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    Clinical Trial Results:
    An Open-Label, Multi-Center Clinical Trial of Eculizumab in Pediatric Patients With Atypical Hemolytic-Uremic Syndrome

    Summary
    EudraCT number
    		 2010-020310-28
    Trial protocol
    		 NL   DE   GB   FR   AT   IT   BE   ES  
    Global end of trial date
    08 Jan 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jul 2016
    First version publication date
    29 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C10-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01193348
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alexion Pharmaceuticals Incorporated
    Sponsor organisation address
    352 Knotter Drive, Cheshire , United States, 06410
    Public contact
    European Clinical Trial Information, Alexion Europe SAS, +33 1 47 10 06 06, clinicaltrials.eu@alxn.com
    Scientific contact
    European Clinical Trial Information, Alexion Europe SAS, +33 1 47 10 06 06, clinicaltrials.eu@alxn.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000876-PIP01-10
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Jun 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Jan 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy and safety of eculizumab in pediatric patients with aHUS to control thrombotic microangiopathy (TMA) as characterized by thrombocytopenia, hemolysis and renal impairment.
    Protection of trial subjects
    - vaccination against N. meningitidis, pneumococcus and haemophilus (per the vaccine label) at least 14 days prior to study drug initiation or otherwise be protected by prophylactic antibiotics. - antibiotic prophylaxis throughout the treatment period for patients under age of two years.
    Background therapy
    		 -
    Evidence for comparator
    		 No comparator was used in this trial.
    Actual start date of recruitment
    30 Sep 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    22
    EEA total number of subjects
    14
    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)
    5
    Children (2-11 years)
    13
    Adolescents (12-17 years)
    4
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 27 patients diagnosed with aHUS signed the informed consent and of these, 22 patients were treated. Five patients were excluded from the study due to failed screening procedure and did not receive eculizumab.

    Pre-assignment
    Screening details
    		 At screening, patients had to have a platelet count < lower limit of normal range (<LLN) and serum creatinine level > 97 percentile for age; and had to exhibit signs or symptoms of hemolysis at the start of the current aHUS event with fragmented RBC and a negative Coombs test.

    Pre-assignment period milestones
    Number of subjects started
    		 27 [1]
    Number of subjects completed
    		 22

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screen failure: 5
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Informed consent form was obtained from parents/legal guardian for 27 pediatric patients. Of these 27 patients, 22 were treated in the study. The 5 other patients were considered as screen failure.
    Period 1
    Period 1 title
    Treatment Period (26 Weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This trial was a single-arm study and blinding was not required.

    Arms
    Arm title
    		 eculizumab
    Arm description
    		 Eculizumab: Fixed dosing is based on body weight cohorts. Adjustment of dose to accommodate patient growth is possible.
    Arm type
    		 Experimental

    Investigational medicinal product name
    eculizumab
    Investigational medicinal product code
    eculizumab
    Other name
    Soliris
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Eculizumab was to be administered intravenously (IV) according to the regimens described below. Fixed dosing is based on body weight cohorts. Adjustment of dose to accommodate patient growth is possible. - If weight ≥ 40 kg: Induction: 900 mg weekly x 4; Maintenance: 1200 mg Wk5; 1200 mg Q2wks - If weight 30 to <40 kg: Induction: 600 mg weekly x 2; Maintenance: 900 mg Wk3; 900 mg Q2wks - If weight 20 to <30 kg: Induction: 600 mg weekly x 2; Maintenance: 600 mg Wk3; 600 mg Q2wks - If weight 10 to <20 kg: Induction: 600 mg weekly x 1; Maintenance: 300 mg Wk2; 300 mg Q2wks - If weight 5 to <10 kg: Induction: 300 mg Weekly x 1; Maintenance: 300 mg Wk2; 300 mg Q3wks

    Number of subjects in period 1
    		eculizumab
    Started
    22
    Completed
    19
    Not completed
    3
         Consent withdrawn by subject
    1
         Positive Shiga-Toxin Result vial Local
    1
         Serious Adverse Event
    1
    Period 2
    Period 2 title
    Extension Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This trial was a single-arm study and blinding was not required

    Arms
    Arm title
    		 eculizumab
    Arm description
    		 Eculizumab: Fixed dosing is based on body weight cohorts. Adjustment of dose to accommodate patient growth is possible.
    Arm type
    		 Experimental

    Investigational medicinal product name
    eculizumab
    Investigational medicinal product code
    eculizumab
    Other name
    Soliris
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Eculizumab was to be administered intravenously (IV) according to the regimens described below. Fixed dosing is based on body weight cohorts. Adjustment of dose to accommodate patient growth is possible. - If weight ≥ 40 kg: Induction: 900 mg weekly x 4; Maintenance: 1200 mg Wk5; 1200 mg Q2wks - If weight 30 to <40 kg: Induction: 600 mg weekly x 2; Maintenance: 900 mg Wk3; 900 mg Q2wks - If weight 20 to <30 kg: Induction: 600 mg weekly x 2; Maintenance: 600 mg Wk3; 600 mg Q2wks - If weight 10 to <20 kg: Induction: 600 mg weekly x 1; Maintenance: 300 mg Wk2; 300 mg Q2wks - If weight 5 to <10 kg: Induction: 300 mg Weekly x 1; Maintenance: 300 mg Wk2; 300 mg Q3wks

    Number of subjects in period 2 [2]
    		eculizumab
    Started
    17
    Completed
    16
    Not completed
    1
         Physician decision
    1
    Notes
    [2] - 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: Patients were allowed to continue participation in the study and to receive eculizumab in an Extension Treatment Period for 26 weeks or until the product is registered and available. Two patients did not continue in the Extension Treatment.
    Period 3
    Period 3 title
    Post Treatment Period (discontinuation)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This trial was a single-arm study and blinding was not required

    Arms
    Arm title
    		 eculizumab
    Arm description
    		 Patients who discontinued eculizumab treatment at any time during the study were followed for one year.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3 [3]
    		eculizumab
    Started
    10
    Completed
    8
    Not completed
    2
         Lost to follow-up
    2
    Notes
    [3] - 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: Patients who discontinued eculizumab treatment at any time were to be followed for one year. It concerned 10 patients: 3 discontinued before completing the 26-week Treatment Period, 2 did not continue in the Extension Treatment, 1 did not complete the Extension Phase, and 4 completed Extension Phase and were not transitioned to commercial eculizumab.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    eculizumab
    Reporting group description
    		 Eculizumab: Fixed dosing is based on body weight cohorts. Adjustment of dose to accommodate patient growth is possible.

    Reporting group values
    		 eculizumab Total
    Number of subjects
    		 22 22
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 5 5
        Children (2-11 years)
    		 13 13
        Adolescents (12-17 years)
    		 4 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 6.6 ( 6.06 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 10
        Male
    		 12 12
    Platelet Category
    Units: Subjects
        < 150 x10^9/L
    		 22 22
        >= 150 x10^9/L
    		 0 0
    LDH category
    Units: Subjects
        <= ULN
    		 3 3
        > ULN
    		 19 19
    Number of patients with eGFR
    Units: Subjects
        <15 mL/min/1.73*m^2
    		 10 10
        15-29 mL/min/1.73*m^2
    		 4 4
        30-44 mL/min/1.73*m^2
    		 2 2
        45-59 mL/min/1.73*m^2
    		 2 2
        60-89 mL/min/1.73*m^2
    		 2 2
        >=90 mL/min/1.73*m^2
    		 2 2
    Chronic kidney disease (CKD)
    Units: Subjects
        Stage 0
    		 0 0
        Stage 1
    		 2 2
        Stage 2
    		 2 2
        Stage 3a
    		 2 2
        Stage 3b
    		 2 2
        Stage 4
    		 4 4
        Stage 5
    		 10 10
    Plasma Therapy Duration
    Units: Subjects
        < 2 months
    		 20 20
        >= 2 months
    		 1 1
        Missing
    		 1 1
    Clinical TMA Manifestation
    Units: Subjects
        First Clinical
    		 16 16
        Multiple
    		 5 5
        Missing
    		 1 1
    Platelet Count
    Units: x10^9/L
        arithmetic mean (standard deviation)
    		 87.5 ( 42.34 ) -
    Lactate dehydrogenase
    Units: U/L
        arithmetic mean (standard deviation)
    		 1943.7 ( 1824.44 ) -
    Hemoglobin
    Units: g/L
        arithmetic mean (standard deviation)
    		 80.2 ( 15.3 ) -
    Creatinine
    Units: umol/L
        arithmetic mean (standard deviation)
    		 154.5 ( 116.43 ) -

    End points

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    End points reporting groups
    Reporting group title
    eculizumab
    Reporting group description
    		 Eculizumab: Fixed dosing is based on body weight cohorts. Adjustment of dose to accommodate patient growth is possible.
    Reporting group title
    eculizumab
    Reporting group description
    		 Eculizumab: Fixed dosing is based on body weight cohorts. Adjustment of dose to accommodate patient growth is possible.
    Reporting group title
    eculizumab
    Reporting group description
    		 Patients who discontinued eculizumab treatment at any time during the study were followed for one year.

    Primary: Proportion of Patients With Complete TMA Response

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    End point title
    		 Proportion of Patients With Complete TMA Response [1]
    End point description
    Proportion of Patients with Complete TMA response was determined and defined by normalization of hematological parameters (platelet count and LDH) and ≥ 25% improvement in serum creatinine from baseline which was sustained for at least two consecutive measurements obtained at least four weeks apart).
    End point type
    Primary
    End point timeframe
    Through 26 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: This study is a single arm trial and the system did not support statistical analyses for this single arm trial.
    End point values
    		 eculizumab
    Number of subjects analysed
    22
    Units: Percentage of participants
        number (confidence interval 95%)
    63.6 (40.7 to 82.8)
    No statistical analyses for this end point

    Secondary: Proportion of Patients With Complete Hematologic Response

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    End point title
    		 Proportion of Patients With Complete Hematologic Response
    End point description
    Proportion of Patients with Complete Hematologic response through 26 weeks of treatment was determined and defined by normalization of platelet count and LDH sustained for at least two consecutive measurements obtained at least four weeks apart.
    End point type
    Secondary
    End point timeframe
    Through 26 weeks
    End point values
    		 eculizumab
    Number of subjects analysed
    22
    Units: Percentage of participants
        number (confidence interval 95%)
    81.8 (59.7 to 94.8)
    No statistical analyses for this end point

    Secondary: Proportion of Patients With Platelet Count Normalization

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    End point title
    		 Proportion of Patients With Platelet Count Normalization
    End point description
    Proportion of Patients with Platelet Count Normalization through 26 weeks of treatment was determined and defined as the platelet count observed to be ≥ 150 x 109/L on at least two consecutive measurements which span a period of at least four weeks.
    End point type
    Secondary
    End point timeframe
    Through 26 weeks
    End point values
    		 eculizumab
    Number of subjects analysed
    22
    Units: Percentage of Participants
        number (confidence interval 95%)
    95.5 (77.2 to 99.9)
    No statistical analyses for this end point

    Secondary: Proportion of Patients With Estimated Glomerular Filtration Rate (eGFR) Improvement

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    End point title
    		 Proportion of Patients With Estimated Glomerular Filtration Rate (eGFR) Improvement
    End point description
    Proportion of Patients with Estimated Glomerular Filtration Rate (eGFR) Improvement was determined and defined as an increase in eGFR by ≥ 15 mL/min/1.73m2 from baseline, sustained for at least two consecutive measurements obtained at least four weeks apart.
    End point type
    Secondary
    End point timeframe
    Through 26 weeks
    End point values
    		 eculizumab
    Number of subjects analysed
    22
    Units: Percentage of Participants
        number (confidence interval 95%)
    86.4 (65.1 to 97.1)
    No statistical analyses for this end point

    Secondary: Platelet Count Change From Baseline to 26 Weeks

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    End point title
    		 Platelet Count Change From Baseline to 26 Weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Through 26 weeks
    End point values
    		 eculizumab
    Number of subjects analysed
    22
    Units: 10^9 cells/L
        least squares mean (confidence interval 95%)
    204.96 (164.44 to 245.49)
    No statistical analyses for this end point

    Secondary: Proportion of Patients With Complete TMA Response

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    End point title
    		 Proportion of Patients With Complete TMA Response
    End point description
    Proportion of Patients with Complete TMA response was determined and defined by normalization of hematological parameters (platelet count and LDH) and ≥ 25% improvement in serum creatinine from baseline which was sustained for at least two consecutive measurements obtained at least four weeks apart).
    End point type
    Secondary
    End point timeframe
    Through End of Study, Median Exposure 55 Weeks
    End point values
    		 eculizumab
    Number of subjects analysed
    22
    Units: Percentage of Participants
        number (confidence interval 95%)
    68.2 (45.1 to 86.1)
    No statistical analyses for this end point

    Secondary: Proportion of Patients With Complete Hematologic Response

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    End point title
    		 Proportion of Patients With Complete Hematologic Response
    End point description
    Proportion of Patients with Complete Hematologic response through end of study was determined and defined by normalization of platelet count and LDH sustained for at least two consecutive measurements obtained at least four weeks apart.
    End point type
    Secondary
    End point timeframe
    Through End of Study, Median Exposure 55 Weeks
    End point values
    		 eculizumab
    Number of subjects analysed
    22
    Units: Percentage of Participants
        number (confidence interval 95%)
    90.9 (70.8 to 98.9)
    No statistical analyses for this end point

    Secondary: Proportion of Patients With Platelet Count Normalization

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    End point title
    		 Proportion of Patients With Platelet Count Normalization
    End point description
    Proportion of Patients with Platelet Count Normalization through end of study was determined and defined as the platelet count observed to be ≥ 150 x 109/L on at least two consecutive measurements which span a period of at least four weeks
    End point type
    Secondary
    End point timeframe
    Through End of Study, Median Exposure 55 Weeks
    End point values
    		 eculizumab
    Number of subjects analysed
    22
    Units: Percentage of Participants
        number (confidence interval 95%)
    95.5 (77.2 to 99.9)
    No statistical analyses for this end point

    Secondary: Proportion of Patients With Estimated Glomerular Filtration Rate (eGFR) Improvement

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    End point title
    		 Proportion of Patients With Estimated Glomerular Filtration Rate (eGFR) Improvement
    End point description
    Proportion of Patients with Estimated Glomerular Filtration Rate (eGFR) Improvement was determined and defined as an increase in eGFR by ≥ 15 mL/min/1.73m2 from baseline, sustained for at least two consecutive measurements obtained at least four weeks apart.
    End point type
    Secondary
    End point timeframe
    Through End of Study, Median Exposure 55 Weeks
    End point values
    		 eculizumab
    Number of subjects analysed
    22
    Units: Percentage of Participants
        number (confidence interval 95%)
    86.4 (65.1 to 97.1)
    No statistical analyses for this end point

    Secondary: Platelet Count Change From Baseline to 52 Weeks

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    End point title
    		 Platelet Count Change From Baseline to 52 Weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Through 52 Weeks
    End point values
    		 eculizumab
    Number of subjects analysed
    22
    Units: 10^9 cells/L
        least squares mean (confidence interval 95%)
    165.43 (98.43 to 232.46)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort 5 to <10kg) N=3

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    End point title
    		 Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort 5 to <10kg) N=3
    End point description
    Pharmacokinetic (PK) parameters Cmin and Cmax were estimated using a population PK model developed from the observed PK concentration data.
    End point type
    Secondary
    End point timeframe
    Induction Phase was between 1 and 4 weeks in length depending on patient weight cohort.Maintenance Phase was started 1 week after induction phase and dosing of eculizumab administration was every 2 weeks or every 3 weeks depending on patient weight cohort
    End point values
    		 eculizumab
    Number of subjects analysed
    3
    Units: microgram(s)/millilitre
    arithmetic mean (standard deviation)
        Min Concentration during induction period
    223.2 ( 19 )
        Max concentration during induction period
    312.8 ( 51.2 )
        Min concentration during maintenance
    187.2 ( 42 )
        Max concentration during maintenance
    499.7 ( 27.8 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort 10 to <20kg) N=7

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    End point title
    		 Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort 10 to <20kg) N=7
    End point description
    Pharmacokinetic (PK) parameters Cmin and Cmax were estimated using a population PK model developed from the observed PK concentration data.
    End point type
    Secondary
    End point timeframe
    Induction Phase was between 1 and 4 weeks in length depending on patient weight cohort.Maintenance Phase was started 1 week after induction phase and dosing of eculizumab administration was every 2 weeks or every 3 weeks depending on patient weight cohort
    End point values
    		 eculizumab
    Number of subjects analysed
    7
    Units: microgram(s)/millilitre
    arithmetic mean (standard deviation)
        Min Concentration during induction period
    297.2 ( 74.7 )
        Max concentration during induction period
    436.2 ( 128.3 )
        Min concentration during maintenance
    241.8 ( 106 )
        Max concentration during maintenance
    459.5 ( 105.5 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort 20 to <30kg) N=6

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    End point title
    		 Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort 20 to <30kg) N=6
    End point description
    Pharmacokinetic (PK) parameters Cmin and Cmax were estimated using a population PK model developed from the observed PK concentration data.
    End point type
    Secondary
    End point timeframe
    Induction Phase was between 1 and 4 weeks in length depending on patient weight cohort. Maintenance Phase was started either 2 weeks or 3 weeks after induction phase depending on patient weight cohort.
    End point values
    		 eculizumab
    Number of subjects analysed
    6
    Units: microgram(s)/millilitre
    arithmetic mean (standard deviation)
        Min Concentration during induction period
    185.1 ( 19.5 )
        Max concentration during induction period
    242.5 ( 24.5 )
        Min concentration during maintenance
    337.6 ( 43.4 )
        Max concentration during maintenance
    579.5 ( 66.5 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort 30 to <40kg) N=1

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    End point title
    		 Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort 30 to <40kg) N=1
    End point description
    Pharmacokinetic (PK) parameters Cmin and Cmax were estimated using a population PK model developed from the observed PK concentration data. Of note, no subjects were in the maintenance phase because the patient in the 30 to<40 kg cohort group was changed to the ≤ 40 kg body weight cohort category. Eculizumab Minimum and Maximum Blood Concentration during Maintenance is not mentioned because Non Applicable because N=6 in the Maintenance Phase because the patient in the 30 - <40kg cohort group changed to the ≥40kg body weight category.
    End point type
    Secondary
    End point timeframe
    Induction Phase was between 1 and 4 weeks in length depending on patient weight cohort. Maintenance Phase was started either 2 weeks or 3 weeks after induction phase depending on patient weight cohort
    End point values
    		 eculizumab
    Number of subjects analysed
    1
    Units: microgram(s)/millilitre
    number (not applicable)
        Min Concentration during induction period
    196.8
        Max concentration during induction period
    282.2
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort ≥40kg) N=5

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    End point title
    		 Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort ≥40kg) N=5
    End point description
    Pharmacokinetic (PK) parameters Cmin and Cmax were estimated using a population PK model developed from the observed PK concentration data. Of note, 6 subjects were considered for the maintenance phase, because the patient in the 30 to <40 kg body weight cohort group was changed to the ≥ 40 kg body weight category.
    End point type
    Secondary
    End point timeframe
    Induction Phase was between 1 and 4 weeks in length depending on patient weight cohort. Maintenance Phase was started either 2 weeks or 3 weeks after induction phase depending on patient weight cohort
    End point values
    		 eculizumab
    Number of subjects analysed
    5
    Units: microgram(s)/millilitre
    arithmetic mean (standard deviation)
        Min Concentration during induction period
    125.5 ( 26.3 )
        Max concentration during induction period
    180.9 ( 42.6 )
        Min concentration during maintenance
    278.4 ( 130.3 )
        Max concentration during maintenance
    572.4 ( 267.7 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Through end of study; exposure to eculizumab in this study extended for a median duration of 12.6 months and ranged from 1 dose to 24.5 months.
    Adverse event reporting additional description
    At every visit, patients were asked a standard non-leading question to elicit any changes in their medical well-being including inquiry about any hospitalization, accidents and new or changed concomitant medication regimens. AEs were also documented from any data collected (e.g. laboratory values, physical examination findings, ECG changes, etc.)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    eculizumab
    Reporting group description
    		 Information on TEAEs was collected during the study (occurrence from the time of first eculizumab infusion and after) and during the Follow-up Period (12 weeks after the last dose of eculizumab).

    Serious adverse events
    		 eculizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 22 (59.09%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Device malfunction
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Medical device complication
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tonsillar haemorrhage
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Device related sepsis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterocolitis viral
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Metabolic disorder
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 eculizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 22 (90.91%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    2
    Hypertension
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    4
    Pallor
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Surgical and medical procedures
    Central venous catheter removal
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Application site eczema
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Chest pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Drug withdrawal syndrome
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Injection site rash
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Injection site haematoma
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Malaise
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    11 / 22 (50.00%)
         occurrences all number
    12
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 22 (40.91%)
         occurrences all number
    9
    Dyspnoea
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Pleural effusion
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Rhinorrhoea
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Psychiatric disorders
    Food aversion
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Mood altered
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Investigations
    Blood bicarbonate decreased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Electrocardiogram T wave inversion
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Electroencephalogram abnormal
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Weight increased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Contusion
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Infusion related reaction
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Joint dislocation
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Scratch
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Nail injury
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Procedural pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Cardiac disorders
    Bundle branch block right
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Pericardial effusion
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Nervous system disorders
    Demyelinating polyneuropathy
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    5
    Sinus headache
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    3
    Leukopenia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Lymphopenia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Neutropenia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Lymphadenopathy
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Thrombocytopenia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Eye disorders
    Eye discharge
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Ulcerative keratitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Vision blurred
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Gastrointestinal disorders
    ABDOMINAL DISCOMFORT
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Abdominal pain
         subjects affected / exposed
    7 / 22 (31.82%)
         occurrences all number
    8
    Abdominal pain upper
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Constipation
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    8 / 22 (36.36%)
         occurrences all number
    8
    Abdominal distension
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Dysphagia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Gastritis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    7 / 22 (31.82%)
         occurrences all number
    7
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Dermatitis diaper
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Eczema
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Increased tendency to bruise
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Purpura
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    4
    Rash erythematous
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Rash papular
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Skin lesion
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Dysuria
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Proteinuria
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Glycosuria
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Microalbuminuria
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Polyuria
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Back pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Muscular weakness
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Neck pain
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Beta haemolytic streptococcal infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Bronchitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Candiduria
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Catheter site infection
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Conjunctivitis viral
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Ear infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Fungal infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Genital candidiasis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    7 / 22 (31.82%)
         occurrences all number
    7
    Oral fungal infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Otitis media
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    2
    Pathogen resistance
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Pyelonephritis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    5
    Sinusitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Skin infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 22 (31.82%)
         occurrences all number
    7
    Urinary tract infection
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    4
    Varicella
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Viral infection
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Iron deficiency
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Metabolic disorder
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Vitamin D deficiency
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Sep 2010
    Modification of protocol inclusion criteria, in particular to include patients with atypical hemolytic-uremic syndrome (aHUS) from 1 month of age and body weight ≥ 5kg
    07 Nov 2011
    Modification to the clinical study protocol to increase the number of patients to be enrolled in the clinical study, to update change in personnel and recruitment period, and to include country-specific requirements in a global version of the protocol.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/21877169
    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
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