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    Clinical Trial Results:
    A Randomized Double-Blind Placebo-Controlled Study to Evaluate the Efficacy and Safety of CINRYZE (C1 Esterase Inhibitor [Human]) for the Treatment of Acute Antibody-Mediated Rejection in Kidney Transplant Subjects

    Summary
    EudraCT number
    		 2015-000726-11
    Trial protocol
    		 NL   DE   ES  
    Global end of trial date
    31 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jun 2020
    First version publication date
    14 Jun 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SHP616-302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02547220
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, United States, MA 02421
    Public contact
    Study Director, Shire, 1 866-842-5335, ClinicalTransparency@takeda.com
    Scientific contact
    Study Director, Shire, 1 866-842-5335, ClinicalTransparency@takeda.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
    31 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of CINRYZE administered with plasmapheresis, plasma exchange, or immune adsorption treatments and sucrose-free intravenous immunoglobulin (IVIg) for the treatment of acute antibody-mediated rejection (AMR) of renal allograft in kidney transplant recipients as measured by the proportion of subjects with new or worsening transplant glomerulopathy (TG) at 6 months after treatment initiation.
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation of Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 May 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United States: 25
    Worldwide total number of subjects
    39
    EEA total number of subjects
    10
    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)
    32
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 49 sites between 20 May 2016 (first subject first visit) and 31 May 2019 (last subject last visit).

    Pre-assignment
    Screening details
    		 A total of 39 subjects were randomized and received treatment.

    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received a total of seven doses, with an initial 100 milliliter (mL) intravenous (IV) infusion containing 5000 units of placebo (100 mL 0.9 percent [%] sodium chloride) on Day 1 followed by 2500 units of placebo (100 mL 0.9% sodium chloride) on Days 3, 5, 7, 9, 11, and 13.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an initial 100 mL IV infusion containing 5000 units of placebo on Day 1 followed by 2500 units of placebo on Days 3, 5, 7, 9, 11, and 13.

    Arm title
    		 CINRYZE
    Arm description
    		 Subjects received a total of seven doses, with an initial 100 mL intravenous (IV) infusion containing 5000 units of CINRYZE on Day 1 followed by 2500 units of CINRYZE in 100 mL of IV infusion on Day 3, 5, 7, 9, 11, and 13.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CINRYZE
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an initial 100 mL IV infusion containing 5000 units of CINRYZE on Day 1 followed by 2500 units of CINRYZE in 100 mL of IV infusion on Day 3, 5, 7, 9, 11, and 13.

    Number of subjects in period 1
    		Placebo CINRYZE
    Started
    19
    20
    Completed
    0
    0
    Not completed
    19
    20
         Consent withdrawn by subject
    1
    -
         Study terminated by sponsor
    18
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received a total of seven doses, with an initial 100 milliliter (mL) intravenous (IV) infusion containing 5000 units of placebo (100 mL 0.9 percent [%] sodium chloride) on Day 1 followed by 2500 units of placebo (100 mL 0.9% sodium chloride) on Days 3, 5, 7, 9, 11, and 13.

    Reporting group title
    CINRYZE
    Reporting group description
    		 Subjects received a total of seven doses, with an initial 100 mL intravenous (IV) infusion containing 5000 units of CINRYZE on Day 1 followed by 2500 units of CINRYZE in 100 mL of IV infusion on Day 3, 5, 7, 9, 11, and 13.

    Reporting group values
    		 Placebo CINRYZE Total
    Number of subjects
    		 19 20
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.9 ± 12.49 49.2 ± 13.45 -
    Gender categorical
    Units: Subjects
        Female
    		 9 5 14
        Male
    		 10 15 25
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 12 13 25
        American Indian or Alaska Native
    		 0 0 0
        Asian/Non-Japanese
    		 5 1 6
        Asian/Japanese
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 2 2
        Black or African American
    		 2 2 4
        Latino
    		 0 1 1
        Unknown
    		 0 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 6 9
        Not Hispanic or Latino
    		 13 10 23
        Unknown or Not Reported
    		 3 4 7

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received a total of seven doses, with an initial 100 milliliter (mL) intravenous (IV) infusion containing 5000 units of placebo (100 mL 0.9 percent [%] sodium chloride) on Day 1 followed by 2500 units of placebo (100 mL 0.9% sodium chloride) on Days 3, 5, 7, 9, 11, and 13.

    Reporting group title
    CINRYZE
    Reporting group description
    		 Subjects received a total of seven doses, with an initial 100 mL intravenous (IV) infusion containing 5000 units of CINRYZE on Day 1 followed by 2500 units of CINRYZE in 100 mL of IV infusion on Day 3, 5, 7, 9, 11, and 13.

    Primary: Percentage of Subjects With New or Worsening Transplant Glomerulopathy (TG) at Month 6 Post-Treatment

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    End point title
    		 Percentage of Subjects With New or Worsening Transplant Glomerulopathy (TG) at Month 6 Post-Treatment
    End point description
    New or worsening TG at month 6 by the standard score was defined as an increase in one or more between qualifying biopsy and 6-month biopsy. New or worsening TG was measured by Banff 2013 criteria (standard score) using allograft glomerulopathy (Cg0-Cg3): Cg0- No GBM double contours by light microscopy (LM) or electron microscopy (EM); Cg1- no GBM double contours by LM but GBM double contours in at least 3 glomerular capillaries by EM; Cg2- Double contours affecting 26 to 50% of peripheral capillary loops in the most affected of nonsclerotic glomeruli; Cg3- Double contours affecting more than 50% of peripheral capillary loops in the most affected of nonsclerotic glomeruli with a score range of 0 (no allograft glomerulopathy) and 3 (severe glomerulopathy). Percentage of subjects with new or worsening TG at Month 6 post treatment was reported. Full analysis set (FAS) was analysed, which consisted of all subjects who had taken at least 1 dose of investigational product.
    End point type
    Primary
    End point timeframe
    Month 6
    End point values
    		 Placebo CINRYZE
    Number of subjects analysed
    19
    20
    Units: Percentage of subjects
        number (not applicable)
    47.4
    50.0
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v CINRYZE
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.6857
    Method
    		 Fisher exact
    Parameter type
    		 Difference in proportion
    Point estimate
    2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.4
         upper limit
    		 34.5
    Notes
    [1] - Difference in proportion was calculated by the difference in proportion of new or worsening TG at 6 months between CINRYZE and placebo

    Secondary: Number of Subjects With All-Cause Graft Failure at Month 48

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    End point title
    		 Number of Subjects With All-Cause Graft Failure at Month 48
    End point description
    Graft failure was determined as the presence of one or more of the following criteria: institution of permanent dialysis (defined as dialysis treatment more than [>] 30 days), current transplant nephrectomy, and/or a clinical determination of cessation of kidney graft function and estimated glomerular filtration rate (eGFR) less than or equal to (<=) 15 milliliter (mL)/minute (min)/1.73 meter (m)^2. This study was prematurely terminated at Month 36 due to futility issue. This endpoint was planned to analyze at Month 48. Hence, data for this endpoint was not collected as planned, analyzed and reported. 
    End point type
    Secondary
    End point timeframe
    Month 48
    End point values
    		 Placebo CINRYZE
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Subjects
    Notes
    [2] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    [3] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Renal Function up to Month 48

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    End point title
    		 Change From Baseline in Renal Function up to Month 48
    End point description
    Renal function was measured as glomerular filtration rate calculated by the modification of diet in renal disease (eGFRMDRD). This study was prematurely terminated at Month 36 due to futility issue. This endpoint was planned to analyse at Month 48. Hence, data for this endpoint was not collected as planned, analysed and reported. 
    End point type
    Secondary
    End point timeframe
    Baseline, up to Month 48
    End point values
    		 Placebo CINRYZE
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: milliliter per minute (mL/min)
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [4] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    [5] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Baseline With Pre-Antibody-Mediated Rejection (AMR) in Renal Function up to Month 48

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    End point title
    		 Change From Baseline With Pre-Antibody-Mediated Rejection (AMR) in Renal Function up to Month 48
    End point description
    Renal function was measured as glomerular filtration rate calculated by the modification of diet in renal disease (eGFRMDRD). Pre-AMR baseline was the highest eGFRMDRD value obtained following the kidney transplant and within 30 days prior to the qualifying AMR episode. This study was prematurely terminated at Month 36 due to futility issue. This endpoint was planned to analyse at Month 48. Hence, data for this endpoint was not collected as planned, analysed and reported. 
    End point type
    Secondary
    End point timeframe
    Pre-AMR Baseline, up to Month 48
    End point values
    		 Placebo CINRYZE
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: mL/min
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [6] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    [7] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Proteinuria Levels at Month 48

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    End point title
    		 Number of Subjects With Proteinuria Levels at Month 48
    End point description
    Proteinuria included spot urine protein, urine creatinine, and urine protein/urine creatinine ratio. This study was prematurely terminated at Month 36 due to futility issue. This endpoint was planned to analyse at Month 48. Hence, data for this endpoint was not collected as planned, analysed and reported. 
    End point type
    Secondary
    End point timeframe
    Month 48
    End point values
    		 Placebo CINRYZE
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: Subjects
    Notes
    [8] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    [9] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Pre-Antibody-Mediated Rejection (AMR) Baseline in Histopathology per Banff Criteria at Month 6

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    End point title
    		 Change From Pre-Antibody-Mediated Rejection (AMR) Baseline in Histopathology per Banff Criteria at Month 6
    End point description
    Histopathological diagnosis of acute rejection was measured by Banff 2013 criteria: Glomerulitis score (g0-g3), allograft glomerulopathy (Cg0-cg3), Tubulitis score (T0-T3), Intimal arteritis score (V0-V3), peritubular capillaritis (PTC) (ptc0-ptc3) and Interstitial Inflammation score (i0-i3). The histopathology was a composite of the sub-scores. Each of the sub-scores or histopathology score ranges from 0 ( no histopathology) to 3 (more severe histopathology). This study was prematurely terminated at Month 36 due to futility issue. Hence, data for this endpoint was not collected as planned, analysed and reported. 
    End point type
    Secondary
    End point timeframe
    Pre-AMR Baseline, Month 6
    End point values
    		 Placebo CINRYZE
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: milliliter
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [10] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    [11] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    No statistical analyses for this end point

    Secondary: Number of Subjects With All-Cause Graft Failure at Month 6

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    End point title
    		 Number of Subjects With All-Cause Graft Failure at Month 6
    End point description
    Graft failure was determined by the presence of one or more of the following criteria: institution of permanent dialysis (defined as dialysis treatment more than [>] 30 days), current transplant nephrectomy, and/or a clinical determination of cessation of kidney graft function and estimated glomerular filtration rate (eGFR) less than or equal to (<=) 15 milliliter (mL)/minute (min)/1.73 meter (m)^2. This study was prematurely terminated at Month 36 due to futility issue. Hence, data for this endpoint was not collected as planned, analysed and reported. 
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    		 Placebo CINRYZE
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: Subjects
    Notes
    [12] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    [13] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Graft Failure due to Antibody-Mediated Rejection (AMR) Episodes at Month 48

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    End point title
    		 Number of Subjects With Graft Failure due to Antibody-Mediated Rejection (AMR) Episodes at Month 48
    End point description
    Graft failure was determined by the presence of one or more of the following criteria: institution of permanent dialysis (defined as dialysis treatment more than [>] 30 days), current transplant nephrectomy, and/or a clinical determination of cessation of kidney graft function and estimated glomerular filtration rate (eGFR) less than or equal to (<=) 15 milliliter (mL)/minute (min)/1.73 meter (m)^2. This study was prematurely terminated at Month 36 due to futility issue. This endpoint was planned to analyse at Month 48. Hence, data for this endpoint was not collected as planned, analysed and reported.
    End point type
    Secondary
    End point timeframe
    Month 48
    End point values
    		 Placebo CINRYZE
    Number of subjects analysed
    0 [14]
    0 [15]
    Units: Subjects
    Notes
    [14] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    [15] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    No statistical analyses for this end point

    Secondary: Time to All-Cause Graft Failure up to Month 48

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    End point title
    		 Time to All-Cause Graft Failure up to Month 48
    End point description
    Graft failure was determined by the presence of one or more of the following criteria: institution of permanent dialysis (defined as dialysis treatment greater than [>] 30 days), current transplant nephrectomy, and/or a clinical determination of cessation of kidney graft function and estimated glomerular filtration rate (eGFR) less than or equal to (<=) 15 milliliter (mL)/minute (min)/1.73 meter (m)^2. Time to all-cause graft failure in months was calculated as (Date of graft failure – Date of first dose + 1)/30.25. This study was prematurely terminated at Month 36 due to futility issue. This endpoint was planned to analyse at Month 48. Hence, data for this endpoint was not collected as planned, analysed and reported.
    End point type
    Secondary
    End point timeframe
    Up to Month 48
    End point values
    		 Placebo CINRYZE
    Number of subjects analysed
    0 [16]
    0 [17]
    Units: Months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [16] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    [17] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    No statistical analyses for this end point

    Secondary: Time to Graft Failure due to Antibody-Mediated Rejection (AMR) Episodes up to Month 48

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    End point title
    		 Time to Graft Failure due to Antibody-Mediated Rejection (AMR) Episodes up to Month 48
    End point description
    Graft failure was determined by the presence of one or more of the following criteria: institution of permanent dialysis (defined as dialysis treatment > 30 days), current transplant nephrectomy, and/or a clinical determination of cessation of kidney graft function and eGFR <=15 mL/ min/1.73m^2. Time to graft failure due to AMR episodes in months was calculated as (Date of graft failure due to AMR – Date of first dose + 1)/30.25. This study was prematurely terminated at Month 36 due to futility issue. This endpoint was planned to analyse at Month 48. Hence, data for this endpoint was not collected as planned, analysed and reported.
    End point type
    Secondary
    End point timeframe
    Up to Month 48
    End point values
    		 Placebo CINRYZE
    Number of subjects analysed
    0 [18]
    0 [19]
    Units: Months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [18] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    [19] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Resolution of the Qualifying Antibody-Mediated Rejection (AMR) Episodes at Month 48

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    End point title
    		 Number of Subjects With Resolution of the Qualifying Antibody-Mediated Rejection (AMR) Episodes at Month 48
    End point description
    Number of subjects with resolution of the qualifying AMR episodes at Month 48. This study was prematurely terminated at Month 36 due to futility issue. This endpoint was planned to analyse at Month 48. Hence, data for this endpoint was not collected as planned, analysed and reported. 
    End point type
    Secondary
    End point timeframe
    Month 48
    End point values
    		 Placebo CINRYZE
    Number of subjects analysed
    0 [20]
    0 [21]
    Units: Subjects
    Notes
    [20] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    [21] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    No statistical analyses for this end point

    Secondary: Time to Resolution of Qualifying Antibody-Mediated Rejection (AMR) Episodes up to Month 48

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    End point title
    		 Time to Resolution of Qualifying Antibody-Mediated Rejection (AMR) Episodes up to Month 48
    End point description
    Time to resolution of qualifying AMR episodes was calculated as (Date of qualifying AMR resolution – Date of first dose + 1)/30.25. Subjects who didn’t had resolution of qualifying AMR episodes and still on-study were censored at the date of last visit; Subjects who had completed the study without resolution of qualifying AMR were censored at the date of study completion; subjects who discontinued from the study without resolution of qualifying AMR were censored at the date of early discontinuation. This study was prematurely terminated at Month 36 due to futility issue. This endpoint was planned to analyse at Month 48. Hence, data for this endpoint was not collected as planned, analysed and reported.
    End point type
    Secondary
    End point timeframe
    Up to Month 48
    End point values
    		 Placebo CINRYZE
    Number of subjects analysed
    0 [22]
    0 [23]
    Units: Months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [22] - This study was prematurely terminated. Hence, data was not collected, analyzed for this end point.
    [23] - This study was prematurely terminated. Hence, data was not collected, analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Were Alive at Month 36

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    End point title
    		 Number of Subjects Who Were Alive at Month 36
    End point description
    Number of subjects who were alive at Month 36 (study terminated instead of Month 48) were reported. Safety analysis set was analysed, which consisted of all subjects who had taken at least 1 dose of investigational product. This study was prematurely terminated at Month 36 due to futility issue. This outcome measure was planned to analyze at Month 48.
    End point type
    Secondary
    End point timeframe
    Month 36
    End point values
    		 Placebo CINRYZE
    Number of subjects analysed
    19
    20
    Units: Subjects
    19
    20
    No statistical analyses for this end point

    Secondary: Time to All-Cause Mortality up to Month 48

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    End point title
    		 Time to All-Cause Mortality up to Month 48
    End point description
    Time to all-cause mortality was calculated as (Date of discontinuation due to death – Date of first dose + 1)/30.25. Subjects who are alive and still on-study were censored at the date of last visit; Subjects who had completed the study were censored at the date of study completion; Subjects who discontinued from the study but not due to death were censored at the date of early discontinuation. This study was prematurely terminated at Month 36 due to futility issue. This endpoint was planned to analyse at Month 48. Hence, data for this endpoint was not collected as planned, analysed and reported.
    End point type
    Secondary
    End point timeframe
    Up to Month 48
    End point values
    		 Placebo CINRYZE
    Number of subjects analysed
    0 [24]
    0 [25]
    Units: Months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [24] - This study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    [25] - This Study was prematurely terminated. Hence, data was not collected, analysed for this end point.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs)
    End point description
    An adverse event (AE) was any untoward, undesired, unplanned clinical event in the form of signs, symptoms, disease, or laboratory or physiological observations occurred in a subject participating in a clinical study with the sponsor's product, regardless of causal relationship. TEAEs were defined as events that started or worsened on or after the date of the first dose of investigational product, but no later than 30 days following the last dose of investigational product, within a treatment period. Safety analysis set was analysed, which consisted of all subjects who had taken at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to study termination (Month 36)
    End point values
    		 Placebo CINRYZE
    Number of subjects analysed
    19
    20
    Units: Subjects
    16
    16
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration up to study termination (Month 36)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of placebo (100 mL 0.9% sodium chloride) on day 1 followed by 2500 units of placebo (100 mL 0.9% sodium chloride) on Days 3, 5, 7, 9, 11, and 13.

    Reporting group title
    CINRYZE
    Reporting group description
    		 Subjects received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of CINRYZE on Day 1 followed by 2500 units of CINRYZE in 100 mL of IV infusion on Day 3, 5, 7, 9, 11, and 13.

    Serious adverse events
    		 Placebo CINRYZE
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 19 (31.58%)
    3 / 20 (15.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site thrombosis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Klebsiella sepsis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo CINRYZE
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 19 (78.95%)
    16 / 20 (80.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 20 (5.00%)
         occurrences all number
    3
    2
    Lymphocele
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Orthostatic hypotension
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Fatigue
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Nodule
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Dry throat
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Sinus disorder
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Throat irritation
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Blood bicarbonate increased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Blood glucose increased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Blood magnesium decreased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Blood potassium increased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Blood urea increased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Blood uric acid increased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Glomerular filtration rate decreased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Neutrophil count increased
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    White blood cell count increased
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Arteriovenous fistula site haematoma
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Citrate toxicity
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    5
    Complications of transplanted kidney
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Toxicity to various agents
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Vascular access complication
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Tremor
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Leukopenia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Constipation
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Diarrhoea
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Dry mouth
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Oesophagitis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Tooth disorder
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Rash pruritic
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Chronic kidney disease
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Proteinuria
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Infections and infestations
    BK virus infection
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Catheter site infection
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Peritonitis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Urosepsis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Folate deficiency
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Metabolic acidosis
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 May 2015
    Amendment:1 Added secondary objective "“To assess the overall subject survival status (proportion and time-to-event)” for consistency with endpoints and analyses". Removed the secondary objective/endpoint of frequency of AMR: “To assess the number of acute AMR episodes treated per protocol during the follow-up period”.
    25 Jun 2015
    Amendment:2 Added an exploratory analysis to determine if early glomerular and/or endothelial pathology observed only on electron microscopy (cg score lesser than < 1b) affects long-term kidney graft survival.
    01 Sep 2016
    Amendment:3 Clarified that intravenous immunoglobulin (IVIg) is to be sucrose-free to avoid potential renal toxicity and dosed at no less than 100 mg/kg to allow more flexibility and adhere to site standard of care. Removed the limit for a maximum enrollment to add greater flexibility. Reorganized the secondary objectives into study entry to 6 months and study entry to 4 years to provide increased structure and clarity to the protocol. Added change in proteinuria as a secondary objective to better assess graft function. Added time to AMR resolution as a secondary objective to better assess CINRYZE effect. Revised the stratification for severity to specify estimated glomerular filtration rate calculated by Modification of Diet in Renal Disease (eGFRMDRD) (ie, <=15 mL/min/1.73 m2 or >15 mL/min/1.73 m2). Revised the definition of graft failure to specify that permanent dialysis is defined as dialysis treatment >30 days, current transplant nephrectomy, or clinical determination of cessation of kidney graft (eGFRMDRD <= 15 mL/min/1.73 m2). Clarified definitions of pre-AMR baseline and resolution of qualifying and recurrent AMR episodes. Revised the inclusion/exclusion criteria. Added criteria for adequate kidney function defined as having a pre-AMR baseline eGFRMDRD >= 20 mL/min/1.72 m2 if the qualifying AMR episode occurs <= 21 days after transplant or pre-AMR baseline eGFRMDRD >= 30 mL/min/1.72 m2 if the qualifying AMR episode occurs >21 days after transplant. Revised the window for subject assessments from ±14 days to ±21 days for months 3 through 12 and to ±28 days for months after Month 12 to allow greater flexibility to subjects and sites. Specified that Conmeds and AEs was collected through 30 days after the last dose of investigational product for each treatment period to ensure adequate information is collected for analysis of safety. Clarified the correct eGFRMDRD formula. Added in the 2013 updated criteria for Banff classification.
    22 Nov 2017
    Amendment:4 Retreatment of recurrent AMR episodes may occur “during the first 180 days after the qualifying biopsy for AMR,” which was updated from “during the first 6 months of the study”. To avoid confusion with the window of the Month 6 visit, the time to allow retreatment was set to 180 days. Serious adverse event procedure for thrombotic and thromboembolic events updated. Correction of typographical error: Units for eGFRMDRD value updated from milliliter per minute (mL/min)/1.72 square meter (m2) to mL/min/1.73 m2.

    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.
    This study was prematurely terminated at Month 36 due to futility issue.
    For support, Contact us.
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