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    Clinical Trial Results:
    A Pivotal Phase 3 Trial to Evaluate the Safety and Efficacy of Clazakizumab for the Treatment of Chronic Active Antibody-Mediated Rejection in Kidney Transplant Recipients

    Summary
    EudraCT number
    2018-003682-34
    Trial protocol
    CZ   HU   BE   DE   NL   AT   ES  
    Global end of trial date
    08 Apr 2024

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Apr 2025
    First version publication date
    19 Apr 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSL300_3001 (previously VKTX01)
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03744910
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Vitaeris: VKTX01
    Sponsors
    Sponsor organisation name
    CSL Behring LLC
    Sponsor organisation address
    1020 First Avenue, King of Prussia, PA, United States, 19406
    Public contact
    Trial Registration Coordinator, CSL Behring LLC, +1 610-878-4697, clinicaltrials@cslbehring.com
    Scientific contact
    Trial Registration Coordinator, CSL Behring LLC, +1 610-878-4697, clinicaltrials@cslbehring.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
    24 Jun 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Apr 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    1. To evaluate the efficacy of clazakizumab in preventing all-cause allograft loss (including death) or irreversible loss of allograft function due to CABMR. 2. To evaluate the efficacy of clazakizumab in slowing/preventing the progressive loss of kidney function (as measured by eGFR using the Modification of Diet in Renal Disease 4 (MDRD4) equation [Interim analysis #2]). 3. To evaluate the safety of clazakizumab.
    Protection of trial subjects
    The study was conducted according to the principles of the World Medical Association’s Declaration of Helsinki and the International Council for Harmonisation (ICH) guidelines for Good Clinical Practice (GCP), CSL Behring has ensured that the study complies with all local, federal or country-specific regulatory requirements. A written informed consent in compliance with Part 50 of Title 21 of the Code of Federal Regulations (CFR), with the Declaration of Helsinki, ICH guidelines, federal and / or local regulations, and advance approval by the Institutional Review Board / Independent Ethics Committee (IRB / IEC) was obtained from each participant prior to entering the study or performing any unusual or non-routine procedure that involves risk to the participant, including washout of any medications. Any amendments to the protocol or informed consent form (ICF) were reviewed and approved by the IRB / IEC before the changes were implemented in the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Oct 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 22
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    United States: 61
    Worldwide total number of subjects
    194
    EEA total number of subjects
    86
    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)
    180
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 139 study sites in 13 countries: Canada, United States, Austria, Czechia, France, Germany, Hungary, Netherlands, Spain, Sweden, Switzerland, Democratic People's Republic of Korea, and Australia.

    Pre-assignment
    Screening details
    A total of 382 participants were screened, of which 188 were screen failures. Of the screened participants, 194 were randomized in a 1:1 ratio to receive study interventions (Clazakizumab or Placebo). Participants who reached the primary endpoint of allograft loss or death are combined and reported as Completed in the participant flow.

    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, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Clazakizumab
    Arm description
    Participants received clazakizumab via subcutaneous (SC) injection once every 4 weeks (Q4W) until the participant: permanently discontinued the investigational product (IP), withdrew from the study, experienced allograft loss, died, or reached the common treatment end date (CTED), whichever occurred first during this study.
    Arm type
    Experimental

    Investigational medicinal product name
    Clazakizumab
    Investigational medicinal product code
    CSL300
    Other name
    Genetically engineered humanized anti-IL-6 mAb
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    12.5 milligram per millilliter (mg/mL) SC injection Q4W.

    Arm title
    Placebo
    Arm description
    Participants received Placebo by SC injection Q4W until the participant: permanently discontinued IP, withdrew from the study, experienced allograft loss, died, or reached the CTED, whichever occurred first during this study.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.9% w/v NaCl, SC injection Q4W.

    Number of subjects in period 1
    Clazakizumab Placebo
    Started
    94
    100
    Completed
    16
    15
    Not completed
    78
    85
         Physician decision
    5
    4
         Withdrew Consent
    1
    8
         Other-unspecified
    4
    1
         Sponsor Decision
    68
    71
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Clazakizumab
    Reporting group description
    Participants received clazakizumab via subcutaneous (SC) injection once every 4 weeks (Q4W) until the participant: permanently discontinued the investigational product (IP), withdrew from the study, experienced allograft loss, died, or reached the common treatment end date (CTED), whichever occurred first during this study.

    Reporting group title
    Placebo
    Reporting group description
    Participants received Placebo by SC injection Q4W until the participant: permanently discontinued IP, withdrew from the study, experienced allograft loss, died, or reached the CTED, whichever occurred first during this study.

    Reporting group values
    Clazakizumab Placebo Total
    Number of subjects
    94 100 194
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    46.3 ( 11.87 ) 47.0 ( 12.24 ) -
    Gender categorical
    Units: Subjects
        Female
    29 26 55
        Male
    65 74 139
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    18 16 34
        Not Hispanic or Latino
    69 78 147
        Not reported
    5 4 9
        Unknown
    2 2 4
    Race (NIH/OMB)
    Units: Subjects
        White
    62 69 131
        Black or African American
    10 7 17
        Korean
    9 13 22
        Other
    6 8 14
        Asian Indian
    3 1 4
        Other Asian
    2 1 3
        American or Alaskan Native
    1 0 1
        Filipino
    1 0 1
        Missing
    0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Clazakizumab
    Reporting group description
    Participants received clazakizumab via subcutaneous (SC) injection once every 4 weeks (Q4W) until the participant: permanently discontinued the investigational product (IP), withdrew from the study, experienced allograft loss, died, or reached the common treatment end date (CTED), whichever occurred first during this study.

    Reporting group title
    Placebo
    Reporting group description
    Participants received Placebo by SC injection Q4W until the participant: permanently discontinued IP, withdrew from the study, experienced allograft loss, died, or reached the CTED, whichever occurred first during this study.

    Primary: Change From Baseline to Week 52 in Estimated Glomerular Filtration Rate (eGFR)

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    End point title
    Change From Baseline to Week 52 in Estimated Glomerular Filtration Rate (eGFR)
    End point description
    This primary outcome measure was the one from the first interim analysis. Analysis was performed on the intent-to-treat (ITT) analysis set. The ITT analysis set consisted of all participants who received at least 1 dose of study drug and who had a baseline assessment and at least 1 post baseline assessment of eGFR.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 52
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    92
    99
    Units: milliliter per minute per 1.73 meter^2
        least squares mean (confidence interval 95%)
    -8.0 (-10.2 to -5.8)
    -5.2 (-7.4 to -3.1)
    Statistical analysis title
    Clazakizumab versus (v) Placebo
    Comparison groups
    Clazakizumab v Placebo
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    Method
    Parameter type
    Treatment difference
    Point estimate
    -2.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.84
         upper limit
    0.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.563
    Notes
    [1] - Pre-specified for interim analysis.

    Primary: Number of Participants With Composite All-cause Allograft Loss or Irreversible Loss of Allograft Function

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    End point title
    Number of Participants With Composite All-cause Allograft Loss or Irreversible Loss of Allograft Function [2]
    End point description
    Composite all-cause allograft loss or irreversible loss of allograft function, defined as time to first occurrence of any of the following components: • eGFR < 15 milliliters per minute per 1.73 square meters (mL/min/1.73 m^2)* • return to dialysis* • allograft nephrectomy • retransplantation • death from any cause, or • a sustained (greater than or equal to [>=] 60 days) 40% decline in eGFR from Baseline. *Total cumulative duration of sustained eGFR < 15 mL/min/1.73 m^2 AND / OR dialysis >= 60 days. If the eGFR < 15 mL/min/1.73 m^2 was the only component reached, the value must be sustained over at least 60 days and must be confirmed by a repeat measurement after >= 60 days from the first measurement. The number of participants with composite all-cause allograft loss or irreversible loss of allograft function are reported here. Time-to-event data were not calculated due to the study’s termination. Analysis was performed on the ITT analysis set.
    End point type
    Primary
    End point timeframe
    From Baseline to 4 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: Statistical analysis assessment was not performed as planned because of early study termination due to futility (at Interim Analysis).
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    92
    99
    Units: participants
    26
    22
    No statistical analyses for this end point

    Primary: Percentage of Participants With Composite All-cause Allograft Loss or Irreversible Loss of Allograft Function

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    End point title
    Percentage of Participants With Composite All-cause Allograft Loss or Irreversible Loss of Allograft Function [3]
    End point description
    Composite all-cause allograft loss or irreversible loss of allograft function, defined as time to first occurrence of any of the following components: • eGFR < 15 mL/min/1.73 m^2* • return to dialysis* • allograft nephrectomy • retransplantation • death from any cause, or • a sustained (>= 60 days) 40% decline in eGFR from Baseline. *Total cumulative duration of sustained eGFR < 15 mL/min/1.73 m^2 AND / OR dialysis >= 60 days. If the eGFR < 15 mL/min/1.73 m^2 was the only component reached, the value must be sustained over at least 60 days and must be confirmed by a repeat measurement after >= 60 days from the first measurement. The percentage of participants with composite allograft loss or irreversible loss of allograft function are reported here. Time-to-event data were not calculated due to the study’s termination. Analysis was performed on the ITT analysis set.
    End point type
    Primary
    End point timeframe
    From Baseline to 4 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: Statistical analysis assessment was not performed as planned because of early study termination due to futility (at Interim Analysis).
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    92
    99
    Units: percentage of participants
        number (not applicable)
    28.3
    22.2
    No statistical analyses for this end point

    Primary: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and Adverse Events of Special Interest (AESIs)

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    End point title
    Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and Adverse Events of Special Interest (AESIs) [4]
    End point description
    Analysis was performed on the safety analysis set (SAS). The SAS consisted of all randomized participants who had received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to 4 years
    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: Statistical analyses have not been specified because only descriptive analyses were planned for safety endpoints.
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    93
    100
    Units: participants
        TEAEs
    89
    88
        Serious TEAEs
    39
    39
        AESIs
    56
    52
    No statistical analyses for this end point

    Primary: Percentage of Participants With TEAEs, Serious TEAEs, and AESIs

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    End point title
    Percentage of Participants With TEAEs, Serious TEAEs, and AESIs [5]
    End point description
    Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to 4 years
    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: Statistical analyses have not been specified because only descriptive analyses were planned for safety endpoints.
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    93
    100
    Units: percentage of participants
    number (not applicable)
        TEAEs
    95.7
    88.0
        Serious TEAEs
    41.9
    39.0
        AESIs
    60.2
    52.0
    No statistical analyses for this end point

    Primary: Number of Participants Who Tested Positive for Polyoma BK Virus (BKV), Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV)

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    End point title
    Number of Participants Who Tested Positive for Polyoma BK Virus (BKV), Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) [6]
    End point description
    Number of participants who tested positive for BKV, CMV or EBV according to the maximum measured viral amount (International Units/mL [IU/mL]) after baseline are reported here. Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug. Here, ‘number analyzed’, 'n' = participants with available data for each specified category. Lower limit of quantification = LLOQ.
    End point type
    Primary
    End point timeframe
    From baseline up to 4 years
    Notes
    [6] - 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: Statistical analyses have not been specified because only descriptive analyses were planned for safety endpoints.
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    93
    100
    Units: participants
        BKV >LLOQ to <320 IU/mL (n=93,99)
    3
    2
        BKV >=320 IU/mL to <3200 IU/mL (n=93,99)
    1
    0
        BKV >=3200 IU/mL (n=93,99)
    1
    0
        CMV >LLOQ to <1000 IU/mL (n=93,99)
    5
    1
        CMV >=1000 IU/mL to <5000 IU/mL (n=93,99)
    2
    2
        CMV >=5000 IU/mL (n=93,99)
    0
    0
        EBV >LLOQ to <10200 IU/mL (n=92,99)
    8
    7
        EBV >=10200 IU/mL to <20400 IU/mL (n=92,99)
    0
    0
        EBV >=20400 IU/mL (n=92,99)
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants With Abnormal Laboratory Test Results

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    End point title
    Number of Participants With Abnormal Laboratory Test Results [7]
    End point description
    Laboratory tests included liver function test (LFTs), complete blood count (CBC), plasma lipids, high-sensitivity C-reactive protein (hsCRP). Only participants with abnormal laboratory test results are reported here. Here, ULN = upper limit of normal, LLN = lower limit of normal, ALT = Alanine aminotransferase and AST = Aspartate aminotransferase. Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug. Here, ‘overall number of participants analyzed’, 'N' = participants with evaluable data for this outcome measure.
    End point type
    Primary
    End point timeframe
    Up to 4 years
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses have not been specified because only descriptive analyses were planned for safety endpoints.
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    93
    99
    Units: participants
        ALT : >ULN to 3 x ULN
    15
    6
        ALT : > 3 to 5 × ULN
    0
    1
        AST : >ULN to 3 x ULN
    11
    4
        AST : > 3 to 5 × ULN
    1
    0
        AST : > 5 × ULN
    0
    2
        Bilirubin: > ULN to 2 × ULN
    20
    6
        Bilirubin: > 2 × ULN
    5
    0
        Neutrophils: < 2.5 to 1.5 10^9/L
    33
    21
        Neutrophils: < 1.5 to 1.0 10^9/L
    15
    5
        Neutrophils: < 1.0 10^9/L
    7
    0
        Platelets: < LLN to 75.0 10^9/L
    39
    10
        Platelets: < 75.0 to 50.0 10^9/L
    1
    0
    No statistical analyses for this end point

    Primary: Percentage of Participants With Abnormal Laboratory Test Results

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    End point title
    Percentage of Participants With Abnormal Laboratory Test Results [8]
    End point description
    Laboratory tests included LFTs, CBC, plasma lipids, hsCRP. Only percentage of participants with abnormal laboratory test results are reported here. Here, ULN = upper limit of normal, LLN = lower limit of normal, ALT = Alanine aminotransferase and AST = Aspartate aminotransferase. Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug. Here, ‘overall number of participants analyzed’ = participants with evaluable data for this outcome measure.
    End point type
    Primary
    End point timeframe
    Up to 4 years
    Notes
    [8] - 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: Statistical analyses have not been specified because only descriptive analyses were planned for safety endpoints.
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    93
    99
    Units: percentage of participants
    number (not applicable)
        ALT : >ULN to 3 x ULN
    16.1
    6.1
        ALT : > 3 to 5 × ULN
    0
    1.0
        AST : >ULN to 3 x ULN
    11.8
    4.0
        AST : > 3 to 5 × ULN
    1.1
    0
        AST : > 5 × ULN
    0
    2.0
        Bilirubin: > ULN to 2 × ULN
    21.5
    6.1
        Bilirubin: > 2 × ULN
    5.4
    0
        Neutrophils: < 2.5 to 1.5 10^9/L
    35.5
    21.2
        Neutrophils: < 1.5 to 1.0 10^9/L
    16.1
    5.1
        Neutrophils: < 1.0 10^9/L
    7.5
    0
        Platelets: < LLN to 75.0 10^9/L
    41.9
    10.1
        Platelets: < 75.0 to 50.0 10^9/L
    1.1
    0
    No statistical analyses for this end point

    Primary: Number of Participants With Abnormal Vital Signs, Electrocardiograms (ECGs), and Physical Examination

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    End point title
    Number of Participants With Abnormal Vital Signs, Electrocardiograms (ECGs), and Physical Examination [9]
    End point description
    Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to 4 years
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses have not been specified because only descriptive analyses were planned for safety endpoints.
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    93
    100
    Units: participants
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants With Positive Anti-drug Antibodies

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    End point title
    Number of Participants With Positive Anti-drug Antibodies [10]
    End point description
    Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug. Here, ‘overall number of participants’ = participants with available data for this outcome measure and 'number analyzed', 'n' = participants with available data for each specified timepoint.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 12, 24, and 48
    Notes
    [10] - 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: Statistical analyses have not been specified because only descriptive analyses were planned for safety endpoints.
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    88
    97
    Units: participants
        Baseline (n=88,97)
    5
    10
        Week 12 (n=74,82)
    3
    8
        Week 24 (n=68,72)
    2
    7
        Week 48 (n=52,52)
    0
    4
    No statistical analyses for this end point

    Primary: Percentage of Participants With Positive Anti-drug Antibodies

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    End point title
    Percentage of Participants With Positive Anti-drug Antibodies [11]
    End point description
    Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug. Here, 'overall number of participants' = participants with available data for this outcome measure and 'number analyzed', 'n' = participants with available data for each specified timepoint.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 12, 24, and 48
    Notes
    [11] - 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: Statistical analyses have not been specified because only descriptive analyses were planned for safety endpoints.
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    88
    97
    Units: percentage of participants
    number (not applicable)
        Baseline (n=88,97)
    5.7
    10.3
        Week 12 (n=74,82)
    4.1
    9.8
        Week 24 (n=68,72)
    2.9
    9.7
        Week 48 (n=52,52)
    0
    7.7
    No statistical analyses for this end point

    Secondary: Number of Participants With Composite All-cause Allograft Loss

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    End point title
    Number of Participants With Composite All-cause Allograft Loss
    End point description
    Composite all-cause allograft loss, defined as, time to first occurrence of any of the following components: • eGFR < 15 mL/min/1.73 m^2 (total cumulative duration of sustained eGFR < 15 mL/min/1.73 m^2 AND / OR dialysis >= 60 days) • return to dialysis • allograft nephrectomy • retransplantation, or • death from any cause. The number of participants with composite all-cause allograft loss are reported here. Analysis was performed on the ITT analysis set. The ITT analysis set consisted of all participants who received at least 1 dose of study drug and who had a baseline assessment and at least 1 post baseline assessment of eGFR.
    End point type
    Secondary
    End point timeframe
    Up to 4 years
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    92
    99
    Units: participants
    17
    14
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Composite All-cause Allograft Loss

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    End point title
    Percentage of Participants With Composite All-cause Allograft Loss
    End point description
    Composite all-cause allograft loss, defined as, time to first occurrence of any of the following components: • eGFR < 15 mL/min/1.73 m^2 (total cumulative duration of sustained eGFR < 15 mL/min/1.73 m^2 AND / OR dialysis >= 60 days) • return to dialysis • allograft nephrectomy • retransplantation, or • death from any cause The percentage of participants with composite all-cause allograft loss are reported here. Analysis was performed on the ITT analysis set. The ITT analysis set consisted of all participants who received at least 1 dose of study drug and who had a baseline assessment and at least 1 post baseline assessment of eGFR.
    End point type
    Secondary
    End point timeframe
    Up to 4 years
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    92
    99
    Units: percentage of participants
        number (not applicable)
    18.5
    14.1
    No statistical analyses for this end point

    Secondary: Number of Participants With Irreversible Loss of Allograft Function

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    End point title
    Number of Participants With Irreversible Loss of Allograft Function
    End point description
    Irreversible loss of allograft function as defined by a 40% decline in eGFR from Baseline sustained for at least 60 days. Analysis was performed on the ITT analysis set. The ITT analysis set consisted of all participants who received at least 1 dose of the investigational product, had a Baseline assessment, and had at least 1 post-baseline assessment of eGFR.
    End point type
    Secondary
    End point timeframe
    From Baseline to 4 years
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    92
    99
    Units: participants
    22
    18
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Irreversible Loss of Allograft Function

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    End point title
    Percentage of Participants With Irreversible Loss of Allograft Function
    End point description
    Irreversible loss of allograft function as defined by a 40% decline in eGFR from Baseline sustained for at least 60 days. Analysis was performed on the ITT analysis set. The ITT analysis set consisted of all participants who received at least 1 dose of the investigational product, had a Baseline assessment, and had at least 1 post-baseline assessment of eGFR.
    End point type
    Secondary
    End point timeframe
    From Baseline to 4 years
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    92
    99
    Units: percentage of participants
        number (not applicable)
    23.9
    18.2
    No statistical analyses for this end point

    Secondary: Number of Participants With Death-censored Allograft Loss

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    End point title
    Number of Participants With Death-censored Allograft Loss
    End point description
    This secondary endpoint assessment was not performed as planned because of early study termination due to futility (at Interim Analysis).
    End point type
    Secondary
    End point timeframe
    From Baseline to 4 years
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: participants
    Notes
    [12] - This secondary endpoint assessment was not performed as planned due to early study termination.
    [13] - This secondary endpoint assessment was not performed as planned due to early study termination.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Death-censored Allograft Loss

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    End point title
    Percentage of Participants With Death-censored Allograft Loss
    End point description
    This secondary endpoint assessment was not performed as planned because of early study termination due to futility (at Interim Analysis).
    End point type
    Secondary
    End point timeframe
    From Baseline to 4 years
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    0 [14]
    0 [15]
    Units: percentage of participants
        number (not applicable)
    Notes
    [14] - This secondary endpoint assessment was not performed as planned due to early study termination.
    [15] - This secondary endpoint assessment was not performed as planned due to early study termination.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Urine Albumin Creatinine Ratio (UACR)

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    End point title
    Change From Baseline in Urine Albumin Creatinine Ratio (UACR)
    End point description
    Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug. Here, ‘overall number of participants analyzed’ = participants with available data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    83
    88
    Units: gram per mole
        arithmetic mean (standard deviation)
    50.734 ( 125.5628 )
    31.178 ( 112.8894 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Mean Fluorescent Intensity for Donor-Specific Antibodies (DSA)

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    End point title
    Percent Change From Baseline in Mean Fluorescent Intensity for Donor-Specific Antibodies (DSA)
    End point description
    Analysis was performed on the SAS. The SAS consisted of all randomized participants who had received at least 1 dose of study drug. Here, ‘overall number of participants analyzed’ = participants with available data for this outcome measure and ‘number analyzed’, 'n' = participants with available data for each specified category
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    39
    45
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        DSA Class I (n=21,16)
    -23.20 (-53.34 to -4.54)
    -39.71 (-69.67 to -20.22)
        DSA Class II (n=39,45)
    -27.15 (-46.32 to -5.05)
    -13.68 (-26.69 to -1.75)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Banff Lesion Grading Score (2015 Criteria) of Pre-treatment to Post-treatment (Week 52) Kidney Biopsies

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    End point title
    Change From Baseline in Banff Lesion Grading Score (2015 Criteria) of Pre-treatment to Post-treatment (Week 52) Kidney Biopsies
    End point description
    This secondary endpoint assessment was not performed as planned because of early study termination due to futility (at Interim Analysis).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    0 [16]
    0 [17]
    Units: score on a scale
        number (not applicable)
    Notes
    [16] - This secondary endpoint assessment was not performed as planned due to early study termination.
    [17] - This secondary endpoint assessment was not performed as planned due to early study termination.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Acute Rejection Episodes of T Cell-mediated Rejection (TCMR) and Antibody-mediated Rejection (ABMR)

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    End point title
    Change From Baseline in Acute Rejection Episodes of T Cell-mediated Rejection (TCMR) and Antibody-mediated Rejection (ABMR)
    End point description
    This secondary endpoint assessment was not performed as planned because of early study termination due to futility (at Interim Analysis).
    End point type
    Secondary
    End point timeframe
    Baseline up to End of treatment (up to approximately 4 years)
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    0 [18]
    0 [19]
    Units: rejections
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [18] - This secondary endpoint assessment was not performed as planned due to early study termination.
    [19] - This secondary endpoint assessment was not performed as planned due to early study termination.
    No statistical analyses for this end point

    Secondary: Overall Participant Survival

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    End point title
    Overall Participant Survival
    End point description
    This secondary endpoint assessment was not performed as planned because of early study termination due to futility (at Interim Analysis).
    End point type
    Secondary
    End point timeframe
    Up to approximately 4 years
    End point values
    Clazakizumab Placebo
    Number of subjects analysed
    0 [20]
    0 [21]
    Units: participants
    Notes
    [20] - This secondary endpoint assessment was not performed as planned due to early study termination.
    [21] - This secondary endpoint assessment was not performed as planned due to early study termination.
    No statistical analyses for this end point

    Secondary: Maximum Concentration at Steady State (Cmax ss) of CSL300

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    End point title
    Maximum Concentration at Steady State (Cmax ss) of CSL300 [22]
    End point description
    A subset of participants (out of the enrolled participants in the main study) had the option to participate in a pharmacokinetic (PK)/ Pharmacodynamic (PD) sub-study. Analysis was performed on the PK/ PD analysis set. The PK/PD substudy analysis set consisted of all participants in the SAS who consented to be a part of the PK / PD substudy and had at least 1 quantifiable PK concentration of investigational product after administration. Here, “overall number of participants analyzed’ = participants with available data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As planned, PK Data is reported for the applicable arm "Clazakizumab" only.
    End point values
    Clazakizumab
    Number of subjects analysed
    3
    Units: nanograms per milliliter
        geometric mean (geometric coefficient of variation)
    3556.8 ( 10.5 )
    No statistical analyses for this end point

    Secondary: Trough Concentrations at Steady State (Ctrough ss) of CSL300

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    End point title
    Trough Concentrations at Steady State (Ctrough ss) of CSL300 [23]
    End point description
    A subset of participants (out of the enrolled participants in the main study) had the option to participate in a PK/PD sub-study. Analysis was performed on the PK/PD analysis set. The PK/PD substudy analysis set consisted of all participants in the SAS who consented to be a part of the PK / PD substudy and had at least 1 quantifiable PK concentration of investigational product after administration. Here, “overall number of participants analyzed’ = participants with available data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As planned, PK Data is reported for the applicable arm "Clazakizumab" only.
    End point values
    Clazakizumab
    Number of subjects analysed
    3
    Units: nanograms per milliliter
        geometric mean (geometric coefficient of variation)
    2366.8 ( 9.2 )
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Curve (AUC0-tau) at Steady State of CSL300

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    End point title
    Area Under the Concentration-time Curve (AUC0-tau) at Steady State of CSL300 [24]
    End point description
    A subset of participants (out of the enrolled participants in the main study) had the option to participate in a PK/PD sub-study. Analysis was performed on the PK/PD analysis set. The PK/PD substudy analysis set consisted of all participants in the SAS who consented to be a part of the PK / PD substudy and had at least 1 quantifiable PK concentration of investigational product after administration. Here, “overall number of participants analyzed’ = participants with available data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As planned, PK Data is reported for the applicable arm "Clazakizumab" only.
    End point values
    Clazakizumab
    Number of subjects analysed
    3
    Units: days*nanograms per milliliter
        geometric mean (geometric coefficient of variation)
    78080.34636 ( 7.19614 )
    No statistical analyses for this end point

    Secondary: Time of Maximum Concentration at Steady State (Tmax ss) of CSL300

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    End point title
    Time of Maximum Concentration at Steady State (Tmax ss) of CSL300 [25]
    End point description
    A subset of participants (out of the enrolled participants in the main study) had the option to participate in a PK/PD sub-study. Analysis was performed on the PK/PD analysis set. The PK/PD substudy analysis set consisted of all participants in the SAS who consented to be a part of the PK / PD substudy and had at least 1 quantifiable PK concentration of investigational product after administration. Here, “overall number of participants analyzed’ = participants with available data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As planned, PK Data is reported for the applicable arm "Clazakizumab" only.
    End point values
    Clazakizumab
    Number of subjects analysed
    3
    Units: day
        median (full range (min-max))
    6.92292 (4.9986 to 11.9299)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 4 years
    Adverse event reporting additional description
    The SAS consisted of all randomized participants who received at least 1 dose of study drug. The participants in the SAS were analyzed according to the actual treatment received.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Clazakizumab
    Reporting group description
    Participants received clazakizumab via SC injection Q4W until the participant: permanently discontinued the IP, withdrew from the study, experienced allograft loss, died, or reached the CTED, whichever occurred first during this study.

    Reporting group title
    Placebo
    Reporting group description
    Participants received Placebo via SC injection Q4W until the participant: permanently discontinued IP, withdrew from the study, experienced allograft loss, died, or reached the CTED, whichever occurred first during this study.

    Serious adverse events
    Clazakizumab Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    39 / 93 (41.94%)
    39 / 100 (39.00%)
         number of deaths (all causes)
    3
    1
         number of deaths resulting from adverse events
    2
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Post transplant lymphoproliferative disorder
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angiopathy
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Transplant rejection
         subjects affected / exposed
    1 / 93 (1.08%)
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic allograft nephropathy
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney transplant rejection
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and pancreas transplant rejection
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatomegaly
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Complications of transplanted pancreas
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural hypertension
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant failure
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm ruptured
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 93 (3.23%)
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphatic obstruction
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 93 (4.30%)
    3 / 100 (3.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Terminal ileitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    13 / 93 (13.98%)
    6 / 100 (6.00%)
         occurrences causally related to treatment / all
    1 / 15
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    2 / 93 (2.15%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Azotaemia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    13 / 93 (13.98%)
    10 / 100 (10.00%)
         occurrences causally related to treatment / all
    0 / 15
    1 / 12
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 93 (3.23%)
    10 / 100 (10.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 93 (2.15%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 93 (1.08%)
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous graft site infection
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteriuria
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syphilis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral diarrhoea
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Clazakizumab Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    81 / 93 (87.10%)
    80 / 100 (80.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 93 (12.90%)
    13 / 100 (13.00%)
         occurrences all number
    12
    15
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    24 / 93 (25.81%)
    11 / 100 (11.00%)
         occurrences all number
    31
    12
    Fatigue
         subjects affected / exposed
    8 / 93 (8.60%)
    8 / 100 (8.00%)
         occurrences all number
    9
    10
    Asthenia
         subjects affected / exposed
    1 / 93 (1.08%)
    5 / 100 (5.00%)
         occurrences all number
    1
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 93 (5.38%)
    8 / 100 (8.00%)
         occurrences all number
    8
    12
    Oropharyngeal pain
         subjects affected / exposed
    8 / 93 (8.60%)
    1 / 100 (1.00%)
         occurrences all number
    8
    1
    Dyspnoea
         subjects affected / exposed
    5 / 93 (5.38%)
    2 / 100 (2.00%)
         occurrences all number
    5
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 93 (6.45%)
    3 / 100 (3.00%)
         occurrences all number
    7
    3
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    9 / 93 (9.68%)
    13 / 100 (13.00%)
         occurrences all number
    12
    15
    Immunosuppressant drug level decreased
         subjects affected / exposed
    4 / 93 (4.30%)
    6 / 100 (6.00%)
         occurrences all number
    9
    10
    Immunosuppressant drug level increased
         subjects affected / exposed
    4 / 93 (4.30%)
    6 / 100 (6.00%)
         occurrences all number
    6
    10
    Weight decreased
         subjects affected / exposed
    3 / 93 (3.23%)
    6 / 100 (6.00%)
         occurrences all number
    3
    6
    Blood bilirubin increased
         subjects affected / exposed
    5 / 93 (5.38%)
    0 / 100 (0.00%)
         occurrences all number
    5
    0
    Neutrophil count decreased
         subjects affected / exposed
    5 / 93 (5.38%)
    0 / 100 (0.00%)
         occurrences all number
    5
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    5 / 93 (5.38%)
    1 / 100 (1.00%)
         occurrences all number
    5
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 93 (10.75%)
    9 / 100 (9.00%)
         occurrences all number
    14
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 93 (17.20%)
    16 / 100 (16.00%)
         occurrences all number
    19
    17
    Neutropenia
         subjects affected / exposed
    15 / 93 (16.13%)
    0 / 100 (0.00%)
         occurrences all number
    22
    0
    Leukopenia
         subjects affected / exposed
    8 / 93 (8.60%)
    1 / 100 (1.00%)
         occurrences all number
    14
    1
    Thrombocytopenia
         subjects affected / exposed
    6 / 93 (6.45%)
    1 / 100 (1.00%)
         occurrences all number
    8
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    21 / 93 (22.58%)
    22 / 100 (22.00%)
         occurrences all number
    24
    25
    Nausea
         subjects affected / exposed
    11 / 93 (11.83%)
    6 / 100 (6.00%)
         occurrences all number
    13
    7
    Abdominal pain
         subjects affected / exposed
    9 / 93 (9.68%)
    7 / 100 (7.00%)
         occurrences all number
    9
    7
    Vomiting
         subjects affected / exposed
    10 / 93 (10.75%)
    6 / 100 (6.00%)
         occurrences all number
    12
    7
    Abdominal pain upper
         subjects affected / exposed
    6 / 93 (6.45%)
    2 / 100 (2.00%)
         occurrences all number
    8
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 93 (5.38%)
    2 / 100 (2.00%)
         occurrences all number
    6
    2
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    8 / 93 (8.60%)
    5 / 100 (5.00%)
         occurrences all number
    9
    5
    Proteinuria
         subjects affected / exposed
    5 / 93 (5.38%)
    8 / 100 (8.00%)
         occurrences all number
    5
    8
    Renal impairment
         subjects affected / exposed
    7 / 93 (7.53%)
    6 / 100 (6.00%)
         occurrences all number
    7
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 93 (6.45%)
    4 / 100 (4.00%)
         occurrences all number
    7
    5
    Back pain
         subjects affected / exposed
    6 / 93 (6.45%)
    4 / 100 (4.00%)
         occurrences all number
    6
    4
    Muscle spasms
         subjects affected / exposed
    5 / 93 (5.38%)
    4 / 100 (4.00%)
         occurrences all number
    5
    5
    Infections and infestations
    COVID-19
         subjects affected / exposed
    28 / 93 (30.11%)
    30 / 100 (30.00%)
         occurrences all number
    31
    31
    Urinary tract infection
         subjects affected / exposed
    12 / 93 (12.90%)
    6 / 100 (6.00%)
         occurrences all number
    21
    9
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 93 (8.60%)
    5 / 100 (5.00%)
         occurrences all number
    8
    6
    Herpes zoster
         subjects affected / exposed
    6 / 93 (6.45%)
    2 / 100 (2.00%)
         occurrences all number
    6
    2
    Nasopharyngitis
         subjects affected / exposed
    5 / 93 (5.38%)
    11 / 100 (11.00%)
         occurrences all number
    6
    13
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    12 / 93 (12.90%)
    13 / 100 (13.00%)
         occurrences all number
    14
    18
    Hyperlipidaemia
         subjects affected / exposed
    2 / 93 (2.15%)
    9 / 100 (9.00%)
         occurrences all number
    2
    11
    Hyperglycaemia
         subjects affected / exposed
    3 / 93 (3.23%)
    5 / 100 (5.00%)
         occurrences all number
    3
    6
    Hyperphosphataemia
         subjects affected / exposed
    7 / 93 (7.53%)
    1 / 100 (1.00%)
         occurrences all number
    7
    1
    Metabolic acidosis
         subjects affected / exposed
    5 / 93 (5.38%)
    3 / 100 (3.00%)
         occurrences all number
    5
    3
    Iron deficiency
         subjects affected / exposed
    1 / 93 (1.08%)
    5 / 100 (5.00%)
         occurrences all number
    1
    5

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Dec 2018
    • Allowed therapies for required Pneumocystis jiroveci pneumonia (PJP) prophylaxis was broadened. • Instructions regarding the determination of DSA eligibility criteria were further clarified and expanded. • The section on biomarkers and pharmacogenomics research was expanded.
    06 Feb 2019
    • The target dose of IP was reduced from 25 mg SC Q4W to 12.5 mg SC Q4W. • The exclusion of participants with prior exposure to clazakizumab was expanded. • The risks and precautions section was updated to reflect updates from the most recent Investigator brochure. • Treatment options for managing hypogammaglobulinemia were added. • The concomitant medications section was updated to reflect changing clinical practice. • The duration of protocol-specified PJP prophylaxis was reduced to the first year of the study.
    29 Oct 2019
    • Inclusion and exclusion criteria were updated. • Due to the potential confounding long-term effects of proteasome inhibitors on the immune system, participants with any prior exposure to proteasome inhibitors were to be excluded from the study. • The requirement for participants to use “highly effective methods of contraception” was amended. • Throughout the protocol, the terminology for discontinuation of IP was clarified so that the term “discontinuation” now refers to permanent discontinuation and the term “withholding” refers to temporary discontinuation. • The dose modification guidelines were clarified and expanded throughout the protocol. • Recommendations regarding concomitant background immunosuppression were clarified. • The first planned formal safety review by the Data Safety and Monitoring Board (DSMB) was changed to occur after 50 participants (instead of 100 participants) had been randomized and received at least 1 dose of IP. • The guidelines for participants with severe hypogammaglobulinemia were amended to add a 4-week waiting period after reduction of background immunosuppression followed by a recheck of IgG levels before implementing treatment with IV immunoglobulin. • Home health visits were added. • Changes were made to clarify the process for reporting pre-existing medical conditions that met the definition of a SAE. • The appearance of Clazakizumab Drug Product in 12.5 mg/mL vials was corrected to state “clear, colorless solution.
    11 Dec 2019
    • Exclusion criteria was amended to allow for participants with fully excised ulcerative colitis to enter the study. • The protocol was revised to include COVID-19 PCR testing at Screening and an additional exclusion criteria was added to exclude participants with an active COVID-19 infection. Serologic blood tests were not required during the study. • The schedule of mandatory in-clinic visits was amended. • The rescreening procedures were amended. • The prohibited medications section was amended.
    04 Feb 2021
    • Inclusion and exclusion criteria were updated. • The definition, End of treatment (EOT) was added to the schedule of events (SOE) and throughout the protocol, and the definition of end of study (EOS) was updated. • A PK/PD sub-study was added to better capture clazakizumab exposures and relate these to IL-6 and hsCRP levels. • Patient-reported outcome assessments were added to the protocol to assess Health-related quality of life (HRQoL).
    30 Apr 2021
    • Clarified the required timing of the biopsy required to determine study eligibility. • Corrected table to reflect administration of subcutaneous clazakizumab. • Removed an exploratory healthcare utilization objective and endpoint. • Outlined that patient-reported outcome assessments would not have been performed for participants randomized prior to the deployment of an electronic clinical outcome assessment solution.
    12 Jul 2022
    • The overall study design and treatment duration was changed. • The frequency of procedures in Years 2 to End of Study was decreased. • The study procedures were updated based upon the changes to the Schedule of Events in Years 2 to End of Study. • Added a new secondary objective. • A corresponding new secondary endpoint was added to the study. • A description of the common treatment end date (CTED) criteria was added throughout the protocol. • Text that was currently described in the Investigator Brochure was removed from the protocol. • Access to study product after the end of the study would now be available at the discretion of the treating physician and offered to participants as agreed upon in their respective country. • Participants who received Intravenous immunoglobulin (IVIG) underwent PK assessments. • The inclusion and exclusion criteria were modified to increase the number of participants. • Text from the Clinical Trials Facilitation and Coordination Group was added to the adequate contraception language. • Participants who permanently discontinue IP remained in the study until the common treatment end date. • Text regarding unblinding procedures was amended to provide clear directions in the case of a suspected unexpected serious adverse reaction (SUSAR). • Text describing dose, administration, storage, accountability, and destruction of IP was deleted. • Text regarding allowed concomitant medication was updated. • Recommendations for immunizations within 6 weeks prior to the start of Screening was added to the protocol. •A detailed description of EOS procedures was provided for participants who completed the study, participants who permanently discontinued IP, participants who withdrew from the study, and participants who were on treatment when the primary endpoint of the study was reached.
    10 Jul 2023
    • The primary objective and endpoint and associated footnote were revised. • The “EOS visit terminology was revised to the “Safety Follow-up Visit (SFV)” or the “Common treatment end visit (CTEV)”, where applicable. • Testing methodology for COVID-19 was expanded to include rapid antigen testing. • Protocol text under the synopsis subsection was modified. • “Secondary Safety Endpoints” was revised to “Safety Endpoints”. • Protocol text was revised to outline the sequence of assessments and also for managing study participants who remain in the study after permanently discontinuing IP. • Text describing calcineurin inhibitor (CNI) monitoring was revised. • “Acceptable” methods of contraception were removed. • Secondary objectives were revised to include the previous primary efficacy objective as the first secondary objective. • Added statement regarding how to manage study participants who reach the endpoint of “a sustained (>= 60 days) 40% decline in eGFR from Baseline”. • Sites increased to 155. • Inclusion and exclusion criteria revised. • Administration of live vaccines was revised to prohibited during the study. • Revised dose range of mycophenolate mofetil (MMF) and mycophenolic acid (MPA) (allowed concomitant medications). • Study schema, Schedule of events table, and footnotes updated. • Revised protocol text: -regarding participants who discontinue IP due to pregnancy. -withholding or discontinuing IP due to AE, abnormal LFTs, neutropenia and / or thrombocytopenia, and BKV, CMV, or EBV viral infection. -emergency unblinding of IP. • Drug product description was updated. • Added statement to refer the reader to the CSL300 Investigator’s Brochure. • Protocol text for procedures and visit schedule were updated. • The timing of the DSA analysis and renal biopsy was revised. • Allowed participant to rescreen for administrative reason.

    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 due to futility after the planned interim analysis based on the change in eGFR from baseline to Week 52 and analysis was conducted where feasible using the data collected by the time of study termination.
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    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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