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    Clinical Trial Results:
    A double-blind, randomized-withdrawal, placebo-controlled study to evaluate the efficacy and safety of human plasma-derived C1-esterase inhibitor as add-on to standard of care for the treatment of refractory antibody mediated rejection in adult renal transplant recipients

    Summary
    EudraCT number
    		 2017-000348-17
    Trial protocol
    		 BE   GB   DE   ES   NL   FR  
    Global end of trial date
    20 Jan 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Dec 2021
    First version publication date
    04 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSL842_3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03221842
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CSL Behring
    Sponsor organisation address
    1020 First Avenue, King of Prussia, United States, 19406
    Public contact
    Trial Registration Coordinator, CSL Behring LLC, +1 610-878-4000, clinicaltrials@cslbehring.com
    Scientific contact
    Trial Registration Coordinator, CSL Behring LLC, +1 610-878-4000, 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
    01 Feb 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jan 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the efficacy of C1-INH in the treatment of refractory antibody mediated rejection (AMR) in renal allograft recipients.
    Protection of trial subjects
    This study was carried out in accordance with the International Council for Harmonisation (ICH), Good Clinical Practice (GCP) guidelines, and standard operating procedures for clinical research and development at CSL Behring.
    Background therapy
    		 Background therapy is standard of care (IVIg with/without plasmapheresis).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Nov 2017
    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: 4
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    United States: 24
    Worldwide total number of subjects
    63
    EEA total number of subjects
    39
    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)
    57
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The Sponsor terminated the study for business reasons. Because of the study termination, there were limitations in interpreting analyses and efficacy results based on small numbers of subjects. No subject reached the 48-month follow-up endpoint.

    Period 1
    Period 1 title
    Period 1 (up to 13 weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 C1-INH
    Arm description
    		 C1-esterase inhibitor (CSL842) C1-esterase inhibitor: C1-esterase inhibitor is a human plasma-derived lyophilised powder for reconstitution administered at a dose of 60 IU/kg
    Arm type
    		 Experimental

    Investigational medicinal product name
    C1-esterase inhibitor (C1-INH)
    Investigational medicinal product code
    Other name
    CSL842
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    C1-esterase inhibitor is a human plasma-derived lyophilised powder for reconstitution at a dose of 60 IU/kg

    Number of subjects in period 1
    		C1-INH
    Started
    63
    Completed
    53
    Not completed
    10
         Physician decision
    2
         Adverse event, non-fatal
    4
         Terminated by sponsor
    1
         Unknown
    2
         Lost to follow-up
    1
    Period 2
    Period 2 title
    Period 2 (up to 14-38 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 C1-INH
    Arm description
    		 C1-esterase inhibitor (CSL842)
    Arm type
    		 Experimental

    Investigational medicinal product name
    C1-esterase inhibitor (C1-INH)
    Investigational medicinal product code
    Other name
    CSL842
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    C1-esterase inhibitor is a human plasma-derived lyophilised powder for reconstitution administered at a dose of 60 IU/kg

    Arm title
    		 Placebo
    Arm description
    		 Excipients of C1-INH plus albumin
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Excipients of C1-INH plus albumin

    Number of subjects in period 2 [1]
    		C1-INH Placebo
    Started
    7
    6
    Completed
    6
    5
    Not completed
    1
    1
         Adverse event, serious fatal
    -
    1
         Lack of efficacy
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only 13 participants that completed Period 1 were eligible to continue to Period 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Period 1 (up to 13 weeks)
    Reporting group description
    		 -

    Reporting group values
    		 Period 1 (up to 13 weeks) Total
    Number of subjects
    		 63 63
    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)
    		 57 57
        From 65-84 years
    		 6 6
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43.3 ( 13.83 ) -
    Gender categorical
    Units: Subjects
        Female
    		 27 27
        Male
    		 36 36

    End points

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    End points reporting groups
    Reporting group title
    C1-INH
    Reporting group description
    		 C1-esterase inhibitor (CSL842) C1-esterase inhibitor: C1-esterase inhibitor is a human plasma-derived lyophilised powder for reconstitution administered at a dose of 60 IU/kg
    Reporting group title
    C1-INH
    Reporting group description
    		 C1-esterase inhibitor (CSL842)

    Reporting group title
    Placebo
    Reporting group description
    		 Excipients of C1-INH plus albumin

    Primary: Number and percent of participants with loss-of-response at the end-of-Treatment Period 2 (TP2)

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    End point title
    		 Number and percent of participants with loss-of-response at the end-of-Treatment Period 2 (TP2) [1]
    End point description
    Loss of response is defined as 1 of the following, whichever occurs first: • Decline in Estimated Glomerular Filtration Rate (eGFR), or • Allograft failure, or • Subject death by any cause.
    End point type
    Primary
    End point timeframe
    Up to approximately 25 weeks
    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: Descriptive statistics were used for this endpoint.
    End point values
    		 C1-INH Placebo
    Number of subjects analysed
    6
    5
    Units: participants
    number (not applicable)
        Number
    2
    2
        Percent
    33.3
    40.0
    No statistical analyses for this end point

    Secondary: Number and percent of Participants With All-cause Allograft Failure During TP2

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    End point title
    		 Number and percent of Participants With All-cause Allograft Failure During TP2
    End point description
    Allograft failure is defined as 1 of the following: • Allograft nephrectomy, institution of permanent dialysis, or return to the transplant waitlist for renal transplant, whichever occurs first, OR • Subject death by any cause
    End point type
    Secondary
    End point timeframe
    Up to 25 weeks
    End point values
    		 C1-INH Placebo
    Number of subjects analysed
    6
    5
    Units: participants
    number (not applicable)
        Number
    0
    1
        Percent
    0
    20
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Estimated Glomerular Filtration Rate at End of Treatment Period 1(TP1)

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    End point title
    		 Absolute Change From Baseline in Estimated Glomerular Filtration Rate at End of Treatment Period 1(TP1)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and 13 weeks
    End point values
    		 C1-INH
    Number of subjects analysed
    63
    Units: mL/min/1.73m*2
        median (full range (min-max))
    -0.75 (-17.0 to 7.5)
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Estimated Glomerular Filtration Rate at end of TP2

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    End point title
    		 Absolute Change From Baseline in Estimated Glomerular Filtration Rate at end of TP2
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and 38 weeks
    End point values
    		 C1-INH Placebo
    Number of subjects analysed
    6
    4
    Units: Absolute Change From Baseline in Estimat
        arithmetic mean (standard deviation)
    7.75 ( 8.454 )
    15.25 ( 10.444 )
    No statistical analyses for this end point

    Secondary: Number and percent of responders at the end-of-TP1

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    End point title
    		 Number and percent of responders at the end-of-TP1
    End point description
    Responders were defined as subjects whose End-of-TP1 eGFR was ≥ 90% of baseline eGFR and ≥ 20 mL/min/1.73 m2.
    End point type
    Secondary
    End point timeframe
    Up to 13 weeks
    End point values
    		 C1-INH
    Number of subjects analysed
    63
    Units: responders
    number (not applicable)
        Number
    33
        Percent
    52.4
    No statistical analyses for this end point

    Secondary: Percent of participants with any adverse event (AE) assessed as related to investigational product

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    End point title
    		 Percent of participants with any adverse event (AE) assessed as related to investigational product
    End point description
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 weeks after the time of first investigational product administration
    End point values
    		 C1-INH Placebo
    Number of subjects analysed
    63
    6
    Units: percentage of participants
        number (not applicable)
    20.6
    16.7
    No statistical analyses for this end point

    Secondary: Mean pre-dose C1-esterase inhibitor functional activity

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    End point title
    		 Mean pre-dose C1-esterase inhibitor functional activity
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 13 weeks
    End point values
    		 C1-INH
    Number of subjects analysed
    20
    Units: percent
    arithmetic mean (standard deviation)
        week 2 (n=14)
    168.86 ( 64.059 )
        week 11 (n=13)
    179.32 ( 58.551 )
    No statistical analyses for this end point

    Secondary: Maximum plasma concentration (Cmax) for C1-INH functional activity

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    End point title
    		 Maximum plasma concentration (Cmax) for C1-INH functional activity
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 72 hours after dose
    End point values
    		 C1-INH
    Number of subjects analysed
    15
    Units: percent
    arithmetic mean (standard deviation)
        Day 10 (n=14)
    270.39 ( 90.166 )
        Day 77 (n=10)
    204.41 ( 78.478 )
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration time curve (AUC0-t) for C1-INH functional activity

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    End point title
    		 Area under the plasma concentration time curve (AUC0-t) for C1-INH functional activity
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 72 hours after dose
    End point values
    		 C1-INH
    Number of subjects analysed
    15
    Units: h*%
    arithmetic mean (standard deviation)
        Day 10 (n=10)
    15229.84819 ( 4149.16754 )
        Day 77 (n=9)
    12742.20883 ( 4445.31881 )
    No statistical analyses for this end point

    Secondary: The rate of change of eGFR during TP2 as defined by the slope of the mean regression of eGFR over time in TP2

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    End point title
    		 The rate of change of eGFR during TP2 as defined by the slope of the mean regression of eGFR over time in TP2
    End point description
    End point type
    Secondary
    End point timeframe
    Screening and up to approximately 38 weeks
    End point values
    		 C1-INH Placebo
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: number
        number (not applicable)
    Notes
    [2] - Because of the study termination, limited efficacy results are presented in this report.
    [3] - Because of the study termination, limited efficacy results are presented in this report.
    No statistical analyses for this end point

    Secondary: Time to all-cause allograft failure through the Follow up Period

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    End point title
    		 Time to all-cause allograft failure through the Follow up Period
    End point description
    End point type
    Secondary
    End point timeframe
    Up to approximately 208 weeks
    End point values
    		 C1-INH Placebo
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: hours
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [4] - No subject completed the follow-up period.
    [5] - Because of the study termination, limited efficacy results are presented in this report.
    No statistical analyses for this end point

    Secondary: Proportion of subjects surviving through the Follow-up Period

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    End point title
    		 Proportion of subjects surviving through the Follow-up Period
    End point description
    End point type
    Secondary
    End point timeframe
    Up to approximately 208 weeks
    End point values
    		 C1-INH Placebo
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: percent of subjects
        number (not applicable)
    Notes
    [6] - No subject completed the follow-up period.
    [7] - Because of the study termination, limited efficacy results are presented in this report.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 42 weeks per participant
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    C1-INH (Period 1)
    Reporting group description
    		 C1-esterase inhibitor (CSL842) C1-esterase inhibitor: C1-esterase inhibitor is a human plasma-derived lyophilised powder for reconstitution administered at a dose of 60 IU/kg

    Reporting group title
    C1-INH (Period 2)
    Reporting group description
    		 -

    Reporting group title
    Placebo (Period 2)
    Reporting group description
    		 -

    Serious adverse events
    		 C1-INH (Period 1) C1-INH (Period 2) Placebo (Period 2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 63 (39.68%)
    1 / 7 (14.29%)
    3 / 6 (50.00%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    1
    Investigations
    Blood creatine increased
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Unevaluable event
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Transplant rejection
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 63 (4.76%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 63 (3.17%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Perinephric collection
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelocaliectasis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    3 / 63 (4.76%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Rhinovirus infection
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethritis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection pseudomonas
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 C1-INH (Period 1) C1-INH (Period 2) Placebo (Period 2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 63 (73.02%)
    4 / 7 (57.14%)
    5 / 6 (83.33%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Refractory cytopenia with unilineage dysplasia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 63 (9.52%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    7
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 63 (6.35%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    4
    1
    0
    Discomfort
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Oedema
         subjects affected / exposed
    8 / 63 (12.70%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    9
    1
    0
    Pain
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    4
    0
    1
    Pyrexia
         subjects affected / exposed
    5 / 63 (7.94%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Cough
         subjects affected / exposed
    4 / 63 (6.35%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    4
    1
    0
    Dyspnoea
         subjects affected / exposed
    5 / 63 (7.94%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    0
    0
    Epistaxis
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    10
    0
    1
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Headache
         subjects affected / exposed
    18 / 63 (28.57%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    32
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 63 (12.70%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    9
    0
    0
    Leukopenia
         subjects affected / exposed
    5 / 63 (7.94%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    7
    0
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Anal pruritus
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    11 / 63 (17.46%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    23
    0
    0
    Nausea
         subjects affected / exposed
    9 / 63 (14.29%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    12
    0
    1
    Vomiting
         subjects affected / exposed
    11 / 63 (17.46%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    13
    0
    0
    Hepatobiliary disorders
    Hepatocellular injury
         subjects affected / exposed
    5 / 63 (7.94%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    1
    Dermatitis papillaris capillitii
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    6 / 63 (9.52%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    0
    0
    Focal segmental glomerulosclerosis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Body tinea
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Conjunctivitis viral
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Cytomegalovirus infection
         subjects affected / exposed
    3 / 63 (4.76%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    Staphylococcal infection
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Trichomoniasis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    1
    Metabolism and nutrition disorders
    Folate deficiency
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    3 / 63 (4.76%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    1
    Hyperphosphataemia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    4 / 63 (6.35%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    0
    Metabolic acidosis
         subjects affected / exposed
    5 / 63 (7.94%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    6
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Nov 2017
    1. A Non-responder Follow-up Period is added for subjects who are non-responders after TP1. These subjects will be followed until graft failure or up to 48 months after enrollment. Statistical analyses are amended to reflect this change. 2. Pregnancy tests are added at monthly intervals. 3. Additional time points are added for C1-INH activity/antigen and collection of retention samples in TP1. 4. Exclusion criterion 3 is deleted. 5. Inclusion criterion 5 is amended. 6. Exclusion criterion 4a (previously 5a) amended to include HBV as part of the viral hepatitis criterion. 7. New exclusion criterion 5 includes a history of HIV as collected in medical history at Screening 8. The criteria used to determine frequency of blood draws for creatinine measurement is changed from an increase of 20% to 10% above the previous value in TP2.
    23 Jan 2019
    1. Plasmapheresis is no longer mandatory if DSA is ≥ 5000 MFI. 2. Dosing at Week 13 is clarified. 3. Mean corpuscular hemoglobin concentration and mean corpuscular volume are not required safety assessments. 4. Week 13 Visit is clarified
    31 Jan 2020
    1. The responder definition is revised. 2. Definition of loss of response is changed. 3. The primary endpoint is changed from time to loss of response to loss of response status (binary: yes/no). 4. The secondary endpoints are revised. 5. The number of planned subjects and sites are increased. 6. Development of recurrent or persistent AMR is added as an efficacy assessment. 7. Timing for collecting serum creatinine is amended. 8. Monitoring of kidney function is added during the Responder Follow-up Period. 9. Exploratory endpoints are amended. 10. Study design rationale is revised to support changes to the primary endpoint. 11. Inclusion criteria 5, 6, and 7 are amended. 12. Exclusion criterion 8 is amended. 13. Dosing of C1-INH and placebo based on body weight is clarified. 14. Measured eGFR timing is clarified. 15. The adverse event observation period is amended.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    27 Mar 2020
    Study sites were notified that a global screening/enrollment hold would be implemented due to the COVID-19 pandemic.
    29 May 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The Sponsor terminated the study due to feasibility of enrolment. Due to study termination, there were limitations in interpreting analyses and efficacy results based on small numbers of subjects. No subject reached the 48-month follow-up endpoint.
    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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