
    0
    0
    1
    1
    Notes
    [24] - Neutralizing anti-IL2 antibody positive N = 3
    [25] - Neutralizing anti-IL2 antibody positive N = 3
    [26] - Neutralizing anti-IL2 antibody positive N = 8
    [27] - Neutralizing anti-IL2 antibody positive N = 5
    No statistical analyses for this end point

    Secondary: Phase 2a: Number of Participants who Achieved an American College of Rheumatology 50 Percent Improvement Criteria (ACR 50) or 70 Percent Improvement Criteria (ACR 70) at Week 12

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    End point title
    		 Phase 2a: Number of Participants who Achieved an American College of Rheumatology 50 Percent Improvement Criteria (ACR 50) or 70 Percent Improvement Criteria (ACR 70) at Week 12
    End point description
    ACR 50 and ACR 70 response defined as at least 50 percent or 70 percent improvement from baseline in both tender and swollen joint counts, and a 50 percent or 70 percent improvement or more in at least 3 of the following 5 criteria: - physician global assessment of disease activity (PGA) - subject global assessment of disease activity (SGA) - patient global assessment of joint pain - subject self-assessment of disability (HAQ-DI) - C-Reactive Protein (CRP)
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Phase 1b and Phase 2a: Placebo Phase 1b and Phase 2a: AMG 592
    Number of subjects analysed
    0 [28]
    0 [29]
    Units: Participants
    Notes
    [28] - No participants were enrolled for Phase 2a.
    [29] - No participants were enrolled for Phase 2a.
    No statistical analyses for this end point

    Secondary: Phase 2a: Change from Baseline in Disease Activity Score (28 Joint) Calculated Using The Erythrocyte Sedimentation Rate Formula (DAS28-ESR) at Week 12

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    End point title
    		 Phase 2a: Change from Baseline in Disease Activity Score (28 Joint) Calculated Using The Erythrocyte Sedimentation Rate Formula (DAS28-ESR) at Week 12
    End point description
    Change from baseline in DAS28-ER at Week 12. DAS28-ESR was to assess disease activity in patients with rheumatoid arthritis. DAS28-ESR is a composite score that includes 4 variables: tender joint count (TJC) (based on 28 joints); swollen joint count (SJC) (based on 28 joints); participant's global assessment of health activity using 100 mm visual analogue scale (VAS): range 0 (no pain) to 100 (maximum pain imaginable); marker of inflammation assessed by ESR in mm/h. DAS28-ESR total score range from 0-10, higher score indicates more disease activity.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Phase 1b and Phase 2a: Placebo Phase 1b and Phase 2a: AMG 592
    Number of subjects analysed
    0 [30]
    0 [31]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [30] - No participants were enrolled for Phase 2a.
    [31] - No participants were enrolled for Phase 2a.
    No statistical analyses for this end point

    Secondary: Phase 2a: Change from Baseline in Disease Activity Score (28 joint) Calculated using the C-reactive Protein Formula (DAS-28-CRP) at Week 12

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    End point title
    		 Phase 2a: Change from Baseline in Disease Activity Score (28 joint) Calculated using the C-reactive Protein Formula (DAS-28-CRP) at Week 12
    End point description
    Change from baseline in DAS28-CRP at Week 12. 2. DAS28-CRP was to assess disease activity in patients with rheumatoid arthritis. DAS28-CRP is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); participant's global assessment of health activity using 100 mm VAS: range 0 (no pain) to 100 (maximum pain imaginable); marker of inflammation assessed by CRP in mg/L. DAS28-CRP total score range from 0-10, higher score indicates more disease activity.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Phase 1b and Phase 2a: Placebo Phase 1b and Phase 2a: AMG 592
    Number of subjects analysed
    0 [32]
    0 [33]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [32] - No participants were enrolled for Phase 2a.
    [33] - No participants were enrolled for Phase 2a.
    No statistical analyses for this end point

    Secondary: Phase 2a: Number of Participants who Experienced a Treatment-emergent Adverse Event (TEAE)

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    End point title
    		 Phase 2a: Number of Participants who Experienced a Treatment-emergent Adverse Event (TEAE)
    End point description
    TEAEs were events with an onset after the administration of the first dose of study treatment. TEAEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE).
    End point type
    Secondary
    End point timeframe
    Baseline up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)
    End point values
    		 Phase 1b and Phase 2a: Placebo Phase 1b and Phase 2a: AMG 592
    Number of subjects analysed
    0 [34]
    0 [35]
    Units: Participants
    Notes
    [34] - No participants were enrolled for Phase 2a.
    [35] - No participants were enrolled for Phase 2a.
    No statistical analyses for this end point

    Secondary: Phase 2a: Number of Participants who Experienced a Clinically Significant Change in Vital Signs

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    End point title
    		 Phase 2a: Number of Participants who Experienced a Clinically Significant Change in Vital Signs
    End point description
    Any changes in systolic/diastolic blood pressure, heart rate, respiratory rate, and temperature that were deemed as clinically significant by the Investigator were reported.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 Phase 1b and Phase 2a: Placebo Phase 1b and Phase 2a: AMG 592
    Number of subjects analysed
    0 [36]
    0 [37]
    Units: Participants
    Notes
    [36] - No participants were enrolled for Phase 2a.
    [37] - No participants were enrolled for Phase 2a.
    No statistical analyses for this end point

    Secondary: Phase 2a: Number of Participants who Experienced a Clinically Significant Change in Laboratory Safety Tests

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    End point title
    		 Phase 2a: Number of Participants who Experienced a Clinically Significant Change in Laboratory Safety Tests
    End point description
    Laboratory safety tests included chemistry and hematology parameters. Clinically significant laboratory safety tests were any events assessed as CTCAE Grade ≥3 at any post-baseline visit. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization indicated; disabling; limited self care ADL. Grade 4 Life-threatening consequences; urgent interventions indicated.
    End point type
    Secondary
    End point timeframe
    Day 1 up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)
    End point values
    		 Phase 1b and Phase 2a: Placebo Phase 1b and Phase 2a: AMG 592
    Number of subjects analysed
    0 [38]
    0 [39]
    Units: Participants
    Notes
    [38] - No participants were enrolled for Phase 2a.
    [39] - No participants were enrolled for Phase 2a.
    No statistical analyses for this end point

    Secondary: Phase 2a: AMG 592 Serum Concentration

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    End point title
    		 Phase 2a: AMG 592 Serum Concentration
    End point description
    A summary of mean serum concentrations of AMG 592 over time.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose) and weeks 2, 4, 6, 8, 10 and 12
    End point values
    		 Phase 1b and Phase 2a: Placebo Phase 1b and Phase 2a: AMG 592
    Number of subjects analysed
    0 [40]
    0 [41]
    Units: ng/mL
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [40] - No participants were enrolled for Phase 2a.
    [41] - No participants were enrolled for Phase 2a.
    No statistical analyses for this end point

    Secondary: Phase 2a: Maximum Observed Serum Concentration (Cmax) of AMG 592

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    End point title
    		 Phase 2a: Maximum Observed Serum Concentration (Cmax) of AMG 592
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose) and weeks 2, 4, 6, 8, 10 and 12
    End point values
    		 Phase 1b and Phase 2a: Placebo Phase 1b and Phase 2a: AMG 592
    Number of subjects analysed
    0 [42]
    0 [43]
    Units: ng/mL
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [42] - No participants were enrolled for Phase 2a.
    [43] - No participants were enrolled for Phase 2a.
    No statistical analyses for this end point

    Secondary: Phase 2a: Time to Maximum Observed Serum Concentration (Tmax) of AMG 592

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    End point title
    		 Phase 2a: Time to Maximum Observed Serum Concentration (Tmax) of AMG 592
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose) and weeks 2, 4, 6, 8, 10 and 12
    End point values
    		 Phase 1b and Phase 2a: Placebo Phase 1b and Phase 2a: AMG 592
    Number of subjects analysed
    0 [44]
    0 [45]
    Units: hours
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [44] - No participants were enrolled for Phase 2a. `
    [45] - No participants were enrolled for Phase 2a.
    No statistical analyses for this end point

    Secondary: Phase 2a: Area Under the Concentration-time Curve (AUC) of AMG 592

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    End point title
    		 Phase 2a: Area Under the Concentration-time Curve (AUC) of AMG 592
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose) and weeks 2, 4, 6, 8, 10 and 12
    End point values
    		 Phase 1b and Phase 2a: Placebo Phase 1b and Phase 2a: AMG 592
    Number of subjects analysed
    0 [46]
    0 [47]
    Units: hr*ng/mL
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [46] - No participants were enrolled for Phase 2a.
    [47] - No participants were enrolled for Phase 2a.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)
    Adverse event reporting additional description
    All-cause mortality is reported for all participants enrolled in the study. Treatment emergent SAEs and other AEs, including disease-related AEs are reported for all participants who received at least one dose of study drug. No data is available for phase 1b medium/high group or phase 2a as the study was terminated prior to participants enrolling.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Phase 1b: Placebo
    Reporting group description
    		 Matching placebo administered via subcutaneous injection for a total of up to 12 weeks. Participants received placebo in 1 of 2 dosing schedules (i.e. dosing schedule A [less frequent] or schedule [more frequent]).

    Reporting group title
    Phase 1b: AMG 592 Cohort 1
    Reporting group description
    		 A low dose of AMG 592 administered via subcutaneous injection using dosing schedule A (less frequent than schedule B) for a total of up to 12 weeks.

    Reporting group title
    Phase 1b: AMG 592 Cohort 2
    Reporting group description
    		 A high dose of AMG 592 administered via subcutaneous injection using dosing schedule A (less frequent than schedule B) for a total of up to 12 weeks.

    Reporting group title
    Phase 1b: AMG 592 Cohort 3
    Reporting group description
    		 A medium dose of AMG 592 administered via subcutaneous injection using dosing schedule B (more frequent than schedule A) for a total of up to 12 weeks.

    Serious adverse events
    		 Phase 1b: Placebo Phase 1b: AMG 592 Cohort 1 Phase 1b: AMG 592 Cohort 2 Phase 1b: AMG 592 Cohort 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         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
    		 Phase 1b: Placebo Phase 1b: AMG 592 Cohort 1 Phase 1b: AMG 592 Cohort 2 Phase 1b: AMG 592 Cohort 3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 8 (37.50%)
    5 / 6 (83.33%)
    11 / 11 (100.00%)
    11 / 11 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    1
    0
    0
    4
    General disorders and administration site conditions
    Administration site reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Asthenia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Chest pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Chills
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    1
    Influenza like illness
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injection site erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    4 / 6 (66.67%)
    2 / 11 (18.18%)
    3 / 11 (27.27%)
         occurrences all number
    0
    15
    4
    9
    Injection site hypersensitivity
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injection site pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Injection site pruritus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    2
    Injection site reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    6 / 11 (54.55%)
    8 / 11 (72.73%)
         occurrences all number
    0
    0
    18
    38
    Injection site swelling
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    2
    0
    1
    Pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    3
    1
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    3
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cough
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 6 (33.33%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Body temperature increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Eosinophil count increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Administration related reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Arthropod bite
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    Dizziness postural
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    2 / 11 (18.18%)
         occurrences all number
    1
    0
    1
    2
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    3 / 11 (27.27%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    3
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    2
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Swelling of eyelid
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Large intestine polyp
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Swollen tongue
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blister
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Drug eruption
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    9
    3
    Pruritus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Rash
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Skin burning sensation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin lesion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Skin swelling
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    3 / 11 (27.27%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    7
    0
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    0
    2
    Bursitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Joint stiffness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Joint swelling
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Pain in extremity
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    4 / 11 (36.36%)
    2 / 11 (18.18%)
         occurrences all number
    1
    0
    5
    3
    Infections and infestations
    Gingivitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 May 2018
    * Clarified aspects of Early Termination and Safety Follow-up visits and that PK, PD, and antibody blood samples could not be drawn through a central or peripheral line. * Changed exclusion criteria: - To allow up to 3 prior biologic or oral synthetic DMARD therapies; updated wash out periods for these prior therapies. - To clarify prohibited medications to allow Vitamin D and calcium to be taken. * Replaced sentinel dosing in phase 1b with longer direct observation after the first dose and close telephone follow-up after the second dose of investigational product. * Incorporated a cohort stopping rule of equal to or greater than 2 grade 3 adverse events to replace the existing equal to or greater than 3 grade 3 adverse event stopping rule. * Included PK sampling at day 92, 99, and 113 and clinical laboratory assessments before day 15 for additional safety review.
    26 Jul 2018
    * Changed participant urine drug/alcohol testing, during screening, from the local laboratory to the central laboratory.
    06 Jun 2019
    * Updated the phase 1b sample size language to allow flexibility for expansion of cohorts, replacement of participants who discontinued product, and over-enrollment of additional eligible participants. * Updated cohort 3 dose to reflect the DLRM recommendation to increase dose. * Reduced the thresholds for white blood cell count and absolute neutrophil count in the exclusion criteria because leukopenia is common in this patient population.

    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.
    The study was terminated prior to the enrollment of phase 1b Cohort 4 and phase 2a cohorts due to data that suggested that there is not sufficient benefit-risk for the use of AMG 592 plus standard of care therapy in this study population.
    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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